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Stroke scale cutoff might not be ideal guide for ordering CTA and detecting large vessel occlusions
BOSTON – (LVO), according to large body of data presented at the 2023 annual meeting of the American Academy of Neurology.
If the goal is not to miss any LVOs, there is no NIHSS score below which these do not occur, according to Theresa Sevilis, DO, regional medical director, TeleSpecialists, Fort Myers, Fla.
For example, her evaluation of a large and nationally representative dataset shows that more than 10% of the LVOs eventually identified and accepted for intervention would be missed with a cutoff of NIHSS score of 6 or higher. Moving the cutoff NIHSS score to 4 or greater, 6% of LVOs among the 23,166 strokes evaluated would have gone undetected.
“The current guidelines do not address low NIHSS score largely due to a paucity of data,” according to Dr. Sevilis, who showed data indicating that there is great variation among institutions in regard to ordering computed tomography angiography (CTA). She indicated that CTA is the current imaging standard for detecting LVO.
Large prospective dataset
The data for this study were derived from the TeleCare database, which captures acute stroke consultations in the emergency departments in 227 facilities in 27 states. Stroke consultations over a 6-month period from July through December 2021 were evaluated. The prospectively collected data were subjected to a multivariate analysis to determine the odds ratio for a CTA performed and LVO found at each NIHSS score of 0 to 5. Scores 6 or above served as the reference.
“Only consults performed within 24 hours [of presentation] were included,” Dr. Sevilis said.
After excluding cases in which no NIHSS score was captured, which represented less than 1% of cases, more than 10,500 cases underwent CTA, providing a rate of 45.5%. The rate of CTA for the whole dataset was 45.5%. Of the study population, 24.6% had a NIHSS score of 6 or above.
“When you are discussing when to perform CTA in patients with a low NIHSS score, you are discussing the majority of patients,” Dr. Sevilis said.
Of those with a NIHSS stroke of 6 or below, 28.2% had a score of 0. Not surprisingly, these were the least likely to have a CTA performed on the basis of an odds ratio of 0.14 and the least likely to have a LVO detected (OR, 0.1). With the exception of a NIHSS stroke score of 1, the likelihood of CTA and LVO climbed incrementally with higher stroke scores. These odds ratios were, respectively, 0.16 and 0.09 for a score of 1; 0.27 and 0.16 for a score of 2; 0.33 and 0.14 for a score of 3; 0.49 and 0.24 for a score of 4; and 0.71 and 0.27 for a score of 5.
In the group with NIHSS score of 6 or above, 24.1% were found to have an LVO. Of these, the proportion accepted for a mechanical thrombectomy was less than half. The intervention acceptance rate for mechanical intervention among LVOs in patients with lower NIHSS scores again fell incrementally by score. The acceptance rate was about 35% among LVO patients with a NIHSS score of 3 or 4 and 25% for those with a score of 0-2.
The interpretation of these data “depends on goals,” Dr. Sevilis said. “If the goal is to not miss a single LVO, then it is important to consider the balance between benefits and risks.”
No consistent cutoff
In participating facilities, the protocol for considering CTA to detect and treat LVOs ranges from neurologist choice to cutoffs of NIHSS scores of 2, 4, and 6, according to Dr. Sevilis. Where the data suggest that a cutoff of 4 or above might be reasonable, she said that NIHSS scoring is not a useful tool for those “who do not want to miss any LVOs.”
These data are based on emergency room stroke consultations and not on confirmed strokes,” Dr. Sevilis emphasized. Indeed, she noted that the final discharge diagnosis was not available. Recognizing that the analysis was not performed on a population with confirmed strokes is particularly important for understanding the limited rate of CTAs performed even in those with relatively high NIHSS scores. She noted this could be explained by many different reasons, including suspicion of hemorrhage or clinical features that took the workup in a different direction.
Reconsidering protocols
Based on the large sample size, Dr. Sevilis contended that it is likely that these data are representative, but she considers this study a first step toward considering protocols and developing guidelines for addressing stroke alerts in the emergency department.
A more important step will be ongoing trials designed specifically to generate data to answer this question. Pascal Jabbour, MD, chief of the division of neurovascular and endovascular neurosurgery, Thomas Jefferson University Hospitals, Philadelphia, is participating in one of these trials. He agreed with the premise that better evidence-based criteria are needed when evaluating acute stroke patients with a potential LVO.
The trial in which he is a coinvestigator, called ENDOLOW, is testing the hypothesis that outcomes will be better if acute stroke patients with a LVO and a low baseline NIHSS score (< 5) are treated with immediate thrombectomy rather than medical management. If this hypothesis is confirmed in the randomized ENDOLOW, it will provide an evidence basis for an approach already being practiced at some centers.
“There should be a very low threshold for CTA,” said Dr. Jabbour in an interview. This imaging “takes less than 2 minutes and it can provide the basis for a life-saving endovascular thrombectomy if a LVO is found.”
It is already well known that LVO is not restricted only to patients with an elevated NIHSS score, he said.
For determining whether to order a CTA, “I do not agree with NIHSS score of 6 or above. There is no absolute number below which risk of missing a LVO is eliminated,” Dr. Jabbour said. He also argued against relying on NIHSS score without considering other clinical features, particularly cortical signs, which should raise suspicion of a LVO regardless of NIHSS score.
One problem is that NIHSS scores are not static. Decompensation can be rapid with the NIHSS score quickly climbing. When this happens, the delay in treatment might lead to a preventable adverse outcome.
“There is a change in the paradigm now that we have more evidence of a benefit from aggressive treatment in the right candidates,” according to Dr. Jabbour, referring to the recently published SELECT2 trial. In that trial, on which Dr. Jabbour served as a coauthor, patients with LVO and large territory infarct were randomized to thrombectomy or medical care within 24 hours of a stroke. It was stopped early for efficacy because of the increased functional independence (20% vs. 7%) in the surgical intervention group.
If the ongoing trials establish better criteria for ruling in or out the presence of LVO in patients with acute stroke, Dr. Jabbour predicted that guidelines will be written to standardize practice.
Dr. Sevilis reports no potential conflicts of interest. Dr. Jabbour has financial relationships with Cerenovus, Medtronic, and Microvention.
BOSTON – (LVO), according to large body of data presented at the 2023 annual meeting of the American Academy of Neurology.
If the goal is not to miss any LVOs, there is no NIHSS score below which these do not occur, according to Theresa Sevilis, DO, regional medical director, TeleSpecialists, Fort Myers, Fla.
For example, her evaluation of a large and nationally representative dataset shows that more than 10% of the LVOs eventually identified and accepted for intervention would be missed with a cutoff of NIHSS score of 6 or higher. Moving the cutoff NIHSS score to 4 or greater, 6% of LVOs among the 23,166 strokes evaluated would have gone undetected.
“The current guidelines do not address low NIHSS score largely due to a paucity of data,” according to Dr. Sevilis, who showed data indicating that there is great variation among institutions in regard to ordering computed tomography angiography (CTA). She indicated that CTA is the current imaging standard for detecting LVO.
Large prospective dataset
The data for this study were derived from the TeleCare database, which captures acute stroke consultations in the emergency departments in 227 facilities in 27 states. Stroke consultations over a 6-month period from July through December 2021 were evaluated. The prospectively collected data were subjected to a multivariate analysis to determine the odds ratio for a CTA performed and LVO found at each NIHSS score of 0 to 5. Scores 6 or above served as the reference.
“Only consults performed within 24 hours [of presentation] were included,” Dr. Sevilis said.
After excluding cases in which no NIHSS score was captured, which represented less than 1% of cases, more than 10,500 cases underwent CTA, providing a rate of 45.5%. The rate of CTA for the whole dataset was 45.5%. Of the study population, 24.6% had a NIHSS score of 6 or above.
“When you are discussing when to perform CTA in patients with a low NIHSS score, you are discussing the majority of patients,” Dr. Sevilis said.
Of those with a NIHSS stroke of 6 or below, 28.2% had a score of 0. Not surprisingly, these were the least likely to have a CTA performed on the basis of an odds ratio of 0.14 and the least likely to have a LVO detected (OR, 0.1). With the exception of a NIHSS stroke score of 1, the likelihood of CTA and LVO climbed incrementally with higher stroke scores. These odds ratios were, respectively, 0.16 and 0.09 for a score of 1; 0.27 and 0.16 for a score of 2; 0.33 and 0.14 for a score of 3; 0.49 and 0.24 for a score of 4; and 0.71 and 0.27 for a score of 5.
In the group with NIHSS score of 6 or above, 24.1% were found to have an LVO. Of these, the proportion accepted for a mechanical thrombectomy was less than half. The intervention acceptance rate for mechanical intervention among LVOs in patients with lower NIHSS scores again fell incrementally by score. The acceptance rate was about 35% among LVO patients with a NIHSS score of 3 or 4 and 25% for those with a score of 0-2.
The interpretation of these data “depends on goals,” Dr. Sevilis said. “If the goal is to not miss a single LVO, then it is important to consider the balance between benefits and risks.”
No consistent cutoff
In participating facilities, the protocol for considering CTA to detect and treat LVOs ranges from neurologist choice to cutoffs of NIHSS scores of 2, 4, and 6, according to Dr. Sevilis. Where the data suggest that a cutoff of 4 or above might be reasonable, she said that NIHSS scoring is not a useful tool for those “who do not want to miss any LVOs.”
These data are based on emergency room stroke consultations and not on confirmed strokes,” Dr. Sevilis emphasized. Indeed, she noted that the final discharge diagnosis was not available. Recognizing that the analysis was not performed on a population with confirmed strokes is particularly important for understanding the limited rate of CTAs performed even in those with relatively high NIHSS scores. She noted this could be explained by many different reasons, including suspicion of hemorrhage or clinical features that took the workup in a different direction.
Reconsidering protocols
Based on the large sample size, Dr. Sevilis contended that it is likely that these data are representative, but she considers this study a first step toward considering protocols and developing guidelines for addressing stroke alerts in the emergency department.
A more important step will be ongoing trials designed specifically to generate data to answer this question. Pascal Jabbour, MD, chief of the division of neurovascular and endovascular neurosurgery, Thomas Jefferson University Hospitals, Philadelphia, is participating in one of these trials. He agreed with the premise that better evidence-based criteria are needed when evaluating acute stroke patients with a potential LVO.
The trial in which he is a coinvestigator, called ENDOLOW, is testing the hypothesis that outcomes will be better if acute stroke patients with a LVO and a low baseline NIHSS score (< 5) are treated with immediate thrombectomy rather than medical management. If this hypothesis is confirmed in the randomized ENDOLOW, it will provide an evidence basis for an approach already being practiced at some centers.
“There should be a very low threshold for CTA,” said Dr. Jabbour in an interview. This imaging “takes less than 2 minutes and it can provide the basis for a life-saving endovascular thrombectomy if a LVO is found.”
It is already well known that LVO is not restricted only to patients with an elevated NIHSS score, he said.
For determining whether to order a CTA, “I do not agree with NIHSS score of 6 or above. There is no absolute number below which risk of missing a LVO is eliminated,” Dr. Jabbour said. He also argued against relying on NIHSS score without considering other clinical features, particularly cortical signs, which should raise suspicion of a LVO regardless of NIHSS score.
One problem is that NIHSS scores are not static. Decompensation can be rapid with the NIHSS score quickly climbing. When this happens, the delay in treatment might lead to a preventable adverse outcome.
“There is a change in the paradigm now that we have more evidence of a benefit from aggressive treatment in the right candidates,” according to Dr. Jabbour, referring to the recently published SELECT2 trial. In that trial, on which Dr. Jabbour served as a coauthor, patients with LVO and large territory infarct were randomized to thrombectomy or medical care within 24 hours of a stroke. It was stopped early for efficacy because of the increased functional independence (20% vs. 7%) in the surgical intervention group.
If the ongoing trials establish better criteria for ruling in or out the presence of LVO in patients with acute stroke, Dr. Jabbour predicted that guidelines will be written to standardize practice.
Dr. Sevilis reports no potential conflicts of interest. Dr. Jabbour has financial relationships with Cerenovus, Medtronic, and Microvention.
BOSTON – (LVO), according to large body of data presented at the 2023 annual meeting of the American Academy of Neurology.
If the goal is not to miss any LVOs, there is no NIHSS score below which these do not occur, according to Theresa Sevilis, DO, regional medical director, TeleSpecialists, Fort Myers, Fla.
For example, her evaluation of a large and nationally representative dataset shows that more than 10% of the LVOs eventually identified and accepted for intervention would be missed with a cutoff of NIHSS score of 6 or higher. Moving the cutoff NIHSS score to 4 or greater, 6% of LVOs among the 23,166 strokes evaluated would have gone undetected.
“The current guidelines do not address low NIHSS score largely due to a paucity of data,” according to Dr. Sevilis, who showed data indicating that there is great variation among institutions in regard to ordering computed tomography angiography (CTA). She indicated that CTA is the current imaging standard for detecting LVO.
Large prospective dataset
The data for this study were derived from the TeleCare database, which captures acute stroke consultations in the emergency departments in 227 facilities in 27 states. Stroke consultations over a 6-month period from July through December 2021 were evaluated. The prospectively collected data were subjected to a multivariate analysis to determine the odds ratio for a CTA performed and LVO found at each NIHSS score of 0 to 5. Scores 6 or above served as the reference.
“Only consults performed within 24 hours [of presentation] were included,” Dr. Sevilis said.
After excluding cases in which no NIHSS score was captured, which represented less than 1% of cases, more than 10,500 cases underwent CTA, providing a rate of 45.5%. The rate of CTA for the whole dataset was 45.5%. Of the study population, 24.6% had a NIHSS score of 6 or above.
“When you are discussing when to perform CTA in patients with a low NIHSS score, you are discussing the majority of patients,” Dr. Sevilis said.
Of those with a NIHSS stroke of 6 or below, 28.2% had a score of 0. Not surprisingly, these were the least likely to have a CTA performed on the basis of an odds ratio of 0.14 and the least likely to have a LVO detected (OR, 0.1). With the exception of a NIHSS stroke score of 1, the likelihood of CTA and LVO climbed incrementally with higher stroke scores. These odds ratios were, respectively, 0.16 and 0.09 for a score of 1; 0.27 and 0.16 for a score of 2; 0.33 and 0.14 for a score of 3; 0.49 and 0.24 for a score of 4; and 0.71 and 0.27 for a score of 5.
In the group with NIHSS score of 6 or above, 24.1% were found to have an LVO. Of these, the proportion accepted for a mechanical thrombectomy was less than half. The intervention acceptance rate for mechanical intervention among LVOs in patients with lower NIHSS scores again fell incrementally by score. The acceptance rate was about 35% among LVO patients with a NIHSS score of 3 or 4 and 25% for those with a score of 0-2.
The interpretation of these data “depends on goals,” Dr. Sevilis said. “If the goal is to not miss a single LVO, then it is important to consider the balance between benefits and risks.”
No consistent cutoff
In participating facilities, the protocol for considering CTA to detect and treat LVOs ranges from neurologist choice to cutoffs of NIHSS scores of 2, 4, and 6, according to Dr. Sevilis. Where the data suggest that a cutoff of 4 or above might be reasonable, she said that NIHSS scoring is not a useful tool for those “who do not want to miss any LVOs.”
These data are based on emergency room stroke consultations and not on confirmed strokes,” Dr. Sevilis emphasized. Indeed, she noted that the final discharge diagnosis was not available. Recognizing that the analysis was not performed on a population with confirmed strokes is particularly important for understanding the limited rate of CTAs performed even in those with relatively high NIHSS scores. She noted this could be explained by many different reasons, including suspicion of hemorrhage or clinical features that took the workup in a different direction.
Reconsidering protocols
Based on the large sample size, Dr. Sevilis contended that it is likely that these data are representative, but she considers this study a first step toward considering protocols and developing guidelines for addressing stroke alerts in the emergency department.
A more important step will be ongoing trials designed specifically to generate data to answer this question. Pascal Jabbour, MD, chief of the division of neurovascular and endovascular neurosurgery, Thomas Jefferson University Hospitals, Philadelphia, is participating in one of these trials. He agreed with the premise that better evidence-based criteria are needed when evaluating acute stroke patients with a potential LVO.
The trial in which he is a coinvestigator, called ENDOLOW, is testing the hypothesis that outcomes will be better if acute stroke patients with a LVO and a low baseline NIHSS score (< 5) are treated with immediate thrombectomy rather than medical management. If this hypothesis is confirmed in the randomized ENDOLOW, it will provide an evidence basis for an approach already being practiced at some centers.
