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The global withdrawal of voxelotor (Oxbryta, Pfizer) has left clinicians who treat sickle cell disease (SCD) with the urgent task of reaching patients taking the medicine, while trying to understand why it was taken off the market.

The National Alliance of Sickle Cell Centers issued a statement urging patients not to stop voxelotor abruptly. Instead, they should work out plans with their physicians and medical teams for weaning plans.

“Don’t lose faith. This a step backward, but we will stay on the path to better outcomes for everyone,” said the alliance in a statement to patients and clinicians.

On September 25, Pfizer said it would withdraw all lots of voxelotor in all markets where it is approved. The New York–based drugmaker also said it was discontinuing all active voxelotor clinical trials and expanded access programs worldwide. The cause was data that suggested “an imbalance in vaso-occlusive crises and fatal events which require further assessment.”

Pfizer told this news organization in an email exchange that it is focused on analyzing the data and will share updates in the future about presenting or publishing on this issue.

The withdrawal came amid increased scrutiny of the drug by the European Medicines Agency (EMA). The EMA in July began a review of voxelotor after data from a clinical trial showed that a higher number of deaths occurred with the drug than with placebo and another trial showed the total number of deaths was higher than anticipated.

On September 26, the EMA’s human medicines committee recommended suspending the marketing authorization of voxelotor, citing new safety data that emerged during the review. The drug had received marketing authorization for the European Union in 2022, the agency said.

The US Food and Drug Administration (FDA), which first cleared voxelotor for sale in 2019, also said it has been conducting a safety review of the drug. The agency continues to examine post-marketing clinical trial data for voxelotor, the real-world registry studies, and data from the FDA Adverse Event Reporting System. At the conclusion of this review, the FDA will communicate any additional findings, if necessary, the agency said.

The FDA said it appeared that more deaths and a higher rate of vaso-occlusive crisis occurred in patients taking voxelotor vs placebo in post-marketing clinical trials.

“Pfizer also observed a higher rate of vaso-occlusive crisis in patients with sickle cell disease receiving Oxbryta in two real-world registry studies,” the FDA said. “Based on the totality of clinical data, Pfizer has determined the benefit of Oxbryta does not outweigh the risk.”
 

Gene Therapy, Tried-and-True Hydroxyurea (HU)

As a field, SCD has drawn more interest in recent years, with significant gains made lately in cutting-edge projects.

The FDA in December approved two gene-editing treatments for patients aged 12 years or older. These are considered “milestone treatments” for a debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the United States. Exagamglogene autotemcel (Casgevy, Vertex Pharmaceuticals and CRISPR Therapeutics) is the first to use the gene-editing tool CRISPR. And lovotibeglogene autotemcel (Lyfgenia, bluebird bio) uses a different gene-editing tool called a lentiviral vector.

These advances have been covered widely by the news media but are not expected to be widely available, with the cost of these extensive treatments estimated around $2-$3 million per patient.

“Gene therapy is amazing in that it can offer a cure, but it’s very expensive and not all patients are suitable for it. Some have so much existing organ damage that it’s not an option for them,” said John Wood, MD, PhD, director of cardiovascular MRI at Children’s Hospital Los Angeles, Los Angeles, who does research on SCD.

“So it really is a great treatment for a very few people,” he said in an interview.

The mainstay of treatment for SCD remains a drug that Lydia Pecker, MD, a pediatric hematologist at Johns Hopkins University in Baltimore, describes as the “first, oldest, and best”: HU.

The FDA approved this in 1998 for use in SCD. It reduces the frequency of painful crises and acute chest syndrome and other complications of SCD that otherwise could be serious or even lethal, Pecker said.

“Older doctors can tell you that what they experienced with sickle cell disease in the hospitals has been completely transformed because of the high uptake of the drug,” she said, adding that it made a “profound” change. “We just don’t have data for any other agent that’s quite like that.”

Voxelotor had been a good second drug to add for some patients, in addition to HU and blood transfusions, Dr. Pecker noted. It was a first-line drug for those for whom transfusion and HU were not options, which constitutes a relatively small number of patients, she said.

“So we have, in the last 5 years, felt more hopeful because we had something else to offer,” she said.

Alexis A. Thompson, MD, MPH, chief of the Division of Hematology at Children’s Hospital of Philadelphia in Pennsylvania, said in an interview that her organization also had patients who appeared to benefit from voxelotor, some of whom had been participants in clinical trials.

Dr. Thompson, who has been a top researcher involved in the study of gene therapy, urged the need for companies to keep seeking to expand the options for people with SCD, even after the setback with voxelotor.

“I hope that there’s an appreciation for the need for continued investment in this very serious condition, for which there are insufficient options for treatments,” Dr. Thompson said. “So ongoing investment is really needed if we expect to make progress.”

Dr. Pecker disclosed ties with Novartis, Afimmune, the American Society of Hematology, and the National Institutes of Health. Thompson reported relationships with bluebird bio, Beam, Editas, Novartis, and Novo Nordisk.
 

A version of this article first appeared on Medscape.com.

The global withdrawal of voxelotor (Oxbryta, Pfizer) has left clinicians who treat sickle cell disease (SCD) with the urgent task of reaching patients taking the medicine, while trying to understand why it was taken off the market.

The National Alliance of Sickle Cell Centers issued a statement urging patients not to stop voxelotor abruptly. Instead, they should work out plans with their physicians and medical teams for weaning plans.

“Don’t lose faith. This a step backward, but we will stay on the path to better outcomes for everyone,” said the alliance in a statement to patients and clinicians.

On September 25, Pfizer said it would withdraw all lots of voxelotor in all markets where it is approved. The New York–based drugmaker also said it was discontinuing all active voxelotor clinical trials and expanded access programs worldwide. The cause was data that suggested “an imbalance in vaso-occlusive crises and fatal events which require further assessment.”

Pfizer told this news organization in an email exchange that it is focused on analyzing the data and will share updates in the future about presenting or publishing on this issue.

The withdrawal came amid increased scrutiny of the drug by the European Medicines Agency (EMA). The EMA in July began a review of voxelotor after data from a clinical trial showed that a higher number of deaths occurred with the drug than with placebo and another trial showed the total number of deaths was higher than anticipated.

On September 26, the EMA’s human medicines committee recommended suspending the marketing authorization of voxelotor, citing new safety data that emerged during the review. The drug had received marketing authorization for the European Union in 2022, the agency said.

The US Food and Drug Administration (FDA), which first cleared voxelotor for sale in 2019, also said it has been conducting a safety review of the drug. The agency continues to examine post-marketing clinical trial data for voxelotor, the real-world registry studies, and data from the FDA Adverse Event Reporting System. At the conclusion of this review, the FDA will communicate any additional findings, if necessary, the agency said.

The FDA said it appeared that more deaths and a higher rate of vaso-occlusive crisis occurred in patients taking voxelotor vs placebo in post-marketing clinical trials.

“Pfizer also observed a higher rate of vaso-occlusive crisis in patients with sickle cell disease receiving Oxbryta in two real-world registry studies,” the FDA said. “Based on the totality of clinical data, Pfizer has determined the benefit of Oxbryta does not outweigh the risk.”
 

Gene Therapy, Tried-and-True Hydroxyurea (HU)

As a field, SCD has drawn more interest in recent years, with significant gains made lately in cutting-edge projects.

The FDA in December approved two gene-editing treatments for patients aged 12 years or older. These are considered “milestone treatments” for a debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the United States. Exagamglogene autotemcel (Casgevy, Vertex Pharmaceuticals and CRISPR Therapeutics) is the first to use the gene-editing tool CRISPR. And lovotibeglogene autotemcel (Lyfgenia, bluebird bio) uses a different gene-editing tool called a lentiviral vector.

These advances have been covered widely by the news media but are not expected to be widely available, with the cost of these extensive treatments estimated around $2-$3 million per patient.

“Gene therapy is amazing in that it can offer a cure, but it’s very expensive and not all patients are suitable for it. Some have so much existing organ damage that it’s not an option for them,” said John Wood, MD, PhD, director of cardiovascular MRI at Children’s Hospital Los Angeles, Los Angeles, who does research on SCD.

“So it really is a great treatment for a very few people,” he said in an interview.

The mainstay of treatment for SCD remains a drug that Lydia Pecker, MD, a pediatric hematologist at Johns Hopkins University in Baltimore, describes as the “first, oldest, and best”: HU.

The FDA approved this in 1998 for use in SCD. It reduces the frequency of painful crises and acute chest syndrome and other complications of SCD that otherwise could be serious or even lethal, Pecker said.

“Older doctors can tell you that what they experienced with sickle cell disease in the hospitals has been completely transformed because of the high uptake of the drug,” she said, adding that it made a “profound” change. “We just don’t have data for any other agent that’s quite like that.”

Voxelotor had been a good second drug to add for some patients, in addition to HU and blood transfusions, Dr. Pecker noted. It was a first-line drug for those for whom transfusion and HU were not options, which constitutes a relatively small number of patients, she said.

“So we have, in the last 5 years, felt more hopeful because we had something else to offer,” she said.

Alexis A. Thompson, MD, MPH, chief of the Division of Hematology at Children’s Hospital of Philadelphia in Pennsylvania, said in an interview that her organization also had patients who appeared to benefit from voxelotor, some of whom had been participants in clinical trials.

Dr. Thompson, who has been a top researcher involved in the study of gene therapy, urged the need for companies to keep seeking to expand the options for people with SCD, even after the setback with voxelotor.

“I hope that there’s an appreciation for the need for continued investment in this very serious condition, for which there are insufficient options for treatments,” Dr. Thompson said. “So ongoing investment is really needed if we expect to make progress.”

Dr. Pecker disclosed ties with Novartis, Afimmune, the American Society of Hematology, and the National Institutes of Health. Thompson reported relationships with bluebird bio, Beam, Editas, Novartis, and Novo Nordisk.
 

A version of this article first appeared on Medscape.com.

The global withdrawal of voxelotor (Oxbryta, Pfizer) has left clinicians who treat sickle cell disease (SCD) with the urgent task of reaching patients taking the medicine, while trying to understand why it was taken off the market.

The National Alliance of Sickle Cell Centers issued a statement urging patients not to stop voxelotor abruptly. Instead, they should work out plans with their physicians and medical teams for weaning plans.

“Don’t lose faith. This a step backward, but we will stay on the path to better outcomes for everyone,” said the alliance in a statement to patients and clinicians.

On September 25, Pfizer said it would withdraw all lots of voxelotor in all markets where it is approved. The New York–based drugmaker also said it was discontinuing all active voxelotor clinical trials and expanded access programs worldwide. The cause was data that suggested “an imbalance in vaso-occlusive crises and fatal events which require further assessment.”

Pfizer told this news organization in an email exchange that it is focused on analyzing the data and will share updates in the future about presenting or publishing on this issue.

The withdrawal came amid increased scrutiny of the drug by the European Medicines Agency (EMA). The EMA in July began a review of voxelotor after data from a clinical trial showed that a higher number of deaths occurred with the drug than with placebo and another trial showed the total number of deaths was higher than anticipated.

On September 26, the EMA’s human medicines committee recommended suspending the marketing authorization of voxelotor, citing new safety data that emerged during the review. The drug had received marketing authorization for the European Union in 2022, the agency said.

The US Food and Drug Administration (FDA), which first cleared voxelotor for sale in 2019, also said it has been conducting a safety review of the drug. The agency continues to examine post-marketing clinical trial data for voxelotor, the real-world registry studies, and data from the FDA Adverse Event Reporting System. At the conclusion of this review, the FDA will communicate any additional findings, if necessary, the agency said.

The FDA said it appeared that more deaths and a higher rate of vaso-occlusive crisis occurred in patients taking voxelotor vs placebo in post-marketing clinical trials.

“Pfizer also observed a higher rate of vaso-occlusive crisis in patients with sickle cell disease receiving Oxbryta in two real-world registry studies,” the FDA said. “Based on the totality of clinical data, Pfizer has determined the benefit of Oxbryta does not outweigh the risk.”
 

Gene Therapy, Tried-and-True Hydroxyurea (HU)

As a field, SCD has drawn more interest in recent years, with significant gains made lately in cutting-edge projects.

The FDA in December approved two gene-editing treatments for patients aged 12 years or older. These are considered “milestone treatments” for a debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the United States. Exagamglogene autotemcel (Casgevy, Vertex Pharmaceuticals and CRISPR Therapeutics) is the first to use the gene-editing tool CRISPR. And lovotibeglogene autotemcel (Lyfgenia, bluebird bio) uses a different gene-editing tool called a lentiviral vector.

These advances have been covered widely by the news media but are not expected to be widely available, with the cost of these extensive treatments estimated around $2-$3 million per patient.

“Gene therapy is amazing in that it can offer a cure, but it’s very expensive and not all patients are suitable for it. Some have so much existing organ damage that it’s not an option for them,” said John Wood, MD, PhD, director of cardiovascular MRI at Children’s Hospital Los Angeles, Los Angeles, who does research on SCD.

“So it really is a great treatment for a very few people,” he said in an interview.

The mainstay of treatment for SCD remains a drug that Lydia Pecker, MD, a pediatric hematologist at Johns Hopkins University in Baltimore, describes as the “first, oldest, and best”: HU.

The FDA approved this in 1998 for use in SCD. It reduces the frequency of painful crises and acute chest syndrome and other complications of SCD that otherwise could be serious or even lethal, Pecker said.

“Older doctors can tell you that what they experienced with sickle cell disease in the hospitals has been completely transformed because of the high uptake of the drug,” she said, adding that it made a “profound” change. “We just don’t have data for any other agent that’s quite like that.”

Voxelotor had been a good second drug to add for some patients, in addition to HU and blood transfusions, Dr. Pecker noted. It was a first-line drug for those for whom transfusion and HU were not options, which constitutes a relatively small number of patients, she said.

“So we have, in the last 5 years, felt more hopeful because we had something else to offer,” she said.

Alexis A. Thompson, MD, MPH, chief of the Division of Hematology at Children’s Hospital of Philadelphia in Pennsylvania, said in an interview that her organization also had patients who appeared to benefit from voxelotor, some of whom had been participants in clinical trials.

Dr. Thompson, who has been a top researcher involved in the study of gene therapy, urged the need for companies to keep seeking to expand the options for people with SCD, even after the setback with voxelotor.

“I hope that there’s an appreciation for the need for continued investment in this very serious condition, for which there are insufficient options for treatments,” Dr. Thompson said. “So ongoing investment is really needed if we expect to make progress.”

Dr. Pecker disclosed ties with Novartis, Afimmune, the American Society of Hematology, and the National Institutes of Health. Thompson reported relationships with bluebird bio, Beam, Editas, Novartis, and Novo Nordisk.
 

A version of this article first appeared on Medscape.com.

Demand for new weight loss drugs has surged over the past few years. 

Led by the antiobesity drugs semaglutide (Wegovy) and tirzepatide (Zepbound), these popular medications — more commonly known as glucagon-like peptide 1 (GLP-1) agonists — have become game changers for shedding excess pounds.

Aside from obesity indications, both drugs have been approved to treat type 2 diabetes under different brand names and have a growing list of other potential benefits, such as reducing inflammation and depression. 

These antiobesity drugs could even have a place in cancer care.

While there’s limited data to support the use of GLP-1 agonists for weight loss in cancer, some oncologists have begun carefully integrating the antiobesity agents into care and studying their effects in this patient population.

The reason: Research suggests that obesity can reduce the effectiveness of cancer therapies, especially in patients with breast cancer, and can increase the risk for treatment-related side effects. 

The idea is that managing patients’ weight will improve their cancer outcomes, explained Lajos Pusztai, MD, PhD, a breast cancer specialist and professor of medicine at Yale School of Medicine in New Haven, Connecticut. 

Although Dr. Pusztai and his oncology peers at Yale don’t yet use GPL-1 agonists, Neil Iyengar, MD, and colleagues have begun doing so to help some patients with breast cancer manage their weight. Dr. Iyengar estimates that a few hundred — almost 40% — of his patients are on the antiobesity drugs.

“For a patient who has really tried to reduce their weight and who is in the obese range, that’s where I think the use of these medications can be considered,” said Dr. Iyengar, a breast cancer oncologist at Memorial Sloan Kettering Cancer Center in New York City. 
 

Why GLP-1s in Cancer?

GLP-1 is a hormone that the small intestine releases after eating. GLP-1 agonists work by mimicking GLP-1 to trigger the release of insulin and reduce the production of glucagon — two processes that help regulate blood sugar. 

These agents, such as Wegovy (or Ozempic when prescribed for diabetes), also slow gastric emptying and can make people feel fuller longer. 

Zebound (or Mounjaro for type 2 diabetes) is considered a dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, which may enhance its weight loss benefits.

In practice, however, these drugs can increase nausea and vomiting from chemotherapy, so Dr. Iyengar typically has patients use them afterwards, during maintenance treatment.

Oncologists don’t prescribe the drugs themselves but instead refer patients to endocrinologists or weight management centers that then write the prescriptions. Taking these drugs involves weekly subcutaneous injections patients can administer themselves.

Endocrinologist Emily Gallagher, MD, PhD, of Mount Sinai Hospital in New York City, estimates she has prescribed the antiobesity drugs to a few hundred patients with cancer and, like Dr. Iyengar, uses the drugs during maintenance treatment with hormone therapy for breast cancer. She also has used these agents in patients with prostate and endometrial cancers and has found the drugs can help counter steroid weight gain in multiple myeloma. 

But, to date, the evidence for using GPL-1 agonists in cancer remains limited and the practice has not yet become widespread.

Research largely comes down to a few small retrospective studies in patients with breast cancer receiving aromatase inhibitors. Although no safety issues have emerged so far, these initial reports suggest that the drugs lead to significantly less weight loss in patients with cancer compared to the general population. 

Dr. Iyengar led one recent study, presented at the 2024 annual meeting of the American Society of Clinical Oncology, in which he and his team assessed outcomes in 75 women with breast cancer who received a GLP-1 agonist. Almost 80% of patients had diabetes, and 60% received hormone therapy, most commonly an aromatase inhibitor. Patients’ median body mass index (BMI) at baseline was 34 kg/m² (range, 23-50 kg/m²).

From baseline, patients lost 6.2 kg, on average, or about 5% of their total body weight, 12 months after initiating GLP-1 therapy. 

In contrast, phase 3 trials show much higher mean weight loss — about two times — in patients without cancer. 

Another recent study also reported modest weight loss results in patients with breast cancer undergoing endocrine therapy. The researchers reported that, at 12 months, Wegovy led to 4.34% reduction in BMI, compared with a 14% change reported in the general population. Zebound, however, was associated with a 2.31% BMI increase overall — though some patients did experience a decrease — compared with a 15% reduction in the general population. 

“These findings indicate a substantially reduced weight loss efficacy in breast cancer patients on endocrine therapy compared to the general population,” the authors concluded.

It’s unclear why the drugs appear to not work as well in patients with cancer. It’s possible that hormone therapy or metabolic changes interfere with their effectiveness, given that some cancer therapies lead to weight gain. Steroids and hormone therapies, for instance, often increase appetite, and some treatments can slow patients’ metabolism or lead to fatigue, which can make it harder to exercise.

Patients with cancer may need a higher dose of GLP-1 agonists to achieve similar weight loss to the general population, Dr. Iyengar noted.

However, Dr. Gallagher said, in her own experience, she hasn’t found the drugs to be less effective in patients with cancer, especially the newer agents, like Wegovy and Zepbound. 

As for safety, Wegovy and Zepbound both carry a black box warning for thyroid C-cell tumors, including medullary thyroid carcinoma. (Recent research, however, has found that GLP-1 agonists do not increase thyroid cancer risk). 

These antiobesity agents are also contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients who have multiple endocrine neoplasia syndrome type 2, which is associated with medullary thyroid carcinoma.

Dr. Gallagher hasn’t seen any secondary tumors — thyroid or otherwise — in her patients with cancer, but she follows the labeling contraindications. Dr. Iyengar also noted that more recent and larger data sets have shown no impact on this risk, which may not actually exist, he said

Dr. Gallagher remains cautious about using GPL-1 agonists in patients who have had bariatric surgery because these agents can compound the slower gastric emptying and intestinal transit from surgery, potentially leading to gastrointestinal obstructions. 

Looking ahead, GPL-1 manufacturers are interested in adding cancer indications to the drug labeling. Both Dr. Iyengar and Dr. Gallagher said their institutions are in talks with companies to participate in large, multicenter, global phase 3 trials.

Dr. Iyengar welcomes the efforts, not only to test the effectiveness of GPL-1 agonists in oncology but also to “nail down” their safety in cancer. 

“I don’t think that there’s mechanistically anything that’s particularly worrisome,” and current observations suggest that these drugs are likely to be safe, Dr. Iyengar said. Even so, “GLP-1 agonists do a lot of things that we don’t fully understand yet.”

The bigger challenge, Dr. Iyengar noted, is that companies will have to show a sizable benefit to using these drugs in patients with cancer to get the Food and Drug Administration’s approval. And to move the needle on cancer-specific outcomes, these antiobesity drugs will need to demonstrate significant, durable weight loss in patients with cancer. 

But if these drugs can do that, “I think it’s going to be one of the biggest advances in medicine and oncology given the obesity and cancer epidemic,” Dr. Iyengar said. 

Dr. Iyengar has adviser and/or researcher ties with companies that make or are developing GPL-1 agonists, including AstraZeneca, Novartis, Gilead, and Pfizer. Dr. Gallagher is a consultant for Novartis, Flare Therapeutics, Reactive Biosciences, and Seagen.

A version of this article first appeared on Medscape.com.

Demand for new weight loss drugs has surged over the past few years. 

Led by the antiobesity drugs semaglutide (Wegovy) and tirzepatide (Zepbound), these popular medications — more commonly known as glucagon-like peptide 1 (GLP-1) agonists — have become game changers for shedding excess pounds.

Aside from obesity indications, both drugs have been approved to treat type 2 diabetes under different brand names and have a growing list of other potential benefits, such as reducing inflammation and depression. 

These antiobesity drugs could even have a place in cancer care.

While there’s limited data to support the use of GLP-1 agonists for weight loss in cancer, some oncologists have begun carefully integrating the antiobesity agents into care and studying their effects in this patient population.

The reason: Research suggests that obesity can reduce the effectiveness of cancer therapies, especially in patients with breast cancer, and can increase the risk for treatment-related side effects. 

The idea is that managing patients’ weight will improve their cancer outcomes, explained Lajos Pusztai, MD, PhD, a breast cancer specialist and professor of medicine at Yale School of Medicine in New Haven, Connecticut. 

Although Dr. Pusztai and his oncology peers at Yale don’t yet use GPL-1 agonists, Neil Iyengar, MD, and colleagues have begun doing so to help some patients with breast cancer manage their weight. Dr. Iyengar estimates that a few hundred — almost 40% — of his patients are on the antiobesity drugs.

“For a patient who has really tried to reduce their weight and who is in the obese range, that’s where I think the use of these medications can be considered,” said Dr. Iyengar, a breast cancer oncologist at Memorial Sloan Kettering Cancer Center in New York City. 
 

Why GLP-1s in Cancer?

GLP-1 is a hormone that the small intestine releases after eating. GLP-1 agonists work by mimicking GLP-1 to trigger the release of insulin and reduce the production of glucagon — two processes that help regulate blood sugar. 

These agents, such as Wegovy (or Ozempic when prescribed for diabetes), also slow gastric emptying and can make people feel fuller longer. 

Zebound (or Mounjaro for type 2 diabetes) is considered a dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, which may enhance its weight loss benefits.

In practice, however, these drugs can increase nausea and vomiting from chemotherapy, so Dr. Iyengar typically has patients use them afterwards, during maintenance treatment.

Oncologists don’t prescribe the drugs themselves but instead refer patients to endocrinologists or weight management centers that then write the prescriptions. Taking these drugs involves weekly subcutaneous injections patients can administer themselves.

Endocrinologist Emily Gallagher, MD, PhD, of Mount Sinai Hospital in New York City, estimates she has prescribed the antiobesity drugs to a few hundred patients with cancer and, like Dr. Iyengar, uses the drugs during maintenance treatment with hormone therapy for breast cancer. She also has used these agents in patients with prostate and endometrial cancers and has found the drugs can help counter steroid weight gain in multiple myeloma. 

But, to date, the evidence for using GPL-1 agonists in cancer remains limited and the practice has not yet become widespread.

Research largely comes down to a few small retrospective studies in patients with breast cancer receiving aromatase inhibitors. Although no safety issues have emerged so far, these initial reports suggest that the drugs lead to significantly less weight loss in patients with cancer compared to the general population. 

Dr. Iyengar led one recent study, presented at the 2024 annual meeting of the American Society of Clinical Oncology, in which he and his team assessed outcomes in 75 women with breast cancer who received a GLP-1 agonist. Almost 80% of patients had diabetes, and 60% received hormone therapy, most commonly an aromatase inhibitor. Patients’ median body mass index (BMI) at baseline was 34 kg/m² (range, 23-50 kg/m²).

From baseline, patients lost 6.2 kg, on average, or about 5% of their total body weight, 12 months after initiating GLP-1 therapy. 

In contrast, phase 3 trials show much higher mean weight loss — about two times — in patients without cancer. 

Another recent study also reported modest weight loss results in patients with breast cancer undergoing endocrine therapy. The researchers reported that, at 12 months, Wegovy led to 4.34% reduction in BMI, compared with a 14% change reported in the general population. Zebound, however, was associated with a 2.31% BMI increase overall — though some patients did experience a decrease — compared with a 15% reduction in the general population. 

“These findings indicate a substantially reduced weight loss efficacy in breast cancer patients on endocrine therapy compared to the general population,” the authors concluded.

It’s unclear why the drugs appear to not work as well in patients with cancer. It’s possible that hormone therapy or metabolic changes interfere with their effectiveness, given that some cancer therapies lead to weight gain. Steroids and hormone therapies, for instance, often increase appetite, and some treatments can slow patients’ metabolism or lead to fatigue, which can make it harder to exercise.

Patients with cancer may need a higher dose of GLP-1 agonists to achieve similar weight loss to the general population, Dr. Iyengar noted.

However, Dr. Gallagher said, in her own experience, she hasn’t found the drugs to be less effective in patients with cancer, especially the newer agents, like Wegovy and Zepbound. 

As for safety, Wegovy and Zepbound both carry a black box warning for thyroid C-cell tumors, including medullary thyroid carcinoma. (Recent research, however, has found that GLP-1 agonists do not increase thyroid cancer risk). 

These antiobesity agents are also contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients who have multiple endocrine neoplasia syndrome type 2, which is associated with medullary thyroid carcinoma.

Dr. Gallagher hasn’t seen any secondary tumors — thyroid or otherwise — in her patients with cancer, but she follows the labeling contraindications. Dr. Iyengar also noted that more recent and larger data sets have shown no impact on this risk, which may not actually exist, he said

Dr. Gallagher remains cautious about using GPL-1 agonists in patients who have had bariatric surgery because these agents can compound the slower gastric emptying and intestinal transit from surgery, potentially leading to gastrointestinal obstructions. 

Looking ahead, GPL-1 manufacturers are interested in adding cancer indications to the drug labeling. Both Dr. Iyengar and Dr. Gallagher said their institutions are in talks with companies to participate in large, multicenter, global phase 3 trials.

Dr. Iyengar welcomes the efforts, not only to test the effectiveness of GPL-1 agonists in oncology but also to “nail down” their safety in cancer. 

“I don’t think that there’s mechanistically anything that’s particularly worrisome,” and current observations suggest that these drugs are likely to be safe, Dr. Iyengar said. Even so, “GLP-1 agonists do a lot of things that we don’t fully understand yet.”

The bigger challenge, Dr. Iyengar noted, is that companies will have to show a sizable benefit to using these drugs in patients with cancer to get the Food and Drug Administration’s approval. And to move the needle on cancer-specific outcomes, these antiobesity drugs will need to demonstrate significant, durable weight loss in patients with cancer. 

But if these drugs can do that, “I think it’s going to be one of the biggest advances in medicine and oncology given the obesity and cancer epidemic,” Dr. Iyengar said. 

Dr. Iyengar has adviser and/or researcher ties with companies that make or are developing GPL-1 agonists, including AstraZeneca, Novartis, Gilead, and Pfizer. Dr. Gallagher is a consultant for Novartis, Flare Therapeutics, Reactive Biosciences, and Seagen.

A version of this article first appeared on Medscape.com.

Demand for new weight loss drugs has surged over the past few years. 

Led by the antiobesity drugs semaglutide (Wegovy) and tirzepatide (Zepbound), these popular medications — more commonly known as glucagon-like peptide 1 (GLP-1) agonists — have become game changers for shedding excess pounds.

Aside from obesity indications, both drugs have been approved to treat type 2 diabetes under different brand names and have a growing list of other potential benefits, such as reducing inflammation and depression. 

These antiobesity drugs could even have a place in cancer care.

While there’s limited data to support the use of GLP-1 agonists for weight loss in cancer, some oncologists have begun carefully integrating the antiobesity agents into care and studying their effects in this patient population.

The reason: Research suggests that obesity can reduce the effectiveness of cancer therapies, especially in patients with breast cancer, and can increase the risk for treatment-related side effects. 

The idea is that managing patients’ weight will improve their cancer outcomes, explained Lajos Pusztai, MD, PhD, a breast cancer specialist and professor of medicine at Yale School of Medicine in New Haven, Connecticut. 

Although Dr. Pusztai and his oncology peers at Yale don’t yet use GPL-1 agonists, Neil Iyengar, MD, and colleagues have begun doing so to help some patients with breast cancer manage their weight. Dr. Iyengar estimates that a few hundred — almost 40% — of his patients are on the antiobesity drugs.

