Gene Therapy

The U.S. Food and Drug Administration on Dec. 8 approved two gene-editing treatments for patients aged 12 years or older with severe sickle cell disease.

These “milestone treatments” mark the first cell-based gene therapies for this debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the United States.

The two therapies are exagamglogene autotemcel, or exa-cel (Casgevy; Vertex Pharmaceuticals and Crispr Therapeutics), and lovotibeglogene autotemcel, or lovo-cel (Lyfgenia; bluebird bio). 

“The approval of the first gene therapies for [sickle cell disease] represents a tremendous step forward for the [sickle cell] community, which has been historically overlooked and underfunded,” said Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, in a statement from the American Society of Hematology, following the approval.

“We are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease, by approving two cell-based gene therapies today,” Nicole Verdun, MD, of the FDA’s Center for Biologics Evaluation and Research, added in an agency press release.

Sickle cell disease involves a mutation in hemoglobin, a protein in red blood cells that provides oxygen to tissues. The mutation leads red blood cells to develop a crescent or sickle shape, which can restrict blood flow and cause severe pain and organ damage, known as vaso-occlusive events or crises. 

Treatment options prior to these approvals primarily included red blood transfusions and hydroxyurea alongside pain management. The only potential curative option has been allogeneic hematopoietic stem cell transplantation, but that comes with significant risks and most patients don’t have an appropriate donor.

Exa-cel

Exa-cel uses CRISPR gene-editing technology. Before the infusion, patients undergo myeloablative conditioning, which removes cells from the bone marrow. These cells are genetically modified to produce fetal hemoglobin. Patients then receive an infusion of the edited cells, which can help restore normal hemoglobin production. 

The FDA approval was based on data from the pivotal CLIMB SCD-121 trial. In an October advisory committee meeting, the FDA highlighted trial data demonstrating that 29 of 31 patients reached the trial’s primary endpoint: freedom from severe vaso-occlusive crises over a 12-month period. In addition, 28 of these patients remained free of vaso-occlusive crises for almost 2 years.

The committee noted that one of the 31 patients died about 9 months after receiving an exa-cel infusion. 

The cell-based gene therapy also increased both fetal and total hemoglobin, with total hemoglobin levels increasing to > 11 g/dL by month 3 and remaining at that level afterward. No patients experienced graft failure or rejection.

The most common side effects included low platelets and white blood cell counts, mouth sores, nausea, musculoskeletal pain, vomiting, and febrile neutropenia. 

Exa-cel could “provide a one-time functional cure” for patients with severe sickle cell disease, according to Franco Locatelli, MD, of Sapienza University of Rome, who presented initial findings last year.

While the current approval is for patients with infusion-dependent sickle cell disease, exa-cel is also being evaluated in patients with another blood disorder, beta-thalassemia.

Lovo-cel

Lovo-cel, a cell-based gene therapy, uses a different technology — a lentiviral vector, or gene delivery vehicle — that can also genetically modify a patient’s blood stem cells. 

Like exa-cel, lovo-cel is a one-time, single-dose infusion that contains the patient’s modified cells. Before the infusion, patients undergo myeloablative conditioning. The patient’s stem cells are then genetically modified to allow them to produce the most common form of hemoglobin, HbA 

This approval was based on data from a single-arm, 24-month study in patients aged 12-50 years who had sickle cell disease and a history of vaso-occlusive events. 

Overall, 88% of patients (28 of 32) achieved complete resolution of vaso-occlusive events 6-18 months after the infusion. 

The most common side effects included stomatitis; febrile neutropenia; and low platelet, white blood cell, and red blood cell counts.

The FDA noted that hematologic cancer has occurred in patients treated with lovo-cel, and the label includes a black-box warning about the risk. 

Dr. Brodsky noted, however, that “while these new gene therapies are potentially life-changing for individuals living with [sickle cell disease], they must be accessible to be effective.”

Access is a potential concern. Exa-cel and lovo-cel could cost about $2 million.
 

A version of this article appeared on Medscape.com.

The U.S. Food and Drug Administration on Dec. 8 approved two gene-editing treatments for patients aged 12 years or older with severe sickle cell disease.

These “milestone treatments” mark the first cell-based gene therapies for this debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the United States.

The two therapies are exagamglogene autotemcel, or exa-cel (Casgevy; Vertex Pharmaceuticals and Crispr Therapeutics), and lovotibeglogene autotemcel, or lovo-cel (Lyfgenia; bluebird bio). 

“The approval of the first gene therapies for [sickle cell disease] represents a tremendous step forward for the [sickle cell] community, which has been historically overlooked and underfunded,” said Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, in a statement from the American Society of Hematology, following the approval.

“We are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease, by approving two cell-based gene therapies today,” Nicole Verdun, MD, of the FDA’s Center for Biologics Evaluation and Research, added in an agency press release.

Sickle cell disease involves a mutation in hemoglobin, a protein in red blood cells that provides oxygen to tissues. The mutation leads red blood cells to develop a crescent or sickle shape, which can restrict blood flow and cause severe pain and organ damage, known as vaso-occlusive events or crises. 

Treatment options prior to these approvals primarily included red blood transfusions and hydroxyurea alongside pain management. The only potential curative option has been allogeneic hematopoietic stem cell transplantation, but that comes with significant risks and most patients don’t have an appropriate donor.

Exa-cel

Exa-cel uses CRISPR gene-editing technology. Before the infusion, patients undergo myeloablative conditioning, which removes cells from the bone marrow. These cells are genetically modified to produce fetal hemoglobin. Patients then receive an infusion of the edited cells, which can help restore normal hemoglobin production. 

The FDA approval was based on data from the pivotal CLIMB SCD-121 trial. In an October advisory committee meeting, the FDA highlighted trial data demonstrating that 29 of 31 patients reached the trial’s primary endpoint: freedom from severe vaso-occlusive crises over a 12-month period. In addition, 28 of these patients remained free of vaso-occlusive crises for almost 2 years.

The committee noted that one of the 31 patients died about 9 months after receiving an exa-cel infusion. 

The cell-based gene therapy also increased both fetal and total hemoglobin, with total hemoglobin levels increasing to > 11 g/dL by month 3 and remaining at that level afterward. No patients experienced graft failure or rejection.

The most common side effects included low platelets and white blood cell counts, mouth sores, nausea, musculoskeletal pain, vomiting, and febrile neutropenia. 

Exa-cel could “provide a one-time functional cure” for patients with severe sickle cell disease, according to Franco Locatelli, MD, of Sapienza University of Rome, who presented initial findings last year.

While the current approval is for patients with infusion-dependent sickle cell disease, exa-cel is also being evaluated in patients with another blood disorder, beta-thalassemia.

Lovo-cel

Lovo-cel, a cell-based gene therapy, uses a different technology — a lentiviral vector, or gene delivery vehicle — that can also genetically modify a patient’s blood stem cells. 

Like exa-cel, lovo-cel is a one-time, single-dose infusion that contains the patient’s modified cells. Before the infusion, patients undergo myeloablative conditioning. The patient’s stem cells are then genetically modified to allow them to produce the most common form of hemoglobin, HbA 

This approval was based on data from a single-arm, 24-month study in patients aged 12-50 years who had sickle cell disease and a history of vaso-occlusive events. 

Overall, 88% of patients (28 of 32) achieved complete resolution of vaso-occlusive events 6-18 months after the infusion. 

The most common side effects included stomatitis; febrile neutropenia; and low platelet, white blood cell, and red blood cell counts.

The FDA noted that hematologic cancer has occurred in patients treated with lovo-cel, and the label includes a black-box warning about the risk. 

Dr. Brodsky noted, however, that “while these new gene therapies are potentially life-changing for individuals living with [sickle cell disease], they must be accessible to be effective.”

Access is a potential concern. Exa-cel and lovo-cel could cost about $2 million.
 

A version of this article appeared on Medscape.com.

The U.S. Food and Drug Administration on Dec. 8 approved two gene-editing treatments for patients aged 12 years or older with severe sickle cell disease.

These “milestone treatments” mark the first cell-based gene therapies for this debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the United States.

The two therapies are exagamglogene autotemcel, or exa-cel (Casgevy; Vertex Pharmaceuticals and Crispr Therapeutics), and lovotibeglogene autotemcel, or lovo-cel (Lyfgenia; bluebird bio). 

“The approval of the first gene therapies for [sickle cell disease] represents a tremendous step forward for the [sickle cell] community, which has been historically overlooked and underfunded,” said Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, in a statement from the American Society of Hematology, following the approval.

“We are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease, by approving two cell-based gene therapies today,” Nicole Verdun, MD, of the FDA’s Center for Biologics Evaluation and Research, added in an agency press release.

Sickle cell disease involves a mutation in hemoglobin, a protein in red blood cells that provides oxygen to tissues. The mutation leads red blood cells to develop a crescent or sickle shape, which can restrict blood flow and cause severe pain and organ damage, known as vaso-occlusive events or crises. 

Treatment options prior to these approvals primarily included red blood transfusions and hydroxyurea alongside pain management. The only potential curative option has been allogeneic hematopoietic stem cell transplantation, but that comes with significant risks and most patients don’t have an appropriate donor.

Exa-cel

Exa-cel uses CRISPR gene-editing technology. Before the infusion, patients undergo myeloablative conditioning, which removes cells from the bone marrow. These cells are genetically modified to produce fetal hemoglobin. Patients then receive an infusion of the edited cells, which can help restore normal hemoglobin production. 

The FDA approval was based on data from the pivotal CLIMB SCD-121 trial. In an October advisory committee meeting, the FDA highlighted trial data demonstrating that 29 of 31 patients reached the trial’s primary endpoint: freedom from severe vaso-occlusive crises over a 12-month period. In addition, 28 of these patients remained free of vaso-occlusive crises for almost 2 years.

The committee noted that one of the 31 patients died about 9 months after receiving an exa-cel infusion. 

The cell-based gene therapy also increased both fetal and total hemoglobin, with total hemoglobin levels increasing to > 11 g/dL by month 3 and remaining at that level afterward. No patients experienced graft failure or rejection.

The most common side effects included low platelets and white blood cell counts, mouth sores, nausea, musculoskeletal pain, vomiting, and febrile neutropenia. 

Exa-cel could “provide a one-time functional cure” for patients with severe sickle cell disease, according to Franco Locatelli, MD, of Sapienza University of Rome, who presented initial findings last year.

While the current approval is for patients with infusion-dependent sickle cell disease, exa-cel is also being evaluated in patients with another blood disorder, beta-thalassemia.

Lovo-cel

Lovo-cel, a cell-based gene therapy, uses a different technology — a lentiviral vector, or gene delivery vehicle — that can also genetically modify a patient’s blood stem cells. 

Like exa-cel, lovo-cel is a one-time, single-dose infusion that contains the patient’s modified cells. Before the infusion, patients undergo myeloablative conditioning. The patient’s stem cells are then genetically modified to allow them to produce the most common form of hemoglobin, HbA 

This approval was based on data from a single-arm, 24-month study in patients aged 12-50 years who had sickle cell disease and a history of vaso-occlusive events. 

Overall, 88% of patients (28 of 32) achieved complete resolution of vaso-occlusive events 6-18 months after the infusion. 

The most common side effects included stomatitis; febrile neutropenia; and low platelet, white blood cell, and red blood cell counts.

The FDA noted that hematologic cancer has occurred in patients treated with lovo-cel, and the label includes a black-box warning about the risk. 

Dr. Brodsky noted, however, that “while these new gene therapies are potentially life-changing for individuals living with [sickle cell disease], they must be accessible to be effective.”

Access is a potential concern. Exa-cel and lovo-cel could cost about $2 million.
 

A version of this article appeared on Medscape.com.

PHOENIX – New therapies are on the horizon for genetic neuromuscular diseases, and this will raise both hopes for patients and challenges for neurologists. Following successful genetic treatments for ALS, hereditary amyloidosis, and spinal muscular atrophy, therapies for conditions like Charcot-Marie-Tooth (CMT) neuropathy are set to change neurology practice, according to Nicolas Madigan, MBBCh, PhD, who spoke at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

“I think we will very soon be in a position to tell these patients that they might actually have a better treatment outcome with a genetic treatment than if they had a sporadic or inflammatory disorder,” said Dr. Madigan, who is an assistant professor of clinical research at Mayo Clinic, Rochester, N.Y.

To illustrate how genetic therapies are changing neurology practice, Dr. Madigan focused his talk on CMT neuropathy, which is the most common hereditary neuropathy and, as a result, has become a prime focus of gene therapy development. “In a city of about a million people, there will be 100-800 patients with one of these disorders,” said Dr. Madigan.
 

Case report illustrates a change in approach

There are more than 100 known genes that can contribute to CMT, but about 90% of patients harbor alterations in one of four genes: PMP22, GJB1, MFN2, and MPZ.

The trick is determining which patients are candidates for genetic testing, according to Dr. Madigan. He presented a case report of a 39-year-old woman who had experienced sensory symptoms for years, with a sudden exacerbation along with allodynia following COVID-19 vaccination. Her cerebrospinal fluid protein was high and outside electromyography indicated mild demyelinating neuropathy, consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). After her insurance denied IVIG treatment, she received solumedrol, but her symptoms worsened and she was referred to Dr. Madigan.