“There should be a very low threshold for CTA,” said Dr. Jabbour in an interview. This imaging “takes less than 2 minutes and it can provide the basis for a life-saving endovascular thrombectomy if a LVO is found.”
It is already well known that LVO is not restricted only to patients with an elevated NIHSS score, he said.
For determining whether to order a CTA, “I do not agree with NIHSS score of 6 or above. There is no absolute number below which risk of missing a LVO is eliminated,” Dr. Jabbour said. He also argued against relying on NIHSS score without considering other clinical features, particularly cortical signs, which should raise suspicion of a LVO regardless of NIHSS score.
One problem is that NIHSS scores are not static. Decompensation can be rapid with the NIHSS score quickly climbing. When this happens, the delay in treatment might lead to a preventable adverse outcome.
“There is a change in the paradigm now that we have more evidence of a benefit from aggressive treatment in the right candidates,” according to Dr. Jabbour, referring to the recently published SELECT2 trial. In that trial, on which Dr. Jabbour served as a coauthor, patients with LVO and large territory infarct were randomized to thrombectomy or medical care within 24 hours of a stroke. It was stopped early for efficacy because of the increased functional independence (20% vs. 7%) in the surgical intervention group.
If the ongoing trials establish better criteria for ruling in or out the presence of LVO in patients with acute stroke, Dr. Jabbour predicted that guidelines will be written to standardize practice.
Dr. Sevilis reports no potential conflicts of interest. Dr. Jabbour has financial relationships with Cerenovus, Medtronic, and Microvention.
FROM AAN 2023
Teriflunomide delays MS symptoms in radiologically isolated syndrome
BOSTON – , according to a double-blind, phase 3 trial presented in the Emerging Science session of the 2023 annual meeting of the American Academy of Neurology.
“These data add to the evidence that early immunomodulation offers clinical benefit even in the presymptomatic phase of MS,” reported Christine Lebrun-Frenay, MD, PhD, head of inflammatory neurological disorders research unit, University of Nice, France. This is the second study to show a benefit from a disease-modifying therapy in asymptomatic RIS patients. The ARISE study, which was presented at the 2022 European Committee for Treatment and Research in MS and has now been published, compared 240 mg of twice-daily dimethyl fumarate with placebo. Dimethyl fumarate was associated with an 82% (hazard ratio, 0.18; P = .007) reduction in the risk of a first demyelinating event after 96 weeks of follow-up.
TERIS trial data
In the new study, called TERIS, the design and outcomes were similar to the ARISE study. Eighty-nine patients meeting standard criteria for RIS were randomized to 14 mg of once-daily teriflunomide or placebo. The majority (71%) were female, and the mean age was 39.8 years. At the time of RIS diagnosis, the mean age was 38 years. At study entry, standardized MRI studies were performed of the brain and spinal cord.
During 2 years of follow-up, 8 of 28 demyelinating events were observed in the active treatment group. The remaining 20 occurred in the placebo group. This translated to a 63% reduction (HR, 0.37; P = .018) in favor of teriflunomide. When graphed, the curves separated at about 6 months and then widened progressively over time.
Distinct from clinically isolated syndrome (CIS), which describes individuals who have a symptomatic episode consistent with a demyelinating event, RIS is based primarily on an MRI that shows lesions highly suggestive of MS. Neither confirms the MS diagnosis, but both are associated with a high likelihood of eventually meeting MS diagnostic criteria. The ARISE and TERIS studies now support therapy to delay demyelinating events.
“With more and more people having brain scans for various reasons, such as headache or head trauma, more of these cases are being discovered,” Dr. Lebrun-Frenay said.
Caution warranted when interpreting the findings
The data support the theory that treatment should begin early in patients with a high likelihood of developing symptomatic MS on the basis of brain lesions. It is logical to assume that preventing damage to the myelin will reduce or delay permanent symptoms and permanent neurologic impairment, but Dr. Lebrun-Frenay suggested that the available data from ARISE and TERIS are not practice changing even though both were multicenter double-blind trials.
“More data from larger groups of patients are needed to confirm the findings,” she said. She expressed concern about not adhering to strict criteria to diagnosis RIS.
“It is important that medical professionals are cautious,” she said, citing the risk of misdiagnosis of pathology of MRI that leads to treatment of patients with a low risk of developing symptomatic MS.
Teriflunomide and dimethyl fumarate, which have long been available as first-line therapies in relapsing-remitting MS, are generally well tolerated. In the TERIS and ARISE studies, mild or moderate events occurred more commonly in the active treatment than the placebo arms, but there were no serious adverse events. However, both can produce more serious adverse events, which, in the case of teriflunomide, include liver toxicity leading to injury and liver failure.
Challenging the traditional definition of MS
The author of the ARISE study, Darin T. Okuda, MD, a professor of neurology at the UT Southwestern Medical Center, Dallas, indicated that his study, now reinforced by the TERIS study, challenges the definition of MS.
“Both ARISE and TERIS demonstrated a significant reduction in seminal clinical event rates related to inflammatory demyelination,” Dr. Okuda said in an interview. They provide evidence that patients are at high risk of the demyelinating events that characterize MS. Given the potential difficulty for accessing therapies of benefit, “how we define multiple sclerosis is highly important.”
“Individuals of younger age with abnormal spinal cord MRI studies along with other paraclinical features related to risk for a first event may be the most ideal group to treat,” he said. However, he agreed with Dr. Lebrun-Frenay that it is not yet clear which RIS patients are the most appropriate candidates.
“Gaining a more refined sense of who we should treat will require more work,” he said.
These data are likely to change the orientation toward RIS, according to Melina Hosseiny, MD, department of radiology, University of California, Los Angeles, Medical Center. She noted that the relationship between RIS and increased risk of MS has long been recognized, and the risk increases with specific features on imaging.
“Studies have shown that spinal cord lesions are associated with a greater than 50% chance of converting to MS,” said Dr. Hosseiny, who was the lead author of a review article on RIS. “Identifying such imaging findings can help identify patients who may benefit from disease-modifying medications.”
Dr. Lebrun-Frenay reports no potential conflicts of interest. Dr. Okuda has financial relationships with Alexion, Biogen, Celgene, EMD Serono, Genzyme, TG Therapeutics, and VielaBio. Dr. Hosseiny reports no potential conflicts of interest.
BOSTON – , according to a double-blind, phase 3 trial presented in the Emerging Science session of the 2023 annual meeting of the American Academy of Neurology.
“These data add to the evidence that early immunomodulation offers clinical benefit even in the presymptomatic phase of MS,” reported Christine Lebrun-Frenay, MD, PhD, head of inflammatory neurological disorders research unit, University of Nice, France. This is the second study to show a benefit from a disease-modifying therapy in asymptomatic RIS patients. The ARISE study, which was presented at the 2022 European Committee for Treatment and Research in MS and has now been published, compared 240 mg of twice-daily dimethyl fumarate with placebo. Dimethyl fumarate was associated with an 82% (hazard ratio, 0.18; P = .007) reduction in the risk of a first demyelinating event after 96 weeks of follow-up.
TERIS trial data
In the new study, called TERIS, the design and outcomes were similar to the ARISE study. Eighty-nine patients meeting standard criteria for RIS were randomized to 14 mg of once-daily teriflunomide or placebo. The majority (71%) were female, and the mean age was 39.8 years. At the time of RIS diagnosis, the mean age was 38 years. At study entry, standardized MRI studies were performed of the brain and spinal cord.
During 2 years of follow-up, 8 of 28 demyelinating events were observed in the active treatment group. The remaining 20 occurred in the placebo group. This translated to a 63% reduction (HR, 0.37; P = .018) in favor of teriflunomide. When graphed, the curves separated at about 6 months and then widened progressively over time.
Distinct from clinically isolated syndrome (CIS), which describes individuals who have a symptomatic episode consistent with a demyelinating event, RIS is based primarily on an MRI that shows lesions highly suggestive of MS. Neither confirms the MS diagnosis, but both are associated with a high likelihood of eventually meeting MS diagnostic criteria. The ARISE and TERIS studies now support therapy to delay demyelinating events.
“With more and more people having brain scans for various reasons, such as headache or head trauma, more of these cases are being discovered,” Dr. Lebrun-Frenay said.
Caution warranted when interpreting the findings
The data support the theory that treatment should begin early in patients with a high likelihood of developing symptomatic MS on the basis of brain lesions. It is logical to assume that preventing damage to the myelin will reduce or delay permanent symptoms and permanent neurologic impairment, but Dr. Lebrun-Frenay suggested that the available data from ARISE and TERIS are not practice changing even though both were multicenter double-blind trials.
“More data from larger groups of patients are needed to confirm the findings,” she said. She expressed concern about not adhering to strict criteria to diagnosis RIS.
“It is important that medical professionals are cautious,” she said, citing the risk of misdiagnosis of pathology of MRI that leads to treatment of patients with a low risk of developing symptomatic MS.
Teriflunomide and dimethyl fumarate, which have long been available as first-line therapies in relapsing-remitting MS, are generally well tolerated. In the TERIS and ARISE studies, mild or moderate events occurred more commonly in the active treatment than the placebo arms, but there were no serious adverse events. However, both can produce more serious adverse events, which, in the case of teriflunomide, include liver toxicity leading to injury and liver failure.
Challenging the traditional definition of MS
The author of the ARISE study, Darin T. Okuda, MD, a professor of neurology at the UT Southwestern Medical Center, Dallas, indicated that his study, now reinforced by the TERIS study, challenges the definition of MS.
“Both ARISE and TERIS demonstrated a significant reduction in seminal clinical event rates related to inflammatory demyelination,” Dr. Okuda said in an interview. They provide evidence that patients are at high risk of the demyelinating events that characterize MS. Given the potential difficulty for accessing therapies of benefit, “how we define multiple sclerosis is highly important.”
“Individuals of younger age with abnormal spinal cord MRI studies along with other paraclinical features related to risk for a first event may be the most ideal group to treat,” he said. However, he agreed with Dr. Lebrun-Frenay that it is not yet clear which RIS patients are the most appropriate candidates.
“Gaining a more refined sense of who we should treat will require more work,” he said.
These data are likely to change the orientation toward RIS, according to Melina Hosseiny, MD, department of radiology, University of California, Los Angeles, Medical Center. She noted that the relationship between RIS and increased risk of MS has long been recognized, and the risk increases with specific features on imaging.
“Studies have shown that spinal cord lesions are associated with a greater than 50% chance of converting to MS,” said Dr. Hosseiny, who was the lead author of a review article on RIS. “Identifying such imaging findings can help identify patients who may benefit from disease-modifying medications.”
Dr. Lebrun-Frenay reports no potential conflicts of interest. Dr. Okuda has financial relationships with Alexion, Biogen, Celgene, EMD Serono, Genzyme, TG Therapeutics, and VielaBio. Dr. Hosseiny reports no potential conflicts of interest.
BOSTON – , according to a double-blind, phase 3 trial presented in the Emerging Science session of the 2023 annual meeting of the American Academy of Neurology.
“These data add to the evidence that early immunomodulation offers clinical benefit even in the presymptomatic phase of MS,” reported Christine Lebrun-Frenay, MD, PhD, head of inflammatory neurological disorders research unit, University of Nice, France. This is the second study to show a benefit from a disease-modifying therapy in asymptomatic RIS patients. The ARISE study, which was presented at the 2022 European Committee for Treatment and Research in MS and has now been published, compared 240 mg of twice-daily dimethyl fumarate with placebo. Dimethyl fumarate was associated with an 82% (hazard ratio, 0.18; P = .007) reduction in the risk of a first demyelinating event after 96 weeks of follow-up.
TERIS trial data
In the new study, called TERIS, the design and outcomes were similar to the ARISE study. Eighty-nine patients meeting standard criteria for RIS were randomized to 14 mg of once-daily teriflunomide or placebo. The majority (71%) were female, and the mean age was 39.8 years. At the time of RIS diagnosis, the mean age was 38 years. At study entry, standardized MRI studies were performed of the brain and spinal cord.
During 2 years of follow-up, 8 of 28 demyelinating events were observed in the active treatment group. The remaining 20 occurred in the placebo group. This translated to a 63% reduction (HR, 0.37; P = .018) in favor of teriflunomide. When graphed, the curves separated at about 6 months and then widened progressively over time.
Distinct from clinically isolated syndrome (CIS), which describes individuals who have a symptomatic episode consistent with a demyelinating event, RIS is based primarily on an MRI that shows lesions highly suggestive of MS. Neither confirms the MS diagnosis, but both are associated with a high likelihood of eventually meeting MS diagnostic criteria. The ARISE and TERIS studies now support therapy to delay demyelinating events.
“With more and more people having brain scans for various reasons, such as headache or head trauma, more of these cases are being discovered,” Dr. Lebrun-Frenay said.
Caution warranted when interpreting the findings
The data support the theory that treatment should begin early in patients with a high likelihood of developing symptomatic MS on the basis of brain lesions. It is logical to assume that preventing damage to the myelin will reduce or delay permanent symptoms and permanent neurologic impairment, but Dr. Lebrun-Frenay suggested that the available data from ARISE and TERIS are not practice changing even though both were multicenter double-blind trials.
“More data from larger groups of patients are needed to confirm the findings,” she said. She expressed concern about not adhering to strict criteria to diagnosis RIS.
“It is important that medical professionals are cautious,” she said, citing the risk of misdiagnosis of pathology of MRI that leads to treatment of patients with a low risk of developing symptomatic MS.
Teriflunomide and dimethyl fumarate, which have long been available as first-line therapies in relapsing-remitting MS, are generally well tolerated. In the TERIS and ARISE studies, mild or moderate events occurred more commonly in the active treatment than the placebo arms, but there were no serious adverse events. However, both can produce more serious adverse events, which, in the case of teriflunomide, include liver toxicity leading to injury and liver failure.
Challenging the traditional definition of MS
The author of the ARISE study, Darin T. Okuda, MD, a professor of neurology at the UT Southwestern Medical Center, Dallas, indicated that his study, now reinforced by the TERIS study, challenges the definition of MS.
“Both ARISE and TERIS demonstrated a significant reduction in seminal clinical event rates related to inflammatory demyelination,” Dr. Okuda said in an interview. They provide evidence that patients are at high risk of the demyelinating events that characterize MS. Given the potential difficulty for accessing therapies of benefit, “how we define multiple sclerosis is highly important.”
“Individuals of younger age with abnormal spinal cord MRI studies along with other paraclinical features related to risk for a first event may be the most ideal group to treat,” he said. However, he agreed with Dr. Lebrun-Frenay that it is not yet clear which RIS patients are the most appropriate candidates.
“Gaining a more refined sense of who we should treat will require more work,” he said.
These data are likely to change the orientation toward RIS, according to Melina Hosseiny, MD, department of radiology, University of California, Los Angeles, Medical Center. She noted that the relationship between RIS and increased risk of MS has long been recognized, and the risk increases with specific features on imaging.
“Studies have shown that spinal cord lesions are associated with a greater than 50% chance of converting to MS,” said Dr. Hosseiny, who was the lead author of a review article on RIS. “Identifying such imaging findings can help identify patients who may benefit from disease-modifying medications.”
Dr. Lebrun-Frenay reports no potential conflicts of interest. Dr. Okuda has financial relationships with Alexion, Biogen, Celgene, EMD Serono, Genzyme, TG Therapeutics, and VielaBio. Dr. Hosseiny reports no potential conflicts of interest.
AT AAN 2023
Novel levodopa delivery system promises continuous dosing without surgery or pump
BOSTON – , according to an early clinical experience described in the Emerging Science session at the 2023 annual meeting of the American Academy of Neurology.
On this device, the attenuation of levodopa fluctuations “translated into dramatic improvements in clinical behavior, including highly significant reductions in OFF time and an increase in ON time with no dyskinesias,” reported C. Warren Olanow, MD, who is a chairman emeritus of the department of neurology at the Icahn School of Medicine at Mount Sinai, New York, and now an employee of the company developing this new device.
A novel strategy
Numerous studies have demonstrated that reductions in the troughs of plasma levodopa associated with oral dosing result in longer ON time with fewer dyskinesias, according to Dr. Olanow, who explained this has led to strategies for numerous strategies to achieve continuous delivery. A device that delivers levodopa into the stomach through a surgically implanted catheter has already received regulatory approval. Other devices delivering levodopa subcutaneously are in development, but Dr. Olanow said each of these has had limitations.
