User login
U.S. study finds unexpectedly high prevalence of myasthenia gravis
PHOENIX – The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.
Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.
However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
True incidence or artifact?
The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.
However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
Understanding the true prevalence
Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.
He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.
It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.
The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.
The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.
The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).
Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.
PHOENIX – The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.
Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.
However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
True incidence or artifact?
The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.
However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
Understanding the true prevalence
Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.
He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.
It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.
The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.
The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.
The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).
Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.
PHOENIX – The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.
Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.
However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
True incidence or artifact?
The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.
However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
Understanding the true prevalence
Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.
He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.
It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.
The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.
The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.
The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).
Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.
AT AANEM 2023
RNA therapeutics will ‘change everything’ in epilepsy
Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.
But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.
“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.
Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.
Dr. Kaye said.
Thank COVID?
Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.
Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.
Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.
RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.
Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.
“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.
“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
Hope for Dravet syndrome
Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.
Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.
The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.
“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.
Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.
“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.
“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.
“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
A promising future
Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”
And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.
Take, for example, a case reported recently in the New England Journal of Medicine.
Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.
One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.
However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”
“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.
The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.
A version of this article first appeared on Medscape.com.
Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.
But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.
“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.
Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.
Dr. Kaye said.
Thank COVID?
Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.
Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.
Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.
RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.
Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.
“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.
“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
Hope for Dravet syndrome
Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.
Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.
The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.
“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.
Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.
“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.
“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.
“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
A promising future
Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”
And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.
Take, for example, a case reported recently in the New England Journal of Medicine.
Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.
One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.
However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”
“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.
The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.
A version of this article first appeared on Medscape.com.
Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.
But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.
“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.
Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.
Dr. Kaye said.
Thank COVID?
Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.
Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.
Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.
RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.
Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.
“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.
“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
Hope for Dravet syndrome
Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.
Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.
The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.
“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.
Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.
“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.
“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.
“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
A promising future
Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”
And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.
Take, for example, a case reported recently in the New England Journal of Medicine.
Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.
One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.
However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”
“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.
The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.
A version of this article first appeared on Medscape.com.
‘Hidden’ cognitive impairments in DMD may worsen outcomes
A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.
“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.
Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.
A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
A tool for continuous cognitive assessment
The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.
Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.
She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.
Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.
She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.
Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.
She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.
Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
Overcoming a significant barrier
The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.
Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”
Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.
A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.
“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.
Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.
A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
A tool for continuous cognitive assessment
The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.
Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.
She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.
Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.
She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.
Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.
She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.
Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
Overcoming a significant barrier
The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.
Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”
Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.
A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.
“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.
Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.
A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
A tool for continuous cognitive assessment
The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.
Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.
She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.
Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.
She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.
Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.
She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.
Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
Overcoming a significant barrier
The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.
Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”
Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.
FROM AANEM 2023
First new treatment in 30 years for rare disease is effective, tolerable, convenient
PHOENIX –
“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.
Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.
The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Filling an unmet need
A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.
Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.
“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.
Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.
The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.
For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.
They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.
Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.
Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.
The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).
Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.
Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.
In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.
The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.
“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.
Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
Promising data
Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”
The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”
Dr. Gable agreed that new options are important to address an unmet need in CIDP.
“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.
“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”
Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.
“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”
The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.
A version of this article first appeared on Medscape.com.
PHOENIX –
“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.
Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.
The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Filling an unmet need
A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.
Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.
“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.
Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.
The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.
For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.
They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.
Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.
Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.
The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).
Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.
Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.
In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.
The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.
“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.
Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
Promising data
Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”
The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”
Dr. Gable agreed that new options are important to address an unmet need in CIDP.
“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.
“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”
Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.
“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”
The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.
A version of this article first appeared on Medscape.com.
PHOENIX –
“This was the largest study of CIDP that has been performed, with over 600 patients screened and 322 enrolled, and was the first to use an adjudication committee to confirm the diagnosis,” said study investigator Richard Lewis, MD, of the department of neurology, Cedars-Sinai Medical Center, Los Angeles.
Furthermore, “this is the first new treatment for CIDP in over 30 years, so it’s very exciting. It is a brief subcutaneous injection, which should be something that patients will appreciate,” he said.
The study was presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
Filling an unmet need
A rare and often-debilitating autoimmune disorder, CIDP is characterized by weakness and numbness that can result in disability, pain, and fatigue and has been linked to IgG autoantibodies.
Treatments include corticosteroids, intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin, and plasma exchange, but not all patients achieve meaningful benefits and many patients complain about safety risks, costs, and burdensome treatment regimens.
“There is an unmet need for a first-line treatment with long-term efficacy that maintains or improves quality of life, has an early onset of action, is well tolerated, is not dependent on plasma donation, and has greater convenience,” the investigators wrote in their abstract.
Efgartigimod, which is approved in its intravenous and subcutaneous forms for the treatment of myasthenia gravis, is a human IgG1 antibody Fc receptor blocker designed to reduce pathogenic IgG autoantibody levels, which may be drivers of pathogenesis in CIDP.
The therapy is a coformulation of efgartigimod and recombinant human hyaluronidase that allows for rapid subcutaneous administration of larger volumes and is administered as a 90-second subcutaneous injection once weekly.
For the ongoing phase 2 ADHERE trial, 322 patients with a diagnosis of CIDP and active disease who were either treatment naive or receiving standard treatments were withdrawn from their treatments prior to day 1 of a run-in period of up to 12 weeks.
They then entered stage A of the study, an open-label phase in which all were treated with 1,000-mg efgartigimod PH20 SC weekly for up to 12 weeks.
Of those patients, 66% showed evidence of clinical improvement and a rapid onset of effect with the efgartigimod PH20 SC treatment, and 70% of the patients were then entered into stage B, a double-blind randomized phase, with 111 of patients receiving continued efgartigimod PH20 SC weekly and 110 receiving placebo for 48 weeks.
Of those moving on to stage B, more than 70% were on IVIg prior to the time of enrollment.
The study met its primary endpoint, with the efgartigimod PH20 SC groups showing a 61% lower risk for relapse on the basis of time to a first adjusted Inflammatory Neuropathy Cause and Treatment deterioration, compared with placebo (hazard ratio, 0.39; P = .000039).