After 6 months of methotrexate treatment, her sensory symptoms had not improved, and she was referred for genetic testing, which revealed a truncating mutation of the MPZ gene. “What I learned from this case really was that, in a young patient with conduction slowing, you might be considering CIDP. It might actually be better to do genetic testing first as opposed to starting inflammatory neuropathy type treatments with respect to cost – the genetic tests costs $300 versus tens of thousands of dollars for IVIG – and for [patient] welfare as well,” said Dr. Madigan.

Specifically, when clinical signs point to inherited neuropathy and there is conduction slowing, “the biggest bang for your buck might to be to go straight to PMP22 deletion or duplication testing and see if you can get a diagnosis. If that is negative or the clinical features are not as you might suspect, then, if you have other supportive features such as a very young age or there’s predominance of motor or sensory symptoms, you could test more broadly with a panel. If both of these are negative, then you could consider exome sequencing if the clinical phenotype really is consistent with that,” said Dr. Madigan.
 

The treatment landscape

With a diagnosis in hand, it’s possible to turn to treatment options, and the CMT landscape is promising. Dr. Madigan’s group recently reviewed 286 CMT clinical trials published between 1999 and 2022, 86% of which were interventions. Most were procedures based on carpal or cubital tunnel release, extracorporeal shockwave therapy, or nerve hydrodissection.

The small-molecule drug combination PXT3003 (Pharnext) – comprising baclofen, naltrexone, and sorbitol – downregulated PMP22 mRNA expression and led to improved myelination in animal models. It is currently being studied in a phase 2 clinical trial. Other approaches include supplements, stem cells, anesthetics, and various devices.

Genetic therapy is in the preclinical stage, including gene replacement using adeno-associated virus (AAV) vectors, gene silencing using antisense oligonucleotides or RNA interference, and gene editing using CRISPR-Cas 9 approaches.

Gene replacement strategies include delivering a normal copy of the gene, a supportive gene, or a gene that delays or reduces axon degeneration. Gene silencing targets PMP22, while CRISPR-Cas9 gene editing aims for PMP22 or neurofilament light polypeptide (NEFL) gene knockout.

The most clinically advanced AAV program delivers neurotrophin-3 via the viral vector to the target muscle, which has been demonstrated to improve symptoms in a mouse model using a muscle-specific promoter. A phase 1/2a trial will test the approach in three patients.

In the antisense space, chemical advances have improved the profile of the RNA, including modifications that influence inflammatory properties, stability, and targeting of specific tissues through conjugation to specific lipids, proteins, or antibodies. A 2018 study sponsored by DTxPharma showed that the formulation could improve outcomes and histologic myelination in a mouse model. In the wake of Novartis’s acquisition of the technology, Dr. Madigan anticipates that clinical trials will likely begin in 2024.

Finally, CRISPR-Cas9 targeting of a promoter region that leads to PMP22 transcription improved remyelination and electrophysiological parameters after injection into the sciatic nerve of mice.
 

A need for genetic counseling

Advances in testing and therapies represent exciting developments, but they also create a need for genetic counselors, according to Dr. Madigan. His clinic has two certified genetic counselors who meet with patients and discuss testing options, including risks and benefits to family members. The counselors also provide psychological support and assist in shared decision-making. They also handle testing paperwork, which eases the burden on physicians.

If the tests are negative, the genetic counselor informs the patient and lets them know of any additional testing required. In case of a positive test, the genetic counselor informs the patient, but the physician also makes contact to discuss clinical implications of the result. “I think it’s working extremely well, and I would encourage all practices to begin to explore those options moving forward,” said Dr. Madigan.

During the Q&A session after the talk, an audience member noted that genetic counselors are not covered by insurance, which places a financial burden on providers to hire them. He noted that his facility has a large clinical genomics department that was able to fund the two counselors, though they are both part-time. “It wasn’t easy. I think there was at least a year of trying to work out how to do it in terms of finding positions and negotiating, but I think once it’s accomplished it’s incredibly cost effective in terms of getting patients what they need from that perspective, and helping with the testing,” said Dr. Madigan.

Dr. Madigan reported no relevant financial disclosures.

PHOENIX – New therapies are on the horizon for genetic neuromuscular diseases, and this will raise both hopes for patients and challenges for neurologists. Following successful genetic treatments for ALS, hereditary amyloidosis, and spinal muscular atrophy, therapies for conditions like Charcot-Marie-Tooth (CMT) neuropathy are set to change neurology practice, according to Nicolas Madigan, MBBCh, PhD, who spoke at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

“I think we will very soon be in a position to tell these patients that they might actually have a better treatment outcome with a genetic treatment than if they had a sporadic or inflammatory disorder,” said Dr. Madigan, who is an assistant professor of clinical research at Mayo Clinic, Rochester, N.Y.

To illustrate how genetic therapies are changing neurology practice, Dr. Madigan focused his talk on CMT neuropathy, which is the most common hereditary neuropathy and, as a result, has become a prime focus of gene therapy development. “In a city of about a million people, there will be 100-800 patients with one of these disorders,” said Dr. Madigan.
 

Case report illustrates a change in approach

There are more than 100 known genes that can contribute to CMT, but about 90% of patients harbor alterations in one of four genes: PMP22, GJB1, MFN2, and MPZ.

The trick is determining which patients are candidates for genetic testing, according to Dr. Madigan. He presented a case report of a 39-year-old woman who had experienced sensory symptoms for years, with a sudden exacerbation along with allodynia following COVID-19 vaccination. Her cerebrospinal fluid protein was high and outside electromyography indicated mild demyelinating neuropathy, consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). After her insurance denied IVIG treatment, she received solumedrol, but her symptoms worsened and she was referred to Dr. Madigan.

After 6 months of methotrexate treatment, her sensory symptoms had not improved, and she was referred for genetic testing, which revealed a truncating mutation of the MPZ gene. “What I learned from this case really was that, in a young patient with conduction slowing, you might be considering CIDP. It might actually be better to do genetic testing first as opposed to starting inflammatory neuropathy type treatments with respect to cost – the genetic tests costs $300 versus tens of thousands of dollars for IVIG – and for [patient] welfare as well,” said Dr. Madigan.

Specifically, when clinical signs point to inherited neuropathy and there is conduction slowing, “the biggest bang for your buck might to be to go straight to PMP22 deletion or duplication testing and see if you can get a diagnosis. If that is negative or the clinical features are not as you might suspect, then, if you have other supportive features such as a very young age or there’s predominance of motor or sensory symptoms, you could test more broadly with a panel. If both of these are negative, then you could consider exome sequencing if the clinical phenotype really is consistent with that,” said Dr. Madigan.
 

The treatment landscape

With a diagnosis in hand, it’s possible to turn to treatment options, and the CMT landscape is promising. Dr. Madigan’s group recently reviewed 286 CMT clinical trials published between 1999 and 2022, 86% of which were interventions. Most were procedures based on carpal or cubital tunnel release, extracorporeal shockwave therapy, or nerve hydrodissection.

The small-molecule drug combination PXT3003 (Pharnext) – comprising baclofen, naltrexone, and sorbitol – downregulated PMP22 mRNA expression and led to improved myelination in animal models. It is currently being studied in a phase 2 clinical trial. Other approaches include supplements, stem cells, anesthetics, and various devices.

Genetic therapy is in the preclinical stage, including gene replacement using adeno-associated virus (AAV) vectors, gene silencing using antisense oligonucleotides or RNA interference, and gene editing using CRISPR-Cas 9 approaches.

Gene replacement strategies include delivering a normal copy of the gene, a supportive gene, or a gene that delays or reduces axon degeneration. Gene silencing targets PMP22, while CRISPR-Cas9 gene editing aims for PMP22 or neurofilament light polypeptide (NEFL) gene knockout.

The most clinically advanced AAV program delivers neurotrophin-3 via the viral vector to the target muscle, which has been demonstrated to improve symptoms in a mouse model using a muscle-specific promoter. A phase 1/2a trial will test the approach in three patients.

In the antisense space, chemical advances have improved the profile of the RNA, including modifications that influence inflammatory properties, stability, and targeting of specific tissues through conjugation to specific lipids, proteins, or antibodies. A 2018 study sponsored by DTxPharma showed that the formulation could improve outcomes and histologic myelination in a mouse model. In the wake of Novartis’s acquisition of the technology, Dr. Madigan anticipates that clinical trials will likely begin in 2024.

Finally, CRISPR-Cas9 targeting of a promoter region that leads to PMP22 transcription improved remyelination and electrophysiological parameters after injection into the sciatic nerve of mice.
 

A need for genetic counseling

Advances in testing and therapies represent exciting developments, but they also create a need for genetic counselors, according to Dr. Madigan. His clinic has two certified genetic counselors who meet with patients and discuss testing options, including risks and benefits to family members. The counselors also provide psychological support and assist in shared decision-making. They also handle testing paperwork, which eases the burden on physicians.

If the tests are negative, the genetic counselor informs the patient and lets them know of any additional testing required. In case of a positive test, the genetic counselor informs the patient, but the physician also makes contact to discuss clinical implications of the result. “I think it’s working extremely well, and I would encourage all practices to begin to explore those options moving forward,” said Dr. Madigan.

During the Q&A session after the talk, an audience member noted that genetic counselors are not covered by insurance, which places a financial burden on providers to hire them. He noted that his facility has a large clinical genomics department that was able to fund the two counselors, though they are both part-time. “It wasn’t easy. I think there was at least a year of trying to work out how to do it in terms of finding positions and negotiating, but I think once it’s accomplished it’s incredibly cost effective in terms of getting patients what they need from that perspective, and helping with the testing,” said Dr. Madigan.

Dr. Madigan reported no relevant financial disclosures.

PHOENIX – New therapies are on the horizon for genetic neuromuscular diseases, and this will raise both hopes for patients and challenges for neurologists. Following successful genetic treatments for ALS, hereditary amyloidosis, and spinal muscular atrophy, therapies for conditions like Charcot-Marie-Tooth (CMT) neuropathy are set to change neurology practice, according to Nicolas Madigan, MBBCh, PhD, who spoke at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

“I think we will very soon be in a position to tell these patients that they might actually have a better treatment outcome with a genetic treatment than if they had a sporadic or inflammatory disorder,” said Dr. Madigan, who is an assistant professor of clinical research at Mayo Clinic, Rochester, N.Y.

To illustrate how genetic therapies are changing neurology practice, Dr. Madigan focused his talk on CMT neuropathy, which is the most common hereditary neuropathy and, as a result, has become a prime focus of gene therapy development. “In a city of about a million people, there will be 100-800 patients with one of these disorders,” said Dr. Madigan.
 

Case report illustrates a change in approach

There are more than 100 known genes that can contribute to CMT, but about 90% of patients harbor alterations in one of four genes: PMP22, GJB1, MFN2, and MPZ.

The trick is determining which patients are candidates for genetic testing, according to Dr. Madigan. He presented a case report of a 39-year-old woman who had experienced sensory symptoms for years, with a sudden exacerbation along with allodynia following COVID-19 vaccination. Her cerebrospinal fluid protein was high and outside electromyography indicated mild demyelinating neuropathy, consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). After her insurance denied IVIG treatment, she received solumedrol, but her symptoms worsened and she was referred to Dr. Madigan.

After 6 months of methotrexate treatment, her sensory symptoms had not improved, and she was referred for genetic testing, which revealed a truncating mutation of the MPZ gene. “What I learned from this case really was that, in a young patient with conduction slowing, you might be considering CIDP. It might actually be better to do genetic testing first as opposed to starting inflammatory neuropathy type treatments with respect to cost – the genetic tests costs $300 versus tens of thousands of dollars for IVIG – and for [patient] welfare as well,” said Dr. Madigan.

Specifically, when clinical signs point to inherited neuropathy and there is conduction slowing, “the biggest bang for your buck might to be to go straight to PMP22 deletion or duplication testing and see if you can get a diagnosis. If that is negative or the clinical features are not as you might suspect, then, if you have other supportive features such as a very young age or there’s predominance of motor or sensory symptoms, you could test more broadly with a panel. If both of these are negative, then you could consider exome sequencing if the clinical phenotype really is consistent with that,” said Dr. Madigan.
 

The treatment landscape

With a diagnosis in hand, it’s possible to turn to treatment options, and the CMT landscape is promising. Dr. Madigan’s group recently reviewed 286 CMT clinical trials published between 1999 and 2022, 86% of which were interventions. Most were procedures based on carpal or cubital tunnel release, extracorporeal shockwave therapy, or nerve hydrodissection.

The small-molecule drug combination PXT3003 (Pharnext) – comprising baclofen, naltrexone, and sorbitol – downregulated PMP22 mRNA expression and led to improved myelination in animal models. It is currently being studied in a phase 2 clinical trial. Other approaches include supplements, stem cells, anesthetics, and various devices.

Genetic therapy is in the preclinical stage, including gene replacement using adeno-associated virus (AAV) vectors, gene silencing using antisense oligonucleotides or RNA interference, and gene editing using CRISPR-Cas 9 approaches.

Gene replacement strategies include delivering a normal copy of the gene, a supportive gene, or a gene that delays or reduces axon degeneration. Gene silencing targets PMP22, while CRISPR-Cas9 gene editing aims for PMP22 or neurofilament light polypeptide (NEFL) gene knockout.

The most clinically advanced AAV program delivers neurotrophin-3 via the viral vector to the target muscle, which has been demonstrated to improve symptoms in a mouse model using a muscle-specific promoter. A phase 1/2a trial will test the approach in three patients.