“The problem with these approaches is they are associated with potentially serious side effects and they require the patient to wear a cumbersome device,” he explained. Relative to the subcutaneous delivery systems, which have been associated with injection site reactions that include painful nodules, and the surgically implanted devices, which also require an external pump, the latest strategy avoids both disadvantages.
Called DopaFuse, the experimental device is designed to deliver the levodopa and carbidopa into the mouth through a micropump within a wearable retainer. Dr. Olanow said that previous experimental studies demonstrated that small doses of levodopa delivered by mouth to the gastrointestinal system reduce levodopa plasma variability. This early clinical study supports that premise. Levodopa delivered into the mouth by way of a propellant in the retainer-mounted pump improved clinical endpoints.
Encouraging trial results
In the study, 16 patients between the ages of 30 and 75 with Parkinson’s disease were enrolled. On day 1, they received an oral dose of levodopa/carbidopa consistent with their current treatment. On day 2, levodopa/carbidopa was delivered through the retainer-mounted device at equivalent doses. On day 3, they received a single morning oral dose and the received the remainder of their levodopa/carbidopa regimen through the device. On days 4 to 14, they received treatment in the same schedule as day 3.
When pharmacokinetics of levodopa on day 3 were compared with those on day 1, the fluctuation index and coefficient of levodopa concentration variability was reduced to a degree that was highly statistically significant (P < .0001). This, in turn, correlated with “striking” reductions in OFF time with equally statistically significant improvement in ON time and ON time without dyskinesias, according to Dr. Olanow.
Relative to an OFF time of 3.2 hours on day 1, the OFF time of 1.6 hours on day 3 represented a 50% reduction (P < .0001). ON time improved from 12.8 hours to 14.5 hours (P < .001). ON time without dyskinesias improved numerically from 8.8 hours to 9.6 hours.
“There were also improvements in activities of daily living when patients were on DopaFuse, which is a hard endpoint to reach in a study with such a small sample size,” Dr. Olanow reported.
There were no serious adverse events. Three patients reported vomiting and two patients each reported headache, but these events were mild and all resolved within a day. Three patients reported buccal lesions, but these also resolved within a day.
“Some patients reported trouble with speaking in the beginning but at the end of the study, patients were reporting that it was easier to speak because of the motor improvements,” Dr. Olanow said.
Overall, the device was well tolerated by the subjects, providing the evidence for the next stages of clinical studies, reported Dr. Olanow.
“If this turns out to be what we hope it is, it will allow us to deliver levodopa without motor complications, without need for a surgical procedure, and without the risk of subcutaneous lesions,” Dr. Olanow said.
More delivery strategies are needed
This device is in an early phase of development, but several specialists in Parkinson’s disease agreed that there is a need for more strategies to provide continuous levodopa in patients with advancing symptoms. Stuart Isaacson, MD, director, Parkinson’s Disease and Movement Disorders Center of Boca Raton, Fla., is among them.
“Novel delivery devices that can provide more continuous levodopa delivery would be an important therapeutic advance,” Dr. Isaacson said. He called levodopa “the cornerstone of treatment through the course of Parkinson’s disease,” but more physiologic dosing in advancing disease has been a challenge.
“While there are many therapies currently available to manage OFF time, many people living with Parkinson’s disease continue to spend only half of their waking day with good ON time,” he added.
The currently approved method of delivering continuous levodopa through a surgically placed catheter into the gastrointestinal system is effective, but has limitations, according to Aaron L. Ellenbogen, MD, a neurologist at Beaumont Hospital, Farmington Hills, Mich.
“One of the challenges with the current treatment landscape of Parkinson’s disease is that medication can be absorbed variably through the gastrointestinal system,” he said. “As the disease progresses, this often becomes more troublesome.” Although this new device is likely to share this issue, Dr. Ellenbogen said that several devices might be useful to match patients with the one that works best for them.
Dr. Olanow is the founder and CEO of Clintrex Research Corporation, through which he also serves as chief medical officer of SynAgile, the company developing DopaFuse. Dr. Isaacson has financial relationships with more than 30 companies, including those that produce levodopa and levodopa delivery systems. Dr. Ellenbogen has financial relationships with Allergan, Acorda, Supernus, and Teva.
BOSTON – , according to an early clinical experience described in the Emerging Science session at the 2023 annual meeting of the American Academy of Neurology.
On this device, the attenuation of levodopa fluctuations “translated into dramatic improvements in clinical behavior, including highly significant reductions in OFF time and an increase in ON time with no dyskinesias,” reported C. Warren Olanow, MD, who is a chairman emeritus of the department of neurology at the Icahn School of Medicine at Mount Sinai, New York, and now an employee of the company developing this new device.
A novel strategy
Numerous studies have demonstrated that reductions in the troughs of plasma levodopa associated with oral dosing result in longer ON time with fewer dyskinesias, according to Dr. Olanow, who explained this has led to strategies for numerous strategies to achieve continuous delivery. A device that delivers levodopa into the stomach through a surgically implanted catheter has already received regulatory approval. Other devices delivering levodopa subcutaneously are in development, but Dr. Olanow said each of these has had limitations.
“The problem with these approaches is they are associated with potentially serious side effects and they require the patient to wear a cumbersome device,” he explained. Relative to the subcutaneous delivery systems, which have been associated with injection site reactions that include painful nodules, and the surgically implanted devices, which also require an external pump, the latest strategy avoids both disadvantages.
Called DopaFuse, the experimental device is designed to deliver the levodopa and carbidopa into the mouth through a micropump within a wearable retainer. Dr. Olanow said that previous experimental studies demonstrated that small doses of levodopa delivered by mouth to the gastrointestinal system reduce levodopa plasma variability. This early clinical study supports that premise. Levodopa delivered into the mouth by way of a propellant in the retainer-mounted pump improved clinical endpoints.
Encouraging trial results
In the study, 16 patients between the ages of 30 and 75 with Parkinson’s disease were enrolled. On day 1, they received an oral dose of levodopa/carbidopa consistent with their current treatment. On day 2, levodopa/carbidopa was delivered through the retainer-mounted device at equivalent doses. On day 3, they received a single morning oral dose and the received the remainder of their levodopa/carbidopa regimen through the device. On days 4 to 14, they received treatment in the same schedule as day 3.
When pharmacokinetics of levodopa on day 3 were compared with those on day 1, the fluctuation index and coefficient of levodopa concentration variability was reduced to a degree that was highly statistically significant (P < .0001). This, in turn, correlated with “striking” reductions in OFF time with equally statistically significant improvement in ON time and ON time without dyskinesias, according to Dr. Olanow.
Relative to an OFF time of 3.2 hours on day 1, the OFF time of 1.6 hours on day 3 represented a 50% reduction (P < .0001). ON time improved from 12.8 hours to 14.5 hours (P < .001). ON time without dyskinesias improved numerically from 8.8 hours to 9.6 hours.
“There were also improvements in activities of daily living when patients were on DopaFuse, which is a hard endpoint to reach in a study with such a small sample size,” Dr. Olanow reported.
There were no serious adverse events. Three patients reported vomiting and two patients each reported headache, but these events were mild and all resolved within a day. Three patients reported buccal lesions, but these also resolved within a day.
“Some patients reported trouble with speaking in the beginning but at the end of the study, patients were reporting that it was easier to speak because of the motor improvements,” Dr. Olanow said.
Overall, the device was well tolerated by the subjects, providing the evidence for the next stages of clinical studies, reported Dr. Olanow.
“If this turns out to be what we hope it is, it will allow us to deliver levodopa without motor complications, without need for a surgical procedure, and without the risk of subcutaneous lesions,” Dr. Olanow said.
More delivery strategies are needed
This device is in an early phase of development, but several specialists in Parkinson’s disease agreed that there is a need for more strategies to provide continuous levodopa in patients with advancing symptoms. Stuart Isaacson, MD, director, Parkinson’s Disease and Movement Disorders Center of Boca Raton, Fla., is among them.
“Novel delivery devices that can provide more continuous levodopa delivery would be an important therapeutic advance,” Dr. Isaacson said. He called levodopa “the cornerstone of treatment through the course of Parkinson’s disease,” but more physiologic dosing in advancing disease has been a challenge.
“While there are many therapies currently available to manage OFF time, many people living with Parkinson’s disease continue to spend only half of their waking day with good ON time,” he added.
The currently approved method of delivering continuous levodopa through a surgically placed catheter into the gastrointestinal system is effective, but has limitations, according to Aaron L. Ellenbogen, MD, a neurologist at Beaumont Hospital, Farmington Hills, Mich.
“One of the challenges with the current treatment landscape of Parkinson’s disease is that medication can be absorbed variably through the gastrointestinal system,” he said. “As the disease progresses, this often becomes more troublesome.” Although this new device is likely to share this issue, Dr. Ellenbogen said that several devices might be useful to match patients with the one that works best for them.
Dr. Olanow is the founder and CEO of Clintrex Research Corporation, through which he also serves as chief medical officer of SynAgile, the company developing DopaFuse. Dr. Isaacson has financial relationships with more than 30 companies, including those that produce levodopa and levodopa delivery systems. Dr. Ellenbogen has financial relationships with Allergan, Acorda, Supernus, and Teva.
BOSTON – , according to an early clinical experience described in the Emerging Science session at the 2023 annual meeting of the American Academy of Neurology.
On this device, the attenuation of levodopa fluctuations “translated into dramatic improvements in clinical behavior, including highly significant reductions in OFF time and an increase in ON time with no dyskinesias,” reported C. Warren Olanow, MD, who is a chairman emeritus of the department of neurology at the Icahn School of Medicine at Mount Sinai, New York, and now an employee of the company developing this new device.
A novel strategy
Numerous studies have demonstrated that reductions in the troughs of plasma levodopa associated with oral dosing result in longer ON time with fewer dyskinesias, according to Dr. Olanow, who explained this has led to strategies for numerous strategies to achieve continuous delivery. A device that delivers levodopa into the stomach through a surgically implanted catheter has already received regulatory approval. Other devices delivering levodopa subcutaneously are in development, but Dr. Olanow said each of these has had limitations.
“The problem with these approaches is they are associated with potentially serious side effects and they require the patient to wear a cumbersome device,” he explained. Relative to the subcutaneous delivery systems, which have been associated with injection site reactions that include painful nodules, and the surgically implanted devices, which also require an external pump, the latest strategy avoids both disadvantages.
Called DopaFuse, the experimental device is designed to deliver the levodopa and carbidopa into the mouth through a micropump within a wearable retainer. Dr. Olanow said that previous experimental studies demonstrated that small doses of levodopa delivered by mouth to the gastrointestinal system reduce levodopa plasma variability. This early clinical study supports that premise. Levodopa delivered into the mouth by way of a propellant in the retainer-mounted pump improved clinical endpoints.
Encouraging trial results
In the study, 16 patients between the ages of 30 and 75 with Parkinson’s disease were enrolled. On day 1, they received an oral dose of levodopa/carbidopa consistent with their current treatment. On day 2, levodopa/carbidopa was delivered through the retainer-mounted device at equivalent doses. On day 3, they received a single morning oral dose and the received the remainder of their levodopa/carbidopa regimen through the device. On days 4 to 14, they received treatment in the same schedule as day 3.
When pharmacokinetics of levodopa on day 3 were compared with those on day 1, the fluctuation index and coefficient of levodopa concentration variability was reduced to a degree that was highly statistically significant (P < .0001). This, in turn, correlated with “striking” reductions in OFF time with equally statistically significant improvement in ON time and ON time without dyskinesias, according to Dr. Olanow.
Relative to an OFF time of 3.2 hours on day 1, the OFF time of 1.6 hours on day 3 represented a 50% reduction (P < .0001). ON time improved from 12.8 hours to 14.5 hours (P < .001). ON time without dyskinesias improved numerically from 8.8 hours to 9.6 hours.
“There were also improvements in activities of daily living when patients were on DopaFuse, which is a hard endpoint to reach in a study with such a small sample size,” Dr. Olanow reported.
There were no serious adverse events. Three patients reported vomiting and two patients each reported headache, but these events were mild and all resolved within a day. Three patients reported buccal lesions, but these also resolved within a day.
“Some patients reported trouble with speaking in the beginning but at the end of the study, patients were reporting that it was easier to speak because of the motor improvements,” Dr. Olanow said.
Overall, the device was well tolerated by the subjects, providing the evidence for the next stages of clinical studies, reported Dr. Olanow.
“If this turns out to be what we hope it is, it will allow us to deliver levodopa without motor complications, without need for a surgical procedure, and without the risk of subcutaneous lesions,” Dr. Olanow said.
More delivery strategies are needed
This device is in an early phase of development, but several specialists in Parkinson’s disease agreed that there is a need for more strategies to provide continuous levodopa in patients with advancing symptoms. Stuart Isaacson, MD, director, Parkinson’s Disease and Movement Disorders Center of Boca Raton, Fla., is among them.
“Novel delivery devices that can provide more continuous levodopa delivery would be an important therapeutic advance,” Dr. Isaacson said. He called levodopa “the cornerstone of treatment through the course of Parkinson’s disease,” but more physiologic dosing in advancing disease has been a challenge.
“While there are many therapies currently available to manage OFF time, many people living with Parkinson’s disease continue to spend only half of their waking day with good ON time,” he added.
The currently approved method of delivering continuous levodopa through a surgically placed catheter into the gastrointestinal system is effective, but has limitations, according to Aaron L. Ellenbogen, MD, a neurologist at Beaumont Hospital, Farmington Hills, Mich.
“One of the challenges with the current treatment landscape of Parkinson’s disease is that medication can be absorbed variably through the gastrointestinal system,” he said. “As the disease progresses, this often becomes more troublesome.” Although this new device is likely to share this issue, Dr. Ellenbogen said that several devices might be useful to match patients with the one that works best for them.
Dr. Olanow is the founder and CEO of Clintrex Research Corporation, through which he also serves as chief medical officer of SynAgile, the company developing DopaFuse. Dr. Isaacson has financial relationships with more than 30 companies, including those that produce levodopa and levodopa delivery systems. Dr. Ellenbogen has financial relationships with Allergan, Acorda, Supernus, and Teva.
FROM AAN 2023
U.S. incidence, prevalence of myasthenia gravis is rising
, an analysis of new claims data shows. Investigators speculate the rise of this rare disorder may be due to “increased diagnosis and more awareness of the disease over time, which has been shown in several studies,” study investigator Ema Rodrigues, DSc, MPH, with Alexion Pharmaceuticals, Boston.
Dr. Rodrigues presented her research at the 2023 annual meeting of the American Academy of Neurology.
Myasthenia gravis is a rare neuromuscular disease characterized by muscle weakness and fatigue caused by the binding of autoantibodies at the neuromuscular junction. It affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat, and limbs.
In Europe, the incidence and prevalence of myasthenia gravis has increased for the past several decades. In the United States, increasing prevalence has also been observed, but recent estimates are lacking, making it tough to gauge the true burden of disease, Dr. Rodrigues explained.
Claims-based analysis
To investigate, Dr. Rodrigues and colleagues analyzed claims data (commercial, Medicare, and Medicaid) and electronic health records representing over 300 million patients in the United States from 2011 to present.
They calculated sex- and age-specific incidence and prevalence of myasthenia gravis for the year 2021 using U.S. Census data.
Prevalent patients were identified as having one or more myasthenia gravis records in 2021 and two or more myasthenia gravis records, at least 30 days apart, from 2016 to 2021. This cohort had 78,225 patients.
Incident patients were identified as those with a myasthenia gravis record in 2021 and no previous myasthenia gravis record from 2019 to 2020. This cohort had 4,214 patients.
For both the prevalent and incident cohort, the distribution of male and female patients was roughly 50/50, with a slightly higher proportion of females in the incident cohort, Dr. Rodrigues reported.
When looking at age groups, there were “very few pediatric patients,” she noted, with less than 1% of the patients under the age of 12. The highest proportion of patients were 65 years or older. The mean age was 67 in the prevalent cohort and 68 in the incident cohort.
In 2021, the overall incidence of myasthenia gravis was 3.2 per 100,000 with similar estimates for males and females (3.2 vs. 3.1 per 100,000, respectively).
Total prevalence was estimated to be 37.0 per 100,000 with sex-specific estimates being comparable at 37.3 and 36.7 per 100,000 for males and females, respectively.