Clinical benefits were also observed on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and in measures of mean grip strength in all groups regardless of prior CIDP medication.
Specifically, efgartigimod patients had a mean improvement of 7.7 points on I-RODS and 12.3 kPa on mean grip strength in stage A, which was maintained in stage B. These were partially lost in patients receiving placebo.
In terms of safety, most adverse events were mild or moderate in severity, and no new safety signals were identified with up to 60 weeks of treatment. There were no increased infection rates with increased exposure.
The findings show that “efgartigimod-PH20, given as a 90-second subcutaneous injection once a week, was effective in treating patients with CIDP who had relapsed when taken off their previous treatment (IVIg or corticosteroids),” said Dr. Lewis.
“[The study] then showed that the majority of patients, over 70%, maintained that improvement, compared with placebo, where over 50% relapsed – most within 8 weeks, so the treatment, which reduces circulating immunoglobulin G by over 70%, is effective in treating CIDP,” he added.
Plans for this ongoing trial include recruiting up to 360 patients until 88 events of clinical deterioration have been observed in stage B.
Promising data
Commenting on the study, Karissa Gable, MD, an associate professor of neurology at Duke University, Durham, N.C., said that the “initial data reported from the ADHERE study is very promising and demonstrated significant efficacy.”
The study’s use of an adjudication committee in confirming the diagnosis is particularly notable, she said. “The trial design demonstrated confirmation of diagnosis and activity of disease and response to drug prior to randomization, which is a novel design that is particularly applicable to patients with CIDP given the rate of misdiagnosis and placebo effect found in other trials.”
Dr. Gable agreed that new options are important to address an unmet need in CIDP.
“The current first-line treatments are generally 80%-90% effective, however, there are limited options with respect to the first line treatments due to side effects and comorbid disease in patients,” she explained.
“Other treatments options are needed and so this is an unmet need in patients with CIDP,” Dr. Gable said. “This medication will be likely to be one that will provide a strong alternate option for treatment.”
Overall, “this is a novel mechanism for drug treatment for CIDP and seems to demonstrate efficacy and good safety and tolerability based on the initial report of the data,” Dr. Gable added.
“It will likely be a promising medication to use for these patients to fill the unmet need for treatment of patients with CIDP.”
The study was sponsored by Argenx. Dr. Lewis disclosed relationships with Argenx and other companies involved in neuromuscular disease therapies. Dr. Gable is on the global medical advisory board steering committee for Argenx and she was the principal investigator at her site for the Adhere study. Dr. Gable has served as a consultant for Immunovant and Takeda as well as Sanofi for CIDP and she is on the Takeda speaker bureau for Huyquvia for treatment of CIDP.
A version of this article first appeared on Medscape.com.
AT AANEM 2023
Duchenne muscular dystrophy gene therapy safe, effective at 4 years
PHOENIX – compared with untreated patients who showed significant decline over the same time period, new research shows.
“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.
The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
Severe type of DMD
Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.
SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.
In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.
The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.
For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.
All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.
At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.
The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.
Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.
No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.
Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).
Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).
Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.
Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.
The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.
Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
Increased function, long-term stability
Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.
“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.
“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.
A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.
In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments.
“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”
She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”
The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.
A version of this article first appeared on Medscape.com.
PHOENIX – compared with untreated patients who showed significant decline over the same time period, new research shows.
“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.
The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
Severe type of DMD
Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.
SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.
In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.
The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.
For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.
All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.
At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.
The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.
Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.
No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.
Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).
Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).
Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.
Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.
The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.
Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
Increased function, long-term stability
Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.
“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.
“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.
A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.
In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments.
“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”
She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”
The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.
A version of this article first appeared on Medscape.com.
PHOENIX – compared with untreated patients who showed significant decline over the same time period, new research shows.
“Functional assessments demonstrated long-term sustained stabilization of motor function that was clinically meaningful, at ages where functional decline would be expected based on natural history,” the investigators noted in their abstract. Furthermore, the treatment, known as delandistrogene moxeparvovec-rokl (SRP-9001), was well tolerated 4 years post treatment.
The study was presented at the annual meeting of the American Association of Neuromuscular Electrodiagnostic Medicine.
Severe type of DMD
Considered one of the most severe forms of muscular dystrophy, DMD causes progressive muscle wasting stemming from the root genetic cause of missing dystrophin in muscle cells. Often referred to as a molecular “shock absorber,” dystrophin stabilizes the sarcolemma during muscle contractions to prevent degeneration.
SRP-9001, a single-dose recombinant gene therapy administered as an intravenous infusion, was designed to deliver a trimmed down form of dystrophin to compensate for the deficit.
In July, the adeno-associated virus vector (AAV)–based SRP-9001 gene therapy was granted accelerated approval by the Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with DMD with a confirmed mutation in the DMD gene.
The therapy is administered over 1-2 hours at a dose of 133 trillion vector genomes per kilogram of body weight.
For Study 101, one of several evaluating the novel therapy, a research team led by senior investigator Jerry Mendell, MD, an attending neurologist at Nationwide Children’s Hospital and professor of pediatrics and neurology at Ohio State University, both in Columbus,evaluated data on four ambulatory male patients aged 4-8 years who received a single IV infusion of the therapy.
All patients also received prednisone 1 mg/kg, 1 day preinfusion and 30 days post infusion.
At 4 years post treatment, there were no new safety events. All treatment-related adverse events occurred mainly within the first 70 days, and all resolved.
The most commonly reported adverse reactions of the gene therapy include vomiting, nausea, increases in liver enzymes, pyrexia (fever), and thrombocytopenia, all of which occurred within 90 days of infusion and been manageable.
Risk mitigation strategies for hepatotoxicity or acute liver injury include pre- and postinfusion monitoring of liver enzymes, the authors noted.
No serious abnormalities were observed in hematologic or chemistry panels, and while three patients had elevated gamma-glutamyl transpeptidase in the first 3 months post treatment, those cases resolved with oral steroid treatment.
Significant improvements in function were observed, with a mean improvement in North Star Ambulatory Assessment (NSAA) scores from baseline of 7.0 points (range, 4-11).