“For a patient who has really tried to reduce their weight and who is in the obese range, that’s where I think the use of these medications can be considered,” said Dr. Iyengar, a breast cancer oncologist at Memorial Sloan Kettering Cancer Center in New York City. 
 

Why GLP-1s in Cancer?

GLP-1 is a hormone that the small intestine releases after eating. GLP-1 agonists work by mimicking GLP-1 to trigger the release of insulin and reduce the production of glucagon — two processes that help regulate blood sugar. 

These agents, such as Wegovy (or Ozempic when prescribed for diabetes), also slow gastric emptying and can make people feel fuller longer. 

Zebound (or Mounjaro for type 2 diabetes) is considered a dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, which may enhance its weight loss benefits.

In practice, however, these drugs can increase nausea and vomiting from chemotherapy, so Dr. Iyengar typically has patients use them afterwards, during maintenance treatment.

Oncologists don’t prescribe the drugs themselves but instead refer patients to endocrinologists or weight management centers that then write the prescriptions. Taking these drugs involves weekly subcutaneous injections patients can administer themselves.

Endocrinologist Emily Gallagher, MD, PhD, of Mount Sinai Hospital in New York City, estimates she has prescribed the antiobesity drugs to a few hundred patients with cancer and, like Dr. Iyengar, uses the drugs during maintenance treatment with hormone therapy for breast cancer. She also has used these agents in patients with prostate and endometrial cancers and has found the drugs can help counter steroid weight gain in multiple myeloma. 

But, to date, the evidence for using GPL-1 agonists in cancer remains limited and the practice has not yet become widespread.

Research largely comes down to a few small retrospective studies in patients with breast cancer receiving aromatase inhibitors. Although no safety issues have emerged so far, these initial reports suggest that the drugs lead to significantly less weight loss in patients with cancer compared to the general population. 

Dr. Iyengar led one recent study, presented at the 2024 annual meeting of the American Society of Clinical Oncology, in which he and his team assessed outcomes in 75 women with breast cancer who received a GLP-1 agonist. Almost 80% of patients had diabetes, and 60% received hormone therapy, most commonly an aromatase inhibitor. Patients’ median body mass index (BMI) at baseline was 34 kg/m² (range, 23-50 kg/m²).

From baseline, patients lost 6.2 kg, on average, or about 5% of their total body weight, 12 months after initiating GLP-1 therapy. 

In contrast, phase 3 trials show much higher mean weight loss — about two times — in patients without cancer. 

Another recent study also reported modest weight loss results in patients with breast cancer undergoing endocrine therapy. The researchers reported that, at 12 months, Wegovy led to 4.34% reduction in BMI, compared with a 14% change reported in the general population. Zebound, however, was associated with a 2.31% BMI increase overall — though some patients did experience a decrease — compared with a 15% reduction in the general population. 

“These findings indicate a substantially reduced weight loss efficacy in breast cancer patients on endocrine therapy compared to the general population,” the authors concluded.

It’s unclear why the drugs appear to not work as well in patients with cancer. It’s possible that hormone therapy or metabolic changes interfere with their effectiveness, given that some cancer therapies lead to weight gain. Steroids and hormone therapies, for instance, often increase appetite, and some treatments can slow patients’ metabolism or lead to fatigue, which can make it harder to exercise.

Patients with cancer may need a higher dose of GLP-1 agonists to achieve similar weight loss to the general population, Dr. Iyengar noted.

However, Dr. Gallagher said, in her own experience, she hasn’t found the drugs to be less effective in patients with cancer, especially the newer agents, like Wegovy and Zepbound. 

As for safety, Wegovy and Zepbound both carry a black box warning for thyroid C-cell tumors, including medullary thyroid carcinoma. (Recent research, however, has found that GLP-1 agonists do not increase thyroid cancer risk). 

These antiobesity agents are also contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients who have multiple endocrine neoplasia syndrome type 2, which is associated with medullary thyroid carcinoma.

Dr. Gallagher hasn’t seen any secondary tumors — thyroid or otherwise — in her patients with cancer, but she follows the labeling contraindications. Dr. Iyengar also noted that more recent and larger data sets have shown no impact on this risk, which may not actually exist, he said

Dr. Gallagher remains cautious about using GPL-1 agonists in patients who have had bariatric surgery because these agents can compound the slower gastric emptying and intestinal transit from surgery, potentially leading to gastrointestinal obstructions. 

Looking ahead, GPL-1 manufacturers are interested in adding cancer indications to the drug labeling. Both Dr. Iyengar and Dr. Gallagher said their institutions are in talks with companies to participate in large, multicenter, global phase 3 trials.

Dr. Iyengar welcomes the efforts, not only to test the effectiveness of GPL-1 agonists in oncology but also to “nail down” their safety in cancer. 

“I don’t think that there’s mechanistically anything that’s particularly worrisome,” and current observations suggest that these drugs are likely to be safe, Dr. Iyengar said. Even so, “GLP-1 agonists do a lot of things that we don’t fully understand yet.”

The bigger challenge, Dr. Iyengar noted, is that companies will have to show a sizable benefit to using these drugs in patients with cancer to get the Food and Drug Administration’s approval. And to move the needle on cancer-specific outcomes, these antiobesity drugs will need to demonstrate significant, durable weight loss in patients with cancer. 

But if these drugs can do that, “I think it’s going to be one of the biggest advances in medicine and oncology given the obesity and cancer epidemic,” Dr. Iyengar said. 

Dr. Iyengar has adviser and/or researcher ties with companies that make or are developing GPL-1 agonists, including AstraZeneca, Novartis, Gilead, and Pfizer. Dr. Gallagher is a consultant for Novartis, Flare Therapeutics, Reactive Biosciences, and Seagen.

A version of this article first appeared on Medscape.com.

Eliezer Masliah, MD, director of the neuroscience division at the National Institute on Aging (NIA), has been “relieved of his position” following an investigation by the National Institutes of Health (NIH) that turned up research misconduct, the NIH said in a statement.

The misconduct involved “falsification and/or fabrication involving reuse and relabel of figure panels representing different experimental results in two publications,” the NIH said.

The agency said it will notify the two journals of its findings so that appropriate action can be taken.

The NIH reportedly launched its probe into potential research misconduct in May 2023 after it received allegations from the Health and Human Service (HHS) Office of Research Integrity (ORI) that month.

The investigation phase began in December 2023 and concluded on September 15, 2024. The institute subsequently notified HHS ORI of its findings.

Dr. Masliah joined the NIH in the summer of 2016 as director of the Division of Neuroscience at the NIA and an NIH intramural researcher investigating synaptic damage in neurodegenerative disorders, publishing “numerous” papers, the NIH said.

Given the findings of their investigation, the NIH said, Dr. Masliah is no longer serving as director of NIA’s Division of Neuroscience.

NIA deputy director Amy Kelley, MD, is now acting director of NIA’s neuroscience division.

Consistent with NIH policies and procedures, any allegations involving Dr. Masliah’s NIH-supported extramural research prior to joining NIH would be referred to HHS ORI, the NIH said.

The NIH announcement came on the same day that Science magazine published an investigative piece suggesting that Dr. Masliah may have fabricated or falsified images or other information in far more than the two studies NIH cited.

According to the article, “scores” of Dr. Masliah’s lab studies conducted at the NIA and the University of California San Diego are “riddled with apparently falsified Western blots — images used to show the presence of proteins — and micrographs of brain tissue. Numerous images seem to have been inappropriately reused within and across papers, sometimes published years apart in different journals, describing divergent experimental conditions.”

The article noted that a neuroscientist and forensic analysts who had previously worked with Science magazine produced a “300-page dossier revealing a steady stream of suspect images between 1997 and 2023 in 132 of his published research papers.”

They concluded that this “pattern of anomalous data raises a credible concern for research misconduct and calls into question a remarkably large body of scientific work,” the Science article stated.
 

A version of this article appeared on Medscape.com.

Eliezer Masliah, MD, director of the neuroscience division at the National Institute on Aging (NIA), has been “relieved of his position” following an investigation by the National Institutes of Health (NIH) that turned up research misconduct, the NIH said in a statement.

The misconduct involved “falsification and/or fabrication involving reuse and relabel of figure panels representing different experimental results in two publications,” the NIH said.

The agency said it will notify the two journals of its findings so that appropriate action can be taken.

The NIH reportedly launched its probe into potential research misconduct in May 2023 after it received allegations from the Health and Human Service (HHS) Office of Research Integrity (ORI) that month.

The investigation phase began in December 2023 and concluded on September 15, 2024. The institute subsequently notified HHS ORI of its findings.

Dr. Masliah joined the NIH in the summer of 2016 as director of the Division of Neuroscience at the NIA and an NIH intramural researcher investigating synaptic damage in neurodegenerative disorders, publishing “numerous” papers, the NIH said.

Given the findings of their investigation, the NIH said, Dr. Masliah is no longer serving as director of NIA’s Division of Neuroscience.

NIA deputy director Amy Kelley, MD, is now acting director of NIA’s neuroscience division.

Consistent with NIH policies and procedures, any allegations involving Dr. Masliah’s NIH-supported extramural research prior to joining NIH would be referred to HHS ORI, the NIH said.

The NIH announcement came on the same day that Science magazine published an investigative piece suggesting that Dr. Masliah may have fabricated or falsified images or other information in far more than the two studies NIH cited.

According to the article, “scores” of Dr. Masliah’s lab studies conducted at the NIA and the University of California San Diego are “riddled with apparently falsified Western blots — images used to show the presence of proteins — and micrographs of brain tissue. Numerous images seem to have been inappropriately reused within and across papers, sometimes published years apart in different journals, describing divergent experimental conditions.”

The article noted that a neuroscientist and forensic analysts who had previously worked with Science magazine produced a “300-page dossier revealing a steady stream of suspect images between 1997 and 2023 in 132 of his published research papers.”

They concluded that this “pattern of anomalous data raises a credible concern for research misconduct and calls into question a remarkably large body of scientific work,” the Science article stated.
 

A version of this article appeared on Medscape.com.

Eliezer Masliah, MD, director of the neuroscience division at the National Institute on Aging (NIA), has been “relieved of his position” following an investigation by the National Institutes of Health (NIH) that turned up research misconduct, the NIH said in a statement.

The misconduct involved “falsification and/or fabrication involving reuse and relabel of figure panels representing different experimental results in two publications,” the NIH said.

The agency said it will notify the two journals of its findings so that appropriate action can be taken.

The NIH reportedly launched its probe into potential research misconduct in May 2023 after it received allegations from the Health and Human Service (HHS) Office of Research Integrity (ORI) that month.

The investigation phase began in December 2023 and concluded on September 15, 2024. The institute subsequently notified HHS ORI of its findings.

Dr. Masliah joined the NIH in the summer of 2016 as director of the Division of Neuroscience at the NIA and an NIH intramural researcher investigating synaptic damage in neurodegenerative disorders, publishing “numerous” papers, the NIH said.

Given the findings of their investigation, the NIH said, Dr. Masliah is no longer serving as director of NIA’s Division of Neuroscience.

NIA deputy director Amy Kelley, MD, is now acting director of NIA’s neuroscience division.

Consistent with NIH policies and procedures, any allegations involving Dr. Masliah’s NIH-supported extramural research prior to joining NIH would be referred to HHS ORI, the NIH said.

The NIH announcement came on the same day that Science magazine published an investigative piece suggesting that Dr. Masliah may have fabricated or falsified images or other information in far more than the two studies NIH cited.

According to the article, “scores” of Dr. Masliah’s lab studies conducted at the NIA and the University of California San Diego are “riddled with apparently falsified Western blots — images used to show the presence of proteins — and micrographs of brain tissue. Numerous images seem to have been inappropriately reused within and across papers, sometimes published years apart in different journals, describing divergent experimental conditions.”

The article noted that a neuroscientist and forensic analysts who had previously worked with Science magazine produced a “300-page dossier revealing a steady stream of suspect images between 1997 and 2023 in 132 of his published research papers.”

They concluded that this “pattern of anomalous data raises a credible concern for research misconduct and calls into question a remarkably large body of scientific work,” the Science article stated.
 

A version of this article appeared on Medscape.com.

EDITOR’S NOTE

This year, we again focus on rare neurological diseases that have new therapies that have been recently approved as well as conditions for which the treatment pipeline is robust. Let’s hope the work of many dedicated researchers adds to the list of rare neurological diseases for which treatment is available.

This year also marks a change of leadership at NORD, our publishing partner in this annual supplement. We here at Neurology Reviews salute the leadership and accomplishments of former NORD CEO Peter Saltonstall and also welcome incoming CEO Pamela Gavin, who has spent many years in NORD leadership roles and was essential in the planning, launch, and early years of this annual supplement. I can think of no one better than Pamela Gavin to continue NORD’s mission into the future.

And finally, a recap of accolades for this annual supplement. For the second year in a row, the Rare Neurological Disease Special Report has won an Azbee award in the category of annual supplement from the American Society of Business Publication Editors. The 2023 issue won a National Gold Award and a Regional Gold Award.

—Glenn Williams, VP, Group Editor, Neurology Reviews and MDedge Neurology

A NOTE FROM NORD

Hello, and Welcome! The National Organization for Rare Disorders (NORD) is pleased to partner with Neurology Reviews to bring you the 2024 edition of the Rare Neurological Disease Report. Through this collaboration, we share cutting-edge research and insights from leading medical experts, including specialists from the NORD Rare Disease Centers of Excellence network, about the latest advances in the treatment of rare neurological conditions.

As healthcare providers, you play a key role in catalyzing advancements and bringing new hope and possibilities to the rare disease community. Your efforts can contribute to shortening the diagnostic odyssey and improving day-to-day care for people living with rare disorders in crucial ways:

Identifying patients: Healthcare providers can recognize the possible signs of a rare disease and initiate further investigation or referral to specialists. Early detection is key as it can lead to a quicker, more accurate diagnosis, better management, and improved outcomes.

Educating other physicians: Many rare diseases are not well-known or understood by the general medical community. Healthcare providers can help bridge this knowledge gap by educating other physicians about rare conditions. They can raise awareness through clinical teaching, seminars, medical literature, or continuing medical education (CME) sessions focused on rare diseases. Raising awareness and providing up-to-date information about rare diseases bolsters diagnostic and treatment capabilities within the medical field.

Providing information to patients: Once a rare disease is identified, healthcare providers can offer valuable support to patients and their families. They can provide potential treatments and management strategies. They can also connect patients with support groups, support programs, educational resources, and specialists with expertise in specific rare conditions. Clear communication and guidance on support resources can positively impact patients’ well-being, empower them to make informed decisions, and help them navigate a complex rare condition.

This issue of the Rare Disease Neurological Special Report features articles by rare disease medical experts on specific diseases with updates on clinical management. Topics include the diagnosis and management of Duchenne muscular dystrophy, the promise of disease-modifying therapies for Huntington’s disease, patient choices and cultural changes around myasthenia gravis, advances in neuromyelitis optica, and untangling chronic inflammatory demyelinating polyneuropathy. In addition, two online-only articles offer timely insights from key opinion leaders on the pros and cons of genetic testing and what clinicians need to know about newborn screening.

You will also find information about the NORD Rare Diseases and Orphan Products Breakthrough Summit. This annual event convenes thought leaders from patient advocacy organizations, industry, academia, medical and research institutions, and government to discuss critical topics facing the rare disease community. 

NORD is deeply appreciative of healthcare professionals like you, who despite long hours and demanding workloads, remain committed to staying up to date on the latest medical advances for the benefit of their patients. Your dedication and hard work make a significant difference to the patients and families we serve, and your commitment does not go unnoticed. Thank you for all that you do.

—Pamela Gavin, NORD Chief Executive Officer

EDITOR’S NOTE

This year, we again focus on rare neurological diseases that have new therapies that have been recently approved as well as conditions for which the treatment pipeline is robust. Let’s hope the work of many dedicated researchers adds to the list of rare neurological diseases for which treatment is available.

This year also marks a change of leadership at NORD, our publishing partner in this annual supplement. We here at Neurology Reviews salute the leadership and accomplishments of former NORD CEO Peter Saltonstall and also welcome incoming CEO Pamela Gavin, who has spent many years in NORD leadership roles and was essential in the planning, launch, and early years of this annual supplement. I can think of no one better than Pamela Gavin to continue NORD’s mission into the future.

And finally, a recap of accolades for this annual supplement. For the second year in a row, the Rare Neurological Disease Special Report has won an Azbee award in the category of annual supplement from the American Society of Business Publication Editors. The 2023 issue won a National Gold Award and a Regional Gold Award.

—Glenn Williams, VP, Group Editor, Neurology Reviews and MDedge Neurology

A NOTE FROM NORD

Hello, and Welcome! The National Organization for Rare Disorders (NORD) is pleased to partner with Neurology Reviews to bring you the 2024 edition of the Rare Neurological Disease Report. Through this collaboration, we share cutting-edge research and insights from leading medical experts, including specialists from the NORD Rare Disease Centers of Excellence network, about the latest advances in the treatment of rare neurological conditions.

As healthcare providers, you play a key role in catalyzing advancements and bringing new hope and possibilities to the rare disease community. Your efforts can contribute to shortening the diagnostic odyssey and improving day-to-day care for people living with rare disorders in crucial ways:

Identifying patients: Healthcare providers can recognize the possible signs of a rare disease and initiate further investigation or referral to specialists. Early detection is key as it can lead to a quicker, more accurate diagnosis, better management, and improved outcomes.

Educating other physicians: Many rare diseases are not well-known or understood by the general medical community. Healthcare providers can help bridge this knowledge gap by educating other physicians about rare conditions. They can raise awareness through clinical teaching, seminars, medical literature, or continuing medical education (CME) sessions focused on rare diseases. Raising awareness and providing up-to-date information about rare diseases bolsters diagnostic and treatment capabilities within the medical field.

Providing information to patients: Once a rare disease is identified, healthcare providers can offer valuable support to patients and their families. They can provide potential treatments and management strategies. They can also connect patients with support groups, support programs, educational resources, and specialists with expertise in specific rare conditions. Clear communication and guidance on support resources can positively impact patients’ well-being, empower them to make informed decisions, and help them navigate a complex rare condition.

This issue of the Rare Disease Neurological Special Report features articles by rare disease medical experts on specific diseases with updates on clinical management. Topics include the diagnosis and management of Duchenne muscular dystrophy, the promise of disease-modifying therapies for Huntington’s disease, patient choices and cultural changes around myasthenia gravis, advances in neuromyelitis optica, and untangling chronic inflammatory demyelinating polyneuropathy. In addition, two online-only articles offer timely insights from key opinion leaders on the pros and cons of genetic testing and what clinicians need to know about newborn screening.

You will also find information about the NORD Rare Diseases and Orphan Products Breakthrough Summit. This annual event convenes thought leaders from patient advocacy organizations, industry, academia, medical and research institutions, and government to discuss critical topics facing the rare disease community. 

NORD is deeply appreciative of healthcare professionals like you, who despite long hours and demanding workloads, remain committed to staying up to date on the latest medical advances for the benefit of their patients. Your dedication and hard work make a significant difference to the patients and families we serve, and your commitment does not go unnoticed. Thank you for all that you do.

—Pamela Gavin, NORD Chief Executive Officer

EDITOR’S NOTE

This year, we again focus on rare neurological diseases that have new therapies that have been recently approved as well as conditions for which the treatment pipeline is robust. Let’s hope the work of many dedicated researchers adds to the list of rare neurological diseases for which treatment is available.

This year also marks a change of leadership at NORD, our publishing partner in this annual supplement. We here at Neurology Reviews salute the leadership and accomplishments of former NORD CEO Peter Saltonstall and also welcome incoming CEO Pamela Gavin, who has spent many years in NORD leadership roles and was essential in the planning, launch, and early years of this annual supplement. I can think of no one better than Pamela Gavin to continue NORD’s mission into the future.

And finally, a recap of accolades for this annual supplement. For the second year in a row, the Rare Neurological Disease Special Report has won an Azbee award in the category of annual supplement from the American Society of Business Publication Editors. The 2023 issue won a National Gold Award and a Regional Gold Award.

—Glenn Williams, VP, Group Editor, Neurology Reviews and MDedge Neurology

A NOTE FROM NORD

Hello, and Welcome! The National Organization for Rare Disorders (NORD) is pleased to partner with Neurology Reviews to bring you the 2024 edition of the Rare Neurological Disease Report. Through this collaboration, we share cutting-edge research and insights from leading medical experts, including specialists from the NORD Rare Disease Centers of Excellence network, about the latest advances in the treatment of rare neurological conditions.

As healthcare providers, you play a key role in catalyzing advancements and bringing new hope and possibilities to the rare disease community. Your efforts can contribute to shortening the diagnostic odyssey and improving day-to-day care for people living with rare disorders in crucial ways:

Identifying patients: Healthcare providers can recognize the possible signs of a rare disease and initiate further investigation or referral to specialists. Early detection is key as it can lead to a quicker, more accurate diagnosis, better management, and improved outcomes.

Educating other physicians: Many rare diseases are not well-known or understood by the general medical community. Healthcare providers can help bridge this knowledge gap by educating other physicians about rare conditions. They can raise awareness through clinical teaching, seminars, medical literature, or continuing medical education (CME) sessions focused on rare diseases. Raising awareness and providing up-to-date information about rare diseases bolsters diagnostic and treatment capabilities within the medical field.

Providing information to patients: Once a rare disease is identified, healthcare providers can offer valuable support to patients and their families. They can provide potential treatments and management strategies. They can also connect patients with support groups, support programs, educational resources, and specialists with expertise in specific rare conditions. Clear communication and guidance on support resources can positively impact patients’ well-being, empower them to make informed decisions, and help them navigate a complex rare condition.

This issue of the Rare Disease Neurological Special Report features articles by rare disease medical experts on specific diseases with updates on clinical management. Topics include the diagnosis and management of Duchenne muscular dystrophy, the promise of disease-modifying therapies for Huntington’s disease, patient choices and cultural changes around myasthenia gravis, advances in neuromyelitis optica, and untangling chronic inflammatory demyelinating polyneuropathy. In addition, two online-only articles offer timely insights from key opinion leaders on the pros and cons of genetic testing and what clinicians need to know about newborn screening.

You will also find information about the NORD Rare Diseases and Orphan Products Breakthrough Summit. This annual event convenes thought leaders from patient advocacy organizations, industry, academia, medical and research institutions, and government to discuss critical topics facing the rare disease community. 

NORD is deeply appreciative of healthcare professionals like you, who despite long hours and demanding workloads, remain committed to staying up to date on the latest medical advances for the benefit of their patients. Your dedication and hard work make a significant difference to the patients and families we serve, and your commitment does not go unnoticed. Thank you for all that you do.

—Pamela Gavin, NORD Chief Executive Officer

Late last week, a US Food and Drug Administration (FDA) panel met to discuss whether to limit the use of nivolumab (Opdivo) and pembrolizumab (Keytruda) in patients with unresectable or metastatic esophageal squamous cell carcinoma and human epidermal growth factor receptor 2 (HER2)–negative, microsatellite stable gastric/gastroesophageal adenocarcinoma.

During the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of restricting the use of these immunotherapy agents to patients with programmed death-ligand 1 (PD-L1) expression of 1% or higher. 

The agency usually follows the ODAC’s advice.

The FDA had originally approved the two immune checkpoint inhibitors for both indications in combination with chemotherapy, regardless of patients’ PD-L1 status. The FDA had also approved nivolumab in combination with ipilimumab for esophageal cancer, regardless of PD-L1 expression. The approvals were based on overall benefit in intent-to-treat populations, not on specific PD-L1 expression subgroups.

Since then, additional studies — including the agency’s own pooled analyses of the approval trials — have found that overall survival benefits are limited to patients with PD-L1 expression of 1% or higher.

These findings have raised concerns that patients with no or low PD-L1 expression face the risks associated with immunotherapy, which include death, but minimal to no benefits.

In response, the FDA has considered changing the labeling for these indications to require a PD-L1 cutoff point of 1% or higher. The move would mirror guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network that already recommend use with chemotherapy only at certain PD-L1 cutoffs.

Before the agency acts, however, the FDA wanted the advice of the ODAC. It asked the 14-member panel whether the risk-benefit assessment is “favorable for the use of PD-1 inhibitors in first line” for the two indications among patients with PD-L1 expression below 1%.

In two nearly unanimous decisions for each indication, the panel voted that risk-benefit assessment was not favorable. In other words, the risks do outweigh the benefits for this patient population with no or low PD-L1 expression.

The determination also applies to tislelizumab (Tevimbra), an immune checkpoint inhibitor under review by the FDA for the same indications.

Voting came after hours of testimony from FDA scientists and the three drug companies involved in the decisions.

Merck, maker of pembrolizumab, was against any labeling change. Nivolumab’s maker, Bristol Myers Squibb (BMS), also wanted to stick with the current PD-L1 agnostic indications but said that any indication change should be class-wide to avoid confusion. BeiGene USA, maker of tislelizumab, had no problem with a PD-L1 cutoff of 1% because its approval trial showed benefit only in patients at that level or higher.

In general, Merck and BMS said the drug benefits correspond with higher PD-L1 expression but noted that patients with low or no PD-L1 expression can sometimes benefit from treatment. The companies had several patients testify to the benefits of the agents and noted patients like this would likely lose access. But an ODAC panelist noted that patients who died from immunotherapy complications weren’t there to respond.

The companies also expressed concern about taking treatment decisions out of the hands of oncologists as well as the need for additional biopsies to determine if tumors cross the proposed PD-L1 threshold at some point during treatment. With this potential new restriction, the companies were worried that insurance companies would be even less likely to pay for their checkpoint inhibitors in low or no PD-L1 expressors.

ODAC wasn’t moved. With consistent findings across multiple trials, the strength of the FDA’s data carried the day.

In a pooled analysis of the three companies’ unresectable or metastatic HER2–negative, microsatellite-stable gastric/gastroesophageal adenocarcinoma approval trials across almost 4000 patients, those with PD-L1 levels below 1% did not demonstrate a significant overall survival benefit (hazard ratio [HR], 0.91; 95% CI, 0.75-1.09). The median overall survival with immunotherapy plus chemotherapy was only 1 month more — 13.4 months vs 12.4 months with chemotherapy alone.

FDA’s pooled analysis for unresectable or metastatic esophageal squamous cell carcinoma also showed no overall survival benefit (HR, 1.1; 95% CI, 0.76-1.58), with a trend suggesting harm. Median overall survival with immunotherapy plus chemotherapy was 14.6 months vs 9.8 months with chemotherapy alone.

Despite the vote on esophageal squamous cell carcinoma, panelists had reservations about making decisions based on just over 160 patients with PD-L1 levels below 1% in the three esophageal squamous cell carcinoma trials.

Still, one panelist said, it’s likely “the best dataset we will get.”

The companies all used different methods to test PD-L1 levels, and attendees called for a single standardized PD-L1 test. Richard Pazdur, MD, head of the FDA’s Oncology Center of Excellence, said the agency has been working with companies for years to get them to agree to such a test, with no luck.

If the FDA ultimately decides to restrict immunotherapy use in this patient population based on PD-L1 levels, insurance company coverage may become more limited. Pazdur asked the companies if they would be willing to expand their patient assistance programs to provide free coverage of immune checkpoint blockers to patients with low or no PD-L1 expression.

BeiGene and BMS seemed open to the idea. Merck said, “We’ll have to ... think about it.”
 

A version of this article first appeared on Medscape.com.

Late last week, a US Food and Drug Administration (FDA) panel met to discuss whether to limit the use of nivolumab (Opdivo) and pembrolizumab (Keytruda) in patients with unresectable or metastatic esophageal squamous cell carcinoma and human epidermal growth factor receptor 2 (HER2)–negative, microsatellite stable gastric/gastroesophageal adenocarcinoma.

During the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of restricting the use of these immunotherapy agents to patients with programmed death-ligand 1 (PD-L1) expression of 1% or higher. 

The agency usually follows the ODAC’s advice.

The FDA had originally approved the two immune checkpoint inhibitors for both indications in combination with chemotherapy, regardless of patients’ PD-L1 status. The FDA had also approved nivolumab in combination with ipilimumab for esophageal cancer, regardless of PD-L1 expression. The approvals were based on overall benefit in intent-to-treat populations, not on specific PD-L1 expression subgroups.

Since then, additional studies — including the agency’s own pooled analyses of the approval trials — have found that overall survival benefits are limited to patients with PD-L1 expression of 1% or higher.

These findings have raised concerns that patients with no or low PD-L1 expression face the risks associated with immunotherapy, which include death, but minimal to no benefits.

In response, the FDA has considered changing the labeling for these indications to require a PD-L1 cutoff point of 1% or higher. The move would mirror guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network that already recommend use with chemotherapy only at certain PD-L1 cutoffs.

Before the agency acts, however, the FDA wanted the advice of the ODAC. It asked the 14-member panel whether the risk-benefit assessment is “favorable for the use of PD-1 inhibitors in first line” for the two indications among patients with PD-L1 expression below 1%.

In two nearly unanimous decisions for each indication, the panel voted that risk-benefit assessment was not favorable. In other words, the risks do outweigh the benefits for this patient population with no or low PD-L1 expression.

The determination also applies to tislelizumab (Tevimbra), an immune checkpoint inhibitor under review by the FDA for the same indications.

Voting came after hours of testimony from FDA scientists and the three drug companies involved in the decisions.

Merck, maker of pembrolizumab, was against any labeling change. Nivolumab’s maker, Bristol Myers Squibb (BMS), also wanted to stick with the current PD-L1 agnostic indications but said that any indication change should be class-wide to avoid confusion. BeiGene USA, maker of tislelizumab, had no problem with a PD-L1 cutoff of 1% because its approval trial showed benefit only in patients at that level or higher.