The incidence and prevalence of myasthenia gravis increased with age, ranging from 0.3 and 0.4 per 100,000, respectively, in children younger than age 2 years, to 10.2 and 116.8 per 100,000, respectively, in people 65 and older.
These estimates are “significantly higher” than those from a prior U.S. analysis from 2003, Dr. Rodrigues told attendees, but they are quite similar to the estimates that were reported in Sweden in 2020.
A limitation of the analysis is that patients who do not seek care regularly may have not been identified due to inclusion criteria, potentially leading to underestimates. Also, no information was available on the myasthenia gravis subtype (ocular vs. generalized).
Underestimated burden
Reached for comment, Richard J. Nowak, MD, MS, director of the Yale Myasthenia Gravis Clinic, Yale School of Medicine, New Haven, Conn., noted that the new report, “albeit limited as a claims-based analysis, presents modern data on incidence and prevalence of myasthenia gravis in the United States.”
“It suggests that the current estimates of myasthenia gravis in the United States are too low and that the true impact/burden of myasthenia gravis is greater. While we are unable to verify the accuracy of the diagnosis, the total myasthenia gravis population is likely to be about 100,000, which is higher than prior estimates.”
“This, in fact, might be driven by greater disease awareness and increased diagnosis along with decreased mortality and longer life expectancy,” Dr. Nowak said.
“Anecdotally, we are most certainly seeing patients with new-onset myasthenia gravis in their 70s, 80s, and even 90s in recent years. The EXPLORE-MG registry published data from a tertiary center on age of onset breakdown showing myasthenia gravis can present at any age,” Dr. Nowak added.
Funding for the study was provided by Alexion, AstraZeneca Rare Disease. Dr. Rodrigues receives compensation and owns stock as an employee of Alexion, AstraZeneca Rare Diseases. Dr. Nowak has no relevant disclosures.
A version of this article originally appeared on Medscape.com.
, an analysis of new claims data shows. Investigators speculate the rise of this rare disorder may be due to “increased diagnosis and more awareness of the disease over time, which has been shown in several studies,” study investigator Ema Rodrigues, DSc, MPH, with Alexion Pharmaceuticals, Boston.
Dr. Rodrigues presented her research at the 2023 annual meeting of the American Academy of Neurology.
Myasthenia gravis is a rare neuromuscular disease characterized by muscle weakness and fatigue caused by the binding of autoantibodies at the neuromuscular junction. It affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat, and limbs.
In Europe, the incidence and prevalence of myasthenia gravis has increased for the past several decades. In the United States, increasing prevalence has also been observed, but recent estimates are lacking, making it tough to gauge the true burden of disease, Dr. Rodrigues explained.
Claims-based analysis
To investigate, Dr. Rodrigues and colleagues analyzed claims data (commercial, Medicare, and Medicaid) and electronic health records representing over 300 million patients in the United States from 2011 to present.
They calculated sex- and age-specific incidence and prevalence of myasthenia gravis for the year 2021 using U.S. Census data.
Prevalent patients were identified as having one or more myasthenia gravis records in 2021 and two or more myasthenia gravis records, at least 30 days apart, from 2016 to 2021. This cohort had 78,225 patients.
Incident patients were identified as those with a myasthenia gravis record in 2021 and no previous myasthenia gravis record from 2019 to 2020. This cohort had 4,214 patients.
For both the prevalent and incident cohort, the distribution of male and female patients was roughly 50/50, with a slightly higher proportion of females in the incident cohort, Dr. Rodrigues reported.
When looking at age groups, there were “very few pediatric patients,” she noted, with less than 1% of the patients under the age of 12. The highest proportion of patients were 65 years or older. The mean age was 67 in the prevalent cohort and 68 in the incident cohort.
In 2021, the overall incidence of myasthenia gravis was 3.2 per 100,000 with similar estimates for males and females (3.2 vs. 3.1 per 100,000, respectively).
Total prevalence was estimated to be 37.0 per 100,000 with sex-specific estimates being comparable at 37.3 and 36.7 per 100,000 for males and females, respectively.
The incidence and prevalence of myasthenia gravis increased with age, ranging from 0.3 and 0.4 per 100,000, respectively, in children younger than age 2 years, to 10.2 and 116.8 per 100,000, respectively, in people 65 and older.
These estimates are “significantly higher” than those from a prior U.S. analysis from 2003, Dr. Rodrigues told attendees, but they are quite similar to the estimates that were reported in Sweden in 2020.
A limitation of the analysis is that patients who do not seek care regularly may have not been identified due to inclusion criteria, potentially leading to underestimates. Also, no information was available on the myasthenia gravis subtype (ocular vs. generalized).
Underestimated burden
Reached for comment, Richard J. Nowak, MD, MS, director of the Yale Myasthenia Gravis Clinic, Yale School of Medicine, New Haven, Conn., noted that the new report, “albeit limited as a claims-based analysis, presents modern data on incidence and prevalence of myasthenia gravis in the United States.”
“It suggests that the current estimates of myasthenia gravis in the United States are too low and that the true impact/burden of myasthenia gravis is greater. While we are unable to verify the accuracy of the diagnosis, the total myasthenia gravis population is likely to be about 100,000, which is higher than prior estimates.”
“This, in fact, might be driven by greater disease awareness and increased diagnosis along with decreased mortality and longer life expectancy,” Dr. Nowak said.
“Anecdotally, we are most certainly seeing patients with new-onset myasthenia gravis in their 70s, 80s, and even 90s in recent years. The EXPLORE-MG registry published data from a tertiary center on age of onset breakdown showing myasthenia gravis can present at any age,” Dr. Nowak added.
Funding for the study was provided by Alexion, AstraZeneca Rare Disease. Dr. Rodrigues receives compensation and owns stock as an employee of Alexion, AstraZeneca Rare Diseases. Dr. Nowak has no relevant disclosures.
A version of this article originally appeared on Medscape.com.
, an analysis of new claims data shows. Investigators speculate the rise of this rare disorder may be due to “increased diagnosis and more awareness of the disease over time, which has been shown in several studies,” study investigator Ema Rodrigues, DSc, MPH, with Alexion Pharmaceuticals, Boston.
Dr. Rodrigues presented her research at the 2023 annual meeting of the American Academy of Neurology.
Myasthenia gravis is a rare neuromuscular disease characterized by muscle weakness and fatigue caused by the binding of autoantibodies at the neuromuscular junction. It affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat, and limbs.
In Europe, the incidence and prevalence of myasthenia gravis has increased for the past several decades. In the United States, increasing prevalence has also been observed, but recent estimates are lacking, making it tough to gauge the true burden of disease, Dr. Rodrigues explained.
Claims-based analysis
To investigate, Dr. Rodrigues and colleagues analyzed claims data (commercial, Medicare, and Medicaid) and electronic health records representing over 300 million patients in the United States from 2011 to present.
They calculated sex- and age-specific incidence and prevalence of myasthenia gravis for the year 2021 using U.S. Census data.
Prevalent patients were identified as having one or more myasthenia gravis records in 2021 and two or more myasthenia gravis records, at least 30 days apart, from 2016 to 2021. This cohort had 78,225 patients.
Incident patients were identified as those with a myasthenia gravis record in 2021 and no previous myasthenia gravis record from 2019 to 2020. This cohort had 4,214 patients.
For both the prevalent and incident cohort, the distribution of male and female patients was roughly 50/50, with a slightly higher proportion of females in the incident cohort, Dr. Rodrigues reported.
When looking at age groups, there were “very few pediatric patients,” she noted, with less than 1% of the patients under the age of 12. The highest proportion of patients were 65 years or older. The mean age was 67 in the prevalent cohort and 68 in the incident cohort.
In 2021, the overall incidence of myasthenia gravis was 3.2 per 100,000 with similar estimates for males and females (3.2 vs. 3.1 per 100,000, respectively).
Total prevalence was estimated to be 37.0 per 100,000 with sex-specific estimates being comparable at 37.3 and 36.7 per 100,000 for males and females, respectively.
The incidence and prevalence of myasthenia gravis increased with age, ranging from 0.3 and 0.4 per 100,000, respectively, in children younger than age 2 years, to 10.2 and 116.8 per 100,000, respectively, in people 65 and older.
These estimates are “significantly higher” than those from a prior U.S. analysis from 2003, Dr. Rodrigues told attendees, but they are quite similar to the estimates that were reported in Sweden in 2020.
A limitation of the analysis is that patients who do not seek care regularly may have not been identified due to inclusion criteria, potentially leading to underestimates. Also, no information was available on the myasthenia gravis subtype (ocular vs. generalized).
Underestimated burden
Reached for comment, Richard J. Nowak, MD, MS, director of the Yale Myasthenia Gravis Clinic, Yale School of Medicine, New Haven, Conn., noted that the new report, “albeit limited as a claims-based analysis, presents modern data on incidence and prevalence of myasthenia gravis in the United States.”
“It suggests that the current estimates of myasthenia gravis in the United States are too low and that the true impact/burden of myasthenia gravis is greater. While we are unable to verify the accuracy of the diagnosis, the total myasthenia gravis population is likely to be about 100,000, which is higher than prior estimates.”
“This, in fact, might be driven by greater disease awareness and increased diagnosis along with decreased mortality and longer life expectancy,” Dr. Nowak said.
“Anecdotally, we are most certainly seeing patients with new-onset myasthenia gravis in their 70s, 80s, and even 90s in recent years. The EXPLORE-MG registry published data from a tertiary center on age of onset breakdown showing myasthenia gravis can present at any age,” Dr. Nowak added.
Funding for the study was provided by Alexion, AstraZeneca Rare Disease. Dr. Rodrigues receives compensation and owns stock as an employee of Alexion, AstraZeneca Rare Diseases. Dr. Nowak has no relevant disclosures.
A version of this article originally appeared on Medscape.com.
From AAN 2023
Head-to-head comparison of migraine meds reveals top options
BOSTON – , a new real-world analysis of data on more than 3 million migraine attacks shows.
The findings “align with results of clinical trials and recommendations from clinical treatment guidelines” and provide insights to complement clinical practice, said study investigator Chia-Chun Chiang, MD, a neurologist with Mayo Clinic, Rochester, Minn.
The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
The power of big data
Despite a wide variety of acute migraine medications that are available, large-scale, head-to-head comparisons of treatment effectiveness from real-world patient experience reports are lacking, Dr. Chiang explained.
“To the best of our knowledge, this is the first study that simultaneously compared multiple acute migraine medications using a Big Data analysis approach based on real-world patient-provided data,” she said.
The researchers extracted more than 10 million self-reported migraine attack records from a migraine smartphone app called Migraine Buddy, where users can document whether a treatment was helpful, somewhat helpful, unsure, or unhelpful.
They analyzed 25 acute medications among seven classes: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, combination analgesics (acetaminophen/aspirin/caffeine), ergots, antiemetics, and opioids. The newer gepants and ditan medication classes of medications were not included because of the relatively lower numbers of usage when data was extracted (2014-2020).
The researchers employed a two-level nested logistic regression model to analyze the odds of treatment effectiveness of each medication by adjusting concurrent medications and the covariance within the same user.
The final analysis included more than 3.1 million migraine attacks among 278,000 users globally.
Using ibuprofen as the reference, triptans, ergots, and antiemetics had the highest efficacy with mean odds ratios of 4.8, 3.02, and 2.67, respectively, followed by opioids (OR, 2.49), NSAIDs (OR, 1.94), combination analgesics (OR, 1.69), others (OR, 1.49), and acetaminophen (OR, 0.83).
Individual medications with the highest patient-reported effectiveness were eletriptan (Relpax; OR, 6.1), zolmitriptan (Zomig; OR, 5.7) and sumatriptan (Zecuity; OR, 5.2).
This migraine medication comparative effectiveness analysis, based on patient-reported outcomes, “supports and complements the treatment recommendations from national headache societies based on randomized controlled trials and meta-analyses and strongly supports the use of triptans,” Dr. Chiang said.
End of trial-and-error?
Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said “This is a great study of Big Data in that it shows the power of the smartphone to collect real-world data and smart researchers like at Mayo Clinic to analyze them.”
“The study sheds light on how different therapeutics compare with each other. The next iteration of this line of research, I would hope, would be to determine if particular medications are effective for a particular migraine population, and even down to individuals with migraine,” said Dr. Lakhan, who wasn’t involved in the study.
“Once those models are appropriately built, long gone will be the era of trial-and-error medicine,” Dr. Lakhan added.
The study had no specific funding. Dr. Chiang has served as a consultant for Satsuma. Dr. Lakhan reports no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
BOSTON – , a new real-world analysis of data on more than 3 million migraine attacks shows.
The findings “align with results of clinical trials and recommendations from clinical treatment guidelines” and provide insights to complement clinical practice, said study investigator Chia-Chun Chiang, MD, a neurologist with Mayo Clinic, Rochester, Minn.
The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
The power of big data
Despite a wide variety of acute migraine medications that are available, large-scale, head-to-head comparisons of treatment effectiveness from real-world patient experience reports are lacking, Dr. Chiang explained.
“To the best of our knowledge, this is the first study that simultaneously compared multiple acute migraine medications using a Big Data analysis approach based on real-world patient-provided data,” she said.
The researchers extracted more than 10 million self-reported migraine attack records from a migraine smartphone app called Migraine Buddy, where users can document whether a treatment was helpful, somewhat helpful, unsure, or unhelpful.
They analyzed 25 acute medications among seven classes: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, combination analgesics (acetaminophen/aspirin/caffeine), ergots, antiemetics, and opioids. The newer gepants and ditan medication classes of medications were not included because of the relatively lower numbers of usage when data was extracted (2014-2020).
The researchers employed a two-level nested logistic regression model to analyze the odds of treatment effectiveness of each medication by adjusting concurrent medications and the covariance within the same user.
The final analysis included more than 3.1 million migraine attacks among 278,000 users globally.
Using ibuprofen as the reference, triptans, ergots, and antiemetics had the highest efficacy with mean odds ratios of 4.8, 3.02, and 2.67, respectively, followed by opioids (OR, 2.49), NSAIDs (OR, 1.94), combination analgesics (OR, 1.69), others (OR, 1.49), and acetaminophen (OR, 0.83).
Individual medications with the highest patient-reported effectiveness were eletriptan (Relpax; OR, 6.1), zolmitriptan (Zomig; OR, 5.7) and sumatriptan (Zecuity; OR, 5.2).
This migraine medication comparative effectiveness analysis, based on patient-reported outcomes, “supports and complements the treatment recommendations from national headache societies based on randomized controlled trials and meta-analyses and strongly supports the use of triptans,” Dr. Chiang said.
End of trial-and-error?
Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said “This is a great study of Big Data in that it shows the power of the smartphone to collect real-world data and smart researchers like at Mayo Clinic to analyze them.”
“The study sheds light on how different therapeutics compare with each other. The next iteration of this line of research, I would hope, would be to determine if particular medications are effective for a particular migraine population, and even down to individuals with migraine,” said Dr. Lakhan, who wasn’t involved in the study.
“Once those models are appropriately built, long gone will be the era of trial-and-error medicine,” Dr. Lakhan added.
The study had no specific funding. Dr. Chiang has served as a consultant for Satsuma. Dr. Lakhan reports no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
BOSTON – , a new real-world analysis of data on more than 3 million migraine attacks shows.
The findings “align with results of clinical trials and recommendations from clinical treatment guidelines” and provide insights to complement clinical practice, said study investigator Chia-Chun Chiang, MD, a neurologist with Mayo Clinic, Rochester, Minn.
The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
The power of big data
Despite a wide variety of acute migraine medications that are available, large-scale, head-to-head comparisons of treatment effectiveness from real-world patient experience reports are lacking, Dr. Chiang explained.
“To the best of our knowledge, this is the first study that simultaneously compared multiple acute migraine medications using a Big Data analysis approach based on real-world patient-provided data,” she said.
The researchers extracted more than 10 million self-reported migraine attack records from a migraine smartphone app called Migraine Buddy, where users can document whether a treatment was helpful, somewhat helpful, unsure, or unhelpful.
They analyzed 25 acute medications among seven classes: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, combination analgesics (acetaminophen/aspirin/caffeine), ergots, antiemetics, and opioids. The newer gepants and ditan medication classes of medications were not included because of the relatively lower numbers of usage when data was extracted (2014-2020).
The researchers employed a two-level nested logistic regression model to analyze the odds of treatment effectiveness of each medication by adjusting concurrent medications and the covariance within the same user.