In the antisense space, chemical advances have improved the profile of the RNA, including modifications that influence inflammatory properties, stability, and targeting of specific tissues through conjugation to specific lipids, proteins, or antibodies. A 2018 study sponsored by DTxPharma showed that the formulation could improve outcomes and histologic myelination in a mouse model. In the wake of Novartis’s acquisition of the technology, Dr. Madigan anticipates that clinical trials will likely begin in 2024.

Finally, CRISPR-Cas9 targeting of a promoter region that leads to PMP22 transcription improved remyelination and electrophysiological parameters after injection into the sciatic nerve of mice.
 

A need for genetic counseling

Advances in testing and therapies represent exciting developments, but they also create a need for genetic counselors, according to Dr. Madigan. His clinic has two certified genetic counselors who meet with patients and discuss testing options, including risks and benefits to family members. The counselors also provide psychological support and assist in shared decision-making. They also handle testing paperwork, which eases the burden on physicians.

If the tests are negative, the genetic counselor informs the patient and lets them know of any additional testing required. In case of a positive test, the genetic counselor informs the patient, but the physician also makes contact to discuss clinical implications of the result. “I think it’s working extremely well, and I would encourage all practices to begin to explore those options moving forward,” said Dr. Madigan.

During the Q&A session after the talk, an audience member noted that genetic counselors are not covered by insurance, which places a financial burden on providers to hire them. He noted that his facility has a large clinical genomics department that was able to fund the two counselors, though they are both part-time. “It wasn’t easy. I think there was at least a year of trying to work out how to do it in terms of finding positions and negotiating, but I think once it’s accomplished it’s incredibly cost effective in terms of getting patients what they need from that perspective, and helping with the testing,” said Dr. Madigan.

Dr. Madigan reported no relevant financial disclosures.

In 2017, Sanofi Genzyme launched a phase 2 clinical trial of a drug designed to target a specific genetic mutation in some patients with Parkinson’s disease. Researchers hoped the drug would slow or even stop disease progression.

Like many before it, the trial yielded disappointing results and the company shut it down in 2021. It was the latest in a string of unsuccessful clinical trials testing disease-modifying Parkinson’s disease drugs.

Although it failed, the Sanofi Genzyme study was different: It was the first to enroll patients with Parkinson’s disease who had a specific genotype and marked the earliest days of precision medicine and gene-specific drug development for the disease.

Once thought to play only a small role in a small number of patients with Parkinson’s disease, a growing body of work has prompted researchers and drug developers to take a longer look at how genetics influence Parkinson’s disease risk and progression.

“We’re about to enter this era of precision medicine for Parkinson’s disease, which makes genetic testing important,” said James Beck, PhD, senior vice president and chief scientific officer for the Parkinson’s Foundation.

“A number of companies have clinical trials or are in preparation for clinical trials to test some specific therapies that would depend upon people having a specific genetic mutation,” he said.

Today, at least four clinical trials of drugs that target specific Parkinson’s disease-related gene variants on LRRK2 and GBA are under way, and more are in the pipeline. Whether these drugs will be effective at modifying the course of the disease remains to be seen. First, the trials must enroll enough patients. And therein lies the challenge: Genetic testing isn’t part of routine Parkinson’s disease care and isn’t covered by most insurance policies. Most patients don’t know their genotype.

It’s a significant roadblock to the future of a precision medicine approach that is based on a patient’s individual genotype, which some experts argue offers the best shot at slowing disease progression.

“To enroll in clinical trials for precision drugs people with Parkinson’s disease have to be aware of their genetic status,” said Roy N. Alcalay, MD, chief of the movement disorders division at Tel Aviv Medical Center in Israel and part-time associate professor at Columbia University in New York. “How can a person with Parkinson’s and a LRRK2 mutation join a precision medicine trial for LRRK2 if she does not know she is a LRRK2 carrier?”
 

Free genetic testing

Previous studies have shown that some genetic variants increase the risk for Parkinson’s disease after exposure to environmental factors such as pesticides. Research has also shown that a patient’s genotype can predict survival time and that certain medications may prove more effective at slowing disease progression in patients with specific genotypes. All of this points to a significant role for genetics in a disorder that is rapidly increasing.

This makes expanding patient access to genetic testing even more important, Dr. Alcalay said, noting that it’s equally important that patients are informed of their genotype, something that doesn’t usually happen in blinded clinical trials.

To that end, Dr. Alcalay hopes a national genetics study he is leading will address access and need-to-know issues. PD GENEration, a project launched in 2019 by the Parkinson’s Foundation, offers patients free genetic testing for seven clinically relevant Parkinson’s disease-related genes.

Testing is done at home or in a nearby clinic and the results are shared with patients during a free genetic counseling session and with site investigators. Patient samples are stored in a genetic data bank that is open to researchers around the world.

“We surveyed clinical trialists in the Parkinson’s disease field prior to initiation of PD GENEration and estimated that over 90% of people with Parkinson’s disease prior to the effort were not aware of their genetic status,” Dr. Alcalay said.

“I think precision medicine in Parkinson’s disease will not happen without PD GENEration or similar efforts.”
 

‘Overwhelming’ patient interest

Participants in the study are screened for variants in seven genes known to be involved in Parkinson’s disease risk: GBA, LRRK2, PRKN, PINK1, SNCA, PARK7, and VPS35.

In less than 3 years, the study has already produced what is thought to be the largest genetic data bank of sequenced sets of Parkinson’s disease-risk genes made accessible to patients. Since the end of 2020, the first year of patient enrollment, the number of participants has increased from 676 to 10,515 and the number of participating clinical sites rose from 12 to 101.

The foundation has spent nearly $20 million on the project so far and plans to spend another $10 million to reach a goal of 15,000 patients. The study, which is funded by private donors, is so successful that the foundation has had to scale back enrollment.

“When we were at a peak, we had over 700 participants enrolling each month,” Dr. Beck said. Beginning in April, the program capped new sign-ups to 200 patients per month and created a waiting list for future enrollment. The waiting list is hundreds of patients long.

“The participants’ response to enroll in PD GENEration demonstrates there is an overwhelming interest by people with Parkinson’s disease to learn more about their genetic risk factors,” Dr. Alcalay said.
 

A research driver

Nearly 60% of participants enrolled so far are male and close to 80% are White. The average age is 69 years and 44% were diagnosed in the past 5 years. Close to 75% had never participated in a clinical trial.

Nearly 13% have tested positive for mutations on at least one of the seven target genes. Previous studies had suggested genetics were involved in only about 10% of cases.

The majority of those with positive results had early-onset Parkinson’s disease, high-risk ancestry, or a first-degree relative with the disease. However, 9% of people who tested positive weren’t in any of those categories.

Genetic information collected by the project is shared with the Global Parkinson’s Genetics Program (GP2), a resource program of the Aligning Science Across Parkinson’s initiative that is focused on the disease’s genetic architecture. Researchers around the world have access to GP2 data to study known gene variants and identify new ones.

PD GENEration participants can choose to be notified if they are carriers of gene variants discovered in the future.

“All DNA samples shared by participants are undergoing research-grade testing,” Dr. Beck said. “Not only do we want to be able to inform people with Parkinson’s disease about their genetic status, but we also want to be able to use this precious resource to further drive research into the genetics of Parkinson’s disease.”
 

Early success

Patient recruitment has long been one of the biggest challenges to any clinical trial’s success. Research suggests that 90% of all clinical trials fail to reach recruitment milestones in their allotted time frame and two-thirds of multicenter trials fold because too few patients sign up. Data from the Parkinson’s Foundation show that only about 1% of all patients with Parkinson’s disease participate in clinical trials.

Increasing those numbers is the primary goal of PD GENEration, Dr. Beck said. And there’s evidence it’s already paying off.

Earlier this year, one of the program’s participating clinical sites, Intermountain Health, in Salt Lake City, Utah, joined a phase 2 clinical trial of an experimental drug that targets a mutation on the GBA1 gene.

“One of the reasons we were able to participate was when we got the call about joining, we were able to say that we had patients with that specific gene mutation, and we could only say that because the patients had been genotyped through PD GENEration,” said Kathleen E. McKee, MD, director of movement disorders, associate medical director of neurosciences research, and PD GENEration principal investigator at Intermountain Health.

Since 2021, Dr. McKee has enrolled hundreds of patients in the foundation’s gene study and hopes to enroll even more. Few patients turn down the opportunity to participate, she added. Knowing their genotype has proven empowering for her patients, most of whom could not afford genetic testing on their own.

“Previously I would tell patients this is not going to change your immediate management,” Dr. McKee said. “Now I tell my patients that these trials are out there, it may actually change how I treat you and what I recommend.”
 

A version of this article appeared on Medscape.com.

In 2017, Sanofi Genzyme launched a phase 2 clinical trial of a drug designed to target a specific genetic mutation in some patients with Parkinson’s disease. Researchers hoped the drug would slow or even stop disease progression.

Like many before it, the trial yielded disappointing results and the company shut it down in 2021. It was the latest in a string of unsuccessful clinical trials testing disease-modifying Parkinson’s disease drugs.

Although it failed, the Sanofi Genzyme study was different: It was the first to enroll patients with Parkinson’s disease who had a specific genotype and marked the earliest days of precision medicine and gene-specific drug development for the disease.

Once thought to play only a small role in a small number of patients with Parkinson’s disease, a growing body of work has prompted researchers and drug developers to take a longer look at how genetics influence Parkinson’s disease risk and progression.

“We’re about to enter this era of precision medicine for Parkinson’s disease, which makes genetic testing important,” said James Beck, PhD, senior vice president and chief scientific officer for the Parkinson’s Foundation.

“A number of companies have clinical trials or are in preparation for clinical trials to test some specific therapies that would depend upon people having a specific genetic mutation,” he said.

Today, at least four clinical trials of drugs that target specific Parkinson’s disease-related gene variants on LRRK2 and GBA are under way, and more are in the pipeline. Whether these drugs will be effective at modifying the course of the disease remains to be seen. First, the trials must enroll enough patients. And therein lies the challenge: Genetic testing isn’t part of routine Parkinson’s disease care and isn’t covered by most insurance policies. Most patients don’t know their genotype.

It’s a significant roadblock to the future of a precision medicine approach that is based on a patient’s individual genotype, which some experts argue offers the best shot at slowing disease progression.

“To enroll in clinical trials for precision drugs people with Parkinson’s disease have to be aware of their genetic status,” said Roy N. Alcalay, MD, chief of the movement disorders division at Tel Aviv Medical Center in Israel and part-time associate professor at Columbia University in New York. “How can a person with Parkinson’s and a LRRK2 mutation join a precision medicine trial for LRRK2 if she does not know she is a LRRK2 carrier?”
 

Free genetic testing

Previous studies have shown that some genetic variants increase the risk for Parkinson’s disease after exposure to environmental factors such as pesticides. Research has also shown that a patient’s genotype can predict survival time and that certain medications may prove more effective at slowing disease progression in patients with specific genotypes. All of this points to a significant role for genetics in a disorder that is rapidly increasing.

This makes expanding patient access to genetic testing even more important, Dr. Alcalay said, noting that it’s equally important that patients are informed of their genotype, something that doesn’t usually happen in blinded clinical trials.

To that end, Dr. Alcalay hopes a national genetics study he is leading will address access and need-to-know issues. PD GENEration, a project launched in 2019 by the Parkinson’s Foundation, offers patients free genetic testing for seven clinically relevant Parkinson’s disease-related genes.

Testing is done at home or in a nearby clinic and the results are shared with patients during a free genetic counseling session and with site investigators. Patient samples are stored in a genetic data bank that is open to researchers around the world.

“We surveyed clinical trialists in the Parkinson’s disease field prior to initiation of PD GENEration and estimated that over 90% of people with Parkinson’s disease prior to the effort were not aware of their genetic status,” Dr. Alcalay said.

“I think precision medicine in Parkinson’s disease will not happen without PD GENEration or similar efforts.”
 

‘Overwhelming’ patient interest

Participants in the study are screened for variants in seven genes known to be involved in Parkinson’s disease risk: GBA, LRRK2, PRKN, PINK1, SNCA, PARK7, and VPS35.

In less than 3 years, the study has already produced what is thought to be the largest genetic data bank of sequenced sets of Parkinson’s disease-risk genes made accessible to patients. Since the end of 2020, the first year of patient enrollment, the number of participants has increased from 676 to 10,515 and the number of participating clinical sites rose from 12 to 101.

The foundation has spent nearly $20 million on the project so far and plans to spend another $10 million to reach a goal of 15,000 patients. The study, which is funded by private donors, is so successful that the foundation has had to scale back enrollment.

“When we were at a peak, we had over 700 participants enrolling each month,” Dr. Beck said. Beginning in April, the program capped new sign-ups to 200 patients per month and created a waiting list for future enrollment. The waiting list is hundreds of patients long.

“The participants’ response to enroll in PD GENEration demonstrates there is an overwhelming interest by people with Parkinson’s disease to learn more about their genetic risk factors,” Dr. Alcalay said.
 

A research driver

Nearly 60% of participants enrolled so far are male and close to 80% are White. The average age is 69 years and 44% were diagnosed in the past 5 years. Close to 75% had never participated in a clinical trial.

Nearly 13% have tested positive for mutations on at least one of the seven target genes. Previous studies had suggested genetics were involved in only about 10% of cases.

The majority of those with positive results had early-onset Parkinson’s disease, high-risk ancestry, or a first-degree relative with the disease. However, 9% of people who tested positive weren’t in any of those categories.