In general, Merck and BMS said the drug benefits correspond with higher PD-L1 expression but noted that patients with low or no PD-L1 expression can sometimes benefit from treatment. The companies had several patients testify to the benefits of the agents and noted patients like this would likely lose access. But an ODAC panelist noted that patients who died from immunotherapy complications weren’t there to respond.

The companies also expressed concern about taking treatment decisions out of the hands of oncologists as well as the need for additional biopsies to determine if tumors cross the proposed PD-L1 threshold at some point during treatment. With this potential new restriction, the companies were worried that insurance companies would be even less likely to pay for their checkpoint inhibitors in low or no PD-L1 expressors.

ODAC wasn’t moved. With consistent findings across multiple trials, the strength of the FDA’s data carried the day.

In a pooled analysis of the three companies’ unresectable or metastatic HER2–negative, microsatellite-stable gastric/gastroesophageal adenocarcinoma approval trials across almost 4000 patients, those with PD-L1 levels below 1% did not demonstrate a significant overall survival benefit (hazard ratio [HR], 0.91; 95% CI, 0.75-1.09). The median overall survival with immunotherapy plus chemotherapy was only 1 month more — 13.4 months vs 12.4 months with chemotherapy alone.

FDA’s pooled analysis for unresectable or metastatic esophageal squamous cell carcinoma also showed no overall survival benefit (HR, 1.1; 95% CI, 0.76-1.58), with a trend suggesting harm. Median overall survival with immunotherapy plus chemotherapy was 14.6 months vs 9.8 months with chemotherapy alone.

Despite the vote on esophageal squamous cell carcinoma, panelists had reservations about making decisions based on just over 160 patients with PD-L1 levels below 1% in the three esophageal squamous cell carcinoma trials.

Still, one panelist said, it’s likely “the best dataset we will get.”

The companies all used different methods to test PD-L1 levels, and attendees called for a single standardized PD-L1 test. Richard Pazdur, MD, head of the FDA’s Oncology Center of Excellence, said the agency has been working with companies for years to get them to agree to such a test, with no luck.

If the FDA ultimately decides to restrict immunotherapy use in this patient population based on PD-L1 levels, insurance company coverage may become more limited. Pazdur asked the companies if they would be willing to expand their patient assistance programs to provide free coverage of immune checkpoint blockers to patients with low or no PD-L1 expression.

BeiGene and BMS seemed open to the idea. Merck said, “We’ll have to ... think about it.”
 

A version of this article first appeared on Medscape.com.

Late last week, a US Food and Drug Administration (FDA) panel met to discuss whether to limit the use of nivolumab (Opdivo) and pembrolizumab (Keytruda) in patients with unresectable or metastatic esophageal squamous cell carcinoma and human epidermal growth factor receptor 2 (HER2)–negative, microsatellite stable gastric/gastroesophageal adenocarcinoma.

During the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of restricting the use of these immunotherapy agents to patients with programmed death-ligand 1 (PD-L1) expression of 1% or higher. 

The agency usually follows the ODAC’s advice.

The FDA had originally approved the two immune checkpoint inhibitors for both indications in combination with chemotherapy, regardless of patients’ PD-L1 status. The FDA had also approved nivolumab in combination with ipilimumab for esophageal cancer, regardless of PD-L1 expression. The approvals were based on overall benefit in intent-to-treat populations, not on specific PD-L1 expression subgroups.

Since then, additional studies — including the agency’s own pooled analyses of the approval trials — have found that overall survival benefits are limited to patients with PD-L1 expression of 1% or higher.

These findings have raised concerns that patients with no or low PD-L1 expression face the risks associated with immunotherapy, which include death, but minimal to no benefits.

In response, the FDA has considered changing the labeling for these indications to require a PD-L1 cutoff point of 1% or higher. The move would mirror guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network that already recommend use with chemotherapy only at certain PD-L1 cutoffs.

Before the agency acts, however, the FDA wanted the advice of the ODAC. It asked the 14-member panel whether the risk-benefit assessment is “favorable for the use of PD-1 inhibitors in first line” for the two indications among patients with PD-L1 expression below 1%.

In two nearly unanimous decisions for each indication, the panel voted that risk-benefit assessment was not favorable. In other words, the risks do outweigh the benefits for this patient population with no or low PD-L1 expression.

The determination also applies to tislelizumab (Tevimbra), an immune checkpoint inhibitor under review by the FDA for the same indications.

Voting came after hours of testimony from FDA scientists and the three drug companies involved in the decisions.

Merck, maker of pembrolizumab, was against any labeling change. Nivolumab’s maker, Bristol Myers Squibb (BMS), also wanted to stick with the current PD-L1 agnostic indications but said that any indication change should be class-wide to avoid confusion. BeiGene USA, maker of tislelizumab, had no problem with a PD-L1 cutoff of 1% because its approval trial showed benefit only in patients at that level or higher.

In general, Merck and BMS said the drug benefits correspond with higher PD-L1 expression but noted that patients with low or no PD-L1 expression can sometimes benefit from treatment. The companies had several patients testify to the benefits of the agents and noted patients like this would likely lose access. But an ODAC panelist noted that patients who died from immunotherapy complications weren’t there to respond.

The companies also expressed concern about taking treatment decisions out of the hands of oncologists as well as the need for additional biopsies to determine if tumors cross the proposed PD-L1 threshold at some point during treatment. With this potential new restriction, the companies were worried that insurance companies would be even less likely to pay for their checkpoint inhibitors in low or no PD-L1 expressors.

ODAC wasn’t moved. With consistent findings across multiple trials, the strength of the FDA’s data carried the day.

In a pooled analysis of the three companies’ unresectable or metastatic HER2–negative, microsatellite-stable gastric/gastroesophageal adenocarcinoma approval trials across almost 4000 patients, those with PD-L1 levels below 1% did not demonstrate a significant overall survival benefit (hazard ratio [HR], 0.91; 95% CI, 0.75-1.09). The median overall survival with immunotherapy plus chemotherapy was only 1 month more — 13.4 months vs 12.4 months with chemotherapy alone.

FDA’s pooled analysis for unresectable or metastatic esophageal squamous cell carcinoma also showed no overall survival benefit (HR, 1.1; 95% CI, 0.76-1.58), with a trend suggesting harm. Median overall survival with immunotherapy plus chemotherapy was 14.6 months vs 9.8 months with chemotherapy alone.

Despite the vote on esophageal squamous cell carcinoma, panelists had reservations about making decisions based on just over 160 patients with PD-L1 levels below 1% in the three esophageal squamous cell carcinoma trials.

Still, one panelist said, it’s likely “the best dataset we will get.”

The companies all used different methods to test PD-L1 levels, and attendees called for a single standardized PD-L1 test. Richard Pazdur, MD, head of the FDA’s Oncology Center of Excellence, said the agency has been working with companies for years to get them to agree to such a test, with no luck.

If the FDA ultimately decides to restrict immunotherapy use in this patient population based on PD-L1 levels, insurance company coverage may become more limited. Pazdur asked the companies if they would be willing to expand their patient assistance programs to provide free coverage of immune checkpoint blockers to patients with low or no PD-L1 expression.

BeiGene and BMS seemed open to the idea. Merck said, “We’ll have to ... think about it.”
 

A version of this article first appeared on Medscape.com.

The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.

As the push toward prompt testing and treatment of rare diseases continues building momentum, it has cast a growing spotlight on genetic testing and its potential. To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
 

The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing

When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.

“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”

Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea

Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.

One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.

Unfortunately, the drawbacks do not stop there.

“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”

Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
 

Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress

Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.

In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.

Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.

“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”

Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
 

Establishing Social Support Networks Typically Falls on the Patient and Loved Ones

Another con in rare genetic diseases is the lack of adoption across the community.

Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.

Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
 

Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases

As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.

In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.

Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”

As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.

Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.

Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.

“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
 

Accessibility and Lack of Geneticists Often a Rate-Limiting Step

The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”

Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.

Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.

In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
 

Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity

Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”

Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family ­— and patient — is different.

“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”

Suggested Reading

Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.

Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.

The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.

As the push toward prompt testing and treatment of rare diseases continues building momentum, it has cast a growing spotlight on genetic testing and its potential. To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
 

The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing

When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.

“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”

Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea

Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.

One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.

Unfortunately, the drawbacks do not stop there.

“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”

Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
 

Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress

Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.

In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.

Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.

“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”

Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
 

Establishing Social Support Networks Typically Falls on the Patient and Loved Ones

Another con in rare genetic diseases is the lack of adoption across the community.

Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.

Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
 

Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases

As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.

In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.

Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”

As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.

Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.

Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.

“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
 

Accessibility and Lack of Geneticists Often a Rate-Limiting Step

The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”

Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.

Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.

In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
 

Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity

Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”

Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family ­— and patient — is different.

“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”

Suggested Reading

Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.

Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.

The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.

As the push toward prompt testing and treatment of rare diseases continues building momentum, it has cast a growing spotlight on genetic testing and its potential. To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
 

The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing

When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.

“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”

Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea

Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.

One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.

Unfortunately, the drawbacks do not stop there.

“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”

Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
 

Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress

Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.

In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.

Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.

“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”

Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
 

Establishing Social Support Networks Typically Falls on the Patient and Loved Ones

Another con in rare genetic diseases is the lack of adoption across the community.

Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.

Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
 

Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases

As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.

In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.

Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”

As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.

Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.

Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.

“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
 

Accessibility and Lack of Geneticists Often a Rate-Limiting Step

The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”

Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.

Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.

In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
 

Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity

Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”

Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family ­— and patient — is different.

“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”

Suggested Reading

Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.

Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.

Unlike conventional immunosuppression, treatments approved since 2017 are giving patients with myasthenia gravis targeted options to better match their needs, desires, and tolerance. Used appropriately, newer treatments can provide dramatic results faster and more safely than broad immunosuppressants. However, according to experts, payers’ willingness to cover costly new therapies remains a work in progress.

The availability of more effective treatments with fewer side effects has brought about a cultural shift, said James F. Howard, Jr, MD. “The physician’s goal now is for the patient to be symptom free with grade 1 or less adverse events. And patients are demanding freedom from all the side effects that our usual course of immune therapy produces.” Dr. Howard is professor of neurology, medicine and allied health and director of the Myasthenia Gravis Clinical Trials and Translational Research Program at the University of North Carolina at Chapel Hill.

courtesy University of North Carolina

The shift has been long in coming. Although myasthenia gravis was identified in the mid-1600s, it took more than 340 years to get the first drug approved specifically for the disorder.

Worldwide prevalence estimates vary widely, from less than 200,000 to 700,000 cases.^1,2 Pathophysiologically, myasthenia gravis stems from autoimmune destruction of neuromuscular junctions (NMJs), which transmit motor neuron impulses to muscle fibers.¹ Symptoms include variable skeletal muscle weakness that can range from mild and transient to life-threatening.

In approximately 80% of cases, autoimmune antibodies target the postsynaptic acetylcholine receptor (AChR). Additional autoimmune targets mainly include muscle-specific kinase (MuSK) and lipoprotein receptor-related protein 4 (LRP4). However, around 10% of patients are seronegative, lacking autoantibodies detectable through conventional radioimmunoassays. Clinical disease does not always correspond with circulating antibody levels, and pathogenesis may require cooperation between multiple autoantibodies attacking the same target.³ Around 10% of MG cases are associated with thymomas.

Among myasthenia gravis treatments, immunosuppressants typically take 4-10 months to begin working and 18-36 months for maximum benefit. “Our new targeted therapies work within 1-2 weeks, with maximum improvement occurring somewhere between 8 and 12 weeks,” Dr. Howard said. Quick onset makes these drugs well suited for primary therapy in recalcitrant myasthenia gravis or as bridges to standard immunotherapy. Targeted drugs also appear to provide effective rescue therapy, although head-to-head studies are needed.
 

Complement Inhibition

In AChR antibody–positive myasthenia gravis, autoantibody binding with the postsynaptic AChR receptor activates complement to attack postsynaptic neuronal membrane. Complement inhibitors approved to date block activation of the terminal complement protein C5.

courtesy George Washington University

For many patients, complement inhibitors deliver dramatic results. Henry J. Kaminski, MD, said that the first patient for whom he prescribed a complement inhibitor outside a clinical trial went from being miserable to traveling internationally within a month. Dr. Kaminski is Meta A. Neumann Professor of Neurology at George Washington University, Washington, DC. 

Eculizumab (Soliris, Alexion), earned Food and Drug Administration (FDA) approval for myasthenia gravis in 2017. Week 26 results in the phase 3 REGAIN trial showed no significant difference in Myasthenia Gravis–Activities of Daily Living (MG-ADL) scores between treatment and placebo. However, said Dr. Howard, primary investigator on the study, the negative result was a statistical aberration stemming from the FDA’s requirement to use worst-rank analysis rather than absolute change scores. What got eculizumab approved were highly positive results in the overwhelming majority of secondary endpoints.⁴ Subsequently, the FDA had the manufacturer rewrite the package insert using common statistical methods, which yielded positive primary results.

Ravulizumab (Ultomiris, Alexion), approved for myasthenia gravis in 2022, reduces eculizumab’s twice-monthly intravenous dosing to every 2 months (after loading doses), with very similar efficacy. The newest complement inhibitor, zilucoplan (Zilbrysq, UCB), administered once daily subcutaneously, earned FDA approval in 2023. Daily subcutaneous dosing provides patient convenience, said Dr. Howard. Because the body does not clear this small molecule as it would a full-size antibody, it is the only complement inhibitor that can be combined with a fragment crystallizable neonatal receptor (FcRn) inhibitor.
 

FcRn Inhibition

The FcRn exists on the surface and intracellular vesicles of many cells, including B cells, but not T cells.⁵FcRn inhibitors block binding of circulating IgG antibodies to the FcRn, preventing their normal recycling, significantly reducing circulating antibodies within days of treatment.

Efgartigimod (Vyvgart, Argenx), earned FDA approval in intravenous form in 2021, followed by a subcutaneous formulation that includes hyaluronidase (Vyvgart Hytrulo) in 2023. Rozanolixizumab (Rystiggo, UCB) earned FDA approval for both AChR antibody–positive and MuSK antibody–positive myasthenia gravis in 2023.

Along with rapid response, said Dr. Howard, complement inhibitors and FcRn inhibitors offer a “hugely improved” side-effect profile. In phase 3 research, the most common side effects for both classes included headache, nausea, and diarrhea.^4,6,7 Because complement inhibitors increase the risk of Neisseria infection, users require immunization against meningococcal infection (or concurrent antibiotic prophylaxis) while on complement inhibitors.
 

Insurance Issues

With many clinicians wondering which targeted therapy to choose for a particular patient, said Dr. Howard and Dr. Kaminski, the main obstacle to wider use of these treatments is payer attitudes and practices. “While many of us would like to see these drugs used earlier in the course of disease,” Dr. Howard explained, “there are numerous restrictions placed on the physician and the patient by whatever insurance the individual has.”

Dr. Kaminski said: “There’s a lot of variability among insurance companies regarding what is expected in terms of getting approval for a certain medication. It frustrates me, thinking this patient may do well with a complement inhibitor or an FcRn inhibitor, but it takes weeks to get them approved.”

Some of his patients have been approved for, and flourished on, complement inhibitors and FcRn inhibitors, he added, and then denied a second round of treatment. Dr. Kaminski said he does not know why these patients were denied, and every time he requests reevaluation, the decision is reversed. “That’s a significant time frame for me and my staff to manage.”

When asked what can be done to address high drug prices, Dr. Howard replied, “I have no idea. I’m not an advocate of high drug prices. But I don’t think people realize the cost of doing clinical trials, which is hundreds of millions of dollars, particularly in rare diseases.”

Presently, Dr. Howard said, FcRn inhibitors are used more frequently than complement inhibitors solely because of cost. Zilucoplan will be priced below existing complement inhibitors, although it is too soon to compare its price with those of FcRn inhibitors.

When eculizumab debuted, said Dr. Howard, it cost nearly $750,000 annually. “But if you look at the number of patients treated, the cost of the drug over this population is probably less than the cost for using a cholesterol-lowering agent to treat hyperlipidemia.”

An Institute for Clinical and Economic Review (ICER) report stated that eculizumab and efgartigimod should both cost less than $20,000 annually to meet commonly used cost-effectiveness thresholds.⁸ However, Dr. Howard said ICER used models based on common diseases and ignored the economic impact of patients’ losing fewer workdays and avoiding long-term immunosuppressant side effects such as diabetes and osteoporosis and related treatment costs. “We’ve got to start looking at total societal cost,” he said.

Leapfrogging Ahead

Not all the new drugs work in every indicated patient, Dr. Howard said. For example, up to 30% of patients do not respond to complement inhibitors. “We don’t understand why. It’s as if we have leapfrogged way ahead in terms of therapeutics, and now we have to go back and answer all the questions – the who, what, where, and why of an individual drug and its response in folks.”

In this climate, said Dr. Kaminski, heavy direct-to-consumer advertising of newer myasthenia gravis therapies creates complications. “My patients are highly excited to see, ‘that’s my disease being advertised on Jeopardy.’ ” Many patients are frustrated with the general lack of awareness regarding myasthenia gravis, he added. “But then I’ve had patients who clearly would never qualify for a certain medication getting mailings to their homes.”

Dr. Howard countered that broader awareness of myasthenia gravis can only help. “There’s increasing recognition of the disease, not only by patients, but to some extent, by the treating clinician. Patients are coming to our offices and saying, ‘am I a candidate for this new drug?’ It’s the responsibility of the clinician to decide.”

Individual physicians’ practice patterns vary greatly, said Dr. Kaminski, and very little quantitative data exist here. But based on personal communications, academic-center neurologists tend to use targeted treatments on patients who have failed conventional treatments.

Conversely, Dr. Howard said that, because community physicians rarely see myasthenia gravis, and targeted treatments remain relatively new, many of these providers rely on prednisone, azathioprine, and mycophenolate mofetil.
 

B-Cell Blockers in Development

Overall, said Dr. Howard, the field of myasthenia gravis treatment development is “very rich. And pharma’s interest in myasthenia has taken off like a rocket. It’s exceptionally gratifying to those of us who take care of these patients whose life is miserable” because of adverse effects and/or nonresponse to current drugs.

“In myasthenia,” added Dr. Kaminski, “we know that T cells are promoting the activity of these auto-reactive B cells.” Many drugs currently in phase 2 or 3 development aim to eliminate B cells or signaling between T and B cells, he said. “That’s where most of the drug development is.”

Leading candidates include telitacicept (Tai’ai, RemeGen), which is both a B-lymphocyte stimulator and a proliferation-inducing ligand. A phase 3 trial (NCT05737160) is ongoing, with primary completion expected in late 2026. A second phase 3 trial (NCT06456580) recently began enrolling. Dr. Howard said that, although early results warranted phase 3 analysis, telitacicept’s phase 2 trial was open label and lacked a placebo group.⁹ The latter is a critical concern because placebo response rates in myasthenia gravis trials average 35%-40%.

Combined with standard care, the FcRn inhibitor nipocalimab (Johnson & Johnson) enabled patients with AChR, MuSK, and/or LRP4 autoantibodies to improve by 4.70 points on the MG-ADL vs 3.25 points for placebo (P = .002) over 24 weeks in phase ^3.10All FcRn inhibitors in development can broadly reduce autoantibody levels, said Dr. Howard. “But what role they will play in myasthenia gravis when they’re several years behind leaders in the field in terms of capturing market remains to be seen.”

Additionally, batoclimab (Immunovant/Harbour BioMed) showed positive topline results in phase 3, and an elevated rate of hypercholesterolemia in treated patients that was transient and consistent with previous research.¹¹ Subsequent to efgartigimod, Dr. Howard said, FcRn inhibitors are full-size antibodies. “I believe that contributes to the adverse events that we see. Efgartigimod is a small FcRn fragment. That’s why it’s a cleaner drug, if you will.”

FcRn inhibitors require periodic retreatment. For example, said Dr. Howard, the ADAPT phase 3 trial of efgartigimod, on which he was lead investigator, employed a cyclic dosing schedule – 4 weeks’ treatment, then observation until patients needed retreatment — because patients demanded it.¹² In clinical practice, some patients have gone more than 25 weeks before needing retreatment. One of his patients went beyond 40 weeks. “Others only get around 6-9 weeks. So patient choice again enters the decision-making process.”

Rituximab targets the CD20 protein on B cells nonspecifically, producing general immunosuppression. “That’s problematic in producing significant immunosuppression,” said Dr. Kaminski. Nevertheless, he said, rituximab is very effective for most patients with MuSK-specific MG, and its application to this indication has revealed differences between the MuSK subtype and AChR antibody–positive myasthenia. Specifically, MuSK antibody–positive patients have short-lived plasmablasts, which rituximab eliminates.¹³

Conversely, said Dr. Kaminski, patients with AChR antibody-positive myasthenia, especially long-term, likely have long-lived plasmablasts producing antibodies. This fact, and these patients’ lack of CD20, likely explain their poor response to rituximab.

A phase 3 trial (NCT04524273) of the CD19 blocker inebilizumab (Uplinza, Amgen) reached primary completion in May. Dr. Howard said that if topline results (unreleased at press time) prove positive, inebilizumab could replace rituximab in MG — provided payers do not reject inebilizumab because of cost.

Packed Early-Development Pipeline

Regarding early-stage projects, said Dr. Howard, the pipeline is packed with compounds that target various aspects of the immune system. “The real question with those is, what’s going to be the side effect profile? All of the trials are very early. We need bigger trials with much longer observation for safety, durability, and degree of efficacy.”

The next potential B cell–targeting game changer, he said, is chimeric antigen receptor (CAR) T cell–based therapy. In a phase 2b trial of Descartes-08 (Cartesian Therapeutics), 71% of treated patients experienced clinically meaningful improvement in MG Composite score at 3 months vs 25% for placebo.¹⁴

In early clinical trials, said Dr. Howard, patients treated with Descartes-08 — which uses autologous mRNA to target B-cell maturation antigen — have shown “exceptional improvement” lasting 20 or more months. Because the drug is not ingrained permanently into the genome, Descartes-08 avoids potentially severe side effects of DNA-targeting CAR T candidates. Dr. Howard hopes a phase 3 trial will commence around January 2025.

The tolerance approach exemplified by CNP-106 (COUR Pharmaceuticals) and a myasthenia gravis tolerogen (Toleranzia) seeks to prevent the immune system from recognizing and reacting to the NMJ abnormalities that produce myasthenia gravis, potentially providing a cure. “We look forward to those trials as they come online in the next 1-2 years,” said Dr. Howard.
 

Unmet Needs

Historically, neurologists believed that all myasthenia gravis symptoms stemmed from muscle fatigue — the more active the muscle, the weaker it gets. However, said Dr. Kaminski, some patients might lack measurable weakness but still complain of fatigue.

Elevated levels of cytokines such as interleukin (IL)–6 or IL-17 also can produce fatigue, he noted. “With the drugs we’re using, certainly the new ones, we’re not specifically targeting this fatigue phenomenon, which has been studied in a very limited fashion.”

In the RAISE-XT zilucoplan trial, participants experienced significant improvement in fatigue scores for up to 60 weeks.¹⁵ Although zilucoplan does not address fatigue directly, said Dr. Howard, improving myasthenia gravis overall helps reduce fatigue.

The Myasthenia Gravis Symptoms Patient Reported Outcome (MG Symptoms PRO), which Dr. Kaminski helped develop, includes questions designed to distinguish muscular fatigue from overall physical fatigue.¹⁶ “I’m very interested in some of the information that’s coming out on long COVID and its effect on muscle,” Dr. Kaminski added. “We might be able to learn from there that there’s still some pathology going on beyond the neuromuscular junction.”

What the field desperately needs, said Dr. Howard, are biomarkers to identify which patients will and will not respond to certain therapeutics. “We’re not there yet.” Such biomarkers are at least 3-7 years from becoming clinical reality.

Promising antibody-independent serum markers include circulating microRNAs. For example, miRNA-150-5p and miRNA-21-5p are elevated in generalized AChR-positive myasthenia gravis and early-onset myasthenia gravis (occurring before age 50) and decline after immunosuppression and thymectomy.¹⁷

Among diagnostic modalities for patients with seronegative myasthenia gravis, said Dr. Kaminski, single-fiber EMG is the most sensitive, at approximately 95%. “It’s not perfect.” Moreover, he said, performing this test accurately requires a highly experienced expert, which many treatment centers lack.

Presently, added Dr. Kaminski, orbital MRI is neither specific nor sensitive enough to be clinically useful. “One needs to be careful with these specialized tests that are published from the best laboratory in the world that does the test, and does it repetitively.” As the search for effective myasthenia gravis biomarkers continues, avoiding false-positive results is as important as avoiding false negatives.

References

1. Bubuioc AM et al. J Med Life. 2021 Jan-Mar;14(1):7-16. doi: 10.25122/jml-2020-0145.

2. Deenen JC et al. J Neuromuscul Dis. 2015;2(1):73-85. doi: 10.3233/JND-140045.

3. Kaminski HJ et al. J Clin Invest. 2024 Jun 17;134(12):e179742. doi: 10.1172/JCI179742.

4. Howard JF Jr et al. Lancet Neurol. 2017 Dec;16(12):976-986. doi: 10.1016/S1474-4422(17)30369-1.

5. Huda R. Front Immunol. 2020 Feb 21:11:240. doi: 10.3389/fimmu.2020.00240.

6. Howard JF Jr et al. Lancet Neurol. 2023 May;22(5):395-406. doi: 10.1016/S1474-4422(23)00080-7.

7. Vu T et al. NEJM Evid. 2022 May;1(5):EVIDoa2100066. doi: 10.1056/EVIDoa2100066.

8. Tice JA et al. October 20, 2021. https://icer.org/assessment/myasthenia-gravis/.

9. Yin J et al. Eur J Neurol. 2024 Aug;31(8):e16322. doi: 10.1111/ene.16322.

10. Antozzi C et al. EAN 2024, Abstract EPR-116. https://www.neurology.org/doi/10.1212/WNL.0000000000203660.

11. Yan C et al. JAMA Neurol. 2024 Mar 4;81(4):336-345. doi: 10.1001/jamaneurol.2024.0044.

12. Howard JF Jr et al. Lancet Neurol. 2021 Jul;20(7):526-536. doi: 10.1016/S1474-4422(21)00159-9.

13. Stathopoulos P et al. JCI Insight. 2017 Sep 7;2(17):e94263. doi: 10.1172/jci.insight.94263.

14. Cartesian Therapeutics. Cartesian Therapeutics announces positive topline results from phase 2b trial of Descartes-08 in patients with myasthenia gravis. 2024 Jul 2. https://ir.cartesiantherapeutics.com/news-releases/news-release-details/cartesian-therapeutics-announces-positive-topline-results-phase.

15. Howard JF Jr et al. Ther Adv Neurol Disord. 2024 Apr 17:17:17562864241243186. doi: 10.1177/17562864241243186.

16. Cleanthous S et al. Orphanet J Rare Dis. 2021 Oct 30;16(1):457. doi: 10.1186/s13023-021-02064-0.

17. Sabre L et al. Front Immunol. 2020 Mar 4:11:213. doi: 10.3389/fimmu.2020.00213.

Unlike conventional immunosuppression, treatments approved since 2017 are giving patients with myasthenia gravis targeted options to better match their needs, desires, and tolerance. Used appropriately, newer treatments can provide dramatic results faster and more safely than broad immunosuppressants. However, according to experts, payers’ willingness to cover costly new therapies remains a work in progress.

The availability of more effective treatments with fewer side effects has brought about a cultural shift, said James F. Howard, Jr, MD. “The physician’s goal now is for the patient to be symptom free with grade 1 or less adverse events. And patients are demanding freedom from all the side effects that our usual course of immune therapy produces.” Dr. Howard is professor of neurology, medicine and allied health and director of the Myasthenia Gravis Clinical Trials and Translational Research Program at the University of North Carolina at Chapel Hill.

courtesy University of North Carolina

The shift has been long in coming. Although myasthenia gravis was identified in the mid-1600s, it took more than 340 years to get the first drug approved specifically for the disorder.

Worldwide prevalence estimates vary widely, from less than 200,000 to 700,000 cases.^1,2 Pathophysiologically, myasthenia gravis stems from autoimmune destruction of neuromuscular junctions (NMJs), which transmit motor neuron impulses to muscle fibers.¹ Symptoms include variable skeletal muscle weakness that can range from mild and transient to life-threatening.

In approximately 80% of cases, autoimmune antibodies target the postsynaptic acetylcholine receptor (AChR). Additional autoimmune targets mainly include muscle-specific kinase (MuSK) and lipoprotein receptor-related protein 4 (LRP4). However, around 10% of patients are seronegative, lacking autoantibodies detectable through conventional radioimmunoassays. Clinical disease does not always correspond with circulating antibody levels, and pathogenesis may require cooperation between multiple autoantibodies attacking the same target.³ Around 10% of MG cases are associated with thymomas.

Among myasthenia gravis treatments, immunosuppressants typically take 4-10 months to begin working and 18-36 months for maximum benefit. “Our new targeted therapies work within 1-2 weeks, with maximum improvement occurring somewhere between 8 and 12 weeks,” Dr. Howard said. Quick onset makes these drugs well suited for primary therapy in recalcitrant myasthenia gravis or as bridges to standard immunotherapy. Targeted drugs also appear to provide effective rescue therapy, although head-to-head studies are needed.
 

Complement Inhibition

In AChR antibody–positive myasthenia gravis, autoantibody binding with the postsynaptic AChR receptor activates complement to attack postsynaptic neuronal membrane. Complement inhibitors approved to date block activation of the terminal complement protein C5.

courtesy George Washington University

For many patients, complement inhibitors deliver dramatic results. Henry J. Kaminski, MD, said that the first patient for whom he prescribed a complement inhibitor outside a clinical trial went from being miserable to traveling internationally within a month. Dr. Kaminski is Meta A. Neumann Professor of Neurology at George Washington University, Washington, DC. 