The final analysis included more than 3.1 million migraine attacks among 278,000 users globally.
Using ibuprofen as the reference, triptans, ergots, and antiemetics had the highest efficacy with mean odds ratios of 4.8, 3.02, and 2.67, respectively, followed by opioids (OR, 2.49), NSAIDs (OR, 1.94), combination analgesics (OR, 1.69), others (OR, 1.49), and acetaminophen (OR, 0.83).
Individual medications with the highest patient-reported effectiveness were eletriptan (Relpax; OR, 6.1), zolmitriptan (Zomig; OR, 5.7) and sumatriptan (Zecuity; OR, 5.2).
This migraine medication comparative effectiveness analysis, based on patient-reported outcomes, “supports and complements the treatment recommendations from national headache societies based on randomized controlled trials and meta-analyses and strongly supports the use of triptans,” Dr. Chiang said.
End of trial-and-error?
Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said “This is a great study of Big Data in that it shows the power of the smartphone to collect real-world data and smart researchers like at Mayo Clinic to analyze them.”
“The study sheds light on how different therapeutics compare with each other. The next iteration of this line of research, I would hope, would be to determine if particular medications are effective for a particular migraine population, and even down to individuals with migraine,” said Dr. Lakhan, who wasn’t involved in the study.
“Once those models are appropriately built, long gone will be the era of trial-and-error medicine,” Dr. Lakhan added.
The study had no specific funding. Dr. Chiang has served as a consultant for Satsuma. Dr. Lakhan reports no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
AT AAN 2023
Oral antiamyloid shows disease-modifying potential Phase 3 trial underway
BOSTON – , represented by positive changes in plasma and imaging biomarkers of Alzheimer’s disease pathology.
Use of the drug, ALZ-801 (Alzheon), led to a significant reduction of plasma phosphorylated–tau 181 (p-tau181) , a marker of amyloid-induced neuronal injury in Alzheimer’s disease, as well as slowing of hippocampal atrophy and stabilization of cognition.
“The 12-month results of our phase 2 trial support the finding that ALZ-801 blocks misfolding of amyloid monomers and subsequent formation of neurotoxic amyloid oligomers, the key initial step in the amyloid aggregation cascade, which leads to a rapid and sustained reduction of brain neurodegeneration as measured by plasma p-tau181,” John Hey, PhD, Alzheon’s chief scientific officer, said in a statement.
“The severalfold greater reduction on the p-tau181 biomarker in plasma compared to plaque-clearing antiamyloid antibodies, combined with preservation of brain hippocampal volume and their positive correlations with cognitive benefits, further validate the disease-modifying effects of ALZ-801 in Alzheimer’s patients,” Dr. Hey added.
The results were presented at the 2023 annual meeting of the American Academy of Neurology.
ALZ-801 is an optimized prodrug of tramiprosate that has been shown to inhibit amyloid-beta 42 aggregation into toxic oligomers.
The ongoing phase 2 study is evaluating the effects of oral ALZ-801 (265 mg twice daily) on biomarkers of Alzheimer’s disease pathology for 84 adults with early Alzheimer’s disease who have either the APOE4/4 or APOE3/4 genotype. These genotypes represent the majority of patients with Alzheimer’s disease.
The mean age of the cohort was 69 years, and 51% are women; 70% had mild cognitive impairment, and 30% had mild Alzheimer’s disease. The mean Mini-Mental State Examination score for the cohort was 26.0. Roughly half were taking a cholinesterase inhibitor.
Significant plasma p-tau181 reduction was observed at 13 weeks. Levels were reduced by 41% by 52 weeks (P = .016). There was also a significant 5% reduction in plasma amyloid-beta 42 and 40 at 52 weeks (P = .002 and P = .005, respectively), Dr. Hey reported.
After 12 months of treatment, hippocampal atrophy was reduced by about 23%, and expansion of ventricular volume was reduced by about 15%, both in comparison with matched controls from the Alzheimer’s Disease Neuroimaging Initiative.
Composite cognitive z-score improved significantly at 13 and 26 weeks and remained above baseline at 52 weeks in comparison with matched ADNI controls. “These are very promising data,” Dr. Hey told conference attendees.
He noted that the safety profile of ALZ-801 remains favorable and consistent with prior safety data. Common adverse events were mild nausea and SARS-CoV-2 infection. There were no drug-related serious events or amyloid-related imaging abnormalities–edema (ARIA-E).
The phase 3 APOLLOE4 study of ALZ-801 is underway. This double-blind, randomized study is comparing oral ALZ-801 with placebo over 78 weeks for roughly 300 adults with early Alzheimer’s disease who have the APOE4/4 genotype. APOLLOE4 is expected to be completed in mid 2024.
The APOLLOE4 study is supported by a $47 million grant from the National Institute on Aging. The U.S. Food and Drug Administration has granted ALZ-801 fast-track designation.
More accessible option?
Reached for comment, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, noted that the “biggest difference between this drug and others is that it is taken orally, rather than delivered through an infusion. This is important and valuable for reducing patient and caregiver burden and increasing ease of use and access.”
It’s also noteworthy that ALZ-801 was not associated with ARIA-E, “which has been reported in other antiamyloid trials and can occasionally be serious,” Dr. Griffin said.
Overall, he said the results are “encouraging, but more work is needed. If studies results continue to be positive, this treatment may provide a more accessible option for people who are at higher risk of ARIA,” Dr. Griffin said.
The study was funded by Alzheon. Dr. Hey is an employee of Alzheon and holds stock in the company. Dr. Griffin has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
BOSTON – , represented by positive changes in plasma and imaging biomarkers of Alzheimer’s disease pathology.
Use of the drug, ALZ-801 (Alzheon), led to a significant reduction of plasma phosphorylated–tau 181 (p-tau181) , a marker of amyloid-induced neuronal injury in Alzheimer’s disease, as well as slowing of hippocampal atrophy and stabilization of cognition.
“The 12-month results of our phase 2 trial support the finding that ALZ-801 blocks misfolding of amyloid monomers and subsequent formation of neurotoxic amyloid oligomers, the key initial step in the amyloid aggregation cascade, which leads to a rapid and sustained reduction of brain neurodegeneration as measured by plasma p-tau181,” John Hey, PhD, Alzheon’s chief scientific officer, said in a statement.
“The severalfold greater reduction on the p-tau181 biomarker in plasma compared to plaque-clearing antiamyloid antibodies, combined with preservation of brain hippocampal volume and their positive correlations with cognitive benefits, further validate the disease-modifying effects of ALZ-801 in Alzheimer’s patients,” Dr. Hey added.
The results were presented at the 2023 annual meeting of the American Academy of Neurology.
ALZ-801 is an optimized prodrug of tramiprosate that has been shown to inhibit amyloid-beta 42 aggregation into toxic oligomers.
The ongoing phase 2 study is evaluating the effects of oral ALZ-801 (265 mg twice daily) on biomarkers of Alzheimer’s disease pathology for 84 adults with early Alzheimer’s disease who have either the APOE4/4 or APOE3/4 genotype. These genotypes represent the majority of patients with Alzheimer’s disease.
The mean age of the cohort was 69 years, and 51% are women; 70% had mild cognitive impairment, and 30% had mild Alzheimer’s disease. The mean Mini-Mental State Examination score for the cohort was 26.0. Roughly half were taking a cholinesterase inhibitor.
Significant plasma p-tau181 reduction was observed at 13 weeks. Levels were reduced by 41% by 52 weeks (P = .016). There was also a significant 5% reduction in plasma amyloid-beta 42 and 40 at 52 weeks (P = .002 and P = .005, respectively), Dr. Hey reported.
After 12 months of treatment, hippocampal atrophy was reduced by about 23%, and expansion of ventricular volume was reduced by about 15%, both in comparison with matched controls from the Alzheimer’s Disease Neuroimaging Initiative.
Composite cognitive z-score improved significantly at 13 and 26 weeks and remained above baseline at 52 weeks in comparison with matched ADNI controls. “These are very promising data,” Dr. Hey told conference attendees.
He noted that the safety profile of ALZ-801 remains favorable and consistent with prior safety data. Common adverse events were mild nausea and SARS-CoV-2 infection. There were no drug-related serious events or amyloid-related imaging abnormalities–edema (ARIA-E).
The phase 3 APOLLOE4 study of ALZ-801 is underway. This double-blind, randomized study is comparing oral ALZ-801 with placebo over 78 weeks for roughly 300 adults with early Alzheimer’s disease who have the APOE4/4 genotype. APOLLOE4 is expected to be completed in mid 2024.
The APOLLOE4 study is supported by a $47 million grant from the National Institute on Aging. The U.S. Food and Drug Administration has granted ALZ-801 fast-track designation.
More accessible option?
Reached for comment, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, noted that the “biggest difference between this drug and others is that it is taken orally, rather than delivered through an infusion. This is important and valuable for reducing patient and caregiver burden and increasing ease of use and access.”
It’s also noteworthy that ALZ-801 was not associated with ARIA-E, “which has been reported in other antiamyloid trials and can occasionally be serious,” Dr. Griffin said.
Overall, he said the results are “encouraging, but more work is needed. If studies results continue to be positive, this treatment may provide a more accessible option for people who are at higher risk of ARIA,” Dr. Griffin said.
The study was funded by Alzheon. Dr. Hey is an employee of Alzheon and holds stock in the company. Dr. Griffin has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
BOSTON – , represented by positive changes in plasma and imaging biomarkers of Alzheimer’s disease pathology.
Use of the drug, ALZ-801 (Alzheon), led to a significant reduction of plasma phosphorylated–tau 181 (p-tau181) , a marker of amyloid-induced neuronal injury in Alzheimer’s disease, as well as slowing of hippocampal atrophy and stabilization of cognition.
“The 12-month results of our phase 2 trial support the finding that ALZ-801 blocks misfolding of amyloid monomers and subsequent formation of neurotoxic amyloid oligomers, the key initial step in the amyloid aggregation cascade, which leads to a rapid and sustained reduction of brain neurodegeneration as measured by plasma p-tau181,” John Hey, PhD, Alzheon’s chief scientific officer, said in a statement.
“The severalfold greater reduction on the p-tau181 biomarker in plasma compared to plaque-clearing antiamyloid antibodies, combined with preservation of brain hippocampal volume and their positive correlations with cognitive benefits, further validate the disease-modifying effects of ALZ-801 in Alzheimer’s patients,” Dr. Hey added.
The results were presented at the 2023 annual meeting of the American Academy of Neurology.
ALZ-801 is an optimized prodrug of tramiprosate that has been shown to inhibit amyloid-beta 42 aggregation into toxic oligomers.
The ongoing phase 2 study is evaluating the effects of oral ALZ-801 (265 mg twice daily) on biomarkers of Alzheimer’s disease pathology for 84 adults with early Alzheimer’s disease who have either the APOE4/4 or APOE3/4 genotype. These genotypes represent the majority of patients with Alzheimer’s disease.
The mean age of the cohort was 69 years, and 51% are women; 70% had mild cognitive impairment, and 30% had mild Alzheimer’s disease. The mean Mini-Mental State Examination score for the cohort was 26.0. Roughly half were taking a cholinesterase inhibitor.
Significant plasma p-tau181 reduction was observed at 13 weeks. Levels were reduced by 41% by 52 weeks (P = .016). There was also a significant 5% reduction in plasma amyloid-beta 42 and 40 at 52 weeks (P = .002 and P = .005, respectively), Dr. Hey reported.
After 12 months of treatment, hippocampal atrophy was reduced by about 23%, and expansion of ventricular volume was reduced by about 15%, both in comparison with matched controls from the Alzheimer’s Disease Neuroimaging Initiative.
Composite cognitive z-score improved significantly at 13 and 26 weeks and remained above baseline at 52 weeks in comparison with matched ADNI controls. “These are very promising data,” Dr. Hey told conference attendees.
He noted that the safety profile of ALZ-801 remains favorable and consistent with prior safety data. Common adverse events were mild nausea and SARS-CoV-2 infection. There were no drug-related serious events or amyloid-related imaging abnormalities–edema (ARIA-E).
The phase 3 APOLLOE4 study of ALZ-801 is underway. This double-blind, randomized study is comparing oral ALZ-801 with placebo over 78 weeks for roughly 300 adults with early Alzheimer’s disease who have the APOE4/4 genotype. APOLLOE4 is expected to be completed in mid 2024.
The APOLLOE4 study is supported by a $47 million grant from the National Institute on Aging. The U.S. Food and Drug Administration has granted ALZ-801 fast-track designation.
More accessible option?
Reached for comment, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, noted that the “biggest difference between this drug and others is that it is taken orally, rather than delivered through an infusion. This is important and valuable for reducing patient and caregiver burden and increasing ease of use and access.”
It’s also noteworthy that ALZ-801 was not associated with ARIA-E, “which has been reported in other antiamyloid trials and can occasionally be serious,” Dr. Griffin said.
Overall, he said the results are “encouraging, but more work is needed. If studies results continue to be positive, this treatment may provide a more accessible option for people who are at higher risk of ARIA,” Dr. Griffin said.
The study was funded by Alzheon. Dr. Hey is an employee of Alzheon and holds stock in the company. Dr. Griffin has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM AAN 2023
Donanemab bests aducanumab in head-to-head Alzheimer’s trial
BOSTON –
Nearly 40% of patients treated with donanemab had amyloid clearance at 6 months compared with less than 2% of those who received aducanumab, which was approved in 2021 amid a great deal of controversy.
Titration for donanemab progressed more quickly, with participants receiving a maximum dose twice as early as those on aducanumab, without any increase in rates of amyloid-related imaging abnormalities (ARIA) – the most common side effect of amyloid drugs.
Early results from the randomized phase 3 TRAILBLAZER-ALZ 4 trial of donanemab come just 3 months after the Food and Drug Administration denied manufacturer Eli Lilly’s request for accelerated approval for the drug.
“This study shows that the drug with the quicker titration scheme, donanemab, produced more amyloid lowering and did it without having more ARIA,” said lead investigator Stephen P. Salloway, MD, director of the Memory and Aging Program at Butler Hospital in Providence, R.I., and a professor of neurology at Brown University.
The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
Multicenter, head-to-head trial
Donanemab received breakthrough therapy designation in 2021. The drug works similarly to aducanumab and lecanemab, which was approved earlier this year. All three bind to different parts of the amyloid molecule and stimulate an immune response to help clear amyloid plaques, although they each have a distinctive binding component.
TRAILBLAZER-ALZ 4 was conducted at 31 sites across the United States, enrolling 140 patients aged 50-85 years with early and symptomatic Alzheimer’s disease. Study participants received donanemab or aducanumab at escalating doses for 18 months.
Donanemab was titrated more quickly, with participants receiving 700 mg via IV infusion once a month for 3 months before reaching the maximum dose of 1,400 mg in the fourth month of the study.
Aducanumab titration was slower, beginning at 1 mg/kg via IV monthly for 2 months, then 3 mg/kg for another 2 months, and 6 mg/kg for 2 more months before reaching the maximum dose of 10 mg/kg in the seventh month.
After 6 months of treatment, PET scan analysis revealed that 37.9% of donanemab-treated patients achieved amyloid clearance compared with just 1.6% of those who received aducanumab (P < .001).
Among patients with intermediate tau levels (n = 27 for donanemab and n = 28 for aducanumab), 38.5% of those who received donanemab achieved amyloid clearance compared with 3.8% of patients in the aducanumab group (P = .008).
Amyloid levels were 65.2% lower in donanemab patients, while levels in those receiving aducanumab were reduced by 17.0% (P < .001). Among those with intermediate tau, amyloid levels decreased with donanemab by 63.9% and 25.4% with aducanumab (P ≤ .001).
Investigators also noted a greater reduction in plasma ptau217 with donanemab.
Adverse events were similar between groups, with 62.0% of the donanemab group and 66.7% of aducanumab-treated participants reporting an adverse event.
There were no serious adverse events due to ARIA with donanemab, but one participant in the aducanumab group had a serious adverse event linked to ARIA.
“Even though the amyloid lowering was greater with donanemab, the rate of ARIA was similar, which suggests that the speed and depth of amyloid removal is not driving ARIA,” Dr. Salloway said.
There are three other Trailblazer trials of donanemab. Unlike in similar trials, participants in all three of these studies who received the trial drug could discontinue treatment once criteria for amyloid clearance were met.