Genetic information collected by the project is shared with the Global Parkinson’s Genetics Program (GP2), a resource program of the Aligning Science Across Parkinson’s initiative that is focused on the disease’s genetic architecture. Researchers around the world have access to GP2 data to study known gene variants and identify new ones.

PD GENEration participants can choose to be notified if they are carriers of gene variants discovered in the future.

“All DNA samples shared by participants are undergoing research-grade testing,” Dr. Beck said. “Not only do we want to be able to inform people with Parkinson’s disease about their genetic status, but we also want to be able to use this precious resource to further drive research into the genetics of Parkinson’s disease.”
 

Early success

Patient recruitment has long been one of the biggest challenges to any clinical trial’s success. Research suggests that 90% of all clinical trials fail to reach recruitment milestones in their allotted time frame and two-thirds of multicenter trials fold because too few patients sign up. Data from the Parkinson’s Foundation show that only about 1% of all patients with Parkinson’s disease participate in clinical trials.

Increasing those numbers is the primary goal of PD GENEration, Dr. Beck said. And there’s evidence it’s already paying off.

Earlier this year, one of the program’s participating clinical sites, Intermountain Health, in Salt Lake City, Utah, joined a phase 2 clinical trial of an experimental drug that targets a mutation on the GBA1 gene.

“One of the reasons we were able to participate was when we got the call about joining, we were able to say that we had patients with that specific gene mutation, and we could only say that because the patients had been genotyped through PD GENEration,” said Kathleen E. McKee, MD, director of movement disorders, associate medical director of neurosciences research, and PD GENEration principal investigator at Intermountain Health.

Since 2021, Dr. McKee has enrolled hundreds of patients in the foundation’s gene study and hopes to enroll even more. Few patients turn down the opportunity to participate, she added. Knowing their genotype has proven empowering for her patients, most of whom could not afford genetic testing on their own.

“Previously I would tell patients this is not going to change your immediate management,” Dr. McKee said. “Now I tell my patients that these trials are out there, it may actually change how I treat you and what I recommend.”
 

A version of this article appeared on Medscape.com.

In 2017, Sanofi Genzyme launched a phase 2 clinical trial of a drug designed to target a specific genetic mutation in some patients with Parkinson’s disease. Researchers hoped the drug would slow or even stop disease progression.

Like many before it, the trial yielded disappointing results and the company shut it down in 2021. It was the latest in a string of unsuccessful clinical trials testing disease-modifying Parkinson’s disease drugs.

Although it failed, the Sanofi Genzyme study was different: It was the first to enroll patients with Parkinson’s disease who had a specific genotype and marked the earliest days of precision medicine and gene-specific drug development for the disease.

Once thought to play only a small role in a small number of patients with Parkinson’s disease, a growing body of work has prompted researchers and drug developers to take a longer look at how genetics influence Parkinson’s disease risk and progression.

“We’re about to enter this era of precision medicine for Parkinson’s disease, which makes genetic testing important,” said James Beck, PhD, senior vice president and chief scientific officer for the Parkinson’s Foundation.

“A number of companies have clinical trials or are in preparation for clinical trials to test some specific therapies that would depend upon people having a specific genetic mutation,” he said.

Today, at least four clinical trials of drugs that target specific Parkinson’s disease-related gene variants on LRRK2 and GBA are under way, and more are in the pipeline. Whether these drugs will be effective at modifying the course of the disease remains to be seen. First, the trials must enroll enough patients. And therein lies the challenge: Genetic testing isn’t part of routine Parkinson’s disease care and isn’t covered by most insurance policies. Most patients don’t know their genotype.

It’s a significant roadblock to the future of a precision medicine approach that is based on a patient’s individual genotype, which some experts argue offers the best shot at slowing disease progression.

“To enroll in clinical trials for precision drugs people with Parkinson’s disease have to be aware of their genetic status,” said Roy N. Alcalay, MD, chief of the movement disorders division at Tel Aviv Medical Center in Israel and part-time associate professor at Columbia University in New York. “How can a person with Parkinson’s and a LRRK2 mutation join a precision medicine trial for LRRK2 if she does not know she is a LRRK2 carrier?”
 

Free genetic testing

Previous studies have shown that some genetic variants increase the risk for Parkinson’s disease after exposure to environmental factors such as pesticides. Research has also shown that a patient’s genotype can predict survival time and that certain medications may prove more effective at slowing disease progression in patients with specific genotypes. All of this points to a significant role for genetics in a disorder that is rapidly increasing.

This makes expanding patient access to genetic testing even more important, Dr. Alcalay said, noting that it’s equally important that patients are informed of their genotype, something that doesn’t usually happen in blinded clinical trials.

To that end, Dr. Alcalay hopes a national genetics study he is leading will address access and need-to-know issues. PD GENEration, a project launched in 2019 by the Parkinson’s Foundation, offers patients free genetic testing for seven clinically relevant Parkinson’s disease-related genes.

Testing is done at home or in a nearby clinic and the results are shared with patients during a free genetic counseling session and with site investigators. Patient samples are stored in a genetic data bank that is open to researchers around the world.

“We surveyed clinical trialists in the Parkinson’s disease field prior to initiation of PD GENEration and estimated that over 90% of people with Parkinson’s disease prior to the effort were not aware of their genetic status,” Dr. Alcalay said.

“I think precision medicine in Parkinson’s disease will not happen without PD GENEration or similar efforts.”
 

‘Overwhelming’ patient interest

Participants in the study are screened for variants in seven genes known to be involved in Parkinson’s disease risk: GBA, LRRK2, PRKN, PINK1, SNCA, PARK7, and VPS35.

In less than 3 years, the study has already produced what is thought to be the largest genetic data bank of sequenced sets of Parkinson’s disease-risk genes made accessible to patients. Since the end of 2020, the first year of patient enrollment, the number of participants has increased from 676 to 10,515 and the number of participating clinical sites rose from 12 to 101.

The foundation has spent nearly $20 million on the project so far and plans to spend another $10 million to reach a goal of 15,000 patients. The study, which is funded by private donors, is so successful that the foundation has had to scale back enrollment.

“When we were at a peak, we had over 700 participants enrolling each month,” Dr. Beck said. Beginning in April, the program capped new sign-ups to 200 patients per month and created a waiting list for future enrollment. The waiting list is hundreds of patients long.

“The participants’ response to enroll in PD GENEration demonstrates there is an overwhelming interest by people with Parkinson’s disease to learn more about their genetic risk factors,” Dr. Alcalay said.
 

A research driver

Nearly 60% of participants enrolled so far are male and close to 80% are White. The average age is 69 years and 44% were diagnosed in the past 5 years. Close to 75% had never participated in a clinical trial.

Nearly 13% have tested positive for mutations on at least one of the seven target genes. Previous studies had suggested genetics were involved in only about 10% of cases.

The majority of those with positive results had early-onset Parkinson’s disease, high-risk ancestry, or a first-degree relative with the disease. However, 9% of people who tested positive weren’t in any of those categories.

Genetic information collected by the project is shared with the Global Parkinson’s Genetics Program (GP2), a resource program of the Aligning Science Across Parkinson’s initiative that is focused on the disease’s genetic architecture. Researchers around the world have access to GP2 data to study known gene variants and identify new ones.

PD GENEration participants can choose to be notified if they are carriers of gene variants discovered in the future.

“All DNA samples shared by participants are undergoing research-grade testing,” Dr. Beck said. “Not only do we want to be able to inform people with Parkinson’s disease about their genetic status, but we also want to be able to use this precious resource to further drive research into the genetics of Parkinson’s disease.”
 

Early success

Patient recruitment has long been one of the biggest challenges to any clinical trial’s success. Research suggests that 90% of all clinical trials fail to reach recruitment milestones in their allotted time frame and two-thirds of multicenter trials fold because too few patients sign up. Data from the Parkinson’s Foundation show that only about 1% of all patients with Parkinson’s disease participate in clinical trials.

Increasing those numbers is the primary goal of PD GENEration, Dr. Beck said. And there’s evidence it’s already paying off.

Earlier this year, one of the program’s participating clinical sites, Intermountain Health, in Salt Lake City, Utah, joined a phase 2 clinical trial of an experimental drug that targets a mutation on the GBA1 gene.

“One of the reasons we were able to participate was when we got the call about joining, we were able to say that we had patients with that specific gene mutation, and we could only say that because the patients had been genotyped through PD GENEration,” said Kathleen E. McKee, MD, director of movement disorders, associate medical director of neurosciences research, and PD GENEration principal investigator at Intermountain Health.

Since 2021, Dr. McKee has enrolled hundreds of patients in the foundation’s gene study and hopes to enroll even more. Few patients turn down the opportunity to participate, she added. Knowing their genotype has proven empowering for her patients, most of whom could not afford genetic testing on their own.

“Previously I would tell patients this is not going to change your immediate management,” Dr. McKee said. “Now I tell my patients that these trials are out there, it may actually change how I treat you and what I recommend.”
 

A version of this article appeared on Medscape.com.

Diffuse large B-cell lymphoma (DLBCL) made headlines earlier this year with the high-profile case of prominent U.S. Congressman Jamie Raskin (D-MD). Yet, until very recently, progress in treating this most common form of lymphoma has been stalled for more than 2 decades.

Significant breakthroughs have come in just the past few weeks and months, through the use of CAR T-cell and immunotherapies and with the approval in April by the Food and Drug Administration of polatuzumab for frontline DLBCL.

“Until the publishing of data from the POLARIX study (NCT03274492), which led to the approval of polatuzumab vedotin plus rituximab-cyclophosphamide, doxorubicin, and prednisone (pola + R-CHP), we had not had a breakthrough in frontline DLBCL therapies since the addition of rituximab 22 years ago,” said Dr. Charalambos Andreadis, MD, of the University of California at San Francisco’s Helen Diller Family Comprehensive Cancer Center.

Andreadis_Charalambos_CA_web.jpg

“Pola + R-CHP is an improvement over the standard-of-care treatment, R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone), giving treatment naive patients an increase in PFS without an increase in side effects,” Dr. Andreadis said.

R-CHP-polatuzumab was approved only for patients with an International Prognostic Indices score between 2 and 5, leaving patients with IPI scores of 0 or 1 with the frontline standard of care (SoC) treatment of R-CHOP, which has a cure rate of between 60% and 70%.

“The highest likelihood of relapse is in the first year following treatment. After 2 years in remission, patients’ chance of relapsing is the same as the general populations’ chance of getting DLBCL for the first time. This is why even a slight increase in the progression-free survival rate with the addition of pola is so significant,” Dr. Andreadis noted.

Historically, patients with relapsed or refractory (RR) DLBCL who did not respond to R-CHOP or who experienced disease relapse less than a year after primary intervention were treated with alternative chemotherapy regimens, often followed by autologous stem cell transplants (ASCT). Randomized control studies have shown that CAR T-cell therapies yield higher success rates than chemotherapy and ASCT, leading to the SoC in RR patients being CAR-T cell therapy directly following failed primary treatment.

“There are many new CAR T-cell platforms in development, as well as novel combination strategies that aim to target critical genetic pathways,” Kieron Dunleavy, MD, professor of medicine at the Lombardi Comprehensive Cancer Center at Georgetown University Hospital, said in an interview. “While access to CAR T-cell therapies is becoming easier and more feasible in many centers, fast access continues to be an issue for many patients, often depending on geography and socioeconomic factors.”

Asked about the latest breakthroughs in treating DLBCL, Dr. Dunleavy said, “A significant proportion of patients with relapsed or refractory DLBCL do not have easy access to CAR T-cell therapies, so this needs to be addressed and improved. Sometimes the rapidity of clinical progression in DLBCL can make these therapies challenging to deliver, considering logistical issues like apheresis and insurance approvals, which are frequently complex. This highlights the need for alternative and ‘easier to deliver’ CAR-T cells and our continued prioritization of developing alternative effective agents for DLBCL.

“Currently, commercially approved CAR T-cells in DLBCL target the CD-19 marker on lymphoma cells but CAR T-cells targeting other and more than one antigen as well as alternative anti CD19 agents like loncastuximab and tafasitamab are similarly FDA approved and available for patients,” Dr. Dunleavy concluded.

Dr. Dunleavy is affiliated with the MedStar Georgetown Lymphoma group, where Rep. Raskin publicly announced that he had completed 4 months of chemotherapy treatment for DLBCL. On April 27, in an open letter to the U.S. public, he wrote that he rang the bell at MedStar to mark his preliminary diagnosis of being “in remission,” with a “90% prognosis of no relapse.”

Interviewed about the latest advances in treating DLBCL, Jason Westin, MD, associate professor of lymphoma and myeloma at the MD Anderson Cancer Center in Houston, said that even with improvements in overall survival possible with CAR T-cell therapies, “usually, a clinical trial should be considered strongly, as it is often the best option for patients, both in a newly diagnosed or in a relapsed setting, as they allow access to tomorrow’s breakthrough therapies today.”

Westin_Jason_TX_web.jpg

Dr. Westin cited the example of bispecific T-cell engagers (BITE) as a promising therapy that is available to patients in clinical trials. These agents bind to one side to the lymphoma cell, but they also have a binding arm for T-cells, so they activate a patient’s own immune cells to kill lymphoma cells, in some cases offering a cure when CAR T-cell therapy has failed.

The first BITE to be approved, mosunetuzumab, is authorized only for the treatment of follicular lymphoma. However, data from a recent clinical study indicated that the agent yields complete responses in 24% of heavily pretreated patients with RR DLBCL.