Eculizumab (Soliris, Alexion), earned Food and Drug Administration (FDA) approval for myasthenia gravis in 2017. Week 26 results in the phase 3 REGAIN trial showed no significant difference in Myasthenia Gravis–Activities of Daily Living (MG-ADL) scores between treatment and placebo. However, said Dr. Howard, primary investigator on the study, the negative result was a statistical aberration stemming from the FDA’s requirement to use worst-rank analysis rather than absolute change scores. What got eculizumab approved were highly positive results in the overwhelming majority of secondary endpoints.⁴ Subsequently, the FDA had the manufacturer rewrite the package insert using common statistical methods, which yielded positive primary results.

Ravulizumab (Ultomiris, Alexion), approved for myasthenia gravis in 2022, reduces eculizumab’s twice-monthly intravenous dosing to every 2 months (after loading doses), with very similar efficacy. The newest complement inhibitor, zilucoplan (Zilbrysq, UCB), administered once daily subcutaneously, earned FDA approval in 2023. Daily subcutaneous dosing provides patient convenience, said Dr. Howard. Because the body does not clear this small molecule as it would a full-size antibody, it is the only complement inhibitor that can be combined with a fragment crystallizable neonatal receptor (FcRn) inhibitor.
 

FcRn Inhibition

The FcRn exists on the surface and intracellular vesicles of many cells, including B cells, but not T cells.⁵FcRn inhibitors block binding of circulating IgG antibodies to the FcRn, preventing their normal recycling, significantly reducing circulating antibodies within days of treatment.

Efgartigimod (Vyvgart, Argenx), earned FDA approval in intravenous form in 2021, followed by a subcutaneous formulation that includes hyaluronidase (Vyvgart Hytrulo) in 2023. Rozanolixizumab (Rystiggo, UCB) earned FDA approval for both AChR antibody–positive and MuSK antibody–positive myasthenia gravis in 2023.

Along with rapid response, said Dr. Howard, complement inhibitors and FcRn inhibitors offer a “hugely improved” side-effect profile. In phase 3 research, the most common side effects for both classes included headache, nausea, and diarrhea.^4,6,7 Because complement inhibitors increase the risk of Neisseria infection, users require immunization against meningococcal infection (or concurrent antibiotic prophylaxis) while on complement inhibitors.
 

Insurance Issues

With many clinicians wondering which targeted therapy to choose for a particular patient, said Dr. Howard and Dr. Kaminski, the main obstacle to wider use of these treatments is payer attitudes and practices. “While many of us would like to see these drugs used earlier in the course of disease,” Dr. Howard explained, “there are numerous restrictions placed on the physician and the patient by whatever insurance the individual has.”

Dr. Kaminski said: “There’s a lot of variability among insurance companies regarding what is expected in terms of getting approval for a certain medication. It frustrates me, thinking this patient may do well with a complement inhibitor or an FcRn inhibitor, but it takes weeks to get them approved.”

Some of his patients have been approved for, and flourished on, complement inhibitors and FcRn inhibitors, he added, and then denied a second round of treatment. Dr. Kaminski said he does not know why these patients were denied, and every time he requests reevaluation, the decision is reversed. “That’s a significant time frame for me and my staff to manage.”

When asked what can be done to address high drug prices, Dr. Howard replied, “I have no idea. I’m not an advocate of high drug prices. But I don’t think people realize the cost of doing clinical trials, which is hundreds of millions of dollars, particularly in rare diseases.”

Presently, Dr. Howard said, FcRn inhibitors are used more frequently than complement inhibitors solely because of cost. Zilucoplan will be priced below existing complement inhibitors, although it is too soon to compare its price with those of FcRn inhibitors.

When eculizumab debuted, said Dr. Howard, it cost nearly $750,000 annually. “But if you look at the number of patients treated, the cost of the drug over this population is probably less than the cost for using a cholesterol-lowering agent to treat hyperlipidemia.”

An Institute for Clinical and Economic Review (ICER) report stated that eculizumab and efgartigimod should both cost less than $20,000 annually to meet commonly used cost-effectiveness thresholds.⁸ However, Dr. Howard said ICER used models based on common diseases and ignored the economic impact of patients’ losing fewer workdays and avoiding long-term immunosuppressant side effects such as diabetes and osteoporosis and related treatment costs. “We’ve got to start looking at total societal cost,” he said.

Leapfrogging Ahead

Not all the new drugs work in every indicated patient, Dr. Howard said. For example, up to 30% of patients do not respond to complement inhibitors. “We don’t understand why. It’s as if we have leapfrogged way ahead in terms of therapeutics, and now we have to go back and answer all the questions – the who, what, where, and why of an individual drug and its response in folks.”

In this climate, said Dr. Kaminski, heavy direct-to-consumer advertising of newer myasthenia gravis therapies creates complications. “My patients are highly excited to see, ‘that’s my disease being advertised on Jeopardy.’ ” Many patients are frustrated with the general lack of awareness regarding myasthenia gravis, he added. “But then I’ve had patients who clearly would never qualify for a certain medication getting mailings to their homes.”

Dr. Howard countered that broader awareness of myasthenia gravis can only help. “There’s increasing recognition of the disease, not only by patients, but to some extent, by the treating clinician. Patients are coming to our offices and saying, ‘am I a candidate for this new drug?’ It’s the responsibility of the clinician to decide.”

Individual physicians’ practice patterns vary greatly, said Dr. Kaminski, and very little quantitative data exist here. But based on personal communications, academic-center neurologists tend to use targeted treatments on patients who have failed conventional treatments.

Conversely, Dr. Howard said that, because community physicians rarely see myasthenia gravis, and targeted treatments remain relatively new, many of these providers rely on prednisone, azathioprine, and mycophenolate mofetil.
 

B-Cell Blockers in Development

Overall, said Dr. Howard, the field of myasthenia gravis treatment development is “very rich. And pharma’s interest in myasthenia has taken off like a rocket. It’s exceptionally gratifying to those of us who take care of these patients whose life is miserable” because of adverse effects and/or nonresponse to current drugs.

“In myasthenia,” added Dr. Kaminski, “we know that T cells are promoting the activity of these auto-reactive B cells.” Many drugs currently in phase 2 or 3 development aim to eliminate B cells or signaling between T and B cells, he said. “That’s where most of the drug development is.”

Leading candidates include telitacicept (Tai’ai, RemeGen), which is both a B-lymphocyte stimulator and a proliferation-inducing ligand. A phase 3 trial (NCT05737160) is ongoing, with primary completion expected in late 2026. A second phase 3 trial (NCT06456580) recently began enrolling. Dr. Howard said that, although early results warranted phase 3 analysis, telitacicept’s phase 2 trial was open label and lacked a placebo group.⁹ The latter is a critical concern because placebo response rates in myasthenia gravis trials average 35%-40%.

Combined with standard care, the FcRn inhibitor nipocalimab (Johnson & Johnson) enabled patients with AChR, MuSK, and/or LRP4 autoantibodies to improve by 4.70 points on the MG-ADL vs 3.25 points for placebo (P = .002) over 24 weeks in phase ^3.10All FcRn inhibitors in development can broadly reduce autoantibody levels, said Dr. Howard. “But what role they will play in myasthenia gravis when they’re several years behind leaders in the field in terms of capturing market remains to be seen.”

Additionally, batoclimab (Immunovant/Harbour BioMed) showed positive topline results in phase 3, and an elevated rate of hypercholesterolemia in treated patients that was transient and consistent with previous research.¹¹ Subsequent to efgartigimod, Dr. Howard said, FcRn inhibitors are full-size antibodies. “I believe that contributes to the adverse events that we see. Efgartigimod is a small FcRn fragment. That’s why it’s a cleaner drug, if you will.”

FcRn inhibitors require periodic retreatment. For example, said Dr. Howard, the ADAPT phase 3 trial of efgartigimod, on which he was lead investigator, employed a cyclic dosing schedule – 4 weeks’ treatment, then observation until patients needed retreatment — because patients demanded it.¹² In clinical practice, some patients have gone more than 25 weeks before needing retreatment. One of his patients went beyond 40 weeks. “Others only get around 6-9 weeks. So patient choice again enters the decision-making process.”

Rituximab targets the CD20 protein on B cells nonspecifically, producing general immunosuppression. “That’s problematic in producing significant immunosuppression,” said Dr. Kaminski. Nevertheless, he said, rituximab is very effective for most patients with MuSK-specific MG, and its application to this indication has revealed differences between the MuSK subtype and AChR antibody–positive myasthenia. Specifically, MuSK antibody–positive patients have short-lived plasmablasts, which rituximab eliminates.¹³

Conversely, said Dr. Kaminski, patients with AChR antibody-positive myasthenia, especially long-term, likely have long-lived plasmablasts producing antibodies. This fact, and these patients’ lack of CD20, likely explain their poor response to rituximab.

A phase 3 trial (NCT04524273) of the CD19 blocker inebilizumab (Uplinza, Amgen) reached primary completion in May. Dr. Howard said that if topline results (unreleased at press time) prove positive, inebilizumab could replace rituximab in MG — provided payers do not reject inebilizumab because of cost.

Packed Early-Development Pipeline

Regarding early-stage projects, said Dr. Howard, the pipeline is packed with compounds that target various aspects of the immune system. “The real question with those is, what’s going to be the side effect profile? All of the trials are very early. We need bigger trials with much longer observation for safety, durability, and degree of efficacy.”

The next potential B cell–targeting game changer, he said, is chimeric antigen receptor (CAR) T cell–based therapy. In a phase 2b trial of Descartes-08 (Cartesian Therapeutics), 71% of treated patients experienced clinically meaningful improvement in MG Composite score at 3 months vs 25% for placebo.¹⁴

In early clinical trials, said Dr. Howard, patients treated with Descartes-08 — which uses autologous mRNA to target B-cell maturation antigen — have shown “exceptional improvement” lasting 20 or more months. Because the drug is not ingrained permanently into the genome, Descartes-08 avoids potentially severe side effects of DNA-targeting CAR T candidates. Dr. Howard hopes a phase 3 trial will commence around January 2025.

The tolerance approach exemplified by CNP-106 (COUR Pharmaceuticals) and a myasthenia gravis tolerogen (Toleranzia) seeks to prevent the immune system from recognizing and reacting to the NMJ abnormalities that produce myasthenia gravis, potentially providing a cure. “We look forward to those trials as they come online in the next 1-2 years,” said Dr. Howard.
 

Unmet Needs

Historically, neurologists believed that all myasthenia gravis symptoms stemmed from muscle fatigue — the more active the muscle, the weaker it gets. However, said Dr. Kaminski, some patients might lack measurable weakness but still complain of fatigue.

Elevated levels of cytokines such as interleukin (IL)–6 or IL-17 also can produce fatigue, he noted. “With the drugs we’re using, certainly the new ones, we’re not specifically targeting this fatigue phenomenon, which has been studied in a very limited fashion.”

In the RAISE-XT zilucoplan trial, participants experienced significant improvement in fatigue scores for up to 60 weeks.¹⁵ Although zilucoplan does not address fatigue directly, said Dr. Howard, improving myasthenia gravis overall helps reduce fatigue.

The Myasthenia Gravis Symptoms Patient Reported Outcome (MG Symptoms PRO), which Dr. Kaminski helped develop, includes questions designed to distinguish muscular fatigue from overall physical fatigue.¹⁶ “I’m very interested in some of the information that’s coming out on long COVID and its effect on muscle,” Dr. Kaminski added. “We might be able to learn from there that there’s still some pathology going on beyond the neuromuscular junction.”

What the field desperately needs, said Dr. Howard, are biomarkers to identify which patients will and will not respond to certain therapeutics. “We’re not there yet.” Such biomarkers are at least 3-7 years from becoming clinical reality.

Promising antibody-independent serum markers include circulating microRNAs. For example, miRNA-150-5p and miRNA-21-5p are elevated in generalized AChR-positive myasthenia gravis and early-onset myasthenia gravis (occurring before age 50) and decline after immunosuppression and thymectomy.¹⁷

Among diagnostic modalities for patients with seronegative myasthenia gravis, said Dr. Kaminski, single-fiber EMG is the most sensitive, at approximately 95%. “It’s not perfect.” Moreover, he said, performing this test accurately requires a highly experienced expert, which many treatment centers lack.

Presently, added Dr. Kaminski, orbital MRI is neither specific nor sensitive enough to be clinically useful. “One needs to be careful with these specialized tests that are published from the best laboratory in the world that does the test, and does it repetitively.” As the search for effective myasthenia gravis biomarkers continues, avoiding false-positive results is as important as avoiding false negatives.

References

1. Bubuioc AM et al. J Med Life. 2021 Jan-Mar;14(1):7-16. doi: 10.25122/jml-2020-0145.

2. Deenen JC et al. J Neuromuscul Dis. 2015;2(1):73-85. doi: 10.3233/JND-140045.

3. Kaminski HJ et al. J Clin Invest. 2024 Jun 17;134(12):e179742. doi: 10.1172/JCI179742.

4. Howard JF Jr et al. Lancet Neurol. 2017 Dec;16(12):976-986. doi: 10.1016/S1474-4422(17)30369-1.

5. Huda R. Front Immunol. 2020 Feb 21:11:240. doi: 10.3389/fimmu.2020.00240.

6. Howard JF Jr et al. Lancet Neurol. 2023 May;22(5):395-406. doi: 10.1016/S1474-4422(23)00080-7.

7. Vu T et al. NEJM Evid. 2022 May;1(5):EVIDoa2100066. doi: 10.1056/EVIDoa2100066.

8. Tice JA et al. October 20, 2021. https://icer.org/assessment/myasthenia-gravis/.

9. Yin J et al. Eur J Neurol. 2024 Aug;31(8):e16322. doi: 10.1111/ene.16322.

10. Antozzi C et al. EAN 2024, Abstract EPR-116. https://www.neurology.org/doi/10.1212/WNL.0000000000203660.

11. Yan C et al. JAMA Neurol. 2024 Mar 4;81(4):336-345. doi: 10.1001/jamaneurol.2024.0044.

12. Howard JF Jr et al. Lancet Neurol. 2021 Jul;20(7):526-536. doi: 10.1016/S1474-4422(21)00159-9.

13. Stathopoulos P et al. JCI Insight. 2017 Sep 7;2(17):e94263. doi: 10.1172/jci.insight.94263.

14. Cartesian Therapeutics. Cartesian Therapeutics announces positive topline results from phase 2b trial of Descartes-08 in patients with myasthenia gravis. 2024 Jul 2. https://ir.cartesiantherapeutics.com/news-releases/news-release-details/cartesian-therapeutics-announces-positive-topline-results-phase.

15. Howard JF Jr et al. Ther Adv Neurol Disord. 2024 Apr 17:17:17562864241243186. doi: 10.1177/17562864241243186.

16. Cleanthous S et al. Orphanet J Rare Dis. 2021 Oct 30;16(1):457. doi: 10.1186/s13023-021-02064-0.

17. Sabre L et al. Front Immunol. 2020 Mar 4:11:213. doi: 10.3389/fimmu.2020.00213.

Unlike conventional immunosuppression, treatments approved since 2017 are giving patients with myasthenia gravis targeted options to better match their needs, desires, and tolerance. Used appropriately, newer treatments can provide dramatic results faster and more safely than broad immunosuppressants. However, according to experts, payers’ willingness to cover costly new therapies remains a work in progress.

The availability of more effective treatments with fewer side effects has brought about a cultural shift, said James F. Howard, Jr, MD. “The physician’s goal now is for the patient to be symptom free with grade 1 or less adverse events. And patients are demanding freedom from all the side effects that our usual course of immune therapy produces.” Dr. Howard is professor of neurology, medicine and allied health and director of the Myasthenia Gravis Clinical Trials and Translational Research Program at the University of North Carolina at Chapel Hill.

courtesy University of North Carolina

The shift has been long in coming. Although myasthenia gravis was identified in the mid-1600s, it took more than 340 years to get the first drug approved specifically for the disorder.

Worldwide prevalence estimates vary widely, from less than 200,000 to 700,000 cases.^1,2 Pathophysiologically, myasthenia gravis stems from autoimmune destruction of neuromuscular junctions (NMJs), which transmit motor neuron impulses to muscle fibers.¹ Symptoms include variable skeletal muscle weakness that can range from mild and transient to life-threatening.

In approximately 80% of cases, autoimmune antibodies target the postsynaptic acetylcholine receptor (AChR). Additional autoimmune targets mainly include muscle-specific kinase (MuSK) and lipoprotein receptor-related protein 4 (LRP4). However, around 10% of patients are seronegative, lacking autoantibodies detectable through conventional radioimmunoassays. Clinical disease does not always correspond with circulating antibody levels, and pathogenesis may require cooperation between multiple autoantibodies attacking the same target.³ Around 10% of MG cases are associated with thymomas.

Among myasthenia gravis treatments, immunosuppressants typically take 4-10 months to begin working and 18-36 months for maximum benefit. “Our new targeted therapies work within 1-2 weeks, with maximum improvement occurring somewhere between 8 and 12 weeks,” Dr. Howard said. Quick onset makes these drugs well suited for primary therapy in recalcitrant myasthenia gravis or as bridges to standard immunotherapy. Targeted drugs also appear to provide effective rescue therapy, although head-to-head studies are needed.
 

Complement Inhibition

In AChR antibody–positive myasthenia gravis, autoantibody binding with the postsynaptic AChR receptor activates complement to attack postsynaptic neuronal membrane. Complement inhibitors approved to date block activation of the terminal complement protein C5.

courtesy George Washington University

For many patients, complement inhibitors deliver dramatic results. Henry J. Kaminski, MD, said that the first patient for whom he prescribed a complement inhibitor outside a clinical trial went from being miserable to traveling internationally within a month. Dr. Kaminski is Meta A. Neumann Professor of Neurology at George Washington University, Washington, DC. 

Eculizumab (Soliris, Alexion), earned Food and Drug Administration (FDA) approval for myasthenia gravis in 2017. Week 26 results in the phase 3 REGAIN trial showed no significant difference in Myasthenia Gravis–Activities of Daily Living (MG-ADL) scores between treatment and placebo. However, said Dr. Howard, primary investigator on the study, the negative result was a statistical aberration stemming from the FDA’s requirement to use worst-rank analysis rather than absolute change scores. What got eculizumab approved were highly positive results in the overwhelming majority of secondary endpoints.⁴ Subsequently, the FDA had the manufacturer rewrite the package insert using common statistical methods, which yielded positive primary results.

Ravulizumab (Ultomiris, Alexion), approved for myasthenia gravis in 2022, reduces eculizumab’s twice-monthly intravenous dosing to every 2 months (after loading doses), with very similar efficacy. The newest complement inhibitor, zilucoplan (Zilbrysq, UCB), administered once daily subcutaneously, earned FDA approval in 2023. Daily subcutaneous dosing provides patient convenience, said Dr. Howard. Because the body does not clear this small molecule as it would a full-size antibody, it is the only complement inhibitor that can be combined with a fragment crystallizable neonatal receptor (FcRn) inhibitor.
 

FcRn Inhibition

The FcRn exists on the surface and intracellular vesicles of many cells, including B cells, but not T cells.⁵FcRn inhibitors block binding of circulating IgG antibodies to the FcRn, preventing their normal recycling, significantly reducing circulating antibodies within days of treatment.

Efgartigimod (Vyvgart, Argenx), earned FDA approval in intravenous form in 2021, followed by a subcutaneous formulation that includes hyaluronidase (Vyvgart Hytrulo) in 2023. Rozanolixizumab (Rystiggo, UCB) earned FDA approval for both AChR antibody–positive and MuSK antibody–positive myasthenia gravis in 2023.

Along with rapid response, said Dr. Howard, complement inhibitors and FcRn inhibitors offer a “hugely improved” side-effect profile. In phase 3 research, the most common side effects for both classes included headache, nausea, and diarrhea.^4,6,7 Because complement inhibitors increase the risk of Neisseria infection, users require immunization against meningococcal infection (or concurrent antibiotic prophylaxis) while on complement inhibitors.
 

Insurance Issues

With many clinicians wondering which targeted therapy to choose for a particular patient, said Dr. Howard and Dr. Kaminski, the main obstacle to wider use of these treatments is payer attitudes and practices. “While many of us would like to see these drugs used earlier in the course of disease,” Dr. Howard explained, “there are numerous restrictions placed on the physician and the patient by whatever insurance the individual has.”

Dr. Kaminski said: “There’s a lot of variability among insurance companies regarding what is expected in terms of getting approval for a certain medication. It frustrates me, thinking this patient may do well with a complement inhibitor or an FcRn inhibitor, but it takes weeks to get them approved.”

Some of his patients have been approved for, and flourished on, complement inhibitors and FcRn inhibitors, he added, and then denied a second round of treatment. Dr. Kaminski said he does not know why these patients were denied, and every time he requests reevaluation, the decision is reversed. “That’s a significant time frame for me and my staff to manage.”

When asked what can be done to address high drug prices, Dr. Howard replied, “I have no idea. I’m not an advocate of high drug prices. But I don’t think people realize the cost of doing clinical trials, which is hundreds of millions of dollars, particularly in rare diseases.”

Presently, Dr. Howard said, FcRn inhibitors are used more frequently than complement inhibitors solely because of cost. Zilucoplan will be priced below existing complement inhibitors, although it is too soon to compare its price with those of FcRn inhibitors.

When eculizumab debuted, said Dr. Howard, it cost nearly $750,000 annually. “But if you look at the number of patients treated, the cost of the drug over this population is probably less than the cost for using a cholesterol-lowering agent to treat hyperlipidemia.”

An Institute for Clinical and Economic Review (ICER) report stated that eculizumab and efgartigimod should both cost less than $20,000 annually to meet commonly used cost-effectiveness thresholds.⁸ However, Dr. Howard said ICER used models based on common diseases and ignored the economic impact of patients’ losing fewer workdays and avoiding long-term immunosuppressant side effects such as diabetes and osteoporosis and related treatment costs. “We’ve got to start looking at total societal cost,” he said.

Leapfrogging Ahead

Not all the new drugs work in every indicated patient, Dr. Howard said. For example, up to 30% of patients do not respond to complement inhibitors. “We don’t understand why. It’s as if we have leapfrogged way ahead in terms of therapeutics, and now we have to go back and answer all the questions – the who, what, where, and why of an individual drug and its response in folks.”

In this climate, said Dr. Kaminski, heavy direct-to-consumer advertising of newer myasthenia gravis therapies creates complications. “My patients are highly excited to see, ‘that’s my disease being advertised on Jeopardy.’ ” Many patients are frustrated with the general lack of awareness regarding myasthenia gravis, he added. “But then I’ve had patients who clearly would never qualify for a certain medication getting mailings to their homes.”

Dr. Howard countered that broader awareness of myasthenia gravis can only help. “There’s increasing recognition of the disease, not only by patients, but to some extent, by the treating clinician. Patients are coming to our offices and saying, ‘am I a candidate for this new drug?’ It’s the responsibility of the clinician to decide.”

Individual physicians’ practice patterns vary greatly, said Dr. Kaminski, and very little quantitative data exist here. But based on personal communications, academic-center neurologists tend to use targeted treatments on patients who have failed conventional treatments.

Conversely, Dr. Howard said that, because community physicians rarely see myasthenia gravis, and targeted treatments remain relatively new, many of these providers rely on prednisone, azathioprine, and mycophenolate mofetil.
 

B-Cell Blockers in Development

Overall, said Dr. Howard, the field of myasthenia gravis treatment development is “very rich. And pharma’s interest in myasthenia has taken off like a rocket. It’s exceptionally gratifying to those of us who take care of these patients whose life is miserable” because of adverse effects and/or nonresponse to current drugs.

“In myasthenia,” added Dr. Kaminski, “we know that T cells are promoting the activity of these auto-reactive B cells.” Many drugs currently in phase 2 or 3 development aim to eliminate B cells or signaling between T and B cells, he said. “That’s where most of the drug development is.”

Leading candidates include telitacicept (Tai’ai, RemeGen), which is both a B-lymphocyte stimulator and a proliferation-inducing ligand. A phase 3 trial (NCT05737160) is ongoing, with primary completion expected in late 2026. A second phase 3 trial (NCT06456580) recently began enrolling. Dr. Howard said that, although early results warranted phase 3 analysis, telitacicept’s phase 2 trial was open label and lacked a placebo group.⁹ The latter is a critical concern because placebo response rates in myasthenia gravis trials average 35%-40%.

Combined with standard care, the FcRn inhibitor nipocalimab (Johnson & Johnson) enabled patients with AChR, MuSK, and/or LRP4 autoantibodies to improve by 4.70 points on the MG-ADL vs 3.25 points for placebo (P = .002) over 24 weeks in phase ^3.10All FcRn inhibitors in development can broadly reduce autoantibody levels, said Dr. Howard. “But what role they will play in myasthenia gravis when they’re several years behind leaders in the field in terms of capturing market remains to be seen.”

Additionally, batoclimab (Immunovant/Harbour BioMed) showed positive topline results in phase 3, and an elevated rate of hypercholesterolemia in treated patients that was transient and consistent with previous research.¹¹ Subsequent to efgartigimod, Dr. Howard said, FcRn inhibitors are full-size antibodies. “I believe that contributes to the adverse events that we see. Efgartigimod is a small FcRn fragment. That’s why it’s a cleaner drug, if you will.”

FcRn inhibitors require periodic retreatment. For example, said Dr. Howard, the ADAPT phase 3 trial of efgartigimod, on which he was lead investigator, employed a cyclic dosing schedule – 4 weeks’ treatment, then observation until patients needed retreatment — because patients demanded it.¹² In clinical practice, some patients have gone more than 25 weeks before needing retreatment. One of his patients went beyond 40 weeks. “Others only get around 6-9 weeks. So patient choice again enters the decision-making process.”

Rituximab targets the CD20 protein on B cells nonspecifically, producing general immunosuppression. “That’s problematic in producing significant immunosuppression,” said Dr. Kaminski. Nevertheless, he said, rituximab is very effective for most patients with MuSK-specific MG, and its application to this indication has revealed differences between the MuSK subtype and AChR antibody–positive myasthenia. Specifically, MuSK antibody–positive patients have short-lived plasmablasts, which rituximab eliminates.¹³

Conversely, said Dr. Kaminski, patients with AChR antibody-positive myasthenia, especially long-term, likely have long-lived plasmablasts producing antibodies. This fact, and these patients’ lack of CD20, likely explain their poor response to rituximab.

A phase 3 trial (NCT04524273) of the CD19 blocker inebilizumab (Uplinza, Amgen) reached primary completion in May. Dr. Howard said that if topline results (unreleased at press time) prove positive, inebilizumab could replace rituximab in MG — provided payers do not reject inebilizumab because of cost.

Packed Early-Development Pipeline

Regarding early-stage projects, said Dr. Howard, the pipeline is packed with compounds that target various aspects of the immune system. “The real question with those is, what’s going to be the side effect profile? All of the trials are very early. We need bigger trials with much longer observation for safety, durability, and degree of efficacy.”

The next potential B cell–targeting game changer, he said, is chimeric antigen receptor (CAR) T cell–based therapy. In a phase 2b trial of Descartes-08 (Cartesian Therapeutics), 71% of treated patients experienced clinically meaningful improvement in MG Composite score at 3 months vs 25% for placebo.¹⁴

In early clinical trials, said Dr. Howard, patients treated with Descartes-08 — which uses autologous mRNA to target B-cell maturation antigen — have shown “exceptional improvement” lasting 20 or more months. Because the drug is not ingrained permanently into the genome, Descartes-08 avoids potentially severe side effects of DNA-targeting CAR T candidates. Dr. Howard hopes a phase 3 trial will commence around January 2025.

The tolerance approach exemplified by CNP-106 (COUR Pharmaceuticals) and a myasthenia gravis tolerogen (Toleranzia) seeks to prevent the immune system from recognizing and reacting to the NMJ abnormalities that produce myasthenia gravis, potentially providing a cure. “We look forward to those trials as they come online in the next 1-2 years,” said Dr. Howard.
 

Unmet Needs

Historically, neurologists believed that all myasthenia gravis symptoms stemmed from muscle fatigue — the more active the muscle, the weaker it gets. However, said Dr. Kaminski, some patients might lack measurable weakness but still complain of fatigue.

Elevated levels of cytokines such as interleukin (IL)–6 or IL-17 also can produce fatigue, he noted. “With the drugs we’re using, certainly the new ones, we’re not specifically targeting this fatigue phenomenon, which has been studied in a very limited fashion.”

In the RAISE-XT zilucoplan trial, participants experienced significant improvement in fatigue scores for up to 60 weeks.¹⁵ Although zilucoplan does not address fatigue directly, said Dr. Howard, improving myasthenia gravis overall helps reduce fatigue.

The Myasthenia Gravis Symptoms Patient Reported Outcome (MG Symptoms PRO), which Dr. Kaminski helped develop, includes questions designed to distinguish muscular fatigue from overall physical fatigue.¹⁶ “I’m very interested in some of the information that’s coming out on long COVID and its effect on muscle,” Dr. Kaminski added. “We might be able to learn from there that there’s still some pathology going on beyond the neuromuscular junction.”

What the field desperately needs, said Dr. Howard, are biomarkers to identify which patients will and will not respond to certain therapeutics. “We’re not there yet.” Such biomarkers are at least 3-7 years from becoming clinical reality.

Promising antibody-independent serum markers include circulating microRNAs. For example, miRNA-150-5p and miRNA-21-5p are elevated in generalized AChR-positive myasthenia gravis and early-onset myasthenia gravis (occurring before age 50) and decline after immunosuppression and thymectomy.¹⁷

Among diagnostic modalities for patients with seronegative myasthenia gravis, said Dr. Kaminski, single-fiber EMG is the most sensitive, at approximately 95%. “It’s not perfect.” Moreover, he said, performing this test accurately requires a highly experienced expert, which many treatment centers lack.