Exploratory analyses further showed that, compared with a propensity score–weighted external control cohort of 21 patients with DMD who did not receive the therapy, those receiving SRP-9001 had a statistically significant difference of 9.4 points in least-squares mean change from baseline to 4 years on the NSAA score (P = .0125).
Similar trends were observed in improvement from baseline in key measures of time to rise, 4-stair climb, and 10- and 100-meter walk/run function tests.
Other reported adverse events include acute serious liver injury, immune-mediated myositis, and myocarditis. Because of the latter risk, the therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.
The current 4-year update on SRP-9001 adds to clinical trial results that have been reported on more than 80 patients treated to date, with favorable results and consistent safety profiles reported at other time points.
Continued FDA approval for the therapy will be contingent upon verification of a clinical benefit in the confirmatory trials, including the EMBARK trial.
Increased function, long-term stability
Discussing the research at the meeting, Craig McDonald, MD, professor and chair of physical medicine & rehabilitation, a professor of pediatrics and study chair of the CINRG Duchenne Natural History Study at University of California Davis Health, noted that top-line results from the ongoing, confirmatory phase 3 EMBARK trial show functional benefits of SRP-9001 not only in 4- to 5-year-olds but also in other older age groups.
“What’s really striking, and in my mind the most impressive, is that when you follow these patients out 3 or 4 years ... you see there is this bump in function followed by long-term stability, whereas the external control cohort predictably shows really quite significant declines in their [NSAA] functional values,” he said in his presentation.
“When you look at each individually treated patient versus their own predicted trajectory using their baseline values on the time function test, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory,” he added.
A caveat that SRP-9001 shares with other gene therapies is the issue of cost – reported in the range of $2 million–$3 million.
In the context of racial and socioeconomic disparities in access to diagnosis and care reported in DMD, Emma Ciafaloni, MD, a professor of neurology and pediatrics at the University of Rochester (N.Y.) Medical Center, underscored the need to consider approval versus access to gene therapies and how to optimize access to the novel treatments.
“We need to consider what the cost is, how it’s going to be accessed, and whether there is a sustainable model,” said Ciafaloni, who was not associated with the study. “There will need to be institutional readiness and support for specialized multidisciplinary clinics for gene therapy.”
She also noted “we need to consider how we can do better on a broader level, because this is not a provider problem or a manufacturer problem — it’s a society problem.”
The study was funded by Sarepta Therapeutics. McDonald reported consulting work for Sarepta Therapeutics and has been an investigator in SRP-9001 research. Ciafaloni reported serving on advisory boards or other relationships with Alexion, Argenx, Biogen, Amicus, Momenta, Medscape, Pfizer, Sanofi/Genzyme, Sarepta, Jansen, NS Pharma, CureSMA, Orphazyme, the Patient-Centered Outcomes Research Institute, PPMD, PTC Therapeutics, and Santhera.
A version of this article first appeared on Medscape.com.
AT AANEM 2023
In myasthenia gravis, antibodies pass open-label tests
PHOENIX – . The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.
The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.
At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.
In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.
Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.
After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.
The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.
“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
A reduction in steroid use?
During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.
As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.
Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
Clinical improvements seen
In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.
MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.
Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.
In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.
The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.
MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.
PHOENIX – . The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.
The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.
At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.
In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.
Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.
After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.
The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.
“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
A reduction in steroid use?
During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.
As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.
Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
Clinical improvements seen
In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.
MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.
Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.
In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.
The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.
MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.
PHOENIX – . The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.
The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.
At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.
In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.
Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.
After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.
The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.
“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
A reduction in steroid use?
During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.
As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.
Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
Clinical improvements seen
In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.
MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.
Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.
In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.
The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.
MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.
AT AANEM 2023
More phase 3 data support use of nemolizumab for prurigo nodularis
reported at the annual Congress of the European Academy of Dermatology and Venereology.
In the OLYMPIA 1 study, clinically significant improvements in both itch and skin lesions were seen after 16 weeks of treatment with nemolizumab compared with placebo (P < .0001).
Indeed, among the 286 patients who participated in the trial (190 on nemolizumab and 96 on placebo), 58.4% of those treated with nemolizumab and 16.7% of those who received placebo had an improvement of 4 points or more in the weekly average peak pruritus numeric rating scale (PP-NRS) at week 16 (P < .0001).
Skin lesions were assessed using an investigators general assessment (IGA) score, where IGA success was defined as a score of 0/1 indicating clear or almost clear skin or where there had been at least a 2-point change from baseline values. Over a quarter (26.3%) of nemolizumab-treated patients met these criteria versus 7.3% for those on placebo (P = .0001).
“These results confirm the results of the OLYMPIA 2 study, the other phase 3 study, and now I hope you understand why we are so excited,” lead investigator Sonja Ständer, MD, of the Center for Chronic Pruritus at University Hospital Münster, Germany, said at the meeting, where she presented the data.
The OLYMPIA 2 study included 274 patients and the results showed a weekly average PP-NRS score improvement of 56.3% vs. 20.9% for placebo and IGA success in 37.7% and 11% of patients, respectively, at 16 weeks.
First-in-class therapy
“We know how difficult it is to treat patients; they are refractory to treatment, frustrated, and this really impacts them regarding their quality of life,” said Dr. Ständer. New options are needed to help patients, and nemolizumab, a first-in-class interleukin-31 (IL-31) receptor alpha antagonist, is one treatment that may answer this call.
Prurigo nodularis is a chronic neuroimmune skin condition characterized by severe itch and multiple nodular skin lesions, Dr. Ständer explained. She added that there is evidence that IL-31 has a key role to play in the development of itch, and in differentiation of keratinocytes, type 2 and type 17 immune responses, and fibrosis associated with the condition.
The OLYMPIA 1 and 2 trials are part of a large developmental program that includes two ongoing trials. One is assessing the durability of response over 24 weeks in 40 patients and the other is a long-term extension trial involving 450 patients from the OLYMPIA 1 and 2 trials.