Another BITE, glofitamab, was approved in Canada in March 2023 for use in RR DLBCL. Based on its high efficacy, it soon may be approved elsewhere.

Dr. Andreadis noted, “We are finally at a point where for both treatment naive and RR DLBCL patients, there are several promising options on the horizon that don’t involve ASCT. Furthermore, these breakthroughs reinforce each other, as there are studies in which therapies like BITE are being brought to the front line and pola to RR cases.”

The growing field of new frontline and RR DLBCL therapies lend credence to the optimism of specialists who treat DLBCL – and to the sanguine note that Congressman Raskin struck in published comments about his treatment for DLBCL.

Dr. Andreadis reported ties with BMS, Novartis, Roche, Genmab, Merck, Gilead, AbbVie, and J&J. Dr. Dunleavy disclosed relationships with ONO Pharmaceuticals, Kymera, Merck, Genentech, AstraZeneca, Amgen, ADC Therapeutics, MorphoSys and Incyte, Kite/Gilead, Cellectar. Dr. Westin reported ties with Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Kymera, Nurix, and MonteRosa.

Diffuse large B-cell lymphoma (DLBCL) made headlines earlier this year with the high-profile case of prominent U.S. Congressman Jamie Raskin (D-MD). Yet, until very recently, progress in treating this most common form of lymphoma has been stalled for more than 2 decades.

Significant breakthroughs have come in just the past few weeks and months, through the use of CAR T-cell and immunotherapies and with the approval in April by the Food and Drug Administration of polatuzumab for frontline DLBCL.

“Until the publishing of data from the POLARIX study (NCT03274492), which led to the approval of polatuzumab vedotin plus rituximab-cyclophosphamide, doxorubicin, and prednisone (pola + R-CHP), we had not had a breakthrough in frontline DLBCL therapies since the addition of rituximab 22 years ago,” said Dr. Charalambos Andreadis, MD, of the University of California at San Francisco’s Helen Diller Family Comprehensive Cancer Center.

Andreadis_Charalambos_CA_web.jpg

“Pola + R-CHP is an improvement over the standard-of-care treatment, R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone), giving treatment naive patients an increase in PFS without an increase in side effects,” Dr. Andreadis said.

R-CHP-polatuzumab was approved only for patients with an International Prognostic Indices score between 2 and 5, leaving patients with IPI scores of 0 or 1 with the frontline standard of care (SoC) treatment of R-CHOP, which has a cure rate of between 60% and 70%.

“The highest likelihood of relapse is in the first year following treatment. After 2 years in remission, patients’ chance of relapsing is the same as the general populations’ chance of getting DLBCL for the first time. This is why even a slight increase in the progression-free survival rate with the addition of pola is so significant,” Dr. Andreadis noted.

Historically, patients with relapsed or refractory (RR) DLBCL who did not respond to R-CHOP or who experienced disease relapse less than a year after primary intervention were treated with alternative chemotherapy regimens, often followed by autologous stem cell transplants (ASCT). Randomized control studies have shown that CAR T-cell therapies yield higher success rates than chemotherapy and ASCT, leading to the SoC in RR patients being CAR-T cell therapy directly following failed primary treatment.

“There are many new CAR T-cell platforms in development, as well as novel combination strategies that aim to target critical genetic pathways,” Kieron Dunleavy, MD, professor of medicine at the Lombardi Comprehensive Cancer Center at Georgetown University Hospital, said in an interview. “While access to CAR T-cell therapies is becoming easier and more feasible in many centers, fast access continues to be an issue for many patients, often depending on geography and socioeconomic factors.”

Asked about the latest breakthroughs in treating DLBCL, Dr. Dunleavy said, “A significant proportion of patients with relapsed or refractory DLBCL do not have easy access to CAR T-cell therapies, so this needs to be addressed and improved. Sometimes the rapidity of clinical progression in DLBCL can make these therapies challenging to deliver, considering logistical issues like apheresis and insurance approvals, which are frequently complex. This highlights the need for alternative and ‘easier to deliver’ CAR-T cells and our continued prioritization of developing alternative effective agents for DLBCL.

“Currently, commercially approved CAR T-cells in DLBCL target the CD-19 marker on lymphoma cells but CAR T-cells targeting other and more than one antigen as well as alternative anti CD19 agents like loncastuximab and tafasitamab are similarly FDA approved and available for patients,” Dr. Dunleavy concluded.

Dr. Dunleavy is affiliated with the MedStar Georgetown Lymphoma group, where Rep. Raskin publicly announced that he had completed 4 months of chemotherapy treatment for DLBCL. On April 27, in an open letter to the U.S. public, he wrote that he rang the bell at MedStar to mark his preliminary diagnosis of being “in remission,” with a “90% prognosis of no relapse.”

Interviewed about the latest advances in treating DLBCL, Jason Westin, MD, associate professor of lymphoma and myeloma at the MD Anderson Cancer Center in Houston, said that even with improvements in overall survival possible with CAR T-cell therapies, “usually, a clinical trial should be considered strongly, as it is often the best option for patients, both in a newly diagnosed or in a relapsed setting, as they allow access to tomorrow’s breakthrough therapies today.”

Westin_Jason_TX_web.jpg

Dr. Westin cited the example of bispecific T-cell engagers (BITE) as a promising therapy that is available to patients in clinical trials. These agents bind to one side to the lymphoma cell, but they also have a binding arm for T-cells, so they activate a patient’s own immune cells to kill lymphoma cells, in some cases offering a cure when CAR T-cell therapy has failed.

The first BITE to be approved, mosunetuzumab, is authorized only for the treatment of follicular lymphoma. However, data from a recent clinical study indicated that the agent yields complete responses in 24% of heavily pretreated patients with RR DLBCL.

Another BITE, glofitamab, was approved in Canada in March 2023 for use in RR DLBCL. Based on its high efficacy, it soon may be approved elsewhere.

Dr. Andreadis noted, “We are finally at a point where for both treatment naive and RR DLBCL patients, there are several promising options on the horizon that don’t involve ASCT. Furthermore, these breakthroughs reinforce each other, as there are studies in which therapies like BITE are being brought to the front line and pola to RR cases.”

The growing field of new frontline and RR DLBCL therapies lend credence to the optimism of specialists who treat DLBCL – and to the sanguine note that Congressman Raskin struck in published comments about his treatment for DLBCL.

Dr. Andreadis reported ties with BMS, Novartis, Roche, Genmab, Merck, Gilead, AbbVie, and J&J. Dr. Dunleavy disclosed relationships with ONO Pharmaceuticals, Kymera, Merck, Genentech, AstraZeneca, Amgen, ADC Therapeutics, MorphoSys and Incyte, Kite/Gilead, Cellectar. Dr. Westin reported ties with Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Kymera, Nurix, and MonteRosa.

Diffuse large B-cell lymphoma (DLBCL) made headlines earlier this year with the high-profile case of prominent U.S. Congressman Jamie Raskin (D-MD). Yet, until very recently, progress in treating this most common form of lymphoma has been stalled for more than 2 decades.

Significant breakthroughs have come in just the past few weeks and months, through the use of CAR T-cell and immunotherapies and with the approval in April by the Food and Drug Administration of polatuzumab for frontline DLBCL.

“Until the publishing of data from the POLARIX study (NCT03274492), which led to the approval of polatuzumab vedotin plus rituximab-cyclophosphamide, doxorubicin, and prednisone (pola + R-CHP), we had not had a breakthrough in frontline DLBCL therapies since the addition of rituximab 22 years ago,” said Dr. Charalambos Andreadis, MD, of the University of California at San Francisco’s Helen Diller Family Comprehensive Cancer Center.

Andreadis_Charalambos_CA_web.jpg

“Pola + R-CHP is an improvement over the standard-of-care treatment, R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone), giving treatment naive patients an increase in PFS without an increase in side effects,” Dr. Andreadis said.

R-CHP-polatuzumab was approved only for patients with an International Prognostic Indices score between 2 and 5, leaving patients with IPI scores of 0 or 1 with the frontline standard of care (SoC) treatment of R-CHOP, which has a cure rate of between 60% and 70%.

“The highest likelihood of relapse is in the first year following treatment. After 2 years in remission, patients’ chance of relapsing is the same as the general populations’ chance of getting DLBCL for the first time. This is why even a slight increase in the progression-free survival rate with the addition of pola is so significant,” Dr. Andreadis noted.

Historically, patients with relapsed or refractory (RR) DLBCL who did not respond to R-CHOP or who experienced disease relapse less than a year after primary intervention were treated with alternative chemotherapy regimens, often followed by autologous stem cell transplants (ASCT). Randomized control studies have shown that CAR T-cell therapies yield higher success rates than chemotherapy and ASCT, leading to the SoC in RR patients being CAR-T cell therapy directly following failed primary treatment.

“There are many new CAR T-cell platforms in development, as well as novel combination strategies that aim to target critical genetic pathways,” Kieron Dunleavy, MD, professor of medicine at the Lombardi Comprehensive Cancer Center at Georgetown University Hospital, said in an interview. “While access to CAR T-cell therapies is becoming easier and more feasible in many centers, fast access continues to be an issue for many patients, often depending on geography and socioeconomic factors.”

Asked about the latest breakthroughs in treating DLBCL, Dr. Dunleavy said, “A significant proportion of patients with relapsed or refractory DLBCL do not have easy access to CAR T-cell therapies, so this needs to be addressed and improved. Sometimes the rapidity of clinical progression in DLBCL can make these therapies challenging to deliver, considering logistical issues like apheresis and insurance approvals, which are frequently complex. This highlights the need for alternative and ‘easier to deliver’ CAR-T cells and our continued prioritization of developing alternative effective agents for DLBCL.

“Currently, commercially approved CAR T-cells in DLBCL target the CD-19 marker on lymphoma cells but CAR T-cells targeting other and more than one antigen as well as alternative anti CD19 agents like loncastuximab and tafasitamab are similarly FDA approved and available for patients,” Dr. Dunleavy concluded.

Dr. Dunleavy is affiliated with the MedStar Georgetown Lymphoma group, where Rep. Raskin publicly announced that he had completed 4 months of chemotherapy treatment for DLBCL. On April 27, in an open letter to the U.S. public, he wrote that he rang the bell at MedStar to mark his preliminary diagnosis of being “in remission,” with a “90% prognosis of no relapse.”

Interviewed about the latest advances in treating DLBCL, Jason Westin, MD, associate professor of lymphoma and myeloma at the MD Anderson Cancer Center in Houston, said that even with improvements in overall survival possible with CAR T-cell therapies, “usually, a clinical trial should be considered strongly, as it is often the best option for patients, both in a newly diagnosed or in a relapsed setting, as they allow access to tomorrow’s breakthrough therapies today.”

Westin_Jason_TX_web.jpg

Dr. Westin cited the example of bispecific T-cell engagers (BITE) as a promising therapy that is available to patients in clinical trials. These agents bind to one side to the lymphoma cell, but they also have a binding arm for T-cells, so they activate a patient’s own immune cells to kill lymphoma cells, in some cases offering a cure when CAR T-cell therapy has failed.

The first BITE to be approved, mosunetuzumab, is authorized only for the treatment of follicular lymphoma. However, data from a recent clinical study indicated that the agent yields complete responses in 24% of heavily pretreated patients with RR DLBCL.

Another BITE, glofitamab, was approved in Canada in March 2023 for use in RR DLBCL. Based on its high efficacy, it soon may be approved elsewhere.

Dr. Andreadis noted, “We are finally at a point where for both treatment naive and RR DLBCL patients, there are several promising options on the horizon that don’t involve ASCT. Furthermore, these breakthroughs reinforce each other, as there are studies in which therapies like BITE are being brought to the front line and pola to RR cases.”

The growing field of new frontline and RR DLBCL therapies lend credence to the optimism of specialists who treat DLBCL – and to the sanguine note that Congressman Raskin struck in published comments about his treatment for DLBCL.

Dr. Andreadis reported ties with BMS, Novartis, Roche, Genmab, Merck, Gilead, AbbVie, and J&J. Dr. Dunleavy disclosed relationships with ONO Pharmaceuticals, Kymera, Merck, Genentech, AstraZeneca, Amgen, ADC Therapeutics, MorphoSys and Incyte, Kite/Gilead, Cellectar. Dr. Westin reported ties with Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Kymera, Nurix, and MonteRosa.

Clinical data have been published for a gene therapy for hemophilia A that is approaching the market – valoctocogene roxaparvovec (Roctavian), currently under review by the U.S. Food and Drug Administration.

Hemophilia A (a deficiency of clotting Factor X) is the most common form of the disease, accounting for about 85% of patients.

The other type is hemophilia B (deficiency of clotting Factor VIII), and a gene therapy for this form of the disease has recently been launched – etranacogene dezaparvovec (Hemgenix), at the enormous price tag of $3.5 million.

Both products are comprised of a one-off intravenous IV infusion that delivers a functional gene via an adeno-associated virus that instructs the body to make the missing clotting factor. The hope is that this one-off infusion will act as a ‘cure’ and that the individual will be freed from life-long prophylaxis and/or treatment.

The new clinical data on valoctocogene roxaparvovec, published online in the New England Journal of Medicine, show that the beneficial effects from the gene are largely durable at 2 years, but they are anticipated to fade with time.

Two years after the one-time infusion, there remained “a significant reduction in the annualized bleeding rates” among 132 men who, at baseline, had severe hemophilia A requiring ongoing factor VIII prophylaxis, said the investigators, led by hematologist Johnny Mahlangu, MBBCh, MMed, of the University of the Witwatersrand, Johannesburg, South Africa.