Presently, added Dr. Kaminski, orbital MRI is neither specific nor sensitive enough to be clinically useful. “One needs to be careful with these specialized tests that are published from the best laboratory in the world that does the test, and does it repetitively.” As the search for effective myasthenia gravis biomarkers continues, avoiding false-positive results is as important as avoiding false negatives.

References

1. Bubuioc AM et al. J Med Life. 2021 Jan-Mar;14(1):7-16. doi: 10.25122/jml-2020-0145.

2. Deenen JC et al. J Neuromuscul Dis. 2015;2(1):73-85. doi: 10.3233/JND-140045.

3. Kaminski HJ et al. J Clin Invest. 2024 Jun 17;134(12):e179742. doi: 10.1172/JCI179742.

4. Howard JF Jr et al. Lancet Neurol. 2017 Dec;16(12):976-986. doi: 10.1016/S1474-4422(17)30369-1.

5. Huda R. Front Immunol. 2020 Feb 21:11:240. doi: 10.3389/fimmu.2020.00240.

6. Howard JF Jr et al. Lancet Neurol. 2023 May;22(5):395-406. doi: 10.1016/S1474-4422(23)00080-7.

7. Vu T et al. NEJM Evid. 2022 May;1(5):EVIDoa2100066. doi: 10.1056/EVIDoa2100066.

8. Tice JA et al. October 20, 2021. https://icer.org/assessment/myasthenia-gravis/.

9. Yin J et al. Eur J Neurol. 2024 Aug;31(8):e16322. doi: 10.1111/ene.16322.

10. Antozzi C et al. EAN 2024, Abstract EPR-116. https://www.neurology.org/doi/10.1212/WNL.0000000000203660.

11. Yan C et al. JAMA Neurol. 2024 Mar 4;81(4):336-345. doi: 10.1001/jamaneurol.2024.0044.

12. Howard JF Jr et al. Lancet Neurol. 2021 Jul;20(7):526-536. doi: 10.1016/S1474-4422(21)00159-9.

13. Stathopoulos P et al. JCI Insight. 2017 Sep 7;2(17):e94263. doi: 10.1172/jci.insight.94263.

14. Cartesian Therapeutics. Cartesian Therapeutics announces positive topline results from phase 2b trial of Descartes-08 in patients with myasthenia gravis. 2024 Jul 2. https://ir.cartesiantherapeutics.com/news-releases/news-release-details/cartesian-therapeutics-announces-positive-topline-results-phase.

15. Howard JF Jr et al. Ther Adv Neurol Disord. 2024 Apr 17:17:17562864241243186. doi: 10.1177/17562864241243186.

16. Cleanthous S et al. Orphanet J Rare Dis. 2021 Oct 30;16(1):457. doi: 10.1186/s13023-021-02064-0.

17. Sabre L et al. Front Immunol. 2020 Mar 4:11:213. doi: 10.3389/fimmu.2020.00213.

Chronic inflammatory demyelinating polyradiculoneuropathy, or CIDP, is a rare immune-mediated nerve disorder characterized by progressive weakness and sensory impairment in the arms and legs, the result of an autoimmune attack on myelin.

Though some clustering of cases may occur in families, and susceptibility genes have been found, it is not considered a genetic disease. It can strike patients of either sex at any age, though most cases will occur in or after midlife.

Because its symptoms can overlap with a broad range of neuropathies, CIDP is notoriously complex to diagnose, relying on nerve conduction studies and careful clinical assessment rather than any definitive blood biomarker. Complicating matters further, CIDP has several variants whose symptoms differ from classical presentations.

Many patients who do not have CIDP end up being treated for it, and many CIDP patients experience delays to diagnosis and treatment that can potentially result in greater nerve damage and worse outcomes.

The good news, CIDP experts say, is that the last few years have seen important advances in diagnosis and treatment – including comprehensive new clinical guidelines and the June 2024 approval by the Food and Drug Administration of a new treatment, efgartigimod alfa and hyaluronidase-qvfc (Vyvgart, argenx). This antibody fragment represents the first non-steroid, non-immunoglobulin option for CIDP.

Despite the difficulties of recruiting patients with a tough-to-confirm disease that affects between 2 and 9 of every 100,000 people, according to the GPS-CIDP Foundation clinical trials have been successfully carried out in CIDP, and new ones continue to recruit. The experimental therapies being explored are based on a wide range of proposed disease pathways.

courtesy University of Minnesota

“It’s a very exciting time,” said Jeffrey Allen, MD, a neurologist at the University of Minnesota, Minneapolis, one of three CIDP experts who spoke about this challenging but treatable syndrome, its diagnosis and management, and the research questions that they hope to see answered.
 

Refining Diagnosis

In classical or typical CIDP, which accounts for most cases, patients present with progressive weakness and numbness that affects the arms and legs symmetrically, with the weakness being both proximal and distal. The disease usually evolves over a period of months, which helps distinguish it from Gullain-Barré syndrome, whose onset is more sudden and progression is less than 4 weeks.

CIDP was first described in the 1970s, and since that time more than a dozen sets of diagnostic criteria have been published. Starting about a decade ago, Dr. Allen and neurologist Richard Lewis, MD, of Cedars-Sinai Medical Center in Los Angeles, California, helped launch an effort to improve them.

“Experts in the field who were seeing patients with CIDP recognized that a lot of referrals coming to them were of people who actually didn’t have it, or they had the disease and were treated for it but didn’t need to be on treatment, or their treatment was very unconventional,” Dr. Allen said. “We wanted to try to put some data behind that.” In 2015 Dr. Allen and Dr. Lewis published a paper that found that nearly half of patients referred with a diagnosis of CIDP failed to meet basic diagnostic requirements.

courtesy Cedars-Sinai Medical Center

Erroneous interpretation of nerve conduction studies “was a significant factor” contributing to the misdiagnoses, Dr. Lewis said. And another major problem was that patients’ response to standard treatment with intravenous immunoglobulins (current treatments have also come to include subcutaneous immunoglobulins) was not being measured objectively. Instead of evaluating patients using grip strength, walking tests, or other objective instruments, clinicians asked patients whether they felt better. “The problem is that IVIg makes people feel good,” Dr. Lewis said, “possibly by reducing normal inflammatory agents in the body.”

The 2015 paper caught the attention of neurologists and neuromuscular specialists worldwide, who reported similar problems with misdiagnosis. “And from there we did other work to try to dissect out what the more specific issues are,” Dr. Allen said. “The electrophysiology was a big one.”

courtesy University of Buffalo

Neurologist Nicholas Silvestri, MD, of the University at Buffalo in New York, one of the centers of excellence recognized by the CIDP-GBS Foundation, affirmed that nerve conduction studies, which essential to diagnosing CIDP, “are not as objective as we think they are. They’re very prone to user error and overinterpretation error. If they’re not performed appropriately, things can look like CIDP when they’re not. Very common forms of neuropathy, like diabetic neuropathy, can be misinterpreted as CIDP.”
 

The Challenge of Variants

After their 2015 paper on diagnostic pitfalls, Dr. Lewis and Dr. Allen, along with colleagues in the United States and Europe, started looking deeper into outcome measures and how to better follow and track patients with CIDP. In 2021 they helped create the first comprehensive clinical guidelines for CIDP in over a decade.

Much of their effort focused on atypical presentations, or what are now called variants, of CIDP — people with predominantly distal disease, asymmetrical symptomology, focal symptoms, or exclusively motor or sensory symptoms. With classical CIDP, “we don’t really have a problem with misdiagnosis,” Dr. Lewis said. With variants, however, misdiagnoses are extremely common. The 2021 guidelines try to address this, proposing differential diagnoses for each of the variants and ways to investigate them.

The guidelines also removed a subgroup of patients previously included as having CIDP. These patients, who comprise about 10% of cases, have antibodies to components of the Node of Ranvier, part of the axonal membrane, and the paranodal myelin. The autoimmune nodopathies do not respond to treatment with immunoglobulins or steroids in the way classical CIDP and its variants do. However, many patients have seen success with the immunotherapy rituximab.

“CIDP is a syndrome, not one disease,” Dr. Lewis said. “So it has been difficult to get guidelines or criteria that are sensitive to all the different forms of the disease, and yet specific for the disease and not overlapping. The nodopathies were pulled out because they don’t respond to usual treatments for CIDP. Hopefully over the years we’ll have even more specific diagnoses and can split out more patients.”
 

A Need for Better Biomarkers

With the neuromuscular autoimmune disease myasthenia gravis, 85% of patients have antibodies against the muscle acetylcholine receptor (AChR). Another 6% will have antibodies against muscle-specific kinase (MuSK).

Antibody profiles have long guided treatment decisions in myasthenia gravis, with AChR-positive patients responding to corticosteroids, IVIg, complement inhibitors, and other agents. MuSK-positive myasthenia gravis patients, similar to people with autoimmune nodopathies, respond poorly to IVIg but can have dramatic responses when treated with B cell–depleting therapies like rituximab.

Antibodies to nodal proteins neurofascin-155 and contactin-1 have been shown to be involved with the nodopathies. Assays for these are now commercially available, and Dr. Allen recommended that clinicians seek them for patients with a more rapid course, with tremor and ataxia, or who do not respond to standard CIDP treatments.

Still, no dominant autoantibody has been identified for the majority of presentations, including classical presentations. “I suspect it’s a heterogeneous group of multiple antibodies causing the disease,” Dr. Silvestri said. “That may explain to an extent the different manifestations and the different responses to treatment.”

Dr. Lewis said he thinks that, while more antibodies are likely to be discovered in the coming years, “we’re still identifying fewer than 20% of CIDP patients by specific antibodies, so we have a long way to go.”
 

Promising Trial Landscape

“CIDP is a challenging disease to study because of the diagnostic issues,” Dr. Allen said. “We know that a [nontrivial] percentage of patients ... can go into a drug-free remission. They actually don’t need treatment during that time. We don’t have any way to measure that. And if you put them in a clinical trial, it’s difficult to measure changes in the trial if they didn’t need the drug in the first place.”

In the global ADHERE trail, which looked at efgartigimod alfa and hyaluronidase-qvfc in CIDP patients, the investigators, led by Dr. Allen and Dr. Lewis, challenged patients to be off therapy for 12 weeks and allowed only those with active disease to enroll. They also used an adjudication panel of CIDP experts to review the records of each patient to assure patients had CIDP.

If two experts on the panel independently agreed that it was CIDP, Dr. Lewis said, then patients were eligible for enrollment. “If they both said they weren’t CIDP, they were not eligible. And if there was an argument between the two of them, then a third adjudicator would come in.”

About half of patients screened (n = 221) ended up included, and adjudication panels are now used in most CIDP trials.

The trial saw a positive outcome for efgartigimod alfa and hyaluronidase-qvfc, an antibody fragment that targets neonatal Fc receptor (FcRn), as a way to reduce to levels of pathogenic IgG autoantibodies. (The treatment was previously approved for myasthenia gravis.) The fact that two thirds of participants in the trial responded pointed to the likelihood that most CIDP patients have an IgG-related disease, Dr. Lewis said.

Different types of therapies are now being investigated in CIDP, among them other FcRn-inhibiting drugs and drugs inhibiting complement. Results from these trials may shed more light on the pathophysiology of the disease, which Dr. Silvestri said would be welcome.

“If I can test for antibodies, I can make a more timely diagnosis,” he said. “I’m assuming that some people with CIDP have non–antibody-driven disease. And in those cases, I want to avoid using drugs like Vyvgart, which are targeting antibodies. I want to give them a different therapy.”

Management: A Delicate Dance

Since the 1990s, the standard of care for CIDP has been IVIg and steroids. Newer subcutaneous immunoglobulin products, which take less time to administer, may be more convenient for patients than traditional IVIg and mitigate some concerning side effects.

Efgartigimod alfa and hyaluronidase-qvfc now offers an entirely different option that, while too new for clinicians to have much experience with in CIDP, represents further convenience for patients, with dosing in one 90-second subcutaneous injection per week.

In general, the sooner people are diagnosed and on therapy, the better they are likely to do, with fewer risks of irreversible axonal loss and disability. Referring to CIDP centers of excellence can help speed a definitive diagnosis.

Some patients will see a complete or near-complete recovery, while others will not. “It’s important to be up front with patients about what the benefit of treatments are, what are the expectations of treatment, what we can potentially get back, and what’s unlikely to come back,” Dr. Allen said. “We know that irreversible deficits are not uncommon in folks with CIDP. Part of that is driven by how severe their disease is or how long they’ve had it.”

Good CIDP management, according to the 2021 guidelines, involves making periodic dose reductions or withdrawing therapies on a trial basis, because people can and do experience remission. “We don’t have any test that tells us if somebody needs treatment or not. So this is the best we can do right now,” Dr. Allen said.

This process can be anxiety provoking for patients. “In my practice, there are no surprises,” he said. “We don’t typically say, ‘we’re going to stop your treatment today.’ It’s a discussion with a lead up that’s usually many months long.”

Management of CIDP also requires discussions to elicit when and whether worsening is occurring, along with a clear sense, by both patient and clinician, of what constitutes worsening.

Serial nerve conduction studies are not very useful, Dr. Lewis said, but objective disability measures are and should be more broadly adopted. These include the Medical Research Council sumscore, a test of 12 muscles that can determine weakness; a hand grip test; and functional disability scales such as Inflammatory Rasch Overall Disability Scale and Inflammatory Neuropathy Cause and Treatment scale. All are quick to administer in the office, and some can be done by the patient at home, providing the clinician useful information between visits.

“We could do a better job with educating [clinicians] on the value of different outcome measures that can really quantify disease activity,” Dr. Allen said, and pointed to the GBS-CIDP Foundation centers of excellence, which exist in most regions of the United States, as an outstanding resource for anyone wanting to know more.

“The centers are really, really helpful when you’re trying to work through some of these issues,” he said.

Suggested Reading

Allen JA and Lewis RA. Neurology. 2015 Aug 11;85(6):498-504. doi: 10.1212/WNL.0000000000001833.

Allen J et al. Neurology. 2024;102(17_supplement_1). doi: 10.1212/WNL-.0000000000206324.

Van den Bergh PYK et al. J Peripher Nerv Syst. 2021 Sep;26(3):242-268. doi: 10.1111/jns.12455.

Chronic inflammatory demyelinating polyradiculoneuropathy, or CIDP, is a rare immune-mediated nerve disorder characterized by progressive weakness and sensory impairment in the arms and legs, the result of an autoimmune attack on myelin.

Though some clustering of cases may occur in families, and susceptibility genes have been found, it is not considered a genetic disease. It can strike patients of either sex at any age, though most cases will occur in or after midlife.

Because its symptoms can overlap with a broad range of neuropathies, CIDP is notoriously complex to diagnose, relying on nerve conduction studies and careful clinical assessment rather than any definitive blood biomarker. Complicating matters further, CIDP has several variants whose symptoms differ from classical presentations.

Many patients who do not have CIDP end up being treated for it, and many CIDP patients experience delays to diagnosis and treatment that can potentially result in greater nerve damage and worse outcomes.

The good news, CIDP experts say, is that the last few years have seen important advances in diagnosis and treatment – including comprehensive new clinical guidelines and the June 2024 approval by the Food and Drug Administration of a new treatment, efgartigimod alfa and hyaluronidase-qvfc (Vyvgart, argenx). This antibody fragment represents the first non-steroid, non-immunoglobulin option for CIDP.

Despite the difficulties of recruiting patients with a tough-to-confirm disease that affects between 2 and 9 of every 100,000 people, according to the GPS-CIDP Foundation clinical trials have been successfully carried out in CIDP, and new ones continue to recruit. The experimental therapies being explored are based on a wide range of proposed disease pathways.

courtesy University of Minnesota

“It’s a very exciting time,” said Jeffrey Allen, MD, a neurologist at the University of Minnesota, Minneapolis, one of three CIDP experts who spoke about this challenging but treatable syndrome, its diagnosis and management, and the research questions that they hope to see answered.
 

Refining Diagnosis

In classical or typical CIDP, which accounts for most cases, patients present with progressive weakness and numbness that affects the arms and legs symmetrically, with the weakness being both proximal and distal. The disease usually evolves over a period of months, which helps distinguish it from Gullain-Barré syndrome, whose onset is more sudden and progression is less than 4 weeks.

CIDP was first described in the 1970s, and since that time more than a dozen sets of diagnostic criteria have been published. Starting about a decade ago, Dr. Allen and neurologist Richard Lewis, MD, of Cedars-Sinai Medical Center in Los Angeles, California, helped launch an effort to improve them.

“Experts in the field who were seeing patients with CIDP recognized that a lot of referrals coming to them were of people who actually didn’t have it, or they had the disease and were treated for it but didn’t need to be on treatment, or their treatment was very unconventional,” Dr. Allen said. “We wanted to try to put some data behind that.” In 2015 Dr. Allen and Dr. Lewis published a paper that found that nearly half of patients referred with a diagnosis of CIDP failed to meet basic diagnostic requirements.

courtesy Cedars-Sinai Medical Center

Erroneous interpretation of nerve conduction studies “was a significant factor” contributing to the misdiagnoses, Dr. Lewis said. And another major problem was that patients’ response to standard treatment with intravenous immunoglobulins (current treatments have also come to include subcutaneous immunoglobulins) was not being measured objectively. Instead of evaluating patients using grip strength, walking tests, or other objective instruments, clinicians asked patients whether they felt better. “The problem is that IVIg makes people feel good,” Dr. Lewis said, “possibly by reducing normal inflammatory agents in the body.”

The 2015 paper caught the attention of neurologists and neuromuscular specialists worldwide, who reported similar problems with misdiagnosis. “And from there we did other work to try to dissect out what the more specific issues are,” Dr. Allen said. “The electrophysiology was a big one.”

courtesy University of Buffalo

Neurologist Nicholas Silvestri, MD, of the University at Buffalo in New York, one of the centers of excellence recognized by the CIDP-GBS Foundation, affirmed that nerve conduction studies, which essential to diagnosing CIDP, “are not as objective as we think they are. They’re very prone to user error and overinterpretation error. If they’re not performed appropriately, things can look like CIDP when they’re not. Very common forms of neuropathy, like diabetic neuropathy, can be misinterpreted as CIDP.”
 

The Challenge of Variants

After their 2015 paper on diagnostic pitfalls, Dr. Lewis and Dr. Allen, along with colleagues in the United States and Europe, started looking deeper into outcome measures and how to better follow and track patients with CIDP. In 2021 they helped create the first comprehensive clinical guidelines for CIDP in over a decade.

Much of their effort focused on atypical presentations, or what are now called variants, of CIDP — people with predominantly distal disease, asymmetrical symptomology, focal symptoms, or exclusively motor or sensory symptoms. With classical CIDP, “we don’t really have a problem with misdiagnosis,” Dr. Lewis said. With variants, however, misdiagnoses are extremely common. The 2021 guidelines try to address this, proposing differential diagnoses for each of the variants and ways to investigate them.

The guidelines also removed a subgroup of patients previously included as having CIDP. These patients, who comprise about 10% of cases, have antibodies to components of the Node of Ranvier, part of the axonal membrane, and the paranodal myelin. The autoimmune nodopathies do not respond to treatment with immunoglobulins or steroids in the way classical CIDP and its variants do. However, many patients have seen success with the immunotherapy rituximab.

“CIDP is a syndrome, not one disease,” Dr. Lewis said. “So it has been difficult to get guidelines or criteria that are sensitive to all the different forms of the disease, and yet specific for the disease and not overlapping. The nodopathies were pulled out because they don’t respond to usual treatments for CIDP. Hopefully over the years we’ll have even more specific diagnoses and can split out more patients.”
 

A Need for Better Biomarkers

With the neuromuscular autoimmune disease myasthenia gravis, 85% of patients have antibodies against the muscle acetylcholine receptor (AChR). Another 6% will have antibodies against muscle-specific kinase (MuSK).

Antibody profiles have long guided treatment decisions in myasthenia gravis, with AChR-positive patients responding to corticosteroids, IVIg, complement inhibitors, and other agents. MuSK-positive myasthenia gravis patients, similar to people with autoimmune nodopathies, respond poorly to IVIg but can have dramatic responses when treated with B cell–depleting therapies like rituximab.

Antibodies to nodal proteins neurofascin-155 and contactin-1 have been shown to be involved with the nodopathies. Assays for these are now commercially available, and Dr. Allen recommended that clinicians seek them for patients with a more rapid course, with tremor and ataxia, or who do not respond to standard CIDP treatments.

Still, no dominant autoantibody has been identified for the majority of presentations, including classical presentations. “I suspect it’s a heterogeneous group of multiple antibodies causing the disease,” Dr. Silvestri said. “That may explain to an extent the different manifestations and the different responses to treatment.”

Dr. Lewis said he thinks that, while more antibodies are likely to be discovered in the coming years, “we’re still identifying fewer than 20% of CIDP patients by specific antibodies, so we have a long way to go.”
 

Promising Trial Landscape

“CIDP is a challenging disease to study because of the diagnostic issues,” Dr. Allen said. “We know that a [nontrivial] percentage of patients ... can go into a drug-free remission. They actually don’t need treatment during that time. We don’t have any way to measure that. And if you put them in a clinical trial, it’s difficult to measure changes in the trial if they didn’t need the drug in the first place.”

In the global ADHERE trail, which looked at efgartigimod alfa and hyaluronidase-qvfc in CIDP patients, the investigators, led by Dr. Allen and Dr. Lewis, challenged patients to be off therapy for 12 weeks and allowed only those with active disease to enroll. They also used an adjudication panel of CIDP experts to review the records of each patient to assure patients had CIDP.

If two experts on the panel independently agreed that it was CIDP, Dr. Lewis said, then patients were eligible for enrollment. “If they both said they weren’t CIDP, they were not eligible. And if there was an argument between the two of them, then a third adjudicator would come in.”

About half of patients screened (n = 221) ended up included, and adjudication panels are now used in most CIDP trials.

The trial saw a positive outcome for efgartigimod alfa and hyaluronidase-qvfc, an antibody fragment that targets neonatal Fc receptor (FcRn), as a way to reduce to levels of pathogenic IgG autoantibodies. (The treatment was previously approved for myasthenia gravis.) The fact that two thirds of participants in the trial responded pointed to the likelihood that most CIDP patients have an IgG-related disease, Dr. Lewis said.

Different types of therapies are now being investigated in CIDP, among them other FcRn-inhibiting drugs and drugs inhibiting complement. Results from these trials may shed more light on the pathophysiology of the disease, which Dr. Silvestri said would be welcome.

“If I can test for antibodies, I can make a more timely diagnosis,” he said. “I’m assuming that some people with CIDP have non–antibody-driven disease. And in those cases, I want to avoid using drugs like Vyvgart, which are targeting antibodies. I want to give them a different therapy.”

Management: A Delicate Dance

Since the 1990s, the standard of care for CIDP has been IVIg and steroids. Newer subcutaneous immunoglobulin products, which take less time to administer, may be more convenient for patients than traditional IVIg and mitigate some concerning side effects.

Efgartigimod alfa and hyaluronidase-qvfc now offers an entirely different option that, while too new for clinicians to have much experience with in CIDP, represents further convenience for patients, with dosing in one 90-second subcutaneous injection per week.

In general, the sooner people are diagnosed and on therapy, the better they are likely to do, with fewer risks of irreversible axonal loss and disability. Referring to CIDP centers of excellence can help speed a definitive diagnosis.

Some patients will see a complete or near-complete recovery, while others will not. “It’s important to be up front with patients about what the benefit of treatments are, what are the expectations of treatment, what we can potentially get back, and what’s unlikely to come back,” Dr. Allen said. “We know that irreversible deficits are not uncommon in folks with CIDP. Part of that is driven by how severe their disease is or how long they’ve had it.”

Good CIDP management, according to the 2021 guidelines, involves making periodic dose reductions or withdrawing therapies on a trial basis, because people can and do experience remission. “We don’t have any test that tells us if somebody needs treatment or not. So this is the best we can do right now,” Dr. Allen said.

This process can be anxiety provoking for patients. “In my practice, there are no surprises,” he said. “We don’t typically say, ‘we’re going to stop your treatment today.’ It’s a discussion with a lead up that’s usually many months long.”

Management of CIDP also requires discussions to elicit when and whether worsening is occurring, along with a clear sense, by both patient and clinician, of what constitutes worsening.

Serial nerve conduction studies are not very useful, Dr. Lewis said, but objective disability measures are and should be more broadly adopted. These include the Medical Research Council sumscore, a test of 12 muscles that can determine weakness; a hand grip test; and functional disability scales such as Inflammatory Rasch Overall Disability Scale and Inflammatory Neuropathy Cause and Treatment scale. All are quick to administer in the office, and some can be done by the patient at home, providing the clinician useful information between visits.

“We could do a better job with educating [clinicians] on the value of different outcome measures that can really quantify disease activity,” Dr. Allen said, and pointed to the GBS-CIDP Foundation centers of excellence, which exist in most regions of the United States, as an outstanding resource for anyone wanting to know more.

“The centers are really, really helpful when you’re trying to work through some of these issues,” he said.

Suggested Reading

Allen JA and Lewis RA. Neurology. 2015 Aug 11;85(6):498-504. doi: 10.1212/WNL.0000000000001833.

Allen J et al. Neurology. 2024;102(17_supplement_1). doi: 10.1212/WNL-.0000000000206324.

Van den Bergh PYK et al. J Peripher Nerv Syst. 2021 Sep;26(3):242-268. doi: 10.1111/jns.12455.

Chronic inflammatory demyelinating polyradiculoneuropathy, or CIDP, is a rare immune-mediated nerve disorder characterized by progressive weakness and sensory impairment in the arms and legs, the result of an autoimmune attack on myelin.

Though some clustering of cases may occur in families, and susceptibility genes have been found, it is not considered a genetic disease. It can strike patients of either sex at any age, though most cases will occur in or after midlife.

Because its symptoms can overlap with a broad range of neuropathies, CIDP is notoriously complex to diagnose, relying on nerve conduction studies and careful clinical assessment rather than any definitive blood biomarker. Complicating matters further, CIDP has several variants whose symptoms differ from classical presentations.

Many patients who do not have CIDP end up being treated for it, and many CIDP patients experience delays to diagnosis and treatment that can potentially result in greater nerve damage and worse outcomes.

The good news, CIDP experts say, is that the last few years have seen important advances in diagnosis and treatment – including comprehensive new clinical guidelines and the June 2024 approval by the Food and Drug Administration of a new treatment, efgartigimod alfa and hyaluronidase-qvfc (Vyvgart, argenx). This antibody fragment represents the first non-steroid, non-immunoglobulin option for CIDP.

Despite the difficulties of recruiting patients with a tough-to-confirm disease that affects between 2 and 9 of every 100,000 people, according to the GPS-CIDP Foundation clinical trials have been successfully carried out in CIDP, and new ones continue to recruit. The experimental therapies being explored are based on a wide range of proposed disease pathways.

courtesy University of Minnesota

“It’s a very exciting time,” said Jeffrey Allen, MD, a neurologist at the University of Minnesota, Minneapolis, one of three CIDP experts who spoke about this challenging but treatable syndrome, its diagnosis and management, and the research questions that they hope to see answered.
 

Refining Diagnosis

In classical or typical CIDP, which accounts for most cases, patients present with progressive weakness and numbness that affects the arms and legs symmetrically, with the weakness being both proximal and distal. The disease usually evolves over a period of months, which helps distinguish it from Gullain-Barré syndrome, whose onset is more sudden and progression is less than 4 weeks.

CIDP was first described in the 1970s, and since that time more than a dozen sets of diagnostic criteria have been published. Starting about a decade ago, Dr. Allen and neurologist Richard Lewis, MD, of Cedars-Sinai Medical Center in Los Angeles, California, helped launch an effort to improve them.

“Experts in the field who were seeing patients with CIDP recognized that a lot of referrals coming to them were of people who actually didn’t have it, or they had the disease and were treated for it but didn’t need to be on treatment, or their treatment was very unconventional,” Dr. Allen said. “We wanted to try to put some data behind that.” In 2015 Dr. Allen and Dr. Lewis published a paper that found that nearly half of patients referred with a diagnosis of CIDP failed to meet basic diagnostic requirements.

courtesy Cedars-Sinai Medical Center

Erroneous interpretation of nerve conduction studies “was a significant factor” contributing to the misdiagnoses, Dr. Lewis said. And another major problem was that patients’ response to standard treatment with intravenous immunoglobulins (current treatments have also come to include subcutaneous immunoglobulins) was not being measured objectively. Instead of evaluating patients using grip strength, walking tests, or other objective instruments, clinicians asked patients whether they felt better. “The problem is that IVIg makes people feel good,” Dr. Lewis said, “possibly by reducing normal inflammatory agents in the body.”

The 2015 paper caught the attention of neurologists and neuromuscular specialists worldwide, who reported similar problems with misdiagnosis. “And from there we did other work to try to dissect out what the more specific issues are,” Dr. Allen said. “The electrophysiology was a big one.”

courtesy University of Buffalo

Neurologist Nicholas Silvestri, MD, of the University at Buffalo in New York, one of the centers of excellence recognized by the CIDP-GBS Foundation, affirmed that nerve conduction studies, which essential to diagnosing CIDP, “are not as objective as we think they are. They’re very prone to user error and overinterpretation error. If they’re not performed appropriately, things can look like CIDP when they’re not. Very common forms of neuropathy, like diabetic neuropathy, can be misinterpreted as CIDP.”
 

The Challenge of Variants

After their 2015 paper on diagnostic pitfalls, Dr. Lewis and Dr. Allen, along with colleagues in the United States and Europe, started looking deeper into outcome measures and how to better follow and track patients with CIDP. In 2021 they helped create the first comprehensive clinical guidelines for CIDP in over a decade.