Inclusion criteria and additional results
For inclusion in the study, adults with prurigo nodularis for at least 6 months had to have 20 or more nodules on the body with a bilateral distribution, an IGA score of 3 or more, and an average PP-NRS of 7 or higher. The latter “was really a high bar for them to qualify for the trial,” said Dr. Ständer.
After an initial 4-week screening period, patients were randomly assigned to 24 weeks of treatment with nemolizumab or placebo given as a subcutaneous injection every 4 weeks. An 8-week “off-treatment” period followed.
The nemolizumab dose was based on the patient’s body weight, with patients weighing less than 90 kg (198 pounds) getting a loading dose of 60 mg followed by further doses of 30 mg; while patients weighing 90 kg or more receiving 50 mg of nemolizumab.
Dr. Ständer reported that nemolizumab met all of the trials’ secondary endpoints; this included at least a 4-point improvement in sleep disturbance. She noted that changes in itch and subsequent sleep disturbance occurred early, at 4 weeks of treatment – after just one injection of nemolizumab.
The response rates seen in the moderate to severe prurigo nodularis population studies are quite unique when compared with conventional therapies, Dr. Ständer maintained. “We’ve never seen something like this before.”
No safety concerns
No significant difference in tolerability was seen between the nemolizumab and placebo groups, Dr. Ständer observed. Any adverse event occurred in 71.7% and 65.3% of patients, respectively, and serious adverse events in 8.6% and 10.5%.
There was a similar rate of adverse events leading to discontinuation, respectively (4.8% vs. 4.2%).
Headache was seen more frequently among those on nemolizumab than those on placebo (7.0% vs. 2.1%), and there was a higher number of eczema cases among those on nemolizumab (5.3% vs. 1.1%). The latter is somewhat paradoxical because nemolizumab is also being studied as a treatment for atopic dermatitis, with good results seen in phase 3 trials. Asked about this finding after her presentation, Dr. Ständer said “we are following up on that to know exactly what is going on; this is a side effect of nemolizumab that is seen also with other biologics.”
JAK inhibitor trial for PN, CPUO
Nemolizumab is not the only promising new approach to treating prurigo nodularis. During a separate late-breaking news session at the meeting, Shawn Kwatra, MD, director of the Johns Hopkins Itch Center in Baltimore, presented “dramatic” data from a “proof-of-concept” phase 2 study with the Janus kinase (JAK) inhibitor abrocitinib (Cibinqo), which is approved for atopic dermatitis in the United States and Europe.
The investigator-initiated trial took a different approach from most other trials, Dr. Kwatra said. The starting point was to look at studying multiple rather than single dermatologic diseases that were perhaps being left a little by the wayside but may share some common ground. Those two diseases were prurigo nodularis and chronic pruritus of unknown origin (CPUO).
“They’re actually very analogous conditions in the way we treat, so I thought those would be a good pair,” Dr. Kwatra said, noting that there were several studies that made him think that JAK inhibition “would be an interesting concept to try.”
On that basis, 10 women with prurigo nodularis (mean age, 58 years) and two women and eight men with CPUO (mean age, 70 years) were recruited and all were treated with abrocitinib at a once-daily oral dose of 200 mg for 12 weeks.
“They all had really intense itch,” before treatment, Dr. Kwatra said. The mean baseline PP-NRS was 9.2 and 8.2 in the prurigo nodularis and CPUO groups, respectively. By the end of treatment, however, “the improvement in itch was pretty dramatic,” especially for prurigo nodularis, he said.
At 12 weeks, the PP-NRS score had fallen to 2.0 in the prurigo nodularis group, equating to a significant 78% change from baseline (P < .001). And, in the CPUO group, the 12-week PP-NRS score was 3.8, nearly a 54% drop from baseline (P = .01).
Sleep disturbance was improved for both conditions, and in the patients with prurigo nodularis, there were improvements in skin lesions. Looking at the patients who responded to treatment, Dr. Kwatra noted that “if you responded, you respond fast, and you respond almost entirely.”
Additional findings from cutaneous transcriptome analysis showed that JAK inhibition with abrocitinib was modulating Th1-, Th2-, Th17-, and Th22-mediated pathways in both groups of patients.
The overall frequency of adverse events was low, and no serious adverse events occurred.
Commenting on the potential use of abrocitinib in managing patients with PN and CPUO, Tiago dos Reis Matos, MD, PhD, MSc, Amsterdam University Medical Centers, told this news organization that JAK1 inhibitors “are showing promising results in treating several diseases.”
Dr. Matos, who was not involved in the study, added that JAK inhibition was “of special interest in prurigo nodularis and chronic pruritus, since these are some of the most difficult diseases to treat with limited therapeutic options.”
Dr. Kwatra observed: “Obviously, we need further development. But we also have clues here about how to design phase 3 trials.”
Galderma funded the OLYMPIA 1 and 2 studies. Dr. Ständer was an investigator for the trial and reported serving as a consultant, speaker, or investigator for multiple pharmaceutical companies, including Galderma.
Johns Hopkins University supported the abrocitinib study with funding from Pfizer. Dr. Kwatra is an advisory board member or consultant to several pharmaceutical companies and is an investigator for Galderma, Incyte, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
reported at the annual Congress of the European Academy of Dermatology and Venereology.
In the OLYMPIA 1 study, clinically significant improvements in both itch and skin lesions were seen after 16 weeks of treatment with nemolizumab compared with placebo (P < .0001).
Indeed, among the 286 patients who participated in the trial (190 on nemolizumab and 96 on placebo), 58.4% of those treated with nemolizumab and 16.7% of those who received placebo had an improvement of 4 points or more in the weekly average peak pruritus numeric rating scale (PP-NRS) at week 16 (P < .0001).
Skin lesions were assessed using an investigators general assessment (IGA) score, where IGA success was defined as a score of 0/1 indicating clear or almost clear skin or where there had been at least a 2-point change from baseline values. Over a quarter (26.3%) of nemolizumab-treated patients met these criteria versus 7.3% for those on placebo (P = .0001).