However, the team predicted that median factor VIII activity would decrease below 10% of normal by year 3 or 5 depending on measurement technique, which would still translate to mild disease with an annualized bleeding rate of less than 1 episode per year.

“Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden,” the team said.
 

New questions

Data from the study “will directly inform therapeutic decision-making” in Europe, where valoctocogene roxaparvovec is already conditionally approved, and the United States, where it is awaiting approval by the FDA, says Lindsey George, MD, a hematologist and gene therapy specialist at Children’s Hospital of Philadelphia, in an accompanying editorial.

The study speaks to an ongoing concern about the durability of gene therapy for hemophilia but also raises new questions, she said.

For instance, while some patients had normal Factor VIII production and activity at 2 years, activity had dropped substantially in others, including in six men who resumed prophylaxis. “The cause of the decrease in factor VIII expression is an unanswered question,” and despite an anticipated U.S. price tag of around $2.5 million per treatment, “it is not possible [at the moment] to predict where an individual patient may fall within this range,” she writes.

Also, some subjects had elevations in liver aminotransferase levels that lasted for several months, including 2 years after infusion in 29% of subjects. Elevations in liver aminotransferase levels were treated with immune suppression for a median of 33 weeks.

“This is a unique finding with an undefined cause and long-term safety implications,” Dr. George said.

Getting to the bottom of such issues will be necessary for hemophilia gene therapy to fulfill its promise as “a one-time, lifelong, disease-ameliorating” fix for the condition, she asserted.
 

Study details

The new report followed up on the initial trial in 134 men who were treated with a single infusion of 6 × 1013 vector genomes per kilogram of body weight.

Among the 132 subjects available for 2-year evaluation, median factor VIII activity was in the range of mild hemophilia (6%-49% of normal) with an 84.5% reduction in bleeding events from baseline. 

More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.  

Overall, at year 2, 4.5% of subjects had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease; and 26.5% had activity in the normal range above 40 IU/dL. The investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.

Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion, investigators noted.

All the subjects developed antibodies to the virus delivery vector, precluding retreatment.

The work was funded by valoctocogene roxaparvovec maker BioMarin Pharmaceuticals. Several investigators are employees. Others reported ties to BioMarin and other companies; Dr. Mahlangu, for instance, reported research grants from BioMarin, Roche, Novo Nordisk, Pfizer, and others. Dr. George reported a research grant from Asklepios Biopharmaceutical and having a patent licensed to the company. The full list of author disclosures can be found with the original article.

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

Clinical data have been published for a gene therapy for hemophilia A that is approaching the market – valoctocogene roxaparvovec (Roctavian), currently under review by the U.S. Food and Drug Administration.

Hemophilia A (a deficiency of clotting Factor X) is the most common form of the disease, accounting for about 85% of patients.

The other type is hemophilia B (deficiency of clotting Factor VIII), and a gene therapy for this form of the disease has recently been launched – etranacogene dezaparvovec (Hemgenix), at the enormous price tag of $3.5 million.

Both products are comprised of a one-off intravenous IV infusion that delivers a functional gene via an adeno-associated virus that instructs the body to make the missing clotting factor. The hope is that this one-off infusion will act as a ‘cure’ and that the individual will be freed from life-long prophylaxis and/or treatment.

The new clinical data on valoctocogene roxaparvovec, published online in the New England Journal of Medicine, show that the beneficial effects from the gene are largely durable at 2 years, but they are anticipated to fade with time.

Two years after the one-time infusion, there remained “a significant reduction in the annualized bleeding rates” among 132 men who, at baseline, had severe hemophilia A requiring ongoing factor VIII prophylaxis, said the investigators, led by hematologist Johnny Mahlangu, MBBCh, MMed, of the University of the Witwatersrand, Johannesburg, South Africa.

However, the team predicted that median factor VIII activity would decrease below 10% of normal by year 3 or 5 depending on measurement technique, which would still translate to mild disease with an annualized bleeding rate of less than 1 episode per year.

“Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden,” the team said.
 

New questions

Data from the study “will directly inform therapeutic decision-making” in Europe, where valoctocogene roxaparvovec is already conditionally approved, and the United States, where it is awaiting approval by the FDA, says Lindsey George, MD, a hematologist and gene therapy specialist at Children’s Hospital of Philadelphia, in an accompanying editorial.

The study speaks to an ongoing concern about the durability of gene therapy for hemophilia but also raises new questions, she said.

For instance, while some patients had normal Factor VIII production and activity at 2 years, activity had dropped substantially in others, including in six men who resumed prophylaxis. “The cause of the decrease in factor VIII expression is an unanswered question,” and despite an anticipated U.S. price tag of around $2.5 million per treatment, “it is not possible [at the moment] to predict where an individual patient may fall within this range,” she writes.

Also, some subjects had elevations in liver aminotransferase levels that lasted for several months, including 2 years after infusion in 29% of subjects. Elevations in liver aminotransferase levels were treated with immune suppression for a median of 33 weeks.

“This is a unique finding with an undefined cause and long-term safety implications,” Dr. George said.

Getting to the bottom of such issues will be necessary for hemophilia gene therapy to fulfill its promise as “a one-time, lifelong, disease-ameliorating” fix for the condition, she asserted.
 

Study details

The new report followed up on the initial trial in 134 men who were treated with a single infusion of 6 × 1013 vector genomes per kilogram of body weight.

Among the 132 subjects available for 2-year evaluation, median factor VIII activity was in the range of mild hemophilia (6%-49% of normal) with an 84.5% reduction in bleeding events from baseline. 

More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.  

Overall, at year 2, 4.5% of subjects had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease; and 26.5% had activity in the normal range above 40 IU/dL. The investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.

Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion, investigators noted.

All the subjects developed antibodies to the virus delivery vector, precluding retreatment.

The work was funded by valoctocogene roxaparvovec maker BioMarin Pharmaceuticals. Several investigators are employees. Others reported ties to BioMarin and other companies; Dr. Mahlangu, for instance, reported research grants from BioMarin, Roche, Novo Nordisk, Pfizer, and others. Dr. George reported a research grant from Asklepios Biopharmaceutical and having a patent licensed to the company. The full list of author disclosures can be found with the original article.

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

Clinical data have been published for a gene therapy for hemophilia A that is approaching the market – valoctocogene roxaparvovec (Roctavian), currently under review by the U.S. Food and Drug Administration.

Hemophilia A (a deficiency of clotting Factor X) is the most common form of the disease, accounting for about 85% of patients.

The other type is hemophilia B (deficiency of clotting Factor VIII), and a gene therapy for this form of the disease has recently been launched – etranacogene dezaparvovec (Hemgenix), at the enormous price tag of $3.5 million.

Both products are comprised of a one-off intravenous IV infusion that delivers a functional gene via an adeno-associated virus that instructs the body to make the missing clotting factor. The hope is that this one-off infusion will act as a ‘cure’ and that the individual will be freed from life-long prophylaxis and/or treatment.

The new clinical data on valoctocogene roxaparvovec, published online in the New England Journal of Medicine, show that the beneficial effects from the gene are largely durable at 2 years, but they are anticipated to fade with time.

Two years after the one-time infusion, there remained “a significant reduction in the annualized bleeding rates” among 132 men who, at baseline, had severe hemophilia A requiring ongoing factor VIII prophylaxis, said the investigators, led by hematologist Johnny Mahlangu, MBBCh, MMed, of the University of the Witwatersrand, Johannesburg, South Africa.

However, the team predicted that median factor VIII activity would decrease below 10% of normal by year 3 or 5 depending on measurement technique, which would still translate to mild disease with an annualized bleeding rate of less than 1 episode per year.

“Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden,” the team said.
 

New questions

Data from the study “will directly inform therapeutic decision-making” in Europe, where valoctocogene roxaparvovec is already conditionally approved, and the United States, where it is awaiting approval by the FDA, says Lindsey George, MD, a hematologist and gene therapy specialist at Children’s Hospital of Philadelphia, in an accompanying editorial.

The study speaks to an ongoing concern about the durability of gene therapy for hemophilia but also raises new questions, she said.

For instance, while some patients had normal Factor VIII production and activity at 2 years, activity had dropped substantially in others, including in six men who resumed prophylaxis. “The cause of the decrease in factor VIII expression is an unanswered question,” and despite an anticipated U.S. price tag of around $2.5 million per treatment, “it is not possible [at the moment] to predict where an individual patient may fall within this range,” she writes.

Also, some subjects had elevations in liver aminotransferase levels that lasted for several months, including 2 years after infusion in 29% of subjects. Elevations in liver aminotransferase levels were treated with immune suppression for a median of 33 weeks.

“This is a unique finding with an undefined cause and long-term safety implications,” Dr. George said.

Getting to the bottom of such issues will be necessary for hemophilia gene therapy to fulfill its promise as “a one-time, lifelong, disease-ameliorating” fix for the condition, she asserted.
 

Study details

The new report followed up on the initial trial in 134 men who were treated with a single infusion of 6 × 1013 vector genomes per kilogram of body weight.

Among the 132 subjects available for 2-year evaluation, median factor VIII activity was in the range of mild hemophilia (6%-49% of normal) with an 84.5% reduction in bleeding events from baseline. 

More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.  

Overall, at year 2, 4.5% of subjects had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease; and 26.5% had activity in the normal range above 40 IU/dL. The investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.

Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion, investigators noted.

All the subjects developed antibodies to the virus delivery vector, precluding retreatment.

The work was funded by valoctocogene roxaparvovec maker BioMarin Pharmaceuticals. Several investigators are employees. Others reported ties to BioMarin and other companies; Dr. Mahlangu, for instance, reported research grants from BioMarin, Roche, Novo Nordisk, Pfizer, and others. Dr. George reported a research grant from Asklepios Biopharmaceutical and having a patent licensed to the company. The full list of author disclosures can be found with the original article.

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

The European Commission has granted conditional marketing authorization for etranacogene dezaparvovec (Hemgenix), the first and only one-time gene therapy for the treatment of severe and moderately severe hemophilia B (congenital factor IX deficiency) in adults without a history of factor IX inhibitors.

The approval means that the product will now be available in all the countries of the European Union as well as the European Economic Area.

The gene therapy was approved in the United States in November 2022. It was launched with a price tag of $3.5 million, making it the most expensive treatment to date.

The treatment comprises a one-time infusion of a functional gene that acts as a blueprint for coagulation factor IX, a protein important for blood clotting, stated the manufacturer, CSL.

People living with hemophilia B currently require lifelong treatment of intravenous infusions of factor IX to maintain sufficient levels, which can have a significant impact on their quality of life and well-being, the company explained in its press release.

The approval was based on findings from the pivotal HOPE-B trial, a single-arm, open-label study of 54 men who relied on factor IX replacement therapy; first results from this trial were reported at the 2020 annual meeting of the American Society of Hematology.

The results showed that patients with hemophilia B treated with the gene therapy demonstrated stable and durable increases in mean factor IX activity (with a mean factor IX activity of 36.9%), which led to an adjusted annualized bleeding rate reduction of 64%.

After receiving the gene therapy, 96% of patients discontinued routine factor IX prophylaxis and mean factor IX consumption was reduced by 97% at 18 months post treatment compared with the lead-in period, the company noted.

“Data from the HOPE-B study demonstrate the potential of Hemgenix to remove the need for routine prophylaxis by providing durable factor IX activity, as well as improved bleeding outcomes and quality of life for people with hemophilia B,” said one of the trialists, Wolfgang Miesbach, MD, PHD, head of coagulation disorders at the Comprehensive Care Center, University Hospital of Frankfurt, Germany.

This European approval “marks an important step forward in the treatment of hemophilia B, which could be transformative for people who are debilitated by bleeds into their muscles, joints, and internal organs, alleviating the burden of lifelong intravenous infusions of factor IX products,” Dr. Miesbach said in the company press release.

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

The European Commission has granted conditional marketing authorization for etranacogene dezaparvovec (Hemgenix), the first and only one-time gene therapy for the treatment of severe and moderately severe hemophilia B (congenital factor IX deficiency) in adults without a history of factor IX inhibitors.

The approval means that the product will now be available in all the countries of the European Union as well as the European Economic Area.

The gene therapy was approved in the United States in November 2022. It was launched with a price tag of $3.5 million, making it the most expensive treatment to date.

The treatment comprises a one-time infusion of a functional gene that acts as a blueprint for coagulation factor IX, a protein important for blood clotting, stated the manufacturer, CSL.

People living with hemophilia B currently require lifelong treatment of intravenous infusions of factor IX to maintain sufficient levels, which can have a significant impact on their quality of life and well-being, the company explained in its press release.

The approval was based on findings from the pivotal HOPE-B trial, a single-arm, open-label study of 54 men who relied on factor IX replacement therapy; first results from this trial were reported at the 2020 annual meeting of the American Society of Hematology.

The results showed that patients with hemophilia B treated with the gene therapy demonstrated stable and durable increases in mean factor IX activity (with a mean factor IX activity of 36.9%), which led to an adjusted annualized bleeding rate reduction of 64%.

After receiving the gene therapy, 96% of patients discontinued routine factor IX prophylaxis and mean factor IX consumption was reduced by 97% at 18 months post treatment compared with the lead-in period, the company noted.

“Data from the HOPE-B study demonstrate the potential of Hemgenix to remove the need for routine prophylaxis by providing durable factor IX activity, as well as improved bleeding outcomes and quality of life for people with hemophilia B,” said one of the trialists, Wolfgang Miesbach, MD, PHD, head of coagulation disorders at the Comprehensive Care Center, University Hospital of Frankfurt, Germany.