That’s precisely what happened with Trailblazer 2, the study on which Lilly based its request for accelerated approval. Ironically, that trial design also contributed to the FDA’s decision to reject that request.
The FDA required data from at least 100 patients who had received donanemab for a minimum of 1 year. While the trial included more than 100 patients, many patients discontinued treatment early after achieving the targeted amount of amyloid clearance.
“They had success, and they got punished for it, in my opinion,” Dr. Salloway said.
Final data from Trailblazer 2 is due in the next month, and if results are positive, Lilly is expected to file for full approval.
Questions remain
“This is an interesting study that suggests donanemab may remove amyloid faster in more people than aducanumab,” said Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, who commented on the findings.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, also commented on the findings. He noted that faster amyloid clearance “means less time for requiring sometimes burdensome and expensive infusions.”
Both Dr. Snyder and Dr. Fillit noted that longer-term results are needed, along with studies of whether amyloid clearance offers a protective benefit against Alzheimer’s dementia. More results from Trailblazer 4 will be reported after 12 months and again at 18 months.
“There are obviously still a lot of questions about these drugs and whether reducing amyloid plaque will actually preserve cognitive function or at least slow decline,” Dr. Fillit said.
It will also be important to understand the timing of treatment, including when anti-amyloid therapies should be administered and for how long.
“It will be important to understand how these results translate to patient care and treatment plans, should this drug receive FDA approval,” Dr. Snyder said. “Patients should have the opportunity to make a decision, alongside their physician, on a treatment path that is right for them.”
The study was funded by Eli Lilly. Dr. Salloway has been a consultant for Biogen, EISAI, Lilly, Genentech, Novo Nordisk, Prothena, and others. Dr. Snyder and Dr. Fillit have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
BOSTON –
Nearly 40% of patients treated with donanemab had amyloid clearance at 6 months compared with less than 2% of those who received aducanumab, which was approved in 2021 amid a great deal of controversy.
Titration for donanemab progressed more quickly, with participants receiving a maximum dose twice as early as those on aducanumab, without any increase in rates of amyloid-related imaging abnormalities (ARIA) – the most common side effect of amyloid drugs.
Early results from the randomized phase 3 TRAILBLAZER-ALZ 4 trial of donanemab come just 3 months after the Food and Drug Administration denied manufacturer Eli Lilly’s request for accelerated approval for the drug.
“This study shows that the drug with the quicker titration scheme, donanemab, produced more amyloid lowering and did it without having more ARIA,” said lead investigator Stephen P. Salloway, MD, director of the Memory and Aging Program at Butler Hospital in Providence, R.I., and a professor of neurology at Brown University.
The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
Multicenter, head-to-head trial
Donanemab received breakthrough therapy designation in 2021. The drug works similarly to aducanumab and lecanemab, which was approved earlier this year. All three bind to different parts of the amyloid molecule and stimulate an immune response to help clear amyloid plaques, although they each have a distinctive binding component.
TRAILBLAZER-ALZ 4 was conducted at 31 sites across the United States, enrolling 140 patients aged 50-85 years with early and symptomatic Alzheimer’s disease. Study participants received donanemab or aducanumab at escalating doses for 18 months.
Donanemab was titrated more quickly, with participants receiving 700 mg via IV infusion once a month for 3 months before reaching the maximum dose of 1,400 mg in the fourth month of the study.
Aducanumab titration was slower, beginning at 1 mg/kg via IV monthly for 2 months, then 3 mg/kg for another 2 months, and 6 mg/kg for 2 more months before reaching the maximum dose of 10 mg/kg in the seventh month.
After 6 months of treatment, PET scan analysis revealed that 37.9% of donanemab-treated patients achieved amyloid clearance compared with just 1.6% of those who received aducanumab (P < .001).
Among patients with intermediate tau levels (n = 27 for donanemab and n = 28 for aducanumab), 38.5% of those who received donanemab achieved amyloid clearance compared with 3.8% of patients in the aducanumab group (P = .008).
Amyloid levels were 65.2% lower in donanemab patients, while levels in those receiving aducanumab were reduced by 17.0% (P < .001). Among those with intermediate tau, amyloid levels decreased with donanemab by 63.9% and 25.4% with aducanumab (P ≤ .001).
Investigators also noted a greater reduction in plasma ptau217 with donanemab.
Adverse events were similar between groups, with 62.0% of the donanemab group and 66.7% of aducanumab-treated participants reporting an adverse event.
There were no serious adverse events due to ARIA with donanemab, but one participant in the aducanumab group had a serious adverse event linked to ARIA.
“Even though the amyloid lowering was greater with donanemab, the rate of ARIA was similar, which suggests that the speed and depth of amyloid removal is not driving ARIA,” Dr. Salloway said.
There are three other Trailblazer trials of donanemab. Unlike in similar trials, participants in all three of these studies who received the trial drug could discontinue treatment once criteria for amyloid clearance were met.
That’s precisely what happened with Trailblazer 2, the study on which Lilly based its request for accelerated approval. Ironically, that trial design also contributed to the FDA’s decision to reject that request.
The FDA required data from at least 100 patients who had received donanemab for a minimum of 1 year. While the trial included more than 100 patients, many patients discontinued treatment early after achieving the targeted amount of amyloid clearance.
“They had success, and they got punished for it, in my opinion,” Dr. Salloway said.
Final data from Trailblazer 2 is due in the next month, and if results are positive, Lilly is expected to file for full approval.
Questions remain
“This is an interesting study that suggests donanemab may remove amyloid faster in more people than aducanumab,” said Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, who commented on the findings.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, also commented on the findings. He noted that faster amyloid clearance “means less time for requiring sometimes burdensome and expensive infusions.”
Both Dr. Snyder and Dr. Fillit noted that longer-term results are needed, along with studies of whether amyloid clearance offers a protective benefit against Alzheimer’s dementia. More results from Trailblazer 4 will be reported after 12 months and again at 18 months.
“There are obviously still a lot of questions about these drugs and whether reducing amyloid plaque will actually preserve cognitive function or at least slow decline,” Dr. Fillit said.
It will also be important to understand the timing of treatment, including when anti-amyloid therapies should be administered and for how long.
“It will be important to understand how these results translate to patient care and treatment plans, should this drug receive FDA approval,” Dr. Snyder said. “Patients should have the opportunity to make a decision, alongside their physician, on a treatment path that is right for them.”
The study was funded by Eli Lilly. Dr. Salloway has been a consultant for Biogen, EISAI, Lilly, Genentech, Novo Nordisk, Prothena, and others. Dr. Snyder and Dr. Fillit have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
BOSTON –
Nearly 40% of patients treated with donanemab had amyloid clearance at 6 months compared with less than 2% of those who received aducanumab, which was approved in 2021 amid a great deal of controversy.
Titration for donanemab progressed more quickly, with participants receiving a maximum dose twice as early as those on aducanumab, without any increase in rates of amyloid-related imaging abnormalities (ARIA) – the most common side effect of amyloid drugs.
Early results from the randomized phase 3 TRAILBLAZER-ALZ 4 trial of donanemab come just 3 months after the Food and Drug Administration denied manufacturer Eli Lilly’s request for accelerated approval for the drug.
“This study shows that the drug with the quicker titration scheme, donanemab, produced more amyloid lowering and did it without having more ARIA,” said lead investigator Stephen P. Salloway, MD, director of the Memory and Aging Program at Butler Hospital in Providence, R.I., and a professor of neurology at Brown University.
The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
Multicenter, head-to-head trial
Donanemab received breakthrough therapy designation in 2021. The drug works similarly to aducanumab and lecanemab, which was approved earlier this year. All three bind to different parts of the amyloid molecule and stimulate an immune response to help clear amyloid plaques, although they each have a distinctive binding component.
TRAILBLAZER-ALZ 4 was conducted at 31 sites across the United States, enrolling 140 patients aged 50-85 years with early and symptomatic Alzheimer’s disease. Study participants received donanemab or aducanumab at escalating doses for 18 months.
Donanemab was titrated more quickly, with participants receiving 700 mg via IV infusion once a month for 3 months before reaching the maximum dose of 1,400 mg in the fourth month of the study.
Aducanumab titration was slower, beginning at 1 mg/kg via IV monthly for 2 months, then 3 mg/kg for another 2 months, and 6 mg/kg for 2 more months before reaching the maximum dose of 10 mg/kg in the seventh month.
After 6 months of treatment, PET scan analysis revealed that 37.9% of donanemab-treated patients achieved amyloid clearance compared with just 1.6% of those who received aducanumab (P < .001).
Among patients with intermediate tau levels (n = 27 for donanemab and n = 28 for aducanumab), 38.5% of those who received donanemab achieved amyloid clearance compared with 3.8% of patients in the aducanumab group (P = .008).
Amyloid levels were 65.2% lower in donanemab patients, while levels in those receiving aducanumab were reduced by 17.0% (P < .001). Among those with intermediate tau, amyloid levels decreased with donanemab by 63.9% and 25.4% with aducanumab (P ≤ .001).
Investigators also noted a greater reduction in plasma ptau217 with donanemab.
Adverse events were similar between groups, with 62.0% of the donanemab group and 66.7% of aducanumab-treated participants reporting an adverse event.
There were no serious adverse events due to ARIA with donanemab, but one participant in the aducanumab group had a serious adverse event linked to ARIA.
“Even though the amyloid lowering was greater with donanemab, the rate of ARIA was similar, which suggests that the speed and depth of amyloid removal is not driving ARIA,” Dr. Salloway said.
There are three other Trailblazer trials of donanemab. Unlike in similar trials, participants in all three of these studies who received the trial drug could discontinue treatment once criteria for amyloid clearance were met.
That’s precisely what happened with Trailblazer 2, the study on which Lilly based its request for accelerated approval. Ironically, that trial design also contributed to the FDA’s decision to reject that request.
The FDA required data from at least 100 patients who had received donanemab for a minimum of 1 year. While the trial included more than 100 patients, many patients discontinued treatment early after achieving the targeted amount of amyloid clearance.
“They had success, and they got punished for it, in my opinion,” Dr. Salloway said.
Final data from Trailblazer 2 is due in the next month, and if results are positive, Lilly is expected to file for full approval.
Questions remain
“This is an interesting study that suggests donanemab may remove amyloid faster in more people than aducanumab,” said Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, who commented on the findings.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, also commented on the findings. He noted that faster amyloid clearance “means less time for requiring sometimes burdensome and expensive infusions.”
Both Dr. Snyder and Dr. Fillit noted that longer-term results are needed, along with studies of whether amyloid clearance offers a protective benefit against Alzheimer’s dementia. More results from Trailblazer 4 will be reported after 12 months and again at 18 months.
“There are obviously still a lot of questions about these drugs and whether reducing amyloid plaque will actually preserve cognitive function or at least slow decline,” Dr. Fillit said.
It will also be important to understand the timing of treatment, including when anti-amyloid therapies should be administered and for how long.
“It will be important to understand how these results translate to patient care and treatment plans, should this drug receive FDA approval,” Dr. Snyder said. “Patients should have the opportunity to make a decision, alongside their physician, on a treatment path that is right for them.”
The study was funded by Eli Lilly. Dr. Salloway has been a consultant for Biogen, EISAI, Lilly, Genentech, Novo Nordisk, Prothena, and others. Dr. Snyder and Dr. Fillit have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM AAN 2023
Machine learning can predict primary progressive MS progression
BOSTON – , according to a proof-of-concept study presented at the 2023 annual meeting of the American Academy of Neurology.
The accuracy was sufficient for the lead author of the study, Michael Gurevich, PhD, head of the Neuroimmunological Laboratory in the Multiple Sclerosis Center of Sheba Medical Center in Ramat Gan, Israel, to say that it is already clinically viable even as the tool is still evolving.
“We are looking at larger sample sizes to improve the accuracy and generalizability of our model, but we can use it now to inform treatment decisions,” Dr. Gurevich said.
In patients with PPMS who have a highly variable course, the model predicts disability progression with an accuracy of approximately 70%, according to the data he presented. He said he believes this is already at a level that it is meaningful for a risk-to-benefit calculation when considering treatment.
Machine learning analyzes blood samples
The study pursues the concept that the genetic information governing highly complex pathophysiological processes is contained in RNA sequencing. While multimodal omics generate data that are too complex for human pattern recognition, there is a growing body of evidence, including that provided by this study, to suggest that machine learning can employ these same RNA profiles and predict disease activity.
In this study, blood samples were collected from patients who participated in the phase 3 clinical ORATORIO trial that led to approval of ocrelizumab for PPMS. Analyses were conducted only on blood samples from those randomized to placebo, who, like those in the active treatment arm, were evaluated at baseline and at 12-week intervals for more than 2 years.
After development of a prediction model and creation of a training dataset, machine learning was applied to the deep sequencing of the blood transcriptome data for predicting two endpoints. One was disease progression at 120 weeks defined as a 1 point or more increase in the Expanded Disability Status Scale (EDSS) among patients with confirmed disability progression for at least 12 weeks (12W-CDP).
The other was change at 120 weeks in brain morphology defined as a 1% or more reduction in brain volume (120W PBVC).
The peripheral blood samples were subjected to RNA sequencing analysis (RNA-Seq) using commercially available analysis techniques. The prediction model for the disability endpoint was based on data generated from the blood transcriptome of 135 patients of which 53 (39%) met the endpoint at 120 weeks. The prediction model for the change in brain morphology was based on the blood transcriptome from 94 patients of which 63 (67%) met the endpoint.
On the basis of 10 genes that most significantly differentiated those who met the disability endpoint from those who did not, machine recognition of patterns after training was able to predict correctly the outcome in 70.9%. The sensitivity was 55.6%, and the specificity was 79.0%. The positive and negative predictive values were 59.0% and 76.8%, respectively.
On the basis of the 12 genes the most significantly differentiated those that reached the 120W PBVC endpoint from those who did not, machine learning resulted in a correct prediction of outcomes in 75.1%. The sensitivity was 78.1%, and the specificity was 66.7%. The positive and negative predictive values were 83.3% and 58.8%, respectively
Typical of a PPMS trial population, the mean age of the patients was about 44 years. The mean disease duration was about 6 years. The majority of patients had an EDSS score below 5.5 at baseline. The baseline T2 lesion number was approximately 50.
If further validated by others and in larger studies, this type of information could play a valuable role in PPMS management, according to Dr. Gurevich. Now that there is an approved therapy for PPMS, it can help clinicians and patients determine whether to initiate treatment early to address the high risk of progression or delay treatment that might not be needed.
A useful tool
In the field of MS, most of the studies performed with machine learning have focused on the analysis of radiological images. However, others are now looking at the blood transcriptome as a potential path to better classifying a highly complex disease with substantial heterogeneity in presentation, progression, and outcome.
For example, machine learning of the blood transcriptome has also shown high accuracy in the diagnosis and classification of MS in patients with clinically isolated syndrome (CIS). One study, published in Cell Reports Medicine, was led by Cinthia Farina, PhD, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan.
Although she did not hear the presentation by Dr. Gurevich, Dr. Farina is enthusiastic about the potential for machine learning to help manage MS through the analysis of the blood transcriptome. “I do believe that transcriptomics in peripheral immune cells may become a useful tool for MS diagnosis and prognosis,” she said.
In her own study, in which machine learning algorithms were developed and trained on the basis of peripheral blood from patients with CIS, the tool proved accurate with a strong potential for being incorporated into routine clinical management.
“Machine learning applied to the blood transcriptomes was extremely efficient with a 95.6% accuracy in discriminating PPMS from RRMS [relapsing-remitting] MS,” she reported.
Dr. Gurevich has no potential financial conflicts of interest to report. He reported funding for the study was provided by Roche. Dr. Farina reports financial relationships with Merck-Serono, Novartis, and Teva.
BOSTON – , according to a proof-of-concept study presented at the 2023 annual meeting of the American Academy of Neurology.
The accuracy was sufficient for the lead author of the study, Michael Gurevich, PhD, head of the Neuroimmunological Laboratory in the Multiple Sclerosis Center of Sheba Medical Center in Ramat Gan, Israel, to say that it is already clinically viable even as the tool is still evolving.
“We are looking at larger sample sizes to improve the accuracy and generalizability of our model, but we can use it now to inform treatment decisions,” Dr. Gurevich said.
In patients with PPMS who have a highly variable course, the model predicts disability progression with an accuracy of approximately 70%, according to the data he presented. He said he believes this is already at a level that it is meaningful for a risk-to-benefit calculation when considering treatment.