“These results confirm the results of the OLYMPIA 2 study, the other phase 3 study, and now I hope you understand why we are so excited,” lead investigator Sonja Ständer, MD, of the Center for Chronic Pruritus at University Hospital Münster, Germany, said at the meeting, where she presented the data.
The OLYMPIA 2 study included 274 patients and the results showed a weekly average PP-NRS score improvement of 56.3% vs. 20.9% for placebo and IGA success in 37.7% and 11% of patients, respectively, at 16 weeks.
First-in-class therapy
“We know how difficult it is to treat patients; they are refractory to treatment, frustrated, and this really impacts them regarding their quality of life,” said Dr. Ständer. New options are needed to help patients, and nemolizumab, a first-in-class interleukin-31 (IL-31) receptor alpha antagonist, is one treatment that may answer this call.
Prurigo nodularis is a chronic neuroimmune skin condition characterized by severe itch and multiple nodular skin lesions, Dr. Ständer explained. She added that there is evidence that IL-31 has a key role to play in the development of itch, and in differentiation of keratinocytes, type 2 and type 17 immune responses, and fibrosis associated with the condition.
The OLYMPIA 1 and 2 trials are part of a large developmental program that includes two ongoing trials. One is assessing the durability of response over 24 weeks in 40 patients and the other is a long-term extension trial involving 450 patients from the OLYMPIA 1 and 2 trials.
Inclusion criteria and additional results
For inclusion in the study, adults with prurigo nodularis for at least 6 months had to have 20 or more nodules on the body with a bilateral distribution, an IGA score of 3 or more, and an average PP-NRS of 7 or higher. The latter “was really a high bar for them to qualify for the trial,” said Dr. Ständer.
After an initial 4-week screening period, patients were randomly assigned to 24 weeks of treatment with nemolizumab or placebo given as a subcutaneous injection every 4 weeks. An 8-week “off-treatment” period followed.
The nemolizumab dose was based on the patient’s body weight, with patients weighing less than 90 kg (198 pounds) getting a loading dose of 60 mg followed by further doses of 30 mg; while patients weighing 90 kg or more receiving 50 mg of nemolizumab.
Dr. Ständer reported that nemolizumab met all of the trials’ secondary endpoints; this included at least a 4-point improvement in sleep disturbance. She noted that changes in itch and subsequent sleep disturbance occurred early, at 4 weeks of treatment – after just one injection of nemolizumab.
The response rates seen in the moderate to severe prurigo nodularis population studies are quite unique when compared with conventional therapies, Dr. Ständer maintained. “We’ve never seen something like this before.”
No safety concerns
No significant difference in tolerability was seen between the nemolizumab and placebo groups, Dr. Ständer observed. Any adverse event occurred in 71.7% and 65.3% of patients, respectively, and serious adverse events in 8.6% and 10.5%.
There was a similar rate of adverse events leading to discontinuation, respectively (4.8% vs. 4.2%).
Headache was seen more frequently among those on nemolizumab than those on placebo (7.0% vs. 2.1%), and there was a higher number of eczema cases among those on nemolizumab (5.3% vs. 1.1%). The latter is somewhat paradoxical because nemolizumab is also being studied as a treatment for atopic dermatitis, with good results seen in phase 3 trials. Asked about this finding after her presentation, Dr. Ständer said “we are following up on that to know exactly what is going on; this is a side effect of nemolizumab that is seen also with other biologics.”
JAK inhibitor trial for PN, CPUO
Nemolizumab is not the only promising new approach to treating prurigo nodularis. During a separate late-breaking news session at the meeting, Shawn Kwatra, MD, director of the Johns Hopkins Itch Center in Baltimore, presented “dramatic” data from a “proof-of-concept” phase 2 study with the Janus kinase (JAK) inhibitor abrocitinib (Cibinqo), which is approved for atopic dermatitis in the United States and Europe.
The investigator-initiated trial took a different approach from most other trials, Dr. Kwatra said. The starting point was to look at studying multiple rather than single dermatologic diseases that were perhaps being left a little by the wayside but may share some common ground. Those two diseases were prurigo nodularis and chronic pruritus of unknown origin (CPUO).
“They’re actually very analogous conditions in the way we treat, so I thought those would be a good pair,” Dr. Kwatra said, noting that there were several studies that made him think that JAK inhibition “would be an interesting concept to try.”
On that basis, 10 women with prurigo nodularis (mean age, 58 years) and two women and eight men with CPUO (mean age, 70 years) were recruited and all were treated with abrocitinib at a once-daily oral dose of 200 mg for 12 weeks.
“They all had really intense itch,” before treatment, Dr. Kwatra said. The mean baseline PP-NRS was 9.2 and 8.2 in the prurigo nodularis and CPUO groups, respectively. By the end of treatment, however, “the improvement in itch was pretty dramatic,” especially for prurigo nodularis, he said.
At 12 weeks, the PP-NRS score had fallen to 2.0 in the prurigo nodularis group, equating to a significant 78% change from baseline (P < .001). And, in the CPUO group, the 12-week PP-NRS score was 3.8, nearly a 54% drop from baseline (P = .01).
Sleep disturbance was improved for both conditions, and in the patients with prurigo nodularis, there were improvements in skin lesions. Looking at the patients who responded to treatment, Dr. Kwatra noted that “if you responded, you respond fast, and you respond almost entirely.”
Additional findings from cutaneous transcriptome analysis showed that JAK inhibition with abrocitinib was modulating Th1-, Th2-, Th17-, and Th22-mediated pathways in both groups of patients.
The overall frequency of adverse events was low, and no serious adverse events occurred.
Commenting on the potential use of abrocitinib in managing patients with PN and CPUO, Tiago dos Reis Matos, MD, PhD, MSc, Amsterdam University Medical Centers, told this news organization that JAK1 inhibitors “are showing promising results in treating several diseases.”
Dr. Matos, who was not involved in the study, added that JAK inhibition was “of special interest in prurigo nodularis and chronic pruritus, since these are some of the most difficult diseases to treat with limited therapeutic options.”