Much of their effort focused on atypical presentations, or what are now called variants, of CIDP — people with predominantly distal disease, asymmetrical symptomology, focal symptoms, or exclusively motor or sensory symptoms. With classical CIDP, “we don’t really have a problem with misdiagnosis,” Dr. Lewis said. With variants, however, misdiagnoses are extremely common. The 2021 guidelines try to address this, proposing differential diagnoses for each of the variants and ways to investigate them.

The guidelines also removed a subgroup of patients previously included as having CIDP. These patients, who comprise about 10% of cases, have antibodies to components of the Node of Ranvier, part of the axonal membrane, and the paranodal myelin. The autoimmune nodopathies do not respond to treatment with immunoglobulins or steroids in the way classical CIDP and its variants do. However, many patients have seen success with the immunotherapy rituximab.

“CIDP is a syndrome, not one disease,” Dr. Lewis said. “So it has been difficult to get guidelines or criteria that are sensitive to all the different forms of the disease, and yet specific for the disease and not overlapping. The nodopathies were pulled out because they don’t respond to usual treatments for CIDP. Hopefully over the years we’ll have even more specific diagnoses and can split out more patients.”
 

A Need for Better Biomarkers

With the neuromuscular autoimmune disease myasthenia gravis, 85% of patients have antibodies against the muscle acetylcholine receptor (AChR). Another 6% will have antibodies against muscle-specific kinase (MuSK).

Antibody profiles have long guided treatment decisions in myasthenia gravis, with AChR-positive patients responding to corticosteroids, IVIg, complement inhibitors, and other agents. MuSK-positive myasthenia gravis patients, similar to people with autoimmune nodopathies, respond poorly to IVIg but can have dramatic responses when treated with B cell–depleting therapies like rituximab.

Antibodies to nodal proteins neurofascin-155 and contactin-1 have been shown to be involved with the nodopathies. Assays for these are now commercially available, and Dr. Allen recommended that clinicians seek them for patients with a more rapid course, with tremor and ataxia, or who do not respond to standard CIDP treatments.

Still, no dominant autoantibody has been identified for the majority of presentations, including classical presentations. “I suspect it’s a heterogeneous group of multiple antibodies causing the disease,” Dr. Silvestri said. “That may explain to an extent the different manifestations and the different responses to treatment.”

Dr. Lewis said he thinks that, while more antibodies are likely to be discovered in the coming years, “we’re still identifying fewer than 20% of CIDP patients by specific antibodies, so we have a long way to go.”
 

Promising Trial Landscape

“CIDP is a challenging disease to study because of the diagnostic issues,” Dr. Allen said. “We know that a [nontrivial] percentage of patients ... can go into a drug-free remission. They actually don’t need treatment during that time. We don’t have any way to measure that. And if you put them in a clinical trial, it’s difficult to measure changes in the trial if they didn’t need the drug in the first place.”

In the global ADHERE trail, which looked at efgartigimod alfa and hyaluronidase-qvfc in CIDP patients, the investigators, led by Dr. Allen and Dr. Lewis, challenged patients to be off therapy for 12 weeks and allowed only those with active disease to enroll. They also used an adjudication panel of CIDP experts to review the records of each patient to assure patients had CIDP.

If two experts on the panel independently agreed that it was CIDP, Dr. Lewis said, then patients were eligible for enrollment. “If they both said they weren’t CIDP, they were not eligible. And if there was an argument between the two of them, then a third adjudicator would come in.”

About half of patients screened (n = 221) ended up included, and adjudication panels are now used in most CIDP trials.

The trial saw a positive outcome for efgartigimod alfa and hyaluronidase-qvfc, an antibody fragment that targets neonatal Fc receptor (FcRn), as a way to reduce to levels of pathogenic IgG autoantibodies. (The treatment was previously approved for myasthenia gravis.) The fact that two thirds of participants in the trial responded pointed to the likelihood that most CIDP patients have an IgG-related disease, Dr. Lewis said.

Different types of therapies are now being investigated in CIDP, among them other FcRn-inhibiting drugs and drugs inhibiting complement. Results from these trials may shed more light on the pathophysiology of the disease, which Dr. Silvestri said would be welcome.

“If I can test for antibodies, I can make a more timely diagnosis,” he said. “I’m assuming that some people with CIDP have non–antibody-driven disease. And in those cases, I want to avoid using drugs like Vyvgart, which are targeting antibodies. I want to give them a different therapy.”

Management: A Delicate Dance

Since the 1990s, the standard of care for CIDP has been IVIg and steroids. Newer subcutaneous immunoglobulin products, which take less time to administer, may be more convenient for patients than traditional IVIg and mitigate some concerning side effects.

Efgartigimod alfa and hyaluronidase-qvfc now offers an entirely different option that, while too new for clinicians to have much experience with in CIDP, represents further convenience for patients, with dosing in one 90-second subcutaneous injection per week.

In general, the sooner people are diagnosed and on therapy, the better they are likely to do, with fewer risks of irreversible axonal loss and disability. Referring to CIDP centers of excellence can help speed a definitive diagnosis.

Some patients will see a complete or near-complete recovery, while others will not. “It’s important to be up front with patients about what the benefit of treatments are, what are the expectations of treatment, what we can potentially get back, and what’s unlikely to come back,” Dr. Allen said. “We know that irreversible deficits are not uncommon in folks with CIDP. Part of that is driven by how severe their disease is or how long they’ve had it.”

Good CIDP management, according to the 2021 guidelines, involves making periodic dose reductions or withdrawing therapies on a trial basis, because people can and do experience remission. “We don’t have any test that tells us if somebody needs treatment or not. So this is the best we can do right now,” Dr. Allen said.

This process can be anxiety provoking for patients. “In my practice, there are no surprises,” he said. “We don’t typically say, ‘we’re going to stop your treatment today.’ It’s a discussion with a lead up that’s usually many months long.”

Management of CIDP also requires discussions to elicit when and whether worsening is occurring, along with a clear sense, by both patient and clinician, of what constitutes worsening.

Serial nerve conduction studies are not very useful, Dr. Lewis said, but objective disability measures are and should be more broadly adopted. These include the Medical Research Council sumscore, a test of 12 muscles that can determine weakness; a hand grip test; and functional disability scales such as Inflammatory Rasch Overall Disability Scale and Inflammatory Neuropathy Cause and Treatment scale. All are quick to administer in the office, and some can be done by the patient at home, providing the clinician useful information between visits.

“We could do a better job with educating [clinicians] on the value of different outcome measures that can really quantify disease activity,” Dr. Allen said, and pointed to the GBS-CIDP Foundation centers of excellence, which exist in most regions of the United States, as an outstanding resource for anyone wanting to know more.

“The centers are really, really helpful when you’re trying to work through some of these issues,” he said.

Suggested Reading

Allen JA and Lewis RA. Neurology. 2015 Aug 11;85(6):498-504. doi: 10.1212/WNL.0000000000001833.

Allen J et al. Neurology. 2024;102(17_supplement_1). doi: 10.1212/WNL-.0000000000206324.

Van den Bergh PYK et al. J Peripher Nerv Syst. 2021 Sep;26(3):242-268. doi: 10.1111/jns.12455.

Urgency of treatment is something that many physicians may not fully appreciate when it comes to neuromyelitis optica (NMO), according to experts on this rare autoimmune demyelinating disorder. This may be partly due to its similar presentation to multiple sclerosis (MS), said Michael Levy, MD, PhD, associate professor, Harvard Medical School, research director, Division of Neuroimmunology & Neuroinfectious Disease, and director, Neuroimmunology Clinic and Research Laboratory, at Massachusetts General Hospital in Boston. But while the two conditions share many clinical characteristics, “immunologically, they are about as different as can be,” he warned.

The urgency of distinction is important because where MS is known to have a relatively gradual progression, NMO is now red-flagged to potentially cause rapid and irreversible damage. While the course of MS might be described as a slow burn, NMO should be treated like a wildfire.

“That message has gotten muddled, particularly because acute treatment in MS has never been shown to affect outcome,” said Jeffrey Bennett, MD, PhD, professor of neurology and ophthalmology at the University of Colorado School of Medicine, Aurora. In contrast, rapid diagnosis and treatment of NMO “means potentially preventing future devastating neurologic injury,” he said.

First described by Dr. Eugène Devic in 1894, and sometimes known as Devic’s disease, NMO is believed to have a prevalence that varies widely depending on ethnicity and gender. A recent report suggests a prevalence of approximately1/100,000 population among Whites with an annual incidence of less than 1/million in this population, while the prevalence is higher among East Asians (approximately 3.5/100,000), and may reach as high as 10/100,000 in Blacks.¹ It has a high female-to-male ratio (up to 9:1) with a mean age of onset of about 40 years, although pediatric cases are described.

It has long been recognized that NMO lacks the “neurocerebritis” of MS, with inflammation predominant in the optic and spinal nerves, but it was not until 2004 that researchers at the Mayo Clinic identified serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) that could reliably distinguish NMO from MS. In 2015, the international consensus diagnostic criteria for neuromyelitis optica² cited core clinical characteristics required for patients with AQP4-IgG-positive NMO spectrum disorder (NMOSD) “including clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.” Rarely, NMO patients can be seronegative for AQP4-IgG, but are still considered to have NMOSD for which non-opticospinal clinical and MRI characteristics findings are described. MS patients testing negative for AQP4-IgG should also be tested for the related myelin oligodendrocyte glycoprotein antibody disease (MOGAD), which has a prevalence about four to five times greater than NMO, Dr. Bennett said.
 

Testing

Because both NMO and MOGAD can be identified by antibodies, they are less commonly misdiagnosed as MS compared to previously. But, prior to the identification of the AQP4-IgG antibody in 2004, the misdiagnosis rate of NMO was probably about 95% said Dr. Levy.

“Of course, before we had the antibody test or clinical criteria, we couldn’t confirm a diagnosis of NMO, so basically everyone had a diagnosis of MS, and after the antibody test became commercially available in 2005/2006, we could confirm the diagnosis, with our study in 2012 showing a much lower misdiagnosis rate of 30%.”³ More recently, the misdiagnosis rates are even lower, he added. A recent study out of Argentina found a rate of only 12%.⁴

The specificity and sensitivity of cell binding assay serum AQP4-IgG testing is roughly 99% and 90%, respectively, better than ELIZA testing (which has a sensitivity in the 60-65% range), said Dr. Bennett. “That’s why we highly emphasize to physicians, that if you have a suspicion for NMOSD you go to a cell binding assay, and make sure that where you’re sending the serum, the lab can do that procedure.” Still, because of the risk of false positives, he urges restraint in testing for the disorder in the absence of a high suspicion for it. “If you test a lot of people indiscriminately for a rare disorder, you get a lot of false positives because the actual true positives are a very small fraction of that group. So, even with a specificity of around 99% that means 1% of the people you test are falsely positive. And if you’re testing a group of people indiscriminately, then your true positives are less than 1% by far, so then most of the people that you pick up are not truly with disease.”

Acute Treatment

While misdiagnosis of NMO as MS is less common than previously, it is still a concern, not only because of the irreversible risks associated with delayed acute treatment, but also the risks of inappropriate preventive MS therapy, which could be harmful to patients with NMO.

Acute flare-ups of NMO and MOGAD are currently all treated with the same decades-old mainstays for acute MS — intravenous steroids and plasma exchange — but the approach is more aggressive. Retrospective studies have shown that, for NMO, plasma exchange has shown an increased likelihood of improvement versus steroids alone, said Dr. Bennett, but since time is of the essence, treatment should begin before a definitive diagnosis is confirmed.

“What’s limiting our patients is, number one, recognizing NMOSD when the attack is happening in your face. You’ve got to know, hey, this is NMOSD or I’m suspicious of NMOSD and hence, I need to treat it urgently because the outcome has a high probability of not being good. You’ve got to realize that this is NMOSD before the test comes back, because by the time it comes back positive in several days, you’re probably missing the optimal window to treat. The point is to know that the presentation in front of you, the MRI pictures in front of you, the laboratory tests that you might have done in terms of spinal fluid analysis, all highly suggest NMOSD. And so hence, I’m going to take the chance that I might be wrong, but I’m going to treat as if it is and wait for the test to come back.”

Realistically, the risks associated with this approach are minor compared with the potential benefit, Dr. Bennett said. “For plasma exchange, there’s the placement of the central line, and the complications that could happen from that. Plasma exchange can lead to metabolic ionic changes in the blood, fluid shifts that might have to be watched in the hospital setting.”

While waiting for diagnostic results, one clue that may emerge from acute treatment is recovery time. “The recovery from MOGAD attacks is really distinct,” said Dr. Levy. “They get better a lot faster. So, if they’re blind in the hospital, and 3 months later they can see again with treatment, that’s MOGAD.” On the other hand, comorbidities such as lupus strongly favor NMO, he added. And another underrecognized, unique symptom of NMO is that about 10% of people may present with protracted episodes of nausea, vomiting, or hiccups, added Dr. Bennett. “What’s important is not that the neurologist recognize this per se in the emergency department, because they’re not going to be called for that patient — the GI doctors will be called for that patient. But when you’re seeing a patient who may have another presentation: a spinal cord attack, a vision attack with optic neuritis, and you ask them simply ‘have you ever had an episode of protracted nausea, vomiting, or hiccups?’ — I can’t tell you how many times I can have someone say ‘that’s weird I was just in the ED 3 months ago for that.’ And then, I know exactly what’s going on.”
 

Prevention of Relapse

Treatment of NMO presents some particular challenges for clinicians because the old treatment, rituximab, an anti-CD20 monoclonal antibody which has been used since 2005, has been so affordable and successful. “It’s hard to get people off,” said Dr. Levy. “It’s still the most commonly used drug for NMO in the US, even though it’s not approved. It’s cheap enough, and so people get started on that as a treatment, and then they just continue it, even as an outpatient.”

But since 2019, four new FDA-approved therapies have entered the scene with even better efficacy: the anti-CD-19 targeted medication inebilizumab (Uplizna, Viela Bio, approved in 2020), which requires two 90-minute infusions per year; the interleukin-6 (IL-6) receptor inhibitor satralizumab (Enspryng, Roche, approved in 2020), which is administered subcutaneously once monthly; and the anti-complement C5 inhibitors eculizumab (Soliris, Alexion Pharmaceuticals, approved in 2019), and ravulizumab (Ultomiris, Alexion Pharmaceuticals, approved in 2024), which require infusions every 2 weeks or every 2 months, respectively.

Both experts point to compelling clinical evidence to prescribe the Food and Drug Administration–approved drugs for newly diagnosed NMO, and to switch existing patients from rituximab to the new drugs. “The data is pretty clear that there’s about a 35% failure rate with rituximab, as opposed to less than 5% with the new drugs,” explained Dr. Levy. But ironically, where insurance companies used to balk at covering rituximab because it was not FDA approved for NMO, they are now balking at the FDA-approved options because of the cost. “Even in an academic center, where we get a discount on the drugs, the biosimilar generic of rituximab costs about $890 per dose,” he said. “So overall, it’s less than $4,000 a year for rituximab. Compare that with the most expensive FDA-approved option, which is eculizumab. That’s $715,000 per year. And then the other three drugs are below that, but none are less than about $290,000 a year.”

Patients are also hesitant to switch from rituximab if they’ve been well-controlled on it. “There’s a process to it, and I always talk my patients through it, but I would say less than half make the switch,” said Dr. Levy. “Most people want to stay. It’s a whole different schedule, and mixing two drugs. Are you going to overlap and overly immune suppress? Is the insurance going to approve it? It becomes more complicated.”

“Insurance companies are sometimes inappropriately pushing physicians, asking for patients to fail rituximab before they’ll approve an FDA-approved drug, which is like playing doctor when they’re not a licensed physician,” added Dr. Bennett. “And I think that is absolutely inappropriate, especially in light of the fact that before there were approved drugs, insurance companies used to deny rituximab because it was ‘experimental’ and ‘too expensive’ — and now it’s a cheaper alternative.”

Requiring failure on rituximab is also unethical, given the potential for irreversible damage, Dr. Levy pointed out. “With NMO we don’t tolerate a failure. That’s also how the trials of the new drugs were done. It was considered unethical to have an outcome of annualized relapse rate, like we used to in MS, where we say, OK if you have two attacks a year, then the drug has failed. With NMO, one failure, one breakthrough, and that drug is worthless. We switch.”
 

A Wealth of Treatment Choices

Patients opting for an FDA-approved treatment now have a “wildly effective” array of new drugs, said Dr. Levy, but choosing can be difficult when each has its own set of advantages and disadvantages. “I have equal numbers of patients on all the drugs, and I show all the data to my patients: efficacy, safety, logistics, cost, and then I ask ‘What are your priorities? Which of these things that I say really rings with you? Is it the infusion schedule? Is it the efficacy? Is it the safety concern? Is it the cost? What are you most concerned about?’ And then we start to have the conversation that way. It’s a shared decision-making process.”

There is definitely an art to finding the best fit for each patient, agreed Dr. Bennett, “both with the urgency of controlling the disease, the particular patient in front of you, their ability to adhere to certain therapies, their ability to have access to infusions, or to self-inject, or to get transported to an infusion center or have access to home infusion.”

Patient empowerment in the decision is very important, added Dr. Levy. “When people make the decision on their own, they’re much more likely to be compliant, rather than me telling them they have to do this. And that’s why I think we haven’t had a single relapse on the new drugs. There have been switches because of intolerance, and cost, and all those issues, but not because of a breakthrough attack.”
 

Future

Looking ahead in the field, Dr. Bennett sees the biggest potential for improvement is in the management of acute attacks, which he describes as “a major treatment gap.” Although plasma exchange is immediately effective in limiting the amount of circulating pathogenic AQP4-IgG “there are other approaches that could be even more beneficial,” he said. “A promising strategy is to use drugs that act immediately on arms of the immune response that are directly injuring brain tissue. These include serum complement and cells such as neutrophils and natural killer cells that release destructive enzymes and inflammatory mediators,” he explained. “Complement inhibitors, such as the C5 inhibitors eculizumab and ravulizumab, currently approved for NMOSD relapse prevention, act immediately to inhibit complement-mediated tissue injury. Similarly, high doses of antihistamines could be used to rapidly stop the release of the destructive enzyme elastase from neutrophils and natural killer cells, while elastase inhibitors could be given to minimize cell injury. Direct clinical studies are needed to find both the optimal treatment window and regimen.”

References

1. Hor JY et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol. 2020 Jun 26:11:501. doi: 10.3389/fneur.2020.00501.

2. Wingerchuk DM et al. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729.

3. Mealy MA et al. Epidemiology of Neuromyelitis Optica in the United States: A Multicenter Analysis. Arch Neurol. 2012 Sep;69(9):1176-80. doi: 10.1001/archneurol.2012.314.

4. Contentti EC et al. Frequency of NMOSD Misdiagnosis in a Cohort From Latin America: Impact and Evaluation of Different Contributors. Mult Scler. 2023 Feb;29(2):277-286. doi: 10.1177/13524585221136259.

Urgency of treatment is something that many physicians may not fully appreciate when it comes to neuromyelitis optica (NMO), according to experts on this rare autoimmune demyelinating disorder. This may be partly due to its similar presentation to multiple sclerosis (MS), said Michael Levy, MD, PhD, associate professor, Harvard Medical School, research director, Division of Neuroimmunology & Neuroinfectious Disease, and director, Neuroimmunology Clinic and Research Laboratory, at Massachusetts General Hospital in Boston. But while the two conditions share many clinical characteristics, “immunologically, they are about as different as can be,” he warned.

The urgency of distinction is important because where MS is known to have a relatively gradual progression, NMO is now red-flagged to potentially cause rapid and irreversible damage. While the course of MS might be described as a slow burn, NMO should be treated like a wildfire.

“That message has gotten muddled, particularly because acute treatment in MS has never been shown to affect outcome,” said Jeffrey Bennett, MD, PhD, professor of neurology and ophthalmology at the University of Colorado School of Medicine, Aurora. In contrast, rapid diagnosis and treatment of NMO “means potentially preventing future devastating neurologic injury,” he said.

First described by Dr. Eugène Devic in 1894, and sometimes known as Devic’s disease, NMO is believed to have a prevalence that varies widely depending on ethnicity and gender. A recent report suggests a prevalence of approximately1/100,000 population among Whites with an annual incidence of less than 1/million in this population, while the prevalence is higher among East Asians (approximately 3.5/100,000), and may reach as high as 10/100,000 in Blacks.¹ It has a high female-to-male ratio (up to 9:1) with a mean age of onset of about 40 years, although pediatric cases are described.

It has long been recognized that NMO lacks the “neurocerebritis” of MS, with inflammation predominant in the optic and spinal nerves, but it was not until 2004 that researchers at the Mayo Clinic identified serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) that could reliably distinguish NMO from MS. In 2015, the international consensus diagnostic criteria for neuromyelitis optica² cited core clinical characteristics required for patients with AQP4-IgG-positive NMO spectrum disorder (NMOSD) “including clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.” Rarely, NMO patients can be seronegative for AQP4-IgG, but are still considered to have NMOSD for which non-opticospinal clinical and MRI characteristics findings are described. MS patients testing negative for AQP4-IgG should also be tested for the related myelin oligodendrocyte glycoprotein antibody disease (MOGAD), which has a prevalence about four to five times greater than NMO, Dr. Bennett said.
 

Testing

Because both NMO and MOGAD can be identified by antibodies, they are less commonly misdiagnosed as MS compared to previously. But, prior to the identification of the AQP4-IgG antibody in 2004, the misdiagnosis rate of NMO was probably about 95% said Dr. Levy.

“Of course, before we had the antibody test or clinical criteria, we couldn’t confirm a diagnosis of NMO, so basically everyone had a diagnosis of MS, and after the antibody test became commercially available in 2005/2006, we could confirm the diagnosis, with our study in 2012 showing a much lower misdiagnosis rate of 30%.”³ More recently, the misdiagnosis rates are even lower, he added. A recent study out of Argentina found a rate of only 12%.⁴

The specificity and sensitivity of cell binding assay serum AQP4-IgG testing is roughly 99% and 90%, respectively, better than ELIZA testing (which has a sensitivity in the 60-65% range), said Dr. Bennett. “That’s why we highly emphasize to physicians, that if you have a suspicion for NMOSD you go to a cell binding assay, and make sure that where you’re sending the serum, the lab can do that procedure.” Still, because of the risk of false positives, he urges restraint in testing for the disorder in the absence of a high suspicion for it. “If you test a lot of people indiscriminately for a rare disorder, you get a lot of false positives because the actual true positives are a very small fraction of that group. So, even with a specificity of around 99% that means 1% of the people you test are falsely positive. And if you’re testing a group of people indiscriminately, then your true positives are less than 1% by far, so then most of the people that you pick up are not truly with disease.”

Acute Treatment

While misdiagnosis of NMO as MS is less common than previously, it is still a concern, not only because of the irreversible risks associated with delayed acute treatment, but also the risks of inappropriate preventive MS therapy, which could be harmful to patients with NMO.

Acute flare-ups of NMO and MOGAD are currently all treated with the same decades-old mainstays for acute MS — intravenous steroids and plasma exchange — but the approach is more aggressive. Retrospective studies have shown that, for NMO, plasma exchange has shown an increased likelihood of improvement versus steroids alone, said Dr. Bennett, but since time is of the essence, treatment should begin before a definitive diagnosis is confirmed.

“What’s limiting our patients is, number one, recognizing NMOSD when the attack is happening in your face. You’ve got to know, hey, this is NMOSD or I’m suspicious of NMOSD and hence, I need to treat it urgently because the outcome has a high probability of not being good. You’ve got to realize that this is NMOSD before the test comes back, because by the time it comes back positive in several days, you’re probably missing the optimal window to treat. The point is to know that the presentation in front of you, the MRI pictures in front of you, the laboratory tests that you might have done in terms of spinal fluid analysis, all highly suggest NMOSD. And so hence, I’m going to take the chance that I might be wrong, but I’m going to treat as if it is and wait for the test to come back.”

Realistically, the risks associated with this approach are minor compared with the potential benefit, Dr. Bennett said. “For plasma exchange, there’s the placement of the central line, and the complications that could happen from that. Plasma exchange can lead to metabolic ionic changes in the blood, fluid shifts that might have to be watched in the hospital setting.”

While waiting for diagnostic results, one clue that may emerge from acute treatment is recovery time. “The recovery from MOGAD attacks is really distinct,” said Dr. Levy. “They get better a lot faster. So, if they’re blind in the hospital, and 3 months later they can see again with treatment, that’s MOGAD.” On the other hand, comorbidities such as lupus strongly favor NMO, he added. And another underrecognized, unique symptom of NMO is that about 10% of people may present with protracted episodes of nausea, vomiting, or hiccups, added Dr. Bennett. “What’s important is not that the neurologist recognize this per se in the emergency department, because they’re not going to be called for that patient — the GI doctors will be called for that patient. But when you’re seeing a patient who may have another presentation: a spinal cord attack, a vision attack with optic neuritis, and you ask them simply ‘have you ever had an episode of protracted nausea, vomiting, or hiccups?’ — I can’t tell you how many times I can have someone say ‘that’s weird I was just in the ED 3 months ago for that.’ And then, I know exactly what’s going on.”
 

Prevention of Relapse

Treatment of NMO presents some particular challenges for clinicians because the old treatment, rituximab, an anti-CD20 monoclonal antibody which has been used since 2005, has been so affordable and successful. “It’s hard to get people off,” said Dr. Levy. “It’s still the most commonly used drug for NMO in the US, even though it’s not approved. It’s cheap enough, and so people get started on that as a treatment, and then they just continue it, even as an outpatient.”

But since 2019, four new FDA-approved therapies have entered the scene with even better efficacy: the anti-CD-19 targeted medication inebilizumab (Uplizna, Viela Bio, approved in 2020), which requires two 90-minute infusions per year; the interleukin-6 (IL-6) receptor inhibitor satralizumab (Enspryng, Roche, approved in 2020), which is administered subcutaneously once monthly; and the anti-complement C5 inhibitors eculizumab (Soliris, Alexion Pharmaceuticals, approved in 2019), and ravulizumab (Ultomiris, Alexion Pharmaceuticals, approved in 2024), which require infusions every 2 weeks or every 2 months, respectively.

Both experts point to compelling clinical evidence to prescribe the Food and Drug Administration–approved drugs for newly diagnosed NMO, and to switch existing patients from rituximab to the new drugs. “The data is pretty clear that there’s about a 35% failure rate with rituximab, as opposed to less than 5% with the new drugs,” explained Dr. Levy. But ironically, where insurance companies used to balk at covering rituximab because it was not FDA approved for NMO, they are now balking at the FDA-approved options because of the cost. “Even in an academic center, where we get a discount on the drugs, the biosimilar generic of rituximab costs about $890 per dose,” he said. “So overall, it’s less than $4,000 a year for rituximab. Compare that with the most expensive FDA-approved option, which is eculizumab. That’s $715,000 per year. And then the other three drugs are below that, but none are less than about $290,000 a year.”

Patients are also hesitant to switch from rituximab if they’ve been well-controlled on it. “There’s a process to it, and I always talk my patients through it, but I would say less than half make the switch,” said Dr. Levy. “Most people want to stay. It’s a whole different schedule, and mixing two drugs. Are you going to overlap and overly immune suppress? Is the insurance going to approve it? It becomes more complicated.”

“Insurance companies are sometimes inappropriately pushing physicians, asking for patients to fail rituximab before they’ll approve an FDA-approved drug, which is like playing doctor when they’re not a licensed physician,” added Dr. Bennett. “And I think that is absolutely inappropriate, especially in light of the fact that before there were approved drugs, insurance companies used to deny rituximab because it was ‘experimental’ and ‘too expensive’ — and now it’s a cheaper alternative.”

Requiring failure on rituximab is also unethical, given the potential for irreversible damage, Dr. Levy pointed out. “With NMO we don’t tolerate a failure. That’s also how the trials of the new drugs were done. It was considered unethical to have an outcome of annualized relapse rate, like we used to in MS, where we say, OK if you have two attacks a year, then the drug has failed. With NMO, one failure, one breakthrough, and that drug is worthless. We switch.”
 

A Wealth of Treatment Choices

Patients opting for an FDA-approved treatment now have a “wildly effective” array of new drugs, said Dr. Levy, but choosing can be difficult when each has its own set of advantages and disadvantages. “I have equal numbers of patients on all the drugs, and I show all the data to my patients: efficacy, safety, logistics, cost, and then I ask ‘What are your priorities? Which of these things that I say really rings with you? Is it the infusion schedule? Is it the efficacy? Is it the safety concern? Is it the cost? What are you most concerned about?’ And then we start to have the conversation that way. It’s a shared decision-making process.”

There is definitely an art to finding the best fit for each patient, agreed Dr. Bennett, “both with the urgency of controlling the disease, the particular patient in front of you, their ability to adhere to certain therapies, their ability to have access to infusions, or to self-inject, or to get transported to an infusion center or have access to home infusion.”

Patient empowerment in the decision is very important, added Dr. Levy. “When people make the decision on their own, they’re much more likely to be compliant, rather than me telling them they have to do this. And that’s why I think we haven’t had a single relapse on the new drugs. There have been switches because of intolerance, and cost, and all those issues, but not because of a breakthrough attack.”
 

Future

Looking ahead in the field, Dr. Bennett sees the biggest potential for improvement is in the management of acute attacks, which he describes as “a major treatment gap.” Although plasma exchange is immediately effective in limiting the amount of circulating pathogenic AQP4-IgG “there are other approaches that could be even more beneficial,” he said. “A promising strategy is to use drugs that act immediately on arms of the immune response that are directly injuring brain tissue. These include serum complement and cells such as neutrophils and natural killer cells that release destructive enzymes and inflammatory mediators,” he explained. “Complement inhibitors, such as the C5 inhibitors eculizumab and ravulizumab, currently approved for NMOSD relapse prevention, act immediately to inhibit complement-mediated tissue injury. Similarly, high doses of antihistamines could be used to rapidly stop the release of the destructive enzyme elastase from neutrophils and natural killer cells, while elastase inhibitors could be given to minimize cell injury. Direct clinical studies are needed to find both the optimal treatment window and regimen.”