Machine learning analyzes blood samples
The study pursues the concept that the genetic information governing highly complex pathophysiological processes is contained in RNA sequencing. While multimodal omics generate data that are too complex for human pattern recognition, there is a growing body of evidence, including that provided by this study, to suggest that machine learning can employ these same RNA profiles and predict disease activity.
In this study, blood samples were collected from patients who participated in the phase 3 clinical ORATORIO trial that led to approval of ocrelizumab for PPMS. Analyses were conducted only on blood samples from those randomized to placebo, who, like those in the active treatment arm, were evaluated at baseline and at 12-week intervals for more than 2 years.
After development of a prediction model and creation of a training dataset, machine learning was applied to the deep sequencing of the blood transcriptome data for predicting two endpoints. One was disease progression at 120 weeks defined as a 1 point or more increase in the Expanded Disability Status Scale (EDSS) among patients with confirmed disability progression for at least 12 weeks (12W-CDP).
The other was change at 120 weeks in brain morphology defined as a 1% or more reduction in brain volume (120W PBVC).
The peripheral blood samples were subjected to RNA sequencing analysis (RNA-Seq) using commercially available analysis techniques. The prediction model for the disability endpoint was based on data generated from the blood transcriptome of 135 patients of which 53 (39%) met the endpoint at 120 weeks. The prediction model for the change in brain morphology was based on the blood transcriptome from 94 patients of which 63 (67%) met the endpoint.
On the basis of 10 genes that most significantly differentiated those who met the disability endpoint from those who did not, machine recognition of patterns after training was able to predict correctly the outcome in 70.9%. The sensitivity was 55.6%, and the specificity was 79.0%. The positive and negative predictive values were 59.0% and 76.8%, respectively.
On the basis of the 12 genes the most significantly differentiated those that reached the 120W PBVC endpoint from those who did not, machine learning resulted in a correct prediction of outcomes in 75.1%. The sensitivity was 78.1%, and the specificity was 66.7%. The positive and negative predictive values were 83.3% and 58.8%, respectively
Typical of a PPMS trial population, the mean age of the patients was about 44 years. The mean disease duration was about 6 years. The majority of patients had an EDSS score below 5.5 at baseline. The baseline T2 lesion number was approximately 50.
If further validated by others and in larger studies, this type of information could play a valuable role in PPMS management, according to Dr. Gurevich. Now that there is an approved therapy for PPMS, it can help clinicians and patients determine whether to initiate treatment early to address the high risk of progression or delay treatment that might not be needed.
A useful tool
In the field of MS, most of the studies performed with machine learning have focused on the analysis of radiological images. However, others are now looking at the blood transcriptome as a potential path to better classifying a highly complex disease with substantial heterogeneity in presentation, progression, and outcome.
For example, machine learning of the blood transcriptome has also shown high accuracy in the diagnosis and classification of MS in patients with clinically isolated syndrome (CIS). One study, published in Cell Reports Medicine, was led by Cinthia Farina, PhD, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan.
Although she did not hear the presentation by Dr. Gurevich, Dr. Farina is enthusiastic about the potential for machine learning to help manage MS through the analysis of the blood transcriptome. “I do believe that transcriptomics in peripheral immune cells may become a useful tool for MS diagnosis and prognosis,” she said.
In her own study, in which machine learning algorithms were developed and trained on the basis of peripheral blood from patients with CIS, the tool proved accurate with a strong potential for being incorporated into routine clinical management.
“Machine learning applied to the blood transcriptomes was extremely efficient with a 95.6% accuracy in discriminating PPMS from RRMS [relapsing-remitting] MS,” she reported.
Dr. Gurevich has no potential financial conflicts of interest to report. He reported funding for the study was provided by Roche. Dr. Farina reports financial relationships with Merck-Serono, Novartis, and Teva.
BOSTON – , according to a proof-of-concept study presented at the 2023 annual meeting of the American Academy of Neurology.
The accuracy was sufficient for the lead author of the study, Michael Gurevich, PhD, head of the Neuroimmunological Laboratory in the Multiple Sclerosis Center of Sheba Medical Center in Ramat Gan, Israel, to say that it is already clinically viable even as the tool is still evolving.
“We are looking at larger sample sizes to improve the accuracy and generalizability of our model, but we can use it now to inform treatment decisions,” Dr. Gurevich said.
In patients with PPMS who have a highly variable course, the model predicts disability progression with an accuracy of approximately 70%, according to the data he presented. He said he believes this is already at a level that it is meaningful for a risk-to-benefit calculation when considering treatment.
Machine learning analyzes blood samples
The study pursues the concept that the genetic information governing highly complex pathophysiological processes is contained in RNA sequencing. While multimodal omics generate data that are too complex for human pattern recognition, there is a growing body of evidence, including that provided by this study, to suggest that machine learning can employ these same RNA profiles and predict disease activity.
In this study, blood samples were collected from patients who participated in the phase 3 clinical ORATORIO trial that led to approval of ocrelizumab for PPMS. Analyses were conducted only on blood samples from those randomized to placebo, who, like those in the active treatment arm, were evaluated at baseline and at 12-week intervals for more than 2 years.
After development of a prediction model and creation of a training dataset, machine learning was applied to the deep sequencing of the blood transcriptome data for predicting two endpoints. One was disease progression at 120 weeks defined as a 1 point or more increase in the Expanded Disability Status Scale (EDSS) among patients with confirmed disability progression for at least 12 weeks (12W-CDP).
The other was change at 120 weeks in brain morphology defined as a 1% or more reduction in brain volume (120W PBVC).
The peripheral blood samples were subjected to RNA sequencing analysis (RNA-Seq) using commercially available analysis techniques. The prediction model for the disability endpoint was based on data generated from the blood transcriptome of 135 patients of which 53 (39%) met the endpoint at 120 weeks. The prediction model for the change in brain morphology was based on the blood transcriptome from 94 patients of which 63 (67%) met the endpoint.
On the basis of 10 genes that most significantly differentiated those who met the disability endpoint from those who did not, machine recognition of patterns after training was able to predict correctly the outcome in 70.9%. The sensitivity was 55.6%, and the specificity was 79.0%. The positive and negative predictive values were 59.0% and 76.8%, respectively.
On the basis of the 12 genes the most significantly differentiated those that reached the 120W PBVC endpoint from those who did not, machine learning resulted in a correct prediction of outcomes in 75.1%. The sensitivity was 78.1%, and the specificity was 66.7%. The positive and negative predictive values were 83.3% and 58.8%, respectively
Typical of a PPMS trial population, the mean age of the patients was about 44 years. The mean disease duration was about 6 years. The majority of patients had an EDSS score below 5.5 at baseline. The baseline T2 lesion number was approximately 50.
If further validated by others and in larger studies, this type of information could play a valuable role in PPMS management, according to Dr. Gurevich. Now that there is an approved therapy for PPMS, it can help clinicians and patients determine whether to initiate treatment early to address the high risk of progression or delay treatment that might not be needed.
A useful tool
In the field of MS, most of the studies performed with machine learning have focused on the analysis of radiological images. However, others are now looking at the blood transcriptome as a potential path to better classifying a highly complex disease with substantial heterogeneity in presentation, progression, and outcome.
For example, machine learning of the blood transcriptome has also shown high accuracy in the diagnosis and classification of MS in patients with clinically isolated syndrome (CIS). One study, published in Cell Reports Medicine, was led by Cinthia Farina, PhD, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan.
Although she did not hear the presentation by Dr. Gurevich, Dr. Farina is enthusiastic about the potential for machine learning to help manage MS through the analysis of the blood transcriptome. “I do believe that transcriptomics in peripheral immune cells may become a useful tool for MS diagnosis and prognosis,” she said.
In her own study, in which machine learning algorithms were developed and trained on the basis of peripheral blood from patients with CIS, the tool proved accurate with a strong potential for being incorporated into routine clinical management.
“Machine learning applied to the blood transcriptomes was extremely efficient with a 95.6% accuracy in discriminating PPMS from RRMS [relapsing-remitting] MS,” she reported.
Dr. Gurevich has no potential financial conflicts of interest to report. He reported funding for the study was provided by Roche. Dr. Farina reports financial relationships with Merck-Serono, Novartis, and Teva.
FROM AAN 2023
Noninvasive testing in midlife flags late-onset epilepsy risk
BOSTON – Noninvasive tests performed in midlife may help identify people who are at risk of late-onset epilepsy, a new study suggests. New data from the Framingham Heart Study show those who scored better on a neurocognitive test that measures executive function were 75% less likely to develop late-onset epilepsy.
An analysis of MRI revealed that those with higher cortical volumes also had a lower risk of epilepsy later in life, while those with higher white matter hyperintensities had an increased risk.
The study could help identify at-risk individuals years before symptoms of epilepsy appear.
,” said lead investigator Maria Stefanidou, MD, assistant professor of neurology at Boston University.
The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
Protection against late-onset epilepsy?
Hypertension and stroke are known risk factors for late-onset epilepsy. Dementia is also a known risk factor. But in about 30% of cases, the cause of epilepsy in older individuals is unknown.
For this study, investigators analyzed data from the offspring cohort of the Framingham Heart Study. Participants were at least 45 years old; underwent neuropsychological evaluation and brain MRI; and had no prior history of stroke, dementia, or epilepsy. Cognitive measures included Visual Reproductions Delayed Recall, Logical Memory Delayed Recall, Similarities, Trail Making B-A (TrB-TrA), and the Hooper Visual Organization Test.
Participants also underwent an MRI to measure total cerebral brain volume, cortical gray matter volume, white matter hyperintensities, and hippocampal volume.
After a mean follow-up of 13.5 years, late-onset epilepsy was diagnosed in 31 of participants who underwent neuropsychological testing (n = 2,349) and in 27 of those who underwent MRI (n = 2,056).
Better performance on the TrB-TrA test (a measure of executive function, processing speed, and occult vascular injury) was associated with a reduced risk of late-onset epilepsy (adjusted hazard ratio, 0.25; P = .011).
The findings held even after adjusting for age, sex, educational level, and known risk factors for late-onset epilepsy, such as hypertension (aHR, 0.30; P = .0401).
Higher white matter hyperintensities, a measure of occult vascular injury, was associated with increased epilepsy risk (aHR, 1.5; P = .042) when adjusted only for age, sex, and education, but was no longer significant after adjusting for hypertension and other risk factors (aHR, 1.47; P = .065).
The analysis also revealed that participants with a higher cortical gray matter volume had a lower risk for late-onset epilepsy (aHR, 0.73; P = .001).
“There is increasing literature supporting that late-onset epilepsy may be secondary to accumulative occult cerebrovascular and neurodegenerative processes that occur during aging,” Dr. Stefanidou said. “Our findings likely reflect that a lesser degree of occult vascular brain injury in midlife may be protective against late-onset epilepsy.”
However, the epidemiological study points to association, not causation, Dr. Stefanidou cautions.
“Further studies will be needed to study our observations in the clinical setting,” she said.
‘Intriguing’ findings
Commenting on the findings, Joseph Sirven, MD, a neurologist at the Mayo Clinic in Jacksonville, Fla., said the findings are “intriguing,” but also raise some questions. “Late-onset epilepsy remains an issue for many and it’s common,” said Dr. Sirven, who has patients with late-onset epilepsy.
Dr. Sirven was particularly interested in the findings on white matter hyperintensities. “Hippocampal volumes have been used but not so much cortical volumes,” he said. “I would like to know more about how white matter changes suggest pathology that would explain epilepsy.”
Study funding was not disclosed. Dr. Stefanidou and Dr. Sirven report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
BOSTON – Noninvasive tests performed in midlife may help identify people who are at risk of late-onset epilepsy, a new study suggests. New data from the Framingham Heart Study show those who scored better on a neurocognitive test that measures executive function were 75% less likely to develop late-onset epilepsy.
An analysis of MRI revealed that those with higher cortical volumes also had a lower risk of epilepsy later in life, while those with higher white matter hyperintensities had an increased risk.
The study could help identify at-risk individuals years before symptoms of epilepsy appear.
,” said lead investigator Maria Stefanidou, MD, assistant professor of neurology at Boston University.
The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
Protection against late-onset epilepsy?
Hypertension and stroke are known risk factors for late-onset epilepsy. Dementia is also a known risk factor. But in about 30% of cases, the cause of epilepsy in older individuals is unknown.
For this study, investigators analyzed data from the offspring cohort of the Framingham Heart Study. Participants were at least 45 years old; underwent neuropsychological evaluation and brain MRI; and had no prior history of stroke, dementia, or epilepsy. Cognitive measures included Visual Reproductions Delayed Recall, Logical Memory Delayed Recall, Similarities, Trail Making B-A (TrB-TrA), and the Hooper Visual Organization Test.
Participants also underwent an MRI to measure total cerebral brain volume, cortical gray matter volume, white matter hyperintensities, and hippocampal volume.
After a mean follow-up of 13.5 years, late-onset epilepsy was diagnosed in 31 of participants who underwent neuropsychological testing (n = 2,349) and in 27 of those who underwent MRI (n = 2,056).
Better performance on the TrB-TrA test (a measure of executive function, processing speed, and occult vascular injury) was associated with a reduced risk of late-onset epilepsy (adjusted hazard ratio, 0.25; P = .011).
The findings held even after adjusting for age, sex, educational level, and known risk factors for late-onset epilepsy, such as hypertension (aHR, 0.30; P = .0401).
Higher white matter hyperintensities, a measure of occult vascular injury, was associated with increased epilepsy risk (aHR, 1.5; P = .042) when adjusted only for age, sex, and education, but was no longer significant after adjusting for hypertension and other risk factors (aHR, 1.47; P = .065).
The analysis also revealed that participants with a higher cortical gray matter volume had a lower risk for late-onset epilepsy (aHR, 0.73; P = .001).
“There is increasing literature supporting that late-onset epilepsy may be secondary to accumulative occult cerebrovascular and neurodegenerative processes that occur during aging,” Dr. Stefanidou said. “Our findings likely reflect that a lesser degree of occult vascular brain injury in midlife may be protective against late-onset epilepsy.”
However, the epidemiological study points to association, not causation, Dr. Stefanidou cautions.
“Further studies will be needed to study our observations in the clinical setting,” she said.
‘Intriguing’ findings
Commenting on the findings, Joseph Sirven, MD, a neurologist at the Mayo Clinic in Jacksonville, Fla., said the findings are “intriguing,” but also raise some questions. “Late-onset epilepsy remains an issue for many and it’s common,” said Dr. Sirven, who has patients with late-onset epilepsy.
Dr. Sirven was particularly interested in the findings on white matter hyperintensities. “Hippocampal volumes have been used but not so much cortical volumes,” he said. “I would like to know more about how white matter changes suggest pathology that would explain epilepsy.”
Study funding was not disclosed. Dr. Stefanidou and Dr. Sirven report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
BOSTON – Noninvasive tests performed in midlife may help identify people who are at risk of late-onset epilepsy, a new study suggests. New data from the Framingham Heart Study show those who scored better on a neurocognitive test that measures executive function were 75% less likely to develop late-onset epilepsy.
An analysis of MRI revealed that those with higher cortical volumes also had a lower risk of epilepsy later in life, while those with higher white matter hyperintensities had an increased risk.
The study could help identify at-risk individuals years before symptoms of epilepsy appear.
,” said lead investigator Maria Stefanidou, MD, assistant professor of neurology at Boston University.
The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
Protection against late-onset epilepsy?
Hypertension and stroke are known risk factors for late-onset epilepsy. Dementia is also a known risk factor. But in about 30% of cases, the cause of epilepsy in older individuals is unknown.
For this study, investigators analyzed data from the offspring cohort of the Framingham Heart Study. Participants were at least 45 years old; underwent neuropsychological evaluation and brain MRI; and had no prior history of stroke, dementia, or epilepsy. Cognitive measures included Visual Reproductions Delayed Recall, Logical Memory Delayed Recall, Similarities, Trail Making B-A (TrB-TrA), and the Hooper Visual Organization Test.
Participants also underwent an MRI to measure total cerebral brain volume, cortical gray matter volume, white matter hyperintensities, and hippocampal volume.
After a mean follow-up of 13.5 years, late-onset epilepsy was diagnosed in 31 of participants who underwent neuropsychological testing (n = 2,349) and in 27 of those who underwent MRI (n = 2,056).
Better performance on the TrB-TrA test (a measure of executive function, processing speed, and occult vascular injury) was associated with a reduced risk of late-onset epilepsy (adjusted hazard ratio, 0.25; P = .011).