Dr. Kwatra observed: “Obviously, we need further development. But we also have clues here about how to design phase 3 trials.”
Galderma funded the OLYMPIA 1 and 2 studies. Dr. Ständer was an investigator for the trial and reported serving as a consultant, speaker, or investigator for multiple pharmaceutical companies, including Galderma.
Johns Hopkins University supported the abrocitinib study with funding from Pfizer. Dr. Kwatra is an advisory board member or consultant to several pharmaceutical companies and is an investigator for Galderma, Incyte, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
reported at the annual Congress of the European Academy of Dermatology and Venereology.
In the OLYMPIA 1 study, clinically significant improvements in both itch and skin lesions were seen after 16 weeks of treatment with nemolizumab compared with placebo (P < .0001).
Indeed, among the 286 patients who participated in the trial (190 on nemolizumab and 96 on placebo), 58.4% of those treated with nemolizumab and 16.7% of those who received placebo had an improvement of 4 points or more in the weekly average peak pruritus numeric rating scale (PP-NRS) at week 16 (P < .0001).
Skin lesions were assessed using an investigators general assessment (IGA) score, where IGA success was defined as a score of 0/1 indicating clear or almost clear skin or where there had been at least a 2-point change from baseline values. Over a quarter (26.3%) of nemolizumab-treated patients met these criteria versus 7.3% for those on placebo (P = .0001).
“These results confirm the results of the OLYMPIA 2 study, the other phase 3 study, and now I hope you understand why we are so excited,” lead investigator Sonja Ständer, MD, of the Center for Chronic Pruritus at University Hospital Münster, Germany, said at the meeting, where she presented the data.
The OLYMPIA 2 study included 274 patients and the results showed a weekly average PP-NRS score improvement of 56.3% vs. 20.9% for placebo and IGA success in 37.7% and 11% of patients, respectively, at 16 weeks.
First-in-class therapy
“We know how difficult it is to treat patients; they are refractory to treatment, frustrated, and this really impacts them regarding their quality of life,” said Dr. Ständer. New options are needed to help patients, and nemolizumab, a first-in-class interleukin-31 (IL-31) receptor alpha antagonist, is one treatment that may answer this call.
Prurigo nodularis is a chronic neuroimmune skin condition characterized by severe itch and multiple nodular skin lesions, Dr. Ständer explained. She added that there is evidence that IL-31 has a key role to play in the development of itch, and in differentiation of keratinocytes, type 2 and type 17 immune responses, and fibrosis associated with the condition.
The OLYMPIA 1 and 2 trials are part of a large developmental program that includes two ongoing trials. One is assessing the durability of response over 24 weeks in 40 patients and the other is a long-term extension trial involving 450 patients from the OLYMPIA 1 and 2 trials.
Inclusion criteria and additional results
For inclusion in the study, adults with prurigo nodularis for at least 6 months had to have 20 or more nodules on the body with a bilateral distribution, an IGA score of 3 or more, and an average PP-NRS of 7 or higher. The latter “was really a high bar for them to qualify for the trial,” said Dr. Ständer.
After an initial 4-week screening period, patients were randomly assigned to 24 weeks of treatment with nemolizumab or placebo given as a subcutaneous injection every 4 weeks. An 8-week “off-treatment” period followed.
The nemolizumab dose was based on the patient’s body weight, with patients weighing less than 90 kg (198 pounds) getting a loading dose of 60 mg followed by further doses of 30 mg; while patients weighing 90 kg or more receiving 50 mg of nemolizumab.
Dr. Ständer reported that nemolizumab met all of the trials’ secondary endpoints; this included at least a 4-point improvement in sleep disturbance. She noted that changes in itch and subsequent sleep disturbance occurred early, at 4 weeks of treatment – after just one injection of nemolizumab.
The response rates seen in the moderate to severe prurigo nodularis population studies are quite unique when compared with conventional therapies, Dr. Ständer maintained. “We’ve never seen something like this before.”
No safety concerns
No significant difference in tolerability was seen between the nemolizumab and placebo groups, Dr. Ständer observed. Any adverse event occurred in 71.7% and 65.3% of patients, respectively, and serious adverse events in 8.6% and 10.5%.
There was a similar rate of adverse events leading to discontinuation, respectively (4.8% vs. 4.2%).
Headache was seen more frequently among those on nemolizumab than those on placebo (7.0% vs. 2.1%), and there was a higher number of eczema cases among those on nemolizumab (5.3% vs. 1.1%). The latter is somewhat paradoxical because nemolizumab is also being studied as a treatment for atopic dermatitis, with good results seen in phase 3 trials. Asked about this finding after her presentation, Dr. Ständer said “we are following up on that to know exactly what is going on; this is a side effect of nemolizumab that is seen also with other biologics.”
JAK inhibitor trial for PN, CPUO
Nemolizumab is not the only promising new approach to treating prurigo nodularis. During a separate late-breaking news session at the meeting, Shawn Kwatra, MD, director of the Johns Hopkins Itch Center in Baltimore, presented “dramatic” data from a “proof-of-concept” phase 2 study with the Janus kinase (JAK) inhibitor abrocitinib (Cibinqo), which is approved for atopic dermatitis in the United States and Europe.
The investigator-initiated trial took a different approach from most other trials, Dr. Kwatra said. The starting point was to look at studying multiple rather than single dermatologic diseases that were perhaps being left a little by the wayside but may share some common ground. Those two diseases were prurigo nodularis and chronic pruritus of unknown origin (CPUO).
“They’re actually very analogous conditions in the way we treat, so I thought those would be a good pair,” Dr. Kwatra said, noting that there were several studies that made him think that JAK inhibition “would be an interesting concept to try.”
On that basis, 10 women with prurigo nodularis (mean age, 58 years) and two women and eight men with CPUO (mean age, 70 years) were recruited and all were treated with abrocitinib at a once-daily oral dose of 200 mg for 12 weeks.
“They all had really intense itch,” before treatment, Dr. Kwatra said. The mean baseline PP-NRS was 9.2 and 8.2 in the prurigo nodularis and CPUO groups, respectively. By the end of treatment, however, “the improvement in itch was pretty dramatic,” especially for prurigo nodularis, he said.