This European approval “marks an important step forward in the treatment of hemophilia B, which could be transformative for people who are debilitated by bleeds into their muscles, joints, and internal organs, alleviating the burden of lifelong intravenous infusions of factor IX products,” Dr. Miesbach said in the company press release.

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

The European Commission has granted conditional marketing authorization for etranacogene dezaparvovec (Hemgenix), the first and only one-time gene therapy for the treatment of severe and moderately severe hemophilia B (congenital factor IX deficiency) in adults without a history of factor IX inhibitors.

The approval means that the product will now be available in all the countries of the European Union as well as the European Economic Area.

The gene therapy was approved in the United States in November 2022. It was launched with a price tag of $3.5 million, making it the most expensive treatment to date.

The treatment comprises a one-time infusion of a functional gene that acts as a blueprint for coagulation factor IX, a protein important for blood clotting, stated the manufacturer, CSL.

People living with hemophilia B currently require lifelong treatment of intravenous infusions of factor IX to maintain sufficient levels, which can have a significant impact on their quality of life and well-being, the company explained in its press release.

The approval was based on findings from the pivotal HOPE-B trial, a single-arm, open-label study of 54 men who relied on factor IX replacement therapy; first results from this trial were reported at the 2020 annual meeting of the American Society of Hematology.

The results showed that patients with hemophilia B treated with the gene therapy demonstrated stable and durable increases in mean factor IX activity (with a mean factor IX activity of 36.9%), which led to an adjusted annualized bleeding rate reduction of 64%.

After receiving the gene therapy, 96% of patients discontinued routine factor IX prophylaxis and mean factor IX consumption was reduced by 97% at 18 months post treatment compared with the lead-in period, the company noted.

“Data from the HOPE-B study demonstrate the potential of Hemgenix to remove the need for routine prophylaxis by providing durable factor IX activity, as well as improved bleeding outcomes and quality of life for people with hemophilia B,” said one of the trialists, Wolfgang Miesbach, MD, PHD, head of coagulation disorders at the Comprehensive Care Center, University Hospital of Frankfurt, Germany.

This European approval “marks an important step forward in the treatment of hemophilia B, which could be transformative for people who are debilitated by bleeds into their muscles, joints, and internal organs, alleviating the burden of lifelong intravenous infusions of factor IX products,” Dr. Miesbach said in the company press release.

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

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

Diorio_Caroline_PA_web.jpg

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

Diorio_Caroline_PA_web.jpg

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

Diorio_Caroline_PA_web.jpg

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

Nearly 90% of beta-thalassemia patients were transfusion free for up to 8 years after treatment with the one-time gene therapy betibeglogene autotemcel (beti-cel), according to a report at the American Society of Hematology annual meeting.

Surveyed at 3 years, patients also reported ongoing benefits from treatment, including positive impacts on employment, school attendance, and physical activity, according to a second report.

The findings address a major question about betibeglogene autotemcel: Its durability. The therapy is priced at over $2 million per treatment, based on the premise that it will benefit patients in the long-term, in part by offsetting the cost of ongoing transfusions. Therefore, proof of long-standing benefit is important.

The Food and Drug Administration approved betibeglogene autotemcel in August 2022 for children and adults with transfusion dependent beta-thalassemia, a condition that causes patients to have absent or reduced levels of hemoglobin due to mutations in the beta-globin gene. Patients typically require transfusions every 2-5 weeks.

The treatment inserts functional copies of the mutated gene into the patients’ hematopoietic stem cells via a replication-defective lentivirus. The cells are then transfused back into the patient.

As of August 2021, 63 patients had undergone treatment and been followed for a median of 41.4 months. So far, durability looks solid.

“We now have up to 8 years efficacy and safety follow-up” with beti-cel. “Patients experience durable transfusion independence,” said Mark Walters, MD, a pediatric hematologist/oncologist at the University of California, San Francisco, who presented the long-term efficacy data at the meeting.

Overall, 89.5% of patients (34/38) in phase 3 testing achieved transfusion independence, meaning that they had hemoglobin levels of at least 9 g/dL without transfusions for a year or more.

The response rate was an improvement over phase 1/2 testing, in which 68% of subjects (15/22) became transfusion free. Improvements in the manufacturing process led to better outcomes in phase 3, Dr. Walters said.

As for quality of life (QoL), improvement “continues through 3 years following treatment,” said Franco Locatelli, MD, a pediatric hematologist/oncologist at Catholic University of the Sacred Heart, Rome, who led the QoL study.

When patients who achieved transfusion independence were surveyed 3 years after treatment, 93% of adults were employed or able to seek employment, up from 67% before treatment. School absences were down among children, almost half of subjects no longer needed symptom management, and 81% reported improvements in physical activity.

There were also improvements on various quality of life scales, including in physical functioning and mental health.

Patient age and underlying thalassemia genotype had no impact on the likelihood of transfusion independence. Those who achieved it also had reductions in markers of ineffective erythropoiesis and iron overload.

On multivariate analysis, the greatest predictor of transfusion independence was having at least 62% of cells transduced prior to reintroduction to the patient.

As for adverse events, seven subjects (11%) developed severe veno-occlusive liver disease that resolved with supportive care. Mucositis and febrile neutropenia are also a concern and related to the busulfan conditioning regimen.

No malignancies, insertional oncogenesis, or lentivirus replication have been observed.

The studies were funded by beti-cel maker Bluebird Bio, and many of the investigators are employees. Others reported ties to Bluebird and a range of other companies. Among his industry ties, Dr. Locatelli is a speaker for Bluebird. Dr. Walters also had industry relationships, but didn’t report any ties to Bluebird.

Nearly 90% of beta-thalassemia patients were transfusion free for up to 8 years after treatment with the one-time gene therapy betibeglogene autotemcel (beti-cel), according to a report at the American Society of Hematology annual meeting.

Surveyed at 3 years, patients also reported ongoing benefits from treatment, including positive impacts on employment, school attendance, and physical activity, according to a second report.

The findings address a major question about betibeglogene autotemcel: Its durability. The therapy is priced at over $2 million per treatment, based on the premise that it will benefit patients in the long-term, in part by offsetting the cost of ongoing transfusions. Therefore, proof of long-standing benefit is important.

The Food and Drug Administration approved betibeglogene autotemcel in August 2022 for children and adults with transfusion dependent beta-thalassemia, a condition that causes patients to have absent or reduced levels of hemoglobin due to mutations in the beta-globin gene. Patients typically require transfusions every 2-5 weeks.

The treatment inserts functional copies of the mutated gene into the patients’ hematopoietic stem cells via a replication-defective lentivirus. The cells are then transfused back into the patient.

As of August 2021, 63 patients had undergone treatment and been followed for a median of 41.4 months. So far, durability looks solid.

“We now have up to 8 years efficacy and safety follow-up” with beti-cel. “Patients experience durable transfusion independence,” said Mark Walters, MD, a pediatric hematologist/oncologist at the University of California, San Francisco, who presented the long-term efficacy data at the meeting.

Overall, 89.5% of patients (34/38) in phase 3 testing achieved transfusion independence, meaning that they had hemoglobin levels of at least 9 g/dL without transfusions for a year or more.

The response rate was an improvement over phase 1/2 testing, in which 68% of subjects (15/22) became transfusion free. Improvements in the manufacturing process led to better outcomes in phase 3, Dr. Walters said.

As for quality of life (QoL), improvement “continues through 3 years following treatment,” said Franco Locatelli, MD, a pediatric hematologist/oncologist at Catholic University of the Sacred Heart, Rome, who led the QoL study.

When patients who achieved transfusion independence were surveyed 3 years after treatment, 93% of adults were employed or able to seek employment, up from 67% before treatment. School absences were down among children, almost half of subjects no longer needed symptom management, and 81% reported improvements in physical activity.

There were also improvements on various quality of life scales, including in physical functioning and mental health.

Patient age and underlying thalassemia genotype had no impact on the likelihood of transfusion independence. Those who achieved it also had reductions in markers of ineffective erythropoiesis and iron overload.

On multivariate analysis, the greatest predictor of transfusion independence was having at least 62% of cells transduced prior to reintroduction to the patient.

As for adverse events, seven subjects (11%) developed severe veno-occlusive liver disease that resolved with supportive care. Mucositis and febrile neutropenia are also a concern and related to the busulfan conditioning regimen.

No malignancies, insertional oncogenesis, or lentivirus replication have been observed.

The studies were funded by beti-cel maker Bluebird Bio, and many of the investigators are employees. Others reported ties to Bluebird and a range of other companies. Among his industry ties, Dr. Locatelli is a speaker for Bluebird. Dr. Walters also had industry relationships, but didn’t report any ties to Bluebird.

Nearly 90% of beta-thalassemia patients were transfusion free for up to 8 years after treatment with the one-time gene therapy betibeglogene autotemcel (beti-cel), according to a report at the American Society of Hematology annual meeting.

Surveyed at 3 years, patients also reported ongoing benefits from treatment, including positive impacts on employment, school attendance, and physical activity, according to a second report.

The findings address a major question about betibeglogene autotemcel: Its durability. The therapy is priced at over $2 million per treatment, based on the premise that it will benefit patients in the long-term, in part by offsetting the cost of ongoing transfusions. Therefore, proof of long-standing benefit is important.

The Food and Drug Administration approved betibeglogene autotemcel in August 2022 for children and adults with transfusion dependent beta-thalassemia, a condition that causes patients to have absent or reduced levels of hemoglobin due to mutations in the beta-globin gene. Patients typically require transfusions every 2-5 weeks.

The treatment inserts functional copies of the mutated gene into the patients’ hematopoietic stem cells via a replication-defective lentivirus. The cells are then transfused back into the patient.

As of August 2021, 63 patients had undergone treatment and been followed for a median of 41.4 months. So far, durability looks solid.

“We now have up to 8 years efficacy and safety follow-up” with beti-cel. “Patients experience durable transfusion independence,” said Mark Walters, MD, a pediatric hematologist/oncologist at the University of California, San Francisco, who presented the long-term efficacy data at the meeting.

Overall, 89.5% of patients (34/38) in phase 3 testing achieved transfusion independence, meaning that they had hemoglobin levels of at least 9 g/dL without transfusions for a year or more.

The response rate was an improvement over phase 1/2 testing, in which 68% of subjects (15/22) became transfusion free. Improvements in the manufacturing process led to better outcomes in phase 3, Dr. Walters said.

As for quality of life (QoL), improvement “continues through 3 years following treatment,” said Franco Locatelli, MD, a pediatric hematologist/oncologist at Catholic University of the Sacred Heart, Rome, who led the QoL study.

When patients who achieved transfusion independence were surveyed 3 years after treatment, 93% of adults were employed or able to seek employment, up from 67% before treatment. School absences were down among children, almost half of subjects no longer needed symptom management, and 81% reported improvements in physical activity.

There were also improvements on various quality of life scales, including in physical functioning and mental health.

Patient age and underlying thalassemia genotype had no impact on the likelihood of transfusion independence. Those who achieved it also had reductions in markers of ineffective erythropoiesis and iron overload.

On multivariate analysis, the greatest predictor of transfusion independence was having at least 62% of cells transduced prior to reintroduction to the patient.

As for adverse events, seven subjects (11%) developed severe veno-occlusive liver disease that resolved with supportive care. Mucositis and febrile neutropenia are also a concern and related to the busulfan conditioning regimen.

No malignancies, insertional oncogenesis, or lentivirus replication have been observed.

The studies were funded by beti-cel maker Bluebird Bio, and many of the investigators are employees. Others reported ties to Bluebird and a range of other companies. Among his industry ties, Dr. Locatelli is a speaker for Bluebird. Dr. Walters also had industry relationships, but didn’t report any ties to Bluebird.

NEW ORLEANS – A gene therapy made headlines recently for becoming the most expensive pharmaceutical ever launched – the price tag was $3.5 million for a one-off treatment with etranacogene dezaparvovec (Hemgenix) for hemophilia B.

Another gene therapy, a treatment for sickle cell anemia now in late clinical development, is expected to come on the market soon. It, too, is expected to bear an exorbitant price tag.

Such potentially curative therapies put financial pressure on publicly and privately funded health insurance.

However, investigators said that the new treatment for patients with sickle cell disease (SCD) in the United States has the potential to be cost-effective. Those who analyzed the costs used a novel method that takes historical health inequities into account.

“When faced with costs of innovative, one-time-administered therapies, budgetary constraints, as we all know too well, can and have driven therapy availability or lack thereof for patients,” said George Goshua, MD, from the Yale University, New Haven, Conn., speaking here at the annual meeting of the American Society of Hematology.

“We believe that quantitative consideration of health inequities, in addition to the important quality considerations, may be an additional helpful metric in this decision-making context,” he said.

He noted that SCD predominantly affects Black Americans, “who have historically been a very marginalized population when it comes to health care.

“Our study shows that, when we compare the costs of gene therapy and existing standard-of-care treatment for SCD using a technique that accounts for historical health disparities, gene therapy could be an equitable therapeutic strategy for all patients with SCD, whether their disease is mild, moderate, or severe,” he said.

Commenting on the study for this news organization, Bosula Oluwole, MD, from the University of Washington, Seattle, who studies sickle cell disease but was not involved in this study, said the cost-analysis approach taken by Dr. Goshua and colleagues is interesting, but she added: “I think we still have a way to go in trying to fully understand the issue.