The findings held even after adjusting for age, sex, educational level, and known risk factors for late-onset epilepsy, such as hypertension (aHR, 0.30; P = .0401).
Higher white matter hyperintensities, a measure of occult vascular injury, was associated with increased epilepsy risk (aHR, 1.5; P = .042) when adjusted only for age, sex, and education, but was no longer significant after adjusting for hypertension and other risk factors (aHR, 1.47; P = .065).
The analysis also revealed that participants with a higher cortical gray matter volume had a lower risk for late-onset epilepsy (aHR, 0.73; P = .001).
“There is increasing literature supporting that late-onset epilepsy may be secondary to accumulative occult cerebrovascular and neurodegenerative processes that occur during aging,” Dr. Stefanidou said. “Our findings likely reflect that a lesser degree of occult vascular brain injury in midlife may be protective against late-onset epilepsy.”
However, the epidemiological study points to association, not causation, Dr. Stefanidou cautions.
“Further studies will be needed to study our observations in the clinical setting,” she said.
‘Intriguing’ findings
Commenting on the findings, Joseph Sirven, MD, a neurologist at the Mayo Clinic in Jacksonville, Fla., said the findings are “intriguing,” but also raise some questions. “Late-onset epilepsy remains an issue for many and it’s common,” said Dr. Sirven, who has patients with late-onset epilepsy.
Dr. Sirven was particularly interested in the findings on white matter hyperintensities. “Hippocampal volumes have been used but not so much cortical volumes,” he said. “I would like to know more about how white matter changes suggest pathology that would explain epilepsy.”
Study funding was not disclosed. Dr. Stefanidou and Dr. Sirven report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AAN 2023
Therapy to reverse muscle dystrophies shows promise
BOSTON – Becker (BMD) and Duchenne muscle dystrophy (DMD) progress largely from irreversible contraction-induced injury of skeletal muscles, making the very positive interim results of an early-phase trial with a drug that prevents these injuries worth attention.
The phase 1b data in BMD, presented at the 2023 annual meeting of the American Academy of Neurology, were sufficiently promising that controlled phase 2 trials in both BMD and DMD are already enrolling, reported Joanne Donovan, MD, PhD, an adjunct professor at Boston University and chief medical officer of Edgewise Therapeutics, the company developing the drug.
Phase 1 study
Early phase studies are largely focused on safety, but the
Moreover, the evidence of a clinical effect was achieved in adult patients with a North Star Ambulatory Assessment (NSAA) score of 15, signifying advanced disease. Only 12 patients were enrolled and there were no controls, but objective evidence of a favorable effect was generated by highly significant reductions in creatine kinase (CK) and fast skeletal muscle (TNNI2) troponin, which are both biomarkers commonly used to track muscular dystrophy progression.
In patients with BMD or DMD, a lack of dystrophin is a key pathogenic feature, according to Dr. Donovan. She explained that dystrophin in muscles connects contractile proteins to membranes and surrounding matrix. In the presence of dystrophin, muscle fibers support each other, but when this protein is absent, contraction causes injury.
The drug in development, currently identified as EDG-5506, is a selective fast myosin inhibitor. This agent was shown to prevent the muscle injury caused by lack of dystrophin in animal models of muscular dystrophy and is now showing the same effect in humans. Preservation of muscle is critical to preventing BMD and DMD progression according to several sets of data, according to Dr. Donovan.
For one, it has been shown that BMD or DMD patients with relatively preserved function as defined by a NSAA score above 32 have minimal muscle damage. As NSAA scores fall below 32 points, muscle mass diminishes and fat accumulates. In natural history studies of BMD, there is a 1.2-point decline in NSAA score over 5 years, and this tracks with muscle loss and not with other variables, such as patient age.
“Progression depends on the degree of muscle loss,” Dr. Donovan stated, providing the rationale for moving forward with EDG-5506.
Proof of concept
In experimental studies, modulation of fast myelin provided complete protection against muscle injury while preserving its contractile function, and this translated into protection against loss of function. Phase 1 studies in BMD patients and healthy controls have already provided evidence that EDG-5506 is well tolerated and safe, but the new phase 1b provides a proof of concept for its ability to inhibit muscle injury in BMD patients.
In this study, called ARCH, 12 adults 18 years of age or older with a dystrophin mutation and a BMD phenotype who could complete a 100-meter timed test were enrolled. The median age at entry was 32 years. Several patients had participated in a previous phase 1 safety study. The daily starting dose of 10 mg was increased from 10 mg to 15 mg at 2 months. The dose was increased again to 20 mg at 6 months, but the data presented by Dr. Donovan were restricted to the first 6 months.
At the interim 6-month analysis, creatine kinase was reduced by 40% and TINN2 was reduced by 84% (both P < 0.001). The significant reductions in these biomarkers and others, such as myoglobin, were mostly achieved within the first month, although further reductions were observed for some biomarkers subsequently.
The NSAA score at 6 months improved on average by about 1 point on treatment. Natural history studies of BMD predict a 1-point reduction in NSAA score over this period of time. The modest improvements from baseline in pain scores at 1 month were sustained at 6 months.
On the basis of a proteomic analysis, 125 proteins mostly associated with metabolic pathways consistent with muscle injury were found to be altered in BMD patients relative to healthy controls. The majority of these proteins, whether assessed collectively or individually, normalized after 1 to 2 months of treatment with EDG-5506 and have remained stable during follow-up to date, according to Dr. Donovan.
As in previous studies, the drug was well tolerated. The three most common treatment-emergent events were dizziness, somnolence, and headache. Each was reported by about 25% of patients, but no patient discontinued therapy as a result of adverse events.
Findings deemed ‘a big deal’
These data, despite the small number of patients in the study and the limited follow-up, “are a big deal,” according to Nicholas E. Johnson, MD, division chief, neuromuscular disorders, Virginia Commonwealth University, Richmond. He pointed out that there are no effective treatments currently for BMD, and the mechanism of action is plausible.
“I am excited about the potential of this treatment, although we clearly need longer follow-up and more patients evaluated on this treatment,” Dr. Johnson said. He said that clinicians with BMD patients should be aware of the phase 2 trial that is now recruiting adult subjects.
“Becker muscular dystrophy is highly disabling. As disease advances, most patients have very limited function,” said Dr. Johnson, emphasizing the urgent unmet need for an effective therapy.
Dr. Donovan is a full time employee of Edgewise Therapeutics, which funded this study. Dr. Johnson has financial relationships with Acceleron, Arthex, AveXis, Avidity, Biogen, Dyne Therapeutics, Entrada, Juvena, ML Bio, Sarepta Therapeutics, Triplet Therapeutics, and Vertex Pharma.
BOSTON – Becker (BMD) and Duchenne muscle dystrophy (DMD) progress largely from irreversible contraction-induced injury of skeletal muscles, making the very positive interim results of an early-phase trial with a drug that prevents these injuries worth attention.
The phase 1b data in BMD, presented at the 2023 annual meeting of the American Academy of Neurology, were sufficiently promising that controlled phase 2 trials in both BMD and DMD are already enrolling, reported Joanne Donovan, MD, PhD, an adjunct professor at Boston University and chief medical officer of Edgewise Therapeutics, the company developing the drug.
Phase 1 study
Early phase studies are largely focused on safety, but the
Moreover, the evidence of a clinical effect was achieved in adult patients with a North Star Ambulatory Assessment (NSAA) score of 15, signifying advanced disease. Only 12 patients were enrolled and there were no controls, but objective evidence of a favorable effect was generated by highly significant reductions in creatine kinase (CK) and fast skeletal muscle (TNNI2) troponin, which are both biomarkers commonly used to track muscular dystrophy progression.
In patients with BMD or DMD, a lack of dystrophin is a key pathogenic feature, according to Dr. Donovan. She explained that dystrophin in muscles connects contractile proteins to membranes and surrounding matrix. In the presence of dystrophin, muscle fibers support each other, but when this protein is absent, contraction causes injury.
The drug in development, currently identified as EDG-5506, is a selective fast myosin inhibitor. This agent was shown to prevent the muscle injury caused by lack of dystrophin in animal models of muscular dystrophy and is now showing the same effect in humans. Preservation of muscle is critical to preventing BMD and DMD progression according to several sets of data, according to Dr. Donovan.
For one, it has been shown that BMD or DMD patients with relatively preserved function as defined by a NSAA score above 32 have minimal muscle damage. As NSAA scores fall below 32 points, muscle mass diminishes and fat accumulates. In natural history studies of BMD, there is a 1.2-point decline in NSAA score over 5 years, and this tracks with muscle loss and not with other variables, such as patient age.
“Progression depends on the degree of muscle loss,” Dr. Donovan stated, providing the rationale for moving forward with EDG-5506.
Proof of concept
In experimental studies, modulation of fast myelin provided complete protection against muscle injury while preserving its contractile function, and this translated into protection against loss of function. Phase 1 studies in BMD patients and healthy controls have already provided evidence that EDG-5506 is well tolerated and safe, but the new phase 1b provides a proof of concept for its ability to inhibit muscle injury in BMD patients.
In this study, called ARCH, 12 adults 18 years of age or older with a dystrophin mutation and a BMD phenotype who could complete a 100-meter timed test were enrolled. The median age at entry was 32 years. Several patients had participated in a previous phase 1 safety study. The daily starting dose of 10 mg was increased from 10 mg to 15 mg at 2 months. The dose was increased again to 20 mg at 6 months, but the data presented by Dr. Donovan were restricted to the first 6 months.
At the interim 6-month analysis, creatine kinase was reduced by 40% and TINN2 was reduced by 84% (both P < 0.001). The significant reductions in these biomarkers and others, such as myoglobin, were mostly achieved within the first month, although further reductions were observed for some biomarkers subsequently.
The NSAA score at 6 months improved on average by about 1 point on treatment. Natural history studies of BMD predict a 1-point reduction in NSAA score over this period of time. The modest improvements from baseline in pain scores at 1 month were sustained at 6 months.
On the basis of a proteomic analysis, 125 proteins mostly associated with metabolic pathways consistent with muscle injury were found to be altered in BMD patients relative to healthy controls. The majority of these proteins, whether assessed collectively or individually, normalized after 1 to 2 months of treatment with EDG-5506 and have remained stable during follow-up to date, according to Dr. Donovan.
As in previous studies, the drug was well tolerated. The three most common treatment-emergent events were dizziness, somnolence, and headache. Each was reported by about 25% of patients, but no patient discontinued therapy as a result of adverse events.
Findings deemed ‘a big deal’
These data, despite the small number of patients in the study and the limited follow-up, “are a big deal,” according to Nicholas E. Johnson, MD, division chief, neuromuscular disorders, Virginia Commonwealth University, Richmond. He pointed out that there are no effective treatments currently for BMD, and the mechanism of action is plausible.
“I am excited about the potential of this treatment, although we clearly need longer follow-up and more patients evaluated on this treatment,” Dr. Johnson said. He said that clinicians with BMD patients should be aware of the phase 2 trial that is now recruiting adult subjects.
“Becker muscular dystrophy is highly disabling. As disease advances, most patients have very limited function,” said Dr. Johnson, emphasizing the urgent unmet need for an effective therapy.
Dr. Donovan is a full time employee of Edgewise Therapeutics, which funded this study. Dr. Johnson has financial relationships with Acceleron, Arthex, AveXis, Avidity, Biogen, Dyne Therapeutics, Entrada, Juvena, ML Bio, Sarepta Therapeutics, Triplet Therapeutics, and Vertex Pharma.
BOSTON – Becker (BMD) and Duchenne muscle dystrophy (DMD) progress largely from irreversible contraction-induced injury of skeletal muscles, making the very positive interim results of an early-phase trial with a drug that prevents these injuries worth attention.
The phase 1b data in BMD, presented at the 2023 annual meeting of the American Academy of Neurology, were sufficiently promising that controlled phase 2 trials in both BMD and DMD are already enrolling, reported Joanne Donovan, MD, PhD, an adjunct professor at Boston University and chief medical officer of Edgewise Therapeutics, the company developing the drug.
Phase 1 study
Early phase studies are largely focused on safety, but the
Moreover, the evidence of a clinical effect was achieved in adult patients with a North Star Ambulatory Assessment (NSAA) score of 15, signifying advanced disease. Only 12 patients were enrolled and there were no controls, but objective evidence of a favorable effect was generated by highly significant reductions in creatine kinase (CK) and fast skeletal muscle (TNNI2) troponin, which are both biomarkers commonly used to track muscular dystrophy progression.
In patients with BMD or DMD, a lack of dystrophin is a key pathogenic feature, according to Dr. Donovan. She explained that dystrophin in muscles connects contractile proteins to membranes and surrounding matrix. In the presence of dystrophin, muscle fibers support each other, but when this protein is absent, contraction causes injury.
The drug in development, currently identified as EDG-5506, is a selective fast myosin inhibitor. This agent was shown to prevent the muscle injury caused by lack of dystrophin in animal models of muscular dystrophy and is now showing the same effect in humans. Preservation of muscle is critical to preventing BMD and DMD progression according to several sets of data, according to Dr. Donovan.
For one, it has been shown that BMD or DMD patients with relatively preserved function as defined by a NSAA score above 32 have minimal muscle damage. As NSAA scores fall below 32 points, muscle mass diminishes and fat accumulates. In natural history studies of BMD, there is a 1.2-point decline in NSAA score over 5 years, and this tracks with muscle loss and not with other variables, such as patient age.
“Progression depends on the degree of muscle loss,” Dr. Donovan stated, providing the rationale for moving forward with EDG-5506.
Proof of concept
In experimental studies, modulation of fast myelin provided complete protection against muscle injury while preserving its contractile function, and this translated into protection against loss of function. Phase 1 studies in BMD patients and healthy controls have already provided evidence that EDG-5506 is well tolerated and safe, but the new phase 1b provides a proof of concept for its ability to inhibit muscle injury in BMD patients.
In this study, called ARCH, 12 adults 18 years of age or older with a dystrophin mutation and a BMD phenotype who could complete a 100-meter timed test were enrolled. The median age at entry was 32 years. Several patients had participated in a previous phase 1 safety study. The daily starting dose of 10 mg was increased from 10 mg to 15 mg at 2 months. The dose was increased again to 20 mg at 6 months, but the data presented by Dr. Donovan were restricted to the first 6 months.
At the interim 6-month analysis, creatine kinase was reduced by 40% and TINN2 was reduced by 84% (both P < 0.001). The significant reductions in these biomarkers and others, such as myoglobin, were mostly achieved within the first month, although further reductions were observed for some biomarkers subsequently.
The NSAA score at 6 months improved on average by about 1 point on treatment. Natural history studies of BMD predict a 1-point reduction in NSAA score over this period of time. The modest improvements from baseline in pain scores at 1 month were sustained at 6 months.
On the basis of a proteomic analysis, 125 proteins mostly associated with metabolic pathways consistent with muscle injury were found to be altered in BMD patients relative to healthy controls. The majority of these proteins, whether assessed collectively or individually, normalized after 1 to 2 months of treatment with EDG-5506 and have remained stable during follow-up to date, according to Dr. Donovan.
As in previous studies, the drug was well tolerated. The three most common treatment-emergent events were dizziness, somnolence, and headache. Each was reported by about 25% of patients, but no patient discontinued therapy as a result of adverse events.
Findings deemed ‘a big deal’
These data, despite the small number of patients in the study and the limited follow-up, “are a big deal,” according to Nicholas E. Johnson, MD, division chief, neuromuscular disorders, Virginia Commonwealth University, Richmond. He pointed out that there are no effective treatments currently for BMD, and the mechanism of action is plausible.
“I am excited about the potential of this treatment, although we clearly need longer follow-up and more patients evaluated on this treatment,” Dr. Johnson said. He said that clinicians with BMD patients should be aware of the phase 2 trial that is now recruiting adult subjects.
“Becker muscular dystrophy is highly disabling. As disease advances, most patients have very limited function,” said Dr. Johnson, emphasizing the urgent unmet need for an effective therapy.
Dr. Donovan is a full time employee of Edgewise Therapeutics, which funded this study. Dr. Johnson has financial relationships with Acceleron, Arthex, AveXis, Avidity, Biogen, Dyne Therapeutics, Entrada, Juvena, ML Bio, Sarepta Therapeutics, Triplet Therapeutics, and Vertex Pharma.
FROM AAN 2023