At 12 weeks, the PP-NRS score had fallen to 2.0 in the prurigo nodularis group, equating to a significant 78% change from baseline (P < .001). And, in the CPUO group, the 12-week PP-NRS score was 3.8, nearly a 54% drop from baseline (P = .01).
Sleep disturbance was improved for both conditions, and in the patients with prurigo nodularis, there were improvements in skin lesions. Looking at the patients who responded to treatment, Dr. Kwatra noted that “if you responded, you respond fast, and you respond almost entirely.”
Additional findings from cutaneous transcriptome analysis showed that JAK inhibition with abrocitinib was modulating Th1-, Th2-, Th17-, and Th22-mediated pathways in both groups of patients.
The overall frequency of adverse events was low, and no serious adverse events occurred.
Commenting on the potential use of abrocitinib in managing patients with PN and CPUO, Tiago dos Reis Matos, MD, PhD, MSc, Amsterdam University Medical Centers, told this news organization that JAK1 inhibitors “are showing promising results in treating several diseases.”
Dr. Matos, who was not involved in the study, added that JAK inhibition was “of special interest in prurigo nodularis and chronic pruritus, since these are some of the most difficult diseases to treat with limited therapeutic options.”
Dr. Kwatra observed: “Obviously, we need further development. But we also have clues here about how to design phase 3 trials.”
Galderma funded the OLYMPIA 1 and 2 studies. Dr. Ständer was an investigator for the trial and reported serving as a consultant, speaker, or investigator for multiple pharmaceutical companies, including Galderma.
Johns Hopkins University supported the abrocitinib study with funding from Pfizer. Dr. Kwatra is an advisory board member or consultant to several pharmaceutical companies and is an investigator for Galderma, Incyte, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
FROM THE EADV CONGRESS
Birch bark–derived treatment reduces daily dressings in patients with epidermolysis bullosa
Additional when compared with a control gel.
In a final, post hoc analysis to come from the trial, 15 of 45 (33%) patients treated with Oleogel-S10 versus 5 of 48 (10.4%) treated with the control gel were reported as no longer needing daily dressing changes at 45 days of follow-up.
Moreover, the effect was sustained, with similar percentages of patients no longer requiring daily dressing changes at 60 days (34% vs. 13%, respectively) and 90 days (36% vs. 11%) of follow-up.
The mean reduction in daily dressing changes was 1.36 for Oleogel-S10 and 0.41 for the control gel (P = .005).
“Patients who, in the beginning, had daily dressing changes had almost three fewer dressing changes every 2 weeks if they were treated with Oleogel-S10,” Dimitra Kiritsi, MD, PhD, of the department of dermatology at the University of Freiburg (Germany), reported at the annual congress of the European Academy of Dermatology and Venereology. By comparison, patients in the control group had just one fewer daily dressing change in 2 weeks.
“You might say okay, but what does this mean in terms of time?” added Dr. Kiritsi. Using historical data on the time required for whole body care (Orphanet J Rare Dis. 2020 Jan 3. doi: 10.1186/s13023-019-1279-y), it was estimated that treatment with Oleogel-S10 was associated with an overall time-saving per week of 11 hours (6.6 hours for the patient and 4.4 hours for the caregiver) and use of the control gel was associated with an overall time-saving of 4 hours (2.4 hours for the patient and 1.6 hours for the caregiver).
“This is, for our patients, important,” said Dr. Kiritsi, as “it is time that they can spend doing something nice with the family” instead, avoiding the pain and distress associated with frequent dressing changes.
Approved in Europe, not in the United States
Oleogel-S10, classified as an herbal product, contains triterpenes derived from birch bark extract, which have been formulated with sunflower oil to form a gel.
Despite being approved for use in Europe, Oleogel-S10 has not yet been approved to treat EB in the United States. The FDA did not approve Amryt Pharma’s new drug application in February 2022. The application had included data from the EASE trial.
EASE included 223 patients with dystrophic or junctional EB, including 156 children, at 58 sites in 28 countries. As such, this makes it the largest treatment study in this rare genetic disease to date.
The trial had consisted of an initial 90-day, double-blind treatment period, during which time 109 patients had used Oleogel-S10 and 114 had used a control gel. This was followed by a 24-month open-label phase, during which time all remaining patients (n = 205) had used Oleogel-S10 on top of their standard of care.
Dr. Kiritsi summarized the main results of the EASE trial as follows.
- Complete healing of target wounds (primary endpoint) in 41.3% of patients treated with Oleogel-S10 and 28.9% of patients treated with the control gel (P = .013).
- Improved total body wound burden measured by both Epidermolysis Bullosa Disease Activity and Scarring Index and Body Surface Area Percentage scores.
- Reduced frequency of dressing changes (1 less per 2 weeks for Oleogel-S10 versus 0 less per 2 weeks for control gel).
- Improved pain among participants aged 4 years and older while their dressings were being changed.
- Reduced rates of wound infection (0.9% Oleogel-S10 vs. 4.4% control gel).
- Similar rates of treatment-emergent adverse events (24.8% vs. 22.8%, respectively), which were mostly deemed to be mild or moderate.
The EASE study – an important trial for EB
EASE is an important trial for EB, the study’s principal investigator Dédée Murrell, MD, DSc, University of New South Wales, Sydney, has pointed out previously.
“This was the first EB study to meet its primary endpoint and demonstrated a statistically significant acceleration of target wound healing by day 45,” Dr. Murrell said in a press release issued by Amryt Pharma to coincide with the online publication of the trial results.
“In addition, the favorable trends we see with key secondary endpoints such as reduced wound burden, pain, and frequency of dressing changes are considered as being very meaningful for patients,” Dr. Murrell said.
The EASE study was funded by Amryt Research Limited. Dr. Kiritsi reported receiving honoraria or consultation fees from Amryt, RHEACELL GmbH, and Fibrx Derm. She also acknowledged grant or research support from DEBRA International, EB Research Partnership, Fritz-Thyssen Foundation, German Research Foundation, and RHEACELL. Dr. Murrell has ties to Amryt and Amicus and is a co-owner of the patent for topical sirolimus for EB simplex.