“When you look over time at the cost for a patient to get gene therapy vs. the standard of care, it might actually be beneficial to have the gene therapy,” Dr. Oluwole said.

She noted, however, that some patients start gene therapy for SCD at older ages and that it’s important to analyze whether the treatment can still be cost-effective or the best therapeutic option for such patients.
 

Adding a D to CEA

Dr. Goshua and colleagues at Yale University and the Harvard T.H. Chan School of Public Health in Boston conducted what they believe is the first study in hematology to use distributional cost-effectiveness analysis (DCEA), developed at the University of York, England.

A University of York website explains that DCEA “is a general umbrella term for economic evaluation studies that provide information about equity in the distribution of costs and effects as well as efficiency in terms of aggregate costs and effects. DCEA can provide distributional breakdowns of who gains most and who bears the largest burdens (opportunity costs) by equity-relevant social variables (e.g., socioeconomic status, ethnicity, location) and disease categories (e.g., severity of illness, rarity, disability).”

The technique can also employ equity weight to evaluate trade-offs between equity and efficiency, the website says.

As Dr. Goshua put it, equity weighting is “a way of quantifying how much we prioritize health care equity.”
 

QALYs considered

Dr. Goshua and colleagues included equity weight in an analysis of 10 years of data on annual health care costs for patients with SCD who were covered by private insurance and were treated with medications (for example, hydroxyurea), antibiotics, blood transfusion, and hematopoietic stem cell transplants. Sex and the frequency of hospitalizations for acute pain crises were factors in the Markov model they created.

The model assumes that a single course of gene therapy for SCD would cost $2.1 million. The estimate was based on the cost of U.S. Food and Drug Administration–approved gene therapies, and it was assumed that the therapy would result in permanent disease remission for all patients.

In addition, the model assumed that all eligible patients in the United States with SCD who are aged 12 years and older would be offered the gene therapy.

In their base-case analysis, gene therapy starting at age 12 would yield 25.5 discounted lifetime quality-adjusted life-years (QALYs) at a cost of $2.4 million, compared with 16.0 discounted lifetime QALYs at a cost of $1.1 million for standard care.

Under traditional cost-effectiveness calculations, the upper limit of the incremental cost-effectiveness ratio (ICER) is estimated to be $100,000 per QALY. Under this scenario, the ICER of gene therapy for SCD at $144,000 per QALY would be considered by health economists or insurers to be too steep a price to pay.

However, applying equity weighting to the formula would bring the price of gene therapy into the $1.4 million to $3 million range.

Dr. Goshua acknowledged that the study is limited by the assumption that gene therapy would be a one-time cost and that patients would not need to undergo repeat therapy or treatment for relapses.

Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle, and a former ASH president, who moderated a briefing the day before Dr. Goshua presented his data, recommended that he and his colleagues use their technique to explore other health inequities, such as in the care of patients with multiple myeloma.

“There’s some evidence that Black patients are not using even the agents we have as [are] some of the other groups, so there may be some distributional inequities there as well,” she said.

The study was funded by ASH and the Yale School of Medicine. Dr. Goshua, Dr. Oluwole, and Dr. Lee have disclosed no relevant financial relationships.

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

NEW ORLEANS – A gene therapy made headlines recently for becoming the most expensive pharmaceutical ever launched – the price tag was $3.5 million for a one-off treatment with etranacogene dezaparvovec (Hemgenix) for hemophilia B.

Another gene therapy, a treatment for sickle cell anemia now in late clinical development, is expected to come on the market soon. It, too, is expected to bear an exorbitant price tag.

Such potentially curative therapies put financial pressure on publicly and privately funded health insurance.

However, investigators said that the new treatment for patients with sickle cell disease (SCD) in the United States has the potential to be cost-effective. Those who analyzed the costs used a novel method that takes historical health inequities into account.

“When faced with costs of innovative, one-time-administered therapies, budgetary constraints, as we all know too well, can and have driven therapy availability or lack thereof for patients,” said George Goshua, MD, from the Yale University, New Haven, Conn., speaking here at the annual meeting of the American Society of Hematology.

“We believe that quantitative consideration of health inequities, in addition to the important quality considerations, may be an additional helpful metric in this decision-making context,” he said.

He noted that SCD predominantly affects Black Americans, “who have historically been a very marginalized population when it comes to health care.

“Our study shows that, when we compare the costs of gene therapy and existing standard-of-care treatment for SCD using a technique that accounts for historical health disparities, gene therapy could be an equitable therapeutic strategy for all patients with SCD, whether their disease is mild, moderate, or severe,” he said.

Commenting on the study for this news organization, Bosula Oluwole, MD, from the University of Washington, Seattle, who studies sickle cell disease but was not involved in this study, said the cost-analysis approach taken by Dr. Goshua and colleagues is interesting, but she added: “I think we still have a way to go in trying to fully understand the issue.

“When you look over time at the cost for a patient to get gene therapy vs. the standard of care, it might actually be beneficial to have the gene therapy,” Dr. Oluwole said.

She noted, however, that some patients start gene therapy for SCD at older ages and that it’s important to analyze whether the treatment can still be cost-effective or the best therapeutic option for such patients.
 

Adding a D to CEA

Dr. Goshua and colleagues at Yale University and the Harvard T.H. Chan School of Public Health in Boston conducted what they believe is the first study in hematology to use distributional cost-effectiveness analysis (DCEA), developed at the University of York, England.

A University of York website explains that DCEA “is a general umbrella term for economic evaluation studies that provide information about equity in the distribution of costs and effects as well as efficiency in terms of aggregate costs and effects. DCEA can provide distributional breakdowns of who gains most and who bears the largest burdens (opportunity costs) by equity-relevant social variables (e.g., socioeconomic status, ethnicity, location) and disease categories (e.g., severity of illness, rarity, disability).”

The technique can also employ equity weight to evaluate trade-offs between equity and efficiency, the website says.

As Dr. Goshua put it, equity weighting is “a way of quantifying how much we prioritize health care equity.”
 

QALYs considered

Dr. Goshua and colleagues included equity weight in an analysis of 10 years of data on annual health care costs for patients with SCD who were covered by private insurance and were treated with medications (for example, hydroxyurea), antibiotics, blood transfusion, and hematopoietic stem cell transplants. Sex and the frequency of hospitalizations for acute pain crises were factors in the Markov model they created.

The model assumes that a single course of gene therapy for SCD would cost $2.1 million. The estimate was based on the cost of U.S. Food and Drug Administration–approved gene therapies, and it was assumed that the therapy would result in permanent disease remission for all patients.

In addition, the model assumed that all eligible patients in the United States with SCD who are aged 12 years and older would be offered the gene therapy.

In their base-case analysis, gene therapy starting at age 12 would yield 25.5 discounted lifetime quality-adjusted life-years (QALYs) at a cost of $2.4 million, compared with 16.0 discounted lifetime QALYs at a cost of $1.1 million for standard care.

Under traditional cost-effectiveness calculations, the upper limit of the incremental cost-effectiveness ratio (ICER) is estimated to be $100,000 per QALY. Under this scenario, the ICER of gene therapy for SCD at $144,000 per QALY would be considered by health economists or insurers to be too steep a price to pay.

However, applying equity weighting to the formula would bring the price of gene therapy into the $1.4 million to $3 million range.

Dr. Goshua acknowledged that the study is limited by the assumption that gene therapy would be a one-time cost and that patients would not need to undergo repeat therapy or treatment for relapses.

Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle, and a former ASH president, who moderated a briefing the day before Dr. Goshua presented his data, recommended that he and his colleagues use their technique to explore other health inequities, such as in the care of patients with multiple myeloma.

“There’s some evidence that Black patients are not using even the agents we have as [are] some of the other groups, so there may be some distributional inequities there as well,” she said.

The study was funded by ASH and the Yale School of Medicine. Dr. Goshua, Dr. Oluwole, and Dr. Lee have disclosed no relevant financial relationships.

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

NEW ORLEANS – A gene therapy made headlines recently for becoming the most expensive pharmaceutical ever launched – the price tag was $3.5 million for a one-off treatment with etranacogene dezaparvovec (Hemgenix) for hemophilia B.

Another gene therapy, a treatment for sickle cell anemia now in late clinical development, is expected to come on the market soon. It, too, is expected to bear an exorbitant price tag.

Such potentially curative therapies put financial pressure on publicly and privately funded health insurance.

However, investigators said that the new treatment for patients with sickle cell disease (SCD) in the United States has the potential to be cost-effective. Those who analyzed the costs used a novel method that takes historical health inequities into account.

“When faced with costs of innovative, one-time-administered therapies, budgetary constraints, as we all know too well, can and have driven therapy availability or lack thereof for patients,” said George Goshua, MD, from the Yale University, New Haven, Conn., speaking here at the annual meeting of the American Society of Hematology.

“We believe that quantitative consideration of health inequities, in addition to the important quality considerations, may be an additional helpful metric in this decision-making context,” he said.

He noted that SCD predominantly affects Black Americans, “who have historically been a very marginalized population when it comes to health care.

“Our study shows that, when we compare the costs of gene therapy and existing standard-of-care treatment for SCD using a technique that accounts for historical health disparities, gene therapy could be an equitable therapeutic strategy for all patients with SCD, whether their disease is mild, moderate, or severe,” he said.

Commenting on the study for this news organization, Bosula Oluwole, MD, from the University of Washington, Seattle, who studies sickle cell disease but was not involved in this study, said the cost-analysis approach taken by Dr. Goshua and colleagues is interesting, but she added: “I think we still have a way to go in trying to fully understand the issue.

“When you look over time at the cost for a patient to get gene therapy vs. the standard of care, it might actually be beneficial to have the gene therapy,” Dr. Oluwole said.

She noted, however, that some patients start gene therapy for SCD at older ages and that it’s important to analyze whether the treatment can still be cost-effective or the best therapeutic option for such patients.
 

Adding a D to CEA

Dr. Goshua and colleagues at Yale University and the Harvard T.H. Chan School of Public Health in Boston conducted what they believe is the first study in hematology to use distributional cost-effectiveness analysis (DCEA), developed at the University of York, England.

A University of York website explains that DCEA “is a general umbrella term for economic evaluation studies that provide information about equity in the distribution of costs and effects as well as efficiency in terms of aggregate costs and effects. DCEA can provide distributional breakdowns of who gains most and who bears the largest burdens (opportunity costs) by equity-relevant social variables (e.g., socioeconomic status, ethnicity, location) and disease categories (e.g., severity of illness, rarity, disability).”

The technique can also employ equity weight to evaluate trade-offs between equity and efficiency, the website says.

As Dr. Goshua put it, equity weighting is “a way of quantifying how much we prioritize health care equity.”
 

QALYs considered

Dr. Goshua and colleagues included equity weight in an analysis of 10 years of data on annual health care costs for patients with SCD who were covered by private insurance and were treated with medications (for example, hydroxyurea), antibiotics, blood transfusion, and hematopoietic stem cell transplants. Sex and the frequency of hospitalizations for acute pain crises were factors in the Markov model they created.

The model assumes that a single course of gene therapy for SCD would cost $2.1 million. The estimate was based on the cost of U.S. Food and Drug Administration–approved gene therapies, and it was assumed that the therapy would result in permanent disease remission for all patients.

In addition, the model assumed that all eligible patients in the United States with SCD who are aged 12 years and older would be offered the gene therapy.

In their base-case analysis, gene therapy starting at age 12 would yield 25.5 discounted lifetime quality-adjusted life-years (QALYs) at a cost of $2.4 million, compared with 16.0 discounted lifetime QALYs at a cost of $1.1 million for standard care.

Under traditional cost-effectiveness calculations, the upper limit of the incremental cost-effectiveness ratio (ICER) is estimated to be $100,000 per QALY. Under this scenario, the ICER of gene therapy for SCD at $144,000 per QALY would be considered by health economists or insurers to be too steep a price to pay.

However, applying equity weighting to the formula would bring the price of gene therapy into the $1.4 million to $3 million range.

Dr. Goshua acknowledged that the study is limited by the assumption that gene therapy would be a one-time cost and that patients would not need to undergo repeat therapy or treatment for relapses.

Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle, and a former ASH president, who moderated a briefing the day before Dr. Goshua presented his data, recommended that he and his colleagues use their technique to explore other health inequities, such as in the care of patients with multiple myeloma.

“There’s some evidence that Black patients are not using even the agents we have as [are] some of the other groups, so there may be some distributional inequities there as well,” she said.

The study was funded by ASH and the Yale School of Medicine. Dr. Goshua, Dr. Oluwole, and Dr. Lee have disclosed no relevant financial relationships.

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

The U.S. Food and Drug Administration has approved etranacogene dezaparvovec (Hemgenix), the first gene therapy option for adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.*

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

FDA_icon3_web.jpg

Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.

The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.

Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.

Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.

Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.

Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.

The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.

Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.

This article was updated 11/23/22.

Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.

The U.S. Food and Drug Administration has approved etranacogene dezaparvovec (Hemgenix), the first gene therapy option for adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.*

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

FDA_icon3_web.jpg

Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.

The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.

Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.

Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.

Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.

Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.

The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.

Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.

This article was updated 11/23/22.

Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.

The U.S. Food and Drug Administration has approved etranacogene dezaparvovec (Hemgenix), the first gene therapy option for adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.*

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

FDA_icon3_web.jpg

Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.

The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.

Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.

Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.

Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.

Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.

The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.

Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.

This article was updated 11/23/22.

Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.