References

1. Hor JY et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol. 2020 Jun 26:11:501. doi: 10.3389/fneur.2020.00501.

2. Wingerchuk DM et al. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729.

3. Mealy MA et al. Epidemiology of Neuromyelitis Optica in the United States: A Multicenter Analysis. Arch Neurol. 2012 Sep;69(9):1176-80. doi: 10.1001/archneurol.2012.314.

4. Contentti EC et al. Frequency of NMOSD Misdiagnosis in a Cohort From Latin America: Impact and Evaluation of Different Contributors. Mult Scler. 2023 Feb;29(2):277-286. doi: 10.1177/13524585221136259.

Urgency of treatment is something that many physicians may not fully appreciate when it comes to neuromyelitis optica (NMO), according to experts on this rare autoimmune demyelinating disorder. This may be partly due to its similar presentation to multiple sclerosis (MS), said Michael Levy, MD, PhD, associate professor, Harvard Medical School, research director, Division of Neuroimmunology & Neuroinfectious Disease, and director, Neuroimmunology Clinic and Research Laboratory, at Massachusetts General Hospital in Boston. But while the two conditions share many clinical characteristics, “immunologically, they are about as different as can be,” he warned.

The urgency of distinction is important because where MS is known to have a relatively gradual progression, NMO is now red-flagged to potentially cause rapid and irreversible damage. While the course of MS might be described as a slow burn, NMO should be treated like a wildfire.

“That message has gotten muddled, particularly because acute treatment in MS has never been shown to affect outcome,” said Jeffrey Bennett, MD, PhD, professor of neurology and ophthalmology at the University of Colorado School of Medicine, Aurora. In contrast, rapid diagnosis and treatment of NMO “means potentially preventing future devastating neurologic injury,” he said.

First described by Dr. Eugène Devic in 1894, and sometimes known as Devic’s disease, NMO is believed to have a prevalence that varies widely depending on ethnicity and gender. A recent report suggests a prevalence of approximately1/100,000 population among Whites with an annual incidence of less than 1/million in this population, while the prevalence is higher among East Asians (approximately 3.5/100,000), and may reach as high as 10/100,000 in Blacks.¹ It has a high female-to-male ratio (up to 9:1) with a mean age of onset of about 40 years, although pediatric cases are described.

It has long been recognized that NMO lacks the “neurocerebritis” of MS, with inflammation predominant in the optic and spinal nerves, but it was not until 2004 that researchers at the Mayo Clinic identified serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) that could reliably distinguish NMO from MS. In 2015, the international consensus diagnostic criteria for neuromyelitis optica² cited core clinical characteristics required for patients with AQP4-IgG-positive NMO spectrum disorder (NMOSD) “including clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.” Rarely, NMO patients can be seronegative for AQP4-IgG, but are still considered to have NMOSD for which non-opticospinal clinical and MRI characteristics findings are described. MS patients testing negative for AQP4-IgG should also be tested for the related myelin oligodendrocyte glycoprotein antibody disease (MOGAD), which has a prevalence about four to five times greater than NMO, Dr. Bennett said.
 

Testing

Because both NMO and MOGAD can be identified by antibodies, they are less commonly misdiagnosed as MS compared to previously. But, prior to the identification of the AQP4-IgG antibody in 2004, the misdiagnosis rate of NMO was probably about 95% said Dr. Levy.

“Of course, before we had the antibody test or clinical criteria, we couldn’t confirm a diagnosis of NMO, so basically everyone had a diagnosis of MS, and after the antibody test became commercially available in 2005/2006, we could confirm the diagnosis, with our study in 2012 showing a much lower misdiagnosis rate of 30%.”³ More recently, the misdiagnosis rates are even lower, he added. A recent study out of Argentina found a rate of only 12%.⁴

The specificity and sensitivity of cell binding assay serum AQP4-IgG testing is roughly 99% and 90%, respectively, better than ELIZA testing (which has a sensitivity in the 60-65% range), said Dr. Bennett. “That’s why we highly emphasize to physicians, that if you have a suspicion for NMOSD you go to a cell binding assay, and make sure that where you’re sending the serum, the lab can do that procedure.” Still, because of the risk of false positives, he urges restraint in testing for the disorder in the absence of a high suspicion for it. “If you test a lot of people indiscriminately for a rare disorder, you get a lot of false positives because the actual true positives are a very small fraction of that group. So, even with a specificity of around 99% that means 1% of the people you test are falsely positive. And if you’re testing a group of people indiscriminately, then your true positives are less than 1% by far, so then most of the people that you pick up are not truly with disease.”

Acute Treatment

While misdiagnosis of NMO as MS is less common than previously, it is still a concern, not only because of the irreversible risks associated with delayed acute treatment, but also the risks of inappropriate preventive MS therapy, which could be harmful to patients with NMO.

Acute flare-ups of NMO and MOGAD are currently all treated with the same decades-old mainstays for acute MS — intravenous steroids and plasma exchange — but the approach is more aggressive. Retrospective studies have shown that, for NMO, plasma exchange has shown an increased likelihood of improvement versus steroids alone, said Dr. Bennett, but since time is of the essence, treatment should begin before a definitive diagnosis is confirmed.

“What’s limiting our patients is, number one, recognizing NMOSD when the attack is happening in your face. You’ve got to know, hey, this is NMOSD or I’m suspicious of NMOSD and hence, I need to treat it urgently because the outcome has a high probability of not being good. You’ve got to realize that this is NMOSD before the test comes back, because by the time it comes back positive in several days, you’re probably missing the optimal window to treat. The point is to know that the presentation in front of you, the MRI pictures in front of you, the laboratory tests that you might have done in terms of spinal fluid analysis, all highly suggest NMOSD. And so hence, I’m going to take the chance that I might be wrong, but I’m going to treat as if it is and wait for the test to come back.”

Realistically, the risks associated with this approach are minor compared with the potential benefit, Dr. Bennett said. “For plasma exchange, there’s the placement of the central line, and the complications that could happen from that. Plasma exchange can lead to metabolic ionic changes in the blood, fluid shifts that might have to be watched in the hospital setting.”

While waiting for diagnostic results, one clue that may emerge from acute treatment is recovery time. “The recovery from MOGAD attacks is really distinct,” said Dr. Levy. “They get better a lot faster. So, if they’re blind in the hospital, and 3 months later they can see again with treatment, that’s MOGAD.” On the other hand, comorbidities such as lupus strongly favor NMO, he added. And another underrecognized, unique symptom of NMO is that about 10% of people may present with protracted episodes of nausea, vomiting, or hiccups, added Dr. Bennett. “What’s important is not that the neurologist recognize this per se in the emergency department, because they’re not going to be called for that patient — the GI doctors will be called for that patient. But when you’re seeing a patient who may have another presentation: a spinal cord attack, a vision attack with optic neuritis, and you ask them simply ‘have you ever had an episode of protracted nausea, vomiting, or hiccups?’ — I can’t tell you how many times I can have someone say ‘that’s weird I was just in the ED 3 months ago for that.’ And then, I know exactly what’s going on.”
 

Prevention of Relapse

Treatment of NMO presents some particular challenges for clinicians because the old treatment, rituximab, an anti-CD20 monoclonal antibody which has been used since 2005, has been so affordable and successful. “It’s hard to get people off,” said Dr. Levy. “It’s still the most commonly used drug for NMO in the US, even though it’s not approved. It’s cheap enough, and so people get started on that as a treatment, and then they just continue it, even as an outpatient.”

But since 2019, four new FDA-approved therapies have entered the scene with even better efficacy: the anti-CD-19 targeted medication inebilizumab (Uplizna, Viela Bio, approved in 2020), which requires two 90-minute infusions per year; the interleukin-6 (IL-6) receptor inhibitor satralizumab (Enspryng, Roche, approved in 2020), which is administered subcutaneously once monthly; and the anti-complement C5 inhibitors eculizumab (Soliris, Alexion Pharmaceuticals, approved in 2019), and ravulizumab (Ultomiris, Alexion Pharmaceuticals, approved in 2024), which require infusions every 2 weeks or every 2 months, respectively.

Both experts point to compelling clinical evidence to prescribe the Food and Drug Administration–approved drugs for newly diagnosed NMO, and to switch existing patients from rituximab to the new drugs. “The data is pretty clear that there’s about a 35% failure rate with rituximab, as opposed to less than 5% with the new drugs,” explained Dr. Levy. But ironically, where insurance companies used to balk at covering rituximab because it was not FDA approved for NMO, they are now balking at the FDA-approved options because of the cost. “Even in an academic center, where we get a discount on the drugs, the biosimilar generic of rituximab costs about $890 per dose,” he said. “So overall, it’s less than $4,000 a year for rituximab. Compare that with the most expensive FDA-approved option, which is eculizumab. That’s $715,000 per year. And then the other three drugs are below that, but none are less than about $290,000 a year.”

Patients are also hesitant to switch from rituximab if they’ve been well-controlled on it. “There’s a process to it, and I always talk my patients through it, but I would say less than half make the switch,” said Dr. Levy. “Most people want to stay. It’s a whole different schedule, and mixing two drugs. Are you going to overlap and overly immune suppress? Is the insurance going to approve it? It becomes more complicated.”

“Insurance companies are sometimes inappropriately pushing physicians, asking for patients to fail rituximab before they’ll approve an FDA-approved drug, which is like playing doctor when they’re not a licensed physician,” added Dr. Bennett. “And I think that is absolutely inappropriate, especially in light of the fact that before there were approved drugs, insurance companies used to deny rituximab because it was ‘experimental’ and ‘too expensive’ — and now it’s a cheaper alternative.”

Requiring failure on rituximab is also unethical, given the potential for irreversible damage, Dr. Levy pointed out. “With NMO we don’t tolerate a failure. That’s also how the trials of the new drugs were done. It was considered unethical to have an outcome of annualized relapse rate, like we used to in MS, where we say, OK if you have two attacks a year, then the drug has failed. With NMO, one failure, one breakthrough, and that drug is worthless. We switch.”
 

A Wealth of Treatment Choices

Patients opting for an FDA-approved treatment now have a “wildly effective” array of new drugs, said Dr. Levy, but choosing can be difficult when each has its own set of advantages and disadvantages. “I have equal numbers of patients on all the drugs, and I show all the data to my patients: efficacy, safety, logistics, cost, and then I ask ‘What are your priorities? Which of these things that I say really rings with you? Is it the infusion schedule? Is it the efficacy? Is it the safety concern? Is it the cost? What are you most concerned about?’ And then we start to have the conversation that way. It’s a shared decision-making process.”

There is definitely an art to finding the best fit for each patient, agreed Dr. Bennett, “both with the urgency of controlling the disease, the particular patient in front of you, their ability to adhere to certain therapies, their ability to have access to infusions, or to self-inject, or to get transported to an infusion center or have access to home infusion.”

Patient empowerment in the decision is very important, added Dr. Levy. “When people make the decision on their own, they’re much more likely to be compliant, rather than me telling them they have to do this. And that’s why I think we haven’t had a single relapse on the new drugs. There have been switches because of intolerance, and cost, and all those issues, but not because of a breakthrough attack.”
 

Future

Looking ahead in the field, Dr. Bennett sees the biggest potential for improvement is in the management of acute attacks, which he describes as “a major treatment gap.” Although plasma exchange is immediately effective in limiting the amount of circulating pathogenic AQP4-IgG “there are other approaches that could be even more beneficial,” he said. “A promising strategy is to use drugs that act immediately on arms of the immune response that are directly injuring brain tissue. These include serum complement and cells such as neutrophils and natural killer cells that release destructive enzymes and inflammatory mediators,” he explained. “Complement inhibitors, such as the C5 inhibitors eculizumab and ravulizumab, currently approved for NMOSD relapse prevention, act immediately to inhibit complement-mediated tissue injury. Similarly, high doses of antihistamines could be used to rapidly stop the release of the destructive enzyme elastase from neutrophils and natural killer cells, while elastase inhibitors could be given to minimize cell injury. Direct clinical studies are needed to find both the optimal treatment window and regimen.”

References

1. Hor JY et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol. 2020 Jun 26:11:501. doi: 10.3389/fneur.2020.00501.

2. Wingerchuk DM et al. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729.

3. Mealy MA et al. Epidemiology of Neuromyelitis Optica in the United States: A Multicenter Analysis. Arch Neurol. 2012 Sep;69(9):1176-80. doi: 10.1001/archneurol.2012.314.

4. Contentti EC et al. Frequency of NMOSD Misdiagnosis in a Cohort From Latin America: Impact and Evaluation of Different Contributors. Mult Scler. 2023 Feb;29(2):277-286. doi: 10.1177/13524585221136259.

Duchenne muscular dystrophy (DMD) is a severe progressive inherited disease characterized by muscle wasting and ultimately culminating in death. Although rare (DMD affects between 1 in 3600 to 1 in 5000 births)¹ it’s “the most common form of muscular dystrophy in childhood. It’s a common enough neuromuscular disorder that pediatricians and family practice physicians are likely to see at least a couple of patients with DMD over the course of their career,” John Brandsema, MD, Neuromuscular Section Head, Division of Neurology, Children’s Hospital of Philadelphia in Pennsylvania, said in an interview. Healthcare providers should therefore be familiar with the disorder so as to provide timely diagnosis and early intervention as well as practical and emotional support to the patient and family/caregivers as they traverse the challenging and often heartbreaking journey with this condition.

Pathophysiology and Disease Trajectory

DMD is caused by pathogenic variants in the X-linked DMD gene, leading to reduction in dystrophin, a protein that serves as a cytoskeletal integrator, stabilizing the plasma membrane of striated muscle cells. Dystrophin is critical for muscle membrane stability.² In particular, mutations in the gene that encodes for dystrophin lead to dysfunction in Dp427m, which is the muscle isoform of dystrophin.^3,4

DMD is one of several types of muscular dystrophies. All are progressive disorders. Over time, healthy muscle fibers disappear and are replaced by fibrotic tissue and fat, making the muscles “less able to generate force for everyday activity.”² Ultimately, the skeletal muscle dysfunction affects not only the patient’s day-to-day mobility but other systems as well. Most patients with DMD eventually die of cardiac and/or respiratory failure between the ages of 20 and 40 years, with a median life expectancy of 22 years — although children born after 1990 have a somewhat higher median life expectancy (28 years), because of the improving standard of care.^3,5

Typically, DMD first presents with developmental delays and weakness in skeletal leg muscles. As the disease goes through stages of progression, it starts involving upper extremities and other systems. (Table 1)

Genetic Causes of DMD

The DMD gene, located on the X chromosome, encodes for the production of dystrophin. Variants of this gene result in the lack of dystrophin protein, leading in turn to muscle fiber degeneration and the progressive symptoms of DMD. Because of the gene’s location on the X chromosome, males (who don’t have a second copy of the X chromosome) cannot compensate for the mutated gene, which is why the disease affects male children. Females with this mutation are carriers and typically do not develop the same severity of symptoms, although they might have milder muscle cramps, weakness, and cardiac issues.³

A female carrier with DMD (or any other X-linked disorder) has a 25% chance to have a carrier daughter, a 25% change of having a noncarrier daughter, a 25% chance of having an affected son, and a 25% chance of having a nonaffected son. A male with the disorder will pass the mutated gene on to his daughters who then become carriers. He cannot pass the disorder on to his sons because males inherit only the Y chromosome from their fathers.³
 

Diagnosing DMD

“It can take as long as 1-3 years for a child to be diagnosed with DMD,” Dr. Brandsema said. “Parents typically have concerns and know that something is ‘off’ about their child and they’re sent to various specialists, but it usually takes time for an accurate diagnosis to be made.” The mean age at diagnosis of DMD is between ages 4 and 5 years.⁶

Early identification of infants at risk for developing DMD can help move the needle toward earlier diagnosis. Newborn screening for DMD has been researched and piloted in several programs.⁶ In 2023, DMD was nominated for inclusion in the Recommended Universal Screening Panel (RUSP) for universal newborn screening. But in May 2024, the advisory committee on Heritable Disorders in Newborns and Children decided to postpone the vote to include DMD in the RUSP, requesting additional information to ensure an evidence-based decision.

In the absence of universal newborn screening for DMD, alternative approaches have been proposed to reduce the delay in clinical diagnosis and specialist referral, including increasing awareness among healthcare providers (eg, pediatricians, pediatric neurologists, and primary care physicians).⁶

The National Task Force for Early Identification of Childhood Neuromuscular Disorders delineates the steps necessary to identify pediatric muscle weakness and signs of neuromuscular disease. Primary care providers are encouraged to engage in regular developmental surveillance. A surveillance aid lays out the timetable for recommended visits, typical developmental milestones, and components of surveillance. Clinical evaluation includes a detailed patient history, family history, and physical examination.

If a neuromuscular condition is suspected, laboratory work should include creatinine phosphokinase (CK).⁶ Elevated serum CK points to leakage of CK through the muscle membrane, suggesting muscle damage. If CK is elevated, genetic testing should be performed; and, if negative, it should be followed by genetic sequencing that tests for small-scale mutations in the DMD gene. If that test is negative, a muscle biopsy should be performed to test for deep intronic mutations in the DMD gene.⁴

The diagnostic process and immediate steps after a confirmed DMD diagnosis is found in Figure 1.

Targeting Inflammation in DMD

Traditionally, corticosteroids have been the only available medical treatment for DMD and they remain a cornerstone of DMD management. A meta-analysis found “moderate evidence” that corticosteroid therapy improves muscle strength and function in the short term (12 months), and strength up to 2 years.¹⁰

The two most common corticosteroids for DMD are prednisone and deflazacort. Deflazacort (Emflaza, PTC Therapeutics) was approved in 2017 to treat patients ages 5 years and older with DMD, subsequently expanded to 2 years and older. Deflazacort has been found to be more effective than prednisone in improving functional outcomes, delaying the onset of cardiomyopathy, and improving overall survival, with fewer adverse effects.¹¹

In 2023, vamorolone (Agamree, Catalyst Pharmaceuticals) was approved by the Food and Drug Administration (FDA) to treat DMD patients (ages 2 years and older). Vamorolone is a dissociative steroidal anti-inflammatory that reduces bone morbidities and is regarded as a safer alternative than prednisone. A clinical trial comparing two doses of vamorolone with prednisone for 24 weeks found that vamorolone 6 mg/kg per day met the primary endpoint (time to stand velocity) and four sequential secondary motor function endpoints, with less bone morbidity, compared to prednisone.¹² A more recent trial found improvements in motor outcomes at 48 weeks with a dose of 6 mg/kg per day of vamorolone. Bone morbidities of prednisone were reversed when the patient transitioned to vamorolone.¹³

“Steroid treatment has been proven to help, usually taken daily, although other schedules have been tried,” Dr. Brandsema said. However, all steroids are fraught with adverse effects and are suboptimal in the long term in reducing the disease burden.

The anti-inflammatory agent givinostat (Duvyzat, ITF Therapeutics), an oral histone deacetylase (HDAC) inhibitor, was approved in March 2024 for the treatment of DMD in patients 6 years of age and older. It is the first nonsteroidal drug to treat patients with all genetic variants of the disease, and it has a unique mechanism of action. Deficits in dystrophin can lead to increased HDAC activity in DMD, reducing the expression of genes involved in muscle regeneration. Givinostat therefore can help to counteract the pathogenic events downstream of dystrophin deficiency by inhibiting HDAC.¹⁴

Approval for givinostat was based on the phase 3 EPIDYS trial, which randomized 179 boys with DMD to receive either givinostat or placebo. Although results of a functional task worsened in both groups over the 12-month study period, the decline was significantly smaller with givinostat versus placebo. The most common adverse events were diarrhea and vomiting.14 Dr. Brandsema noted that monitoring of triglycerides and platelet count is required, as hypertriglyceridemia and thrombocytopenia can occur. This treatment was studied in tandem with corticosteroids as a combination approach to muscle stabilization.
 

New Pharmacotherapeutic Options: Exon-Skipping Agents

Today’s treatments have expanded beyond corticosteroids, with newer therapeutic options that include targeted exon-skipping therapies and, more recently, gene therapies. “These new treatment paradigms have changed the face of DMD treatment,” Dr. Brandsema said.

courtesy Children's Hospital of Philadelphia

Gene Transfer Therapies

Gene transfer therapies, a new class of agents, utilize a nonpathogenic viral vector (adeno-associated virus) to transfer specific genes to patients with DMD. Gene therapy involves overexpressing the micro-dystrophin gene to restore functional dystrophin expression.¹⁶

Multiple clinical trials of gene therapy are currently in progress. In 2023, delandistrogene moxeparvovec-rokl (Elevidys, Serepta) was granted accelerated FDA approval for ambulatory individuals with DMD between the ages of 4 and 5 years of age and a confirmed mutation in the DMD gene. It received expanded approval in June 2024 to include ambulatory and nonambulatory individuals aged 4 years and older with DMD and a confirmed mutation in the DMD gene (with the exception of exon 8 or 9 mutations).

The approval was based on preliminary data from two double-blind, placebo-controlled studies and two open-label studies, which enrolled a total of 218 male patients (including those who received placebo) with a confirmed disease-causing mutation in the DMD gene. 

Delandistrogene moxeparvovec-rokl is delivered as a one-time infusion and has been associated with side effects and “a lot of potential issues,” Dr. Brandsema said. “We’ve seen cardiac effects, immune system effects, increased muscle inflammation and hepatic complications, and some people who became quite unwell were hospitalized for a long time.”

Fortunately, he added, “these seem to be rare but they do happen. Once the medication has been delivered, it’s permanently in the body, so you’re managing the side effects potentially on a long-term basis.”

It is critical to discuss the risks and benefits of this treatment with the family and caregivers and with the patient as well, if he old enough and able to participate in the decision-making progress. “We don’t want to give unrealistic expectations and we want people to be aware of the potential downside of this treatment,” he said. “This is a very complex discussion because the trajectory of the disease is so devastating and this treatment does hold out hope that other therapies don’t necessarily have.”
 

Nonpharmacologic Interventions

Physical therapy is a mainstay in DMD treatment, addressing protection of fragile muscles, preservation of strength, and prevention of muscle contractures.¹⁶ Given the respiratory impairments that occur with DMD progression, respiratory monitoring and therapy are essential; however, the number and type of evaluations and interventions vary with the stage of the disease, intensifying as the disease progresses.¹⁶ Similarly, cardiac monitoring should begin early, with patients screened for cardiac complications, and should intensify through the stages of disease progression.¹⁶

Bone health is compromised in patients with DMD, both as a result of corticosteroid treatment and as part of the disease itself. Fractures may be asymptomatic and may go unnoticed. Thus, bone health surveillance and maintenance are critical components of DMD management.¹⁶

Patients with DMD often experience gastrointestinal issues. They may experience weight gain because of lack of mobility and corticosteroid use in early stages, or weight loss as a result of diet or fluid imbalance, low bone density, or dysphagia in later stages. Patients should be closely followed by a nutritionist, a gastroenterologist as needed, and a physical therapist.¹⁶

Psychosocial support “should be developed and implemented across the lifespan in a manner that promotes thinking about the future and sets expectations that individuals will actively participate in their care and daily activities.”⁹ This includes psychological care, neuropsychological evaluations, and educational support.
 

Assisting Patients and Families Through the DMD Journey

DMD care is best delivered in a multidisciplinary setting, where physicians of relevant specialties, physical and occupational therapists, nutritionists, social workers, and genetic counselors collaborate. At Children’s Hospital of Philadelphia, DMD care is delivered through this collaborative model.

Unfortunately, Dr. Brandsema said, many patients don’t have this type of multidisciplinary resource available. “One specialist, such as a pulmonologist or neurologist, might have to be the sole source of care.” Or parents may have to ferry their child to multiple specialists in disparate locations, placing extra stress on an already-stressed family system.

“It’s helpful to connect the family with a comprehensive care center, if possible,” Dr. Brandsema advised. If that’s not available, then he suggests recommending educational opportunities and resources through national organizations such as the Muscular Dystrophy Association; Parent Project MD; NORD; Friends, Family and Duchenne; and Cure Duchenne. Families and caregivers, along with affected individuals, can get education and support from people who understand the day-to-day reality of living with this disease.

One of the major challenges that families face is navigating the high cost of treating DMD, especially the new medications, Dr. Brandsema said. “The authorization process can be intensive and long, and the family may need to take an active role, together with the provider team, in advocating for the patient to get access.”

courtesy Children's Hospital of Philadelphia

Managing DMD Across the Lifespan

Another dimension of DMD care is providing resources and help to young people with DMD as they transition into adulthood. “In the past, we had limited treatment and mortality typically took place in the early 20s, so there weren’t a lot of patients who were adults. But as medication options have expanded and management of cardiac and respiratory failure has improved, we see a more significant proportion of adults who require adult-appropriate clinics — or, at the very least, specialists who are conversant in care or can provide care across the lifespan,” Dr. Brandsema said.

The DMD Care Considerations Working Group provides recommendations regarding care across the lifespan,⁹ as does the Adult North Star Network, of Muscular Dystrophy UK.^17,18

Dr. Brandsema emphasized that, despite their disability, many adults with DMD “still engage with the community, and live life to its fullest.” It is to be hoped that, with ongoing research, earlier diagnosis, and improved treatment options, the future will look bright for people with DMD.

Dr. Brandsema has served as a consultant for Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech, Marathon, Momenta/Janssen, NS Pharma, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is on the medical advisory council member for Cure SMA and is a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Biohaven, Catabasis, CSL Behring, Cytokinetics, Dyne, Fibrogen, Genentech, Ionis, Lilly, ML Bio, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Ms. Kaschak has nothing to disclose.
 

References

1. Venugopal V and Pavlakis S. Duchenne Muscular Dystrophy. 2023 Jul 10. In: StatPearls [Internet]. Treasure Island, Florida: StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482346/.

2. Gao QQ and McNally EM. Compr Physiol. 2015 Jul 1;5(3):1223-39. doi: 10.1002/cphy.c140048.

3. Duan D et al. Nat Rev Dis Primers. 2021 Feb 18;7(1):13. doi: 10.1038/s41572-021-00248-3.

4. Aartsma-Rus A et al. J Pediatr. 2019 Jan:204:305-313.e14. doi: 10.1016/j.jpeds.2018.10.043.

5. Broomfield J et al. Neurology. 2021 Dec 7;97(23):e2304-e2314. doi: 10.1212/WNL.0000000000012910.

6. Mercuri E et al. Front Pediatr. 2023 Nov 10:11:1276144. doi: 10.1212/WNL.0000000000012910.

7. Birnkrant DJ et al. Lancet Neurol. 2018 Mar;17(3):251-267. doi: 10.1016/S1474-4422(18)30024-3.

8. Birnkrant DJ et al. Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5.

9. Birnkrant DJ et al. Lancet Neurol. 2018 May;17(5):445-455. doi: 10.1016/S1474-4422(18)30026-7.

10. Matthews E et al. Cochrane Database Syst Rev. 2016 May 5;2016(5):CD003725. doi: 10.1002/14651858.CD003725.pub4.

11. Bylo M et al. Ann Pharmacother. 2020 Aug;54(8):788-794. doi: 10.1177/1060028019900500.

12. Guglieri M et al. JAMA Neurol. 2022 Oct 1;79(10):1005-1014. doi: 10.1001/jamaneurol.2022.2480.

13. Dang UJ et al. Neurology. 2024 Mar 12;102(5):e208112. doi: 10.1212/WNL.0000000000208112.

14. Mercuri E et al. Lancet Neurol. 2024 Apr;23(4):393-403. doi: 10.1016/S1474-4422(24)00036-X.

15. Gushchina LV et al. Mol Ther Nucleic Acids. 2022 Nov 9:30:479-492. doi: 10.1016/j.omtn.2022.10.025.

16. Patterson G et al. Eur J Pharmacol. 2023 May 15:947:175675. doi: 10.1016/j.ejphar.2023.175675.

17. Quinlivan R et al. J Neuromuscul Dis. 2021;8(6):899-926. doi: 10.3233/JND-200609.

18. Narayan S et al. J Neuromuscul Dis. 2022;9(3):365-381. doi: 10.3233/JND-210707.

Duchenne muscular dystrophy (DMD) is a severe progressive inherited disease characterized by muscle wasting and ultimately culminating in death. Although rare (DMD affects between 1 in 3600 to 1 in 5000 births)¹ it’s “the most common form of muscular dystrophy in childhood. It’s a common enough neuromuscular disorder that pediatricians and family practice physicians are likely to see at least a couple of patients with DMD over the course of their career,” John Brandsema, MD, Neuromuscular Section Head, Division of Neurology, Children’s Hospital of Philadelphia in Pennsylvania, said in an interview. Healthcare providers should therefore be familiar with the disorder so as to provide timely diagnosis and early intervention as well as practical and emotional support to the patient and family/caregivers as they traverse the challenging and often heartbreaking journey with this condition.

Pathophysiology and Disease Trajectory

DMD is caused by pathogenic variants in the X-linked DMD gene, leading to reduction in dystrophin, a protein that serves as a cytoskeletal integrator, stabilizing the plasma membrane of striated muscle cells. Dystrophin is critical for muscle membrane stability.² In particular, mutations in the gene that encodes for dystrophin lead to dysfunction in Dp427m, which is the muscle isoform of dystrophin.^3,4

DMD is one of several types of muscular dystrophies. All are progressive disorders. Over time, healthy muscle fibers disappear and are replaced by fibrotic tissue and fat, making the muscles “less able to generate force for everyday activity.”² Ultimately, the skeletal muscle dysfunction affects not only the patient’s day-to-day mobility but other systems as well. Most patients with DMD eventually die of cardiac and/or respiratory failure between the ages of 20 and 40 years, with a median life expectancy of 22 years — although children born after 1990 have a somewhat higher median life expectancy (28 years), because of the improving standard of care.^3,5

Typically, DMD first presents with developmental delays and weakness in skeletal leg muscles. As the disease goes through stages of progression, it starts involving upper extremities and other systems. (Table 1)

Genetic Causes of DMD

The DMD gene, located on the X chromosome, encodes for the production of dystrophin. Variants of this gene result in the lack of dystrophin protein, leading in turn to muscle fiber degeneration and the progressive symptoms of DMD. Because of the gene’s location on the X chromosome, males (who don’t have a second copy of the X chromosome) cannot compensate for the mutated gene, which is why the disease affects male children. Females with this mutation are carriers and typically do not develop the same severity of symptoms, although they might have milder muscle cramps, weakness, and cardiac issues.³

A female carrier with DMD (or any other X-linked disorder) has a 25% chance to have a carrier daughter, a 25% change of having a noncarrier daughter, a 25% chance of having an affected son, and a 25% chance of having a nonaffected son. A male with the disorder will pass the mutated gene on to his daughters who then become carriers. He cannot pass the disorder on to his sons because males inherit only the Y chromosome from their fathers.³
 

Diagnosing DMD

“It can take as long as 1-3 years for a child to be diagnosed with DMD,” Dr. Brandsema said. “Parents typically have concerns and know that something is ‘off’ about their child and they’re sent to various specialists, but it usually takes time for an accurate diagnosis to be made.” The mean age at diagnosis of DMD is between ages 4 and 5 years.⁶

Early identification of infants at risk for developing DMD can help move the needle toward earlier diagnosis. Newborn screening for DMD has been researched and piloted in several programs.⁶ In 2023, DMD was nominated for inclusion in the Recommended Universal Screening Panel (RUSP) for universal newborn screening. But in May 2024, the advisory committee on Heritable Disorders in Newborns and Children decided to postpone the vote to include DMD in the RUSP, requesting additional information to ensure an evidence-based decision.

In the absence of universal newborn screening for DMD, alternative approaches have been proposed to reduce the delay in clinical diagnosis and specialist referral, including increasing awareness among healthcare providers (eg, pediatricians, pediatric neurologists, and primary care physicians).⁶

The National Task Force for Early Identification of Childhood Neuromuscular Disorders delineates the steps necessary to identify pediatric muscle weakness and signs of neuromuscular disease. Primary care providers are encouraged to engage in regular developmental surveillance. A surveillance aid lays out the timetable for recommended visits, typical developmental milestones, and components of surveillance. Clinical evaluation includes a detailed patient history, family history, and physical examination.

If a neuromuscular condition is suspected, laboratory work should include creatinine phosphokinase (CK).⁶ Elevated serum CK points to leakage of CK through the muscle membrane, suggesting muscle damage. If CK is elevated, genetic testing should be performed; and, if negative, it should be followed by genetic sequencing that tests for small-scale mutations in the DMD gene. If that test is negative, a muscle biopsy should be performed to test for deep intronic mutations in the DMD gene.⁴

The diagnostic process and immediate steps after a confirmed DMD diagnosis is found in Figure 1.

Targeting Inflammation in DMD

Traditionally, corticosteroids have been the only available medical treatment for DMD and they remain a cornerstone of DMD management. A meta-analysis found “moderate evidence” that corticosteroid therapy improves muscle strength and function in the short term (12 months), and strength up to 2 years.¹⁰

The two most common corticosteroids for DMD are prednisone and deflazacort. Deflazacort (Emflaza, PTC Therapeutics) was approved in 2017 to treat patients ages 5 years and older with DMD, subsequently expanded to 2 years and older. Deflazacort has been found to be more effective than prednisone in improving functional outcomes, delaying the onset of cardiomyopathy, and improving overall survival, with fewer adverse effects.¹¹

In 2023, vamorolone (Agamree, Catalyst Pharmaceuticals) was approved by the Food and Drug Administration (FDA) to treat DMD patients (ages 2 years and older). Vamorolone is a dissociative steroidal anti-inflammatory that reduces bone morbidities and is regarded as a safer alternative than prednisone. A clinical trial comparing two doses of vamorolone with prednisone for 24 weeks found that vamorolone 6 mg/kg per day met the primary endpoint (time to stand velocity) and four sequential secondary motor function endpoints, with less bone morbidity, compared to prednisone.¹² A more recent trial found improvements in motor outcomes at 48 weeks with a dose of 6 mg/kg per day of vamorolone. Bone morbidities of prednisone were reversed when the patient transitioned to vamorolone.¹³

“Steroid treatment has been proven to help, usually taken daily, although other schedules have been tried,” Dr. Brandsema said. However, all steroids are fraught with adverse effects and are suboptimal in the long term in reducing the disease burden.

The anti-inflammatory agent givinostat (Duvyzat, ITF Therapeutics), an oral histone deacetylase (HDAC) inhibitor, was approved in March 2024 for the treatment of DMD in patients 6 years of age and older. It is the first nonsteroidal drug to treat patients with all genetic variants of the disease, and it has a unique mechanism of action. Deficits in dystrophin can lead to increased HDAC activity in DMD, reducing the expression of genes involved in muscle regeneration. Givinostat therefore can help to counteract the pathogenic events downstream of dystrophin deficiency by inhibiting HDAC.¹⁴

Approval for givinostat was based on the phase 3 EPIDYS trial, which randomized 179 boys with DMD to receive either givinostat or placebo. Although results of a functional task worsened in both groups over the 12-month study period, the decline was significantly smaller with givinostat versus placebo. The most common adverse events were diarrhea and vomiting.14 Dr. Brandsema noted that monitoring of triglycerides and platelet count is required, as hypertriglyceridemia and thrombocytopenia can occur. This treatment was studied in tandem with corticosteroids as a combination approach to muscle stabilization.
 

New Pharmacotherapeutic Options: Exon-Skipping Agents

Today’s treatments have expanded beyond corticosteroids, with newer therapeutic options that include targeted exon-skipping therapies and, more recently, gene therapies. “These new treatment paradigms have changed the face of DMD treatment,” Dr. Brandsema said.

courtesy Children's Hospital of Philadelphia

Gene Transfer Therapies

Gene transfer therapies, a new class of agents, utilize a nonpathogenic viral vector (adeno-associated virus) to transfer specific genes to patients with DMD. Gene therapy involves overexpressing the micro-dystrophin gene to restore functional dystrophin expression.¹⁶

Multiple clinical trials of gene therapy are currently in progress. In 2023, delandistrogene moxeparvovec-rokl (Elevidys, Serepta) was granted accelerated FDA approval for ambulatory individuals with DMD between the ages of 4 and 5 years of age and a confirmed mutation in the DMD gene. It received expanded approval in June 2024 to include ambulatory and nonambulatory individuals aged 4 years and older with DMD and a confirmed mutation in the DMD gene (with the exception of exon 8 or 9 mutations).

The approval was based on preliminary data from two double-blind, placebo-controlled studies and two open-label studies, which enrolled a total of 218 male patients (including those who received placebo) with a confirmed disease-causing mutation in the DMD gene. 

Delandistrogene moxeparvovec-rokl is delivered as a one-time infusion and has been associated with side effects and “a lot of potential issues,” Dr. Brandsema said. “We’ve seen cardiac effects, immune system effects, increased muscle inflammation and hepatic complications, and some people who became quite unwell were hospitalized for a long time.”

Fortunately, he added, “these seem to be rare but they do happen. Once the medication has been delivered, it’s permanently in the body, so you’re managing the side effects potentially on a long-term basis.”

It is critical to discuss the risks and benefits of this treatment with the family and caregivers and with the patient as well, if he old enough and able to participate in the decision-making progress. “We don’t want to give unrealistic expectations and we want people to be aware of the potential downside of this treatment,” he said. “This is a very complex discussion because the trajectory of the disease is so devastating and this treatment does hold out hope that other therapies don’t necessarily have.”
 

Nonpharmacologic Interventions

Physical therapy is a mainstay in DMD treatment, addressing protection of fragile muscles, preservation of strength, and prevention of muscle contractures.¹⁶ Given the respiratory impairments that occur with DMD progression, respiratory monitoring and therapy are essential; however, the number and type of evaluations and interventions vary with the stage of the disease, intensifying as the disease progresses.¹⁶ Similarly, cardiac monitoring should begin early, with patients screened for cardiac complications, and should intensify through the stages of disease progression.¹⁶

Bone health is compromised in patients with DMD, both as a result of corticosteroid treatment and as part of the disease itself. Fractures may be asymptomatic and may go unnoticed. Thus, bone health surveillance and maintenance are critical components of DMD management.¹⁶

Patients with DMD often experience gastrointestinal issues. They may experience weight gain because of lack of mobility and corticosteroid use in early stages, or weight loss as a result of diet or fluid imbalance, low bone density, or dysphagia in later stages. Patients should be closely followed by a nutritionist, a gastroenterologist as needed, and a physical therapist.¹⁶

Psychosocial support “should be developed and implemented across the lifespan in a manner that promotes thinking about the future and sets expectations that individuals will actively participate in their care and daily activities.”⁹ This includes psychological care, neuropsychological evaluations, and educational support.
 

Assisting Patients and Families Through the DMD Journey

DMD care is best delivered in a multidisciplinary setting, where physicians of relevant specialties, physical and occupational therapists, nutritionists, social workers, and genetic counselors collaborate. At Children’s Hospital of Philadelphia, DMD care is delivered through this collaborative model.

Unfortunately, Dr. Brandsema said, many patients don’t have this type of multidisciplinary resource available. “One specialist, such as a pulmonologist or neurologist, might have to be the sole source of care.” Or parents may have to ferry their child to multiple specialists in disparate locations, placing extra stress on an already-stressed family system.

“It’s helpful to connect the family with a comprehensive care center, if possible,” Dr. Brandsema advised. If that’s not available, then he suggests recommending educational opportunities and resources through national organizations such as the Muscular Dystrophy Association; Parent Project MD; NORD; Friends, Family and Duchenne; and Cure Duchenne. Families and caregivers, along with affected individuals, can get education and support from people who understand the day-to-day reality of living with this disease.

One of the major challenges that families face is navigating the high cost of treating DMD, especially the new medications, Dr. Brandsema said. “The authorization process can be intensive and long, and the family may need to take an active role, together with the provider team, in advocating for the patient to get access.”

courtesy Children's Hospital of Philadelphia

Managing DMD Across the Lifespan

Another dimension of DMD care is providing resources and help to young people with DMD as they transition into adulthood. “In the past, we had limited treatment and mortality typically took place in the early 20s, so there weren’t a lot of patients who were adults. But as medication options have expanded and management of cardiac and respiratory failure has improved, we see a more significant proportion of adults who require adult-appropriate clinics — or, at the very least, specialists who are conversant in care or can provide care across the lifespan,” Dr. Brandsema said.

The DMD Care Considerations Working Group provides recommendations regarding care across the lifespan,⁹ as does the Adult North Star Network, of Muscular Dystrophy UK.^17,18

Dr. Brandsema emphasized that, despite their disability, many adults with DMD “still engage with the community, and live life to its fullest.” It is to be hoped that, with ongoing research, earlier diagnosis, and improved treatment options, the future will look bright for people with DMD.

Dr. Brandsema has served as a consultant for Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech, Marathon, Momenta/Janssen, NS Pharma, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is on the medical advisory council member for Cure SMA and is a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Biohaven, Catabasis, CSL Behring, Cytokinetics, Dyne, Fibrogen, Genentech, Ionis, Lilly, ML Bio, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Ms. Kaschak has nothing to disclose.
 

References

1. Venugopal V and Pavlakis S. Duchenne Muscular Dystrophy. 2023 Jul 10. In: StatPearls [Internet]. Treasure Island, Florida: StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482346/.

2. Gao QQ and McNally EM. Compr Physiol. 2015 Jul 1;5(3):1223-39. doi: 10.1002/cphy.c140048.

3. Duan D et al. Nat Rev Dis Primers. 2021 Feb 18;7(1):13. doi: 10.1038/s41572-021-00248-3.

4. Aartsma-Rus A et al. J Pediatr. 2019 Jan:204:305-313.e14. doi: 10.1016/j.jpeds.2018.10.043.

5. Broomfield J et al. Neurology. 2021 Dec 7;97(23):e2304-e2314. doi: 10.1212/WNL.0000000000012910.

6. Mercuri E et al. Front Pediatr. 2023 Nov 10:11:1276144. doi: 10.1212/WNL.0000000000012910.

7. Birnkrant DJ et al. Lancet Neurol. 2018 Mar;17(3):251-267. doi: 10.1016/S1474-4422(18)30024-3.

8. Birnkrant DJ et al. Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5.

9. Birnkrant DJ et al. Lancet Neurol. 2018 May;17(5):445-455. doi: 10.1016/S1474-4422(18)30026-7.

10. Matthews E et al. Cochrane Database Syst Rev. 2016 May 5;2016(5):CD003725. doi: 10.1002/14651858.CD003725.pub4.

11. Bylo M et al. Ann Pharmacother. 2020 Aug;54(8):788-794. doi: 10.1177/1060028019900500.

12. Guglieri M et al. JAMA Neurol. 2022 Oct 1;79(10):1005-1014. doi: 10.1001/jamaneurol.2022.2480.

13. Dang UJ et al. Neurology. 2024 Mar 12;102(5):e208112. doi: 10.1212/WNL.0000000000208112.

14. Mercuri E et al. Lancet Neurol. 2024 Apr;23(4):393-403. doi: 10.1016/S1474-4422(24)00036-X.

15. Gushchina LV et al. Mol Ther Nucleic Acids. 2022 Nov 9:30:479-492. doi: 10.1016/j.omtn.2022.10.025.

16. Patterson G et al. Eur J Pharmacol. 2023 May 15:947:175675. doi: 10.1016/j.ejphar.2023.175675.

17. Quinlivan R et al. J Neuromuscul Dis. 2021;8(6):899-926. doi: 10.3233/JND-200609.

18. Narayan S et al. J Neuromuscul Dis. 2022;9(3):365-381. doi: 10.3233/JND-210707.

Duchenne muscular dystrophy (DMD) is a severe progressive inherited disease characterized by muscle wasting and ultimately culminating in death. Although rare (DMD affects between 1 in 3600 to 1 in 5000 births)¹ it’s “the most common form of muscular dystrophy in childhood. It’s a common enough neuromuscular disorder that pediatricians and family practice physicians are likely to see at least a couple of patients with DMD over the course of their career,” John Brandsema, MD, Neuromuscular Section Head, Division of Neurology, Children’s Hospital of Philadelphia in Pennsylvania, said in an interview. Healthcare providers should therefore be familiar with the disorder so as to provide timely diagnosis and early intervention as well as practical and emotional support to the patient and family/caregivers as they traverse the challenging and often heartbreaking journey with this condition.

Pathophysiology and Disease Trajectory

DMD is caused by pathogenic variants in the X-linked DMD gene, leading to reduction in dystrophin, a protein that serves as a cytoskeletal integrator, stabilizing the plasma membrane of striated muscle cells. Dystrophin is critical for muscle membrane stability.² In particular, mutations in the gene that encodes for dystrophin lead to dysfunction in Dp427m, which is the muscle isoform of dystrophin.^3,4

DMD is one of several types of muscular dystrophies. All are progressive disorders. Over time, healthy muscle fibers disappear and are replaced by fibrotic tissue and fat, making the muscles “less able to generate force for everyday activity.”² Ultimately, the skeletal muscle dysfunction affects not only the patient’s day-to-day mobility but other systems as well. Most patients with DMD eventually die of cardiac and/or respiratory failure between the ages of 20 and 40 years, with a median life expectancy of 22 years — although children born after 1990 have a somewhat higher median life expectancy (28 years), because of the improving standard of care.^3,5

Typically, DMD first presents with developmental delays and weakness in skeletal leg muscles. As the disease goes through stages of progression, it starts involving upper extremities and other systems. (Table 1)

Genetic Causes of DMD

The DMD gene, located on the X chromosome, encodes for the production of dystrophin. Variants of this gene result in the lack of dystrophin protein, leading in turn to muscle fiber degeneration and the progressive symptoms of DMD. Because of the gene’s location on the X chromosome, males (who don’t have a second copy of the X chromosome) cannot compensate for the mutated gene, which is why the disease affects male children. Females with this mutation are carriers and typically do not develop the same severity of symptoms, although they might have milder muscle cramps, weakness, and cardiac issues.³

A female carrier with DMD (or any other X-linked disorder) has a 25% chance to have a carrier daughter, a 25% change of having a noncarrier daughter, a 25% chance of having an affected son, and a 25% chance of having a nonaffected son. A male with the disorder will pass the mutated gene on to his daughters who then become carriers. He cannot pass the disorder on to his sons because males inherit only the Y chromosome from their fathers.³
 

Diagnosing DMD

“It can take as long as 1-3 years for a child to be diagnosed with DMD,” Dr. Brandsema said. “Parents typically have concerns and know that something is ‘off’ about their child and they’re sent to various specialists, but it usually takes time for an accurate diagnosis to be made.” The mean age at diagnosis of DMD is between ages 4 and 5 years.⁶

Early identification of infants at risk for developing DMD can help move the needle toward earlier diagnosis. Newborn screening for DMD has been researched and piloted in several programs.⁶ In 2023, DMD was nominated for inclusion in the Recommended Universal Screening Panel (RUSP) for universal newborn screening. But in May 2024, the advisory committee on Heritable Disorders in Newborns and Children decided to postpone the vote to include DMD in the RUSP, requesting additional information to ensure an evidence-based decision.

In the absence of universal newborn screening for DMD, alternative approaches have been proposed to reduce the delay in clinical diagnosis and specialist referral, including increasing awareness among healthcare providers (eg, pediatricians, pediatric neurologists, and primary care physicians).⁶

The National Task Force for Early Identification of Childhood Neuromuscular Disorders delineates the steps necessary to identify pediatric muscle weakness and signs of neuromuscular disease. Primary care providers are encouraged to engage in regular developmental surveillance. A surveillance aid lays out the timetable for recommended visits, typical developmental milestones, and components of surveillance. Clinical evaluation includes a detailed patient history, family history, and physical examination.

If a neuromuscular condition is suspected, laboratory work should include creatinine phosphokinase (CK).⁶ Elevated serum CK points to leakage of CK through the muscle membrane, suggesting muscle damage. If CK is elevated, genetic testing should be performed; and, if negative, it should be followed by genetic sequencing that tests for small-scale mutations in the DMD gene. If that test is negative, a muscle biopsy should be performed to test for deep intronic mutations in the DMD gene.⁴

The diagnostic process and immediate steps after a confirmed DMD diagnosis is found in Figure 1.

Targeting Inflammation in DMD

Traditionally, corticosteroids have been the only available medical treatment for DMD and they remain a cornerstone of DMD management. A meta-analysis found “moderate evidence” that corticosteroid therapy improves muscle strength and function in the short term (12 months), and strength up to 2 years.¹⁰

The two most common corticosteroids for DMD are prednisone and deflazacort. Deflazacort (Emflaza, PTC Therapeutics) was approved in 2017 to treat patients ages 5 years and older with DMD, subsequently expanded to 2 years and older. Deflazacort has been found to be more effective than prednisone in improving functional outcomes, delaying the onset of cardiomyopathy, and improving overall survival, with fewer adverse effects.¹¹

In 2023, vamorolone (Agamree, Catalyst Pharmaceuticals) was approved by the Food and Drug Administration (FDA) to treat DMD patients (ages 2 years and older). Vamorolone is a dissociative steroidal anti-inflammatory that reduces bone morbidities and is regarded as a safer alternative than prednisone. A clinical trial comparing two doses of vamorolone with prednisone for 24 weeks found that vamorolone 6 mg/kg per day met the primary endpoint (time to stand velocity) and four sequential secondary motor function endpoints, with less bone morbidity, compared to prednisone.¹² A more recent trial found improvements in motor outcomes at 48 weeks with a dose of 6 mg/kg per day of vamorolone. Bone morbidities of prednisone were reversed when the patient transitioned to vamorolone.¹³

“Steroid treatment has been proven to help, usually taken daily, although other schedules have been tried,” Dr. Brandsema said. However, all steroids are fraught with adverse effects and are suboptimal in the long term in reducing the disease burden.

The anti-inflammatory agent givinostat (Duvyzat, ITF Therapeutics), an oral histone deacetylase (HDAC) inhibitor, was approved in March 2024 for the treatment of DMD in patients 6 years of age and older. It is the first nonsteroidal drug to treat patients with all genetic variants of the disease, and it has a unique mechanism of action. Deficits in dystrophin can lead to increased HDAC activity in DMD, reducing the expression of genes involved in muscle regeneration. Givinostat therefore can help to counteract the pathogenic events downstream of dystrophin deficiency by inhibiting HDAC.¹⁴

Approval for givinostat was based on the phase 3 EPIDYS trial, which randomized 179 boys with DMD to receive either givinostat or placebo. Although results of a functional task worsened in both groups over the 12-month study period, the decline was significantly smaller with givinostat versus placebo. The most common adverse events were diarrhea and vomiting.14 Dr. Brandsema noted that monitoring of triglycerides and platelet count is required, as hypertriglyceridemia and thrombocytopenia can occur. This treatment was studied in tandem with corticosteroids as a combination approach to muscle stabilization.
 

New Pharmacotherapeutic Options: Exon-Skipping Agents

Today’s treatments have expanded beyond corticosteroids, with newer therapeutic options that include targeted exon-skipping therapies and, more recently, gene therapies. “These new treatment paradigms have changed the face of DMD treatment,” Dr. Brandsema said.

courtesy Children's Hospital of Philadelphia

Gene Transfer Therapies

Gene transfer therapies, a new class of agents, utilize a nonpathogenic viral vector (adeno-associated virus) to transfer specific genes to patients with DMD. Gene therapy involves overexpressing the micro-dystrophin gene to restore functional dystrophin expression.¹⁶

Multiple clinical trials of gene therapy are currently in progress. In 2023, delandistrogene moxeparvovec-rokl (Elevidys, Serepta) was granted accelerated FDA approval for ambulatory individuals with DMD between the ages of 4 and 5 years of age and a confirmed mutation in the DMD gene. It received expanded approval in June 2024 to include ambulatory and nonambulatory individuals aged 4 years and older with DMD and a confirmed mutation in the DMD gene (with the exception of exon 8 or 9 mutations).

The approval was based on preliminary data from two double-blind, placebo-controlled studies and two open-label studies, which enrolled a total of 218 male patients (including those who received placebo) with a confirmed disease-causing mutation in the DMD gene. 

Delandistrogene moxeparvovec-rokl is delivered as a one-time infusion and has been associated with side effects and “a lot of potential issues,” Dr. Brandsema said. “We’ve seen cardiac effects, immune system effects, increased muscle inflammation and hepatic complications, and some people who became quite unwell were hospitalized for a long time.”

Fortunately, he added, “these seem to be rare but they do happen. Once the medication has been delivered, it’s permanently in the body, so you’re managing the side effects potentially on a long-term basis.”

It is critical to discuss the risks and benefits of this treatment with the family and caregivers and with the patient as well, if he old enough and able to participate in the decision-making progress. “We don’t want to give unrealistic expectations and we want people to be aware of the potential downside of this treatment,” he said. “This is a very complex discussion because the trajectory of the disease is so devastating and this treatment does hold out hope that other therapies don’t necessarily have.”
 

Nonpharmacologic Interventions

Physical therapy is a mainstay in DMD treatment, addressing protection of fragile muscles, preservation of strength, and prevention of muscle contractures.¹⁶ Given the respiratory impairments that occur with DMD progression, respiratory monitoring and therapy are essential; however, the number and type of evaluations and interventions vary with the stage of the disease, intensifying as the disease progresses.¹⁶ Similarly, cardiac monitoring should begin early, with patients screened for cardiac complications, and should intensify through the stages of disease progression.¹⁶

Bone health is compromised in patients with DMD, both as a result of corticosteroid treatment and as part of the disease itself. Fractures may be asymptomatic and may go unnoticed. Thus, bone health surveillance and maintenance are critical components of DMD management.¹⁶

Patients with DMD often experience gastrointestinal issues. They may experience weight gain because of lack of mobility and corticosteroid use in early stages, or weight loss as a result of diet or fluid imbalance, low bone density, or dysphagia in later stages. Patients should be closely followed by a nutritionist, a gastroenterologist as needed, and a physical therapist.¹⁶

Psychosocial support “should be developed and implemented across the lifespan in a manner that promotes thinking about the future and sets expectations that individuals will actively participate in their care and daily activities.”⁹ This includes psychological care, neuropsychological evaluations, and educational support.
 

Assisting Patients and Families Through the DMD Journey

DMD care is best delivered in a multidisciplinary setting, where physicians of relevant specialties, physical and occupational therapists, nutritionists, social workers, and genetic counselors collaborate. At Children’s Hospital of Philadelphia, DMD care is delivered through this collaborative model.

Unfortunately, Dr. Brandsema said, many patients don’t have this type of multidisciplinary resource available. “One specialist, such as a pulmonologist or neurologist, might have to be the sole source of care.” Or parents may have to ferry their child to multiple specialists in disparate locations, placing extra stress on an already-stressed family system.

“It’s helpful to connect the family with a comprehensive care center, if possible,” Dr. Brandsema advised. If that’s not available, then he suggests recommending educational opportunities and resources through national organizations such as the Muscular Dystrophy Association; Parent Project MD; NORD; Friends, Family and Duchenne; and Cure Duchenne. Families and caregivers, along with affected individuals, can get education and support from people who understand the day-to-day reality of living with this disease.

One of the major challenges that families face is navigating the high cost of treating DMD, especially the new medications, Dr. Brandsema said. “The authorization process can be intensive and long, and the family may need to take an active role, together with the provider team, in advocating for the patient to get access.”

courtesy Children's Hospital of Philadelphia

Managing DMD Across the Lifespan

Another dimension of DMD care is providing resources and help to young people with DMD as they transition into adulthood. “In the past, we had limited treatment and mortality typically took place in the early 20s, so there weren’t a lot of patients who were adults. But as medication options have expanded and management of cardiac and respiratory failure has improved, we see a more significant proportion of adults who require adult-appropriate clinics — or, at the very least, specialists who are conversant in care or can provide care across the lifespan,” Dr. Brandsema said.

The DMD Care Considerations Working Group provides recommendations regarding care across the lifespan,⁹ as does the Adult North Star Network, of Muscular Dystrophy UK.^17,18

Dr. Brandsema emphasized that, despite their disability, many adults with DMD “still engage with the community, and live life to its fullest.” It is to be hoped that, with ongoing research, earlier diagnosis, and improved treatment options, the future will look bright for people with DMD.

Dr. Brandsema has served as a consultant for Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech, Marathon, Momenta/Janssen, NS Pharma, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is on the medical advisory council member for Cure SMA and is a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Biohaven, Catabasis, CSL Behring, Cytokinetics, Dyne, Fibrogen, Genentech, Ionis, Lilly, ML Bio, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Ms. Kaschak has nothing to disclose.
 

References

1. Venugopal V and Pavlakis S. Duchenne Muscular Dystrophy. 2023 Jul 10. In: StatPearls [Internet]. Treasure Island, Florida: StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482346/.

2. Gao QQ and McNally EM. Compr Physiol. 2015 Jul 1;5(3):1223-39. doi: 10.1002/cphy.c140048.

3. Duan D et al. Nat Rev Dis Primers. 2021 Feb 18;7(1):13. doi: 10.1038/s41572-021-00248-3.

4. Aartsma-Rus A et al. J Pediatr. 2019 Jan:204:305-313.e14. doi: 10.1016/j.jpeds.2018.10.043.

5. Broomfield J et al. Neurology. 2021 Dec 7;97(23):e2304-e2314. doi: 10.1212/WNL.0000000000012910.

6. Mercuri E et al. Front Pediatr. 2023 Nov 10:11:1276144. doi: 10.1212/WNL.0000000000012910.

7. Birnkrant DJ et al. Lancet Neurol. 2018 Mar;17(3):251-267. doi: 10.1016/S1474-4422(18)30024-3.

8. Birnkrant DJ et al. Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5.

9. Birnkrant DJ et al. Lancet Neurol. 2018 May;17(5):445-455. doi: 10.1016/S1474-4422(18)30026-7.

10. Matthews E et al. Cochrane Database Syst Rev. 2016 May 5;2016(5):CD003725. doi: 10.1002/14651858.CD003725.pub4.

11. Bylo M et al. Ann Pharmacother. 2020 Aug;54(8):788-794. doi: 10.1177/1060028019900500.

12. Guglieri M et al. JAMA Neurol. 2022 Oct 1;79(10):1005-1014. doi: 10.1001/jamaneurol.2022.2480.

13. Dang UJ et al. Neurology. 2024 Mar 12;102(5):e208112. doi: 10.1212/WNL.0000000000208112.

14. Mercuri E et al. Lancet Neurol. 2024 Apr;23(4):393-403. doi: 10.1016/S1474-4422(24)00036-X.

15. Gushchina LV et al. Mol Ther Nucleic Acids. 2022 Nov 9:30:479-492. doi: 10.1016/j.omtn.2022.10.025.

16. Patterson G et al. Eur J Pharmacol. 2023 May 15:947:175675. doi: 10.1016/j.ejphar.2023.175675.

17. Quinlivan R et al. J Neuromuscul Dis. 2021;8(6):899-926. doi: 10.3233/JND-200609.

18. Narayan S et al. J Neuromuscul Dis. 2022;9(3):365-381. doi: 10.3233/JND-210707.