A version of this article appeared on Medscape.com.
Additional when compared with a control gel.
In a final, post hoc analysis to come from the trial, 15 of 45 (33%) patients treated with Oleogel-S10 versus 5 of 48 (10.4%) treated with the control gel were reported as no longer needing daily dressing changes at 45 days of follow-up.
Moreover, the effect was sustained, with similar percentages of patients no longer requiring daily dressing changes at 60 days (34% vs. 13%, respectively) and 90 days (36% vs. 11%) of follow-up.
The mean reduction in daily dressing changes was 1.36 for Oleogel-S10 and 0.41 for the control gel (P = .005).
“Patients who, in the beginning, had daily dressing changes had almost three fewer dressing changes every 2 weeks if they were treated with Oleogel-S10,” Dimitra Kiritsi, MD, PhD, of the department of dermatology at the University of Freiburg (Germany), reported at the annual congress of the European Academy of Dermatology and Venereology. By comparison, patients in the control group had just one fewer daily dressing change in 2 weeks.
“You might say okay, but what does this mean in terms of time?” added Dr. Kiritsi. Using historical data on the time required for whole body care (Orphanet J Rare Dis. 2020 Jan 3. doi: 10.1186/s13023-019-1279-y), it was estimated that treatment with Oleogel-S10 was associated with an overall time-saving per week of 11 hours (6.6 hours for the patient and 4.4 hours for the caregiver) and use of the control gel was associated with an overall time-saving of 4 hours (2.4 hours for the patient and 1.6 hours for the caregiver).
“This is, for our patients, important,” said Dr. Kiritsi, as “it is time that they can spend doing something nice with the family” instead, avoiding the pain and distress associated with frequent dressing changes.
Approved in Europe, not in the United States
Oleogel-S10, classified as an herbal product, contains triterpenes derived from birch bark extract, which have been formulated with sunflower oil to form a gel.
Despite being approved for use in Europe, Oleogel-S10 has not yet been approved to treat EB in the United States. The FDA did not approve Amryt Pharma’s new drug application in February 2022. The application had included data from the EASE trial.
EASE included 223 patients with dystrophic or junctional EB, including 156 children, at 58 sites in 28 countries. As such, this makes it the largest treatment study in this rare genetic disease to date.
The trial had consisted of an initial 90-day, double-blind treatment period, during which time 109 patients had used Oleogel-S10 and 114 had used a control gel. This was followed by a 24-month open-label phase, during which time all remaining patients (n = 205) had used Oleogel-S10 on top of their standard of care.
Dr. Kiritsi summarized the main results of the EASE trial as follows.
- Complete healing of target wounds (primary endpoint) in 41.3% of patients treated with Oleogel-S10 and 28.9% of patients treated with the control gel (P = .013).
- Improved total body wound burden measured by both Epidermolysis Bullosa Disease Activity and Scarring Index and Body Surface Area Percentage scores.
- Reduced frequency of dressing changes (1 less per 2 weeks for Oleogel-S10 versus 0 less per 2 weeks for control gel).
- Improved pain among participants aged 4 years and older while their dressings were being changed.
- Reduced rates of wound infection (0.9% Oleogel-S10 vs. 4.4% control gel).
- Similar rates of treatment-emergent adverse events (24.8% vs. 22.8%, respectively), which were mostly deemed to be mild or moderate.
The EASE study – an important trial for EB
EASE is an important trial for EB, the study’s principal investigator Dédée Murrell, MD, DSc, University of New South Wales, Sydney, has pointed out previously.
“This was the first EB study to meet its primary endpoint and demonstrated a statistically significant acceleration of target wound healing by day 45,” Dr. Murrell said in a press release issued by Amryt Pharma to coincide with the online publication of the trial results.
“In addition, the favorable trends we see with key secondary endpoints such as reduced wound burden, pain, and frequency of dressing changes are considered as being very meaningful for patients,” Dr. Murrell said.
The EASE study was funded by Amryt Research Limited. Dr. Kiritsi reported receiving honoraria or consultation fees from Amryt, RHEACELL GmbH, and Fibrx Derm. She also acknowledged grant or research support from DEBRA International, EB Research Partnership, Fritz-Thyssen Foundation, German Research Foundation, and RHEACELL. Dr. Murrell has ties to Amryt and Amicus and is a co-owner of the patent for topical sirolimus for EB simplex.
A version of this article appeared on Medscape.com.
Additional when compared with a control gel.
In a final, post hoc analysis to come from the trial, 15 of 45 (33%) patients treated with Oleogel-S10 versus 5 of 48 (10.4%) treated with the control gel were reported as no longer needing daily dressing changes at 45 days of follow-up.
Moreover, the effect was sustained, with similar percentages of patients no longer requiring daily dressing changes at 60 days (34% vs. 13%, respectively) and 90 days (36% vs. 11%) of follow-up.
The mean reduction in daily dressing changes was 1.36 for Oleogel-S10 and 0.41 for the control gel (P = .005).
“Patients who, in the beginning, had daily dressing changes had almost three fewer dressing changes every 2 weeks if they were treated with Oleogel-S10,” Dimitra Kiritsi, MD, PhD, of the department of dermatology at the University of Freiburg (Germany), reported at the annual congress of the European Academy of Dermatology and Venereology. By comparison, patients in the control group had just one fewer daily dressing change in 2 weeks.
“You might say okay, but what does this mean in terms of time?” added Dr. Kiritsi. Using historical data on the time required for whole body care (Orphanet J Rare Dis. 2020 Jan 3. doi: 10.1186/s13023-019-1279-y), it was estimated that treatment with Oleogel-S10 was associated with an overall time-saving per week of 11 hours (6.6 hours for the patient and 4.4 hours for the caregiver) and use of the control gel was associated with an overall time-saving of 4 hours (2.4 hours for the patient and 1.6 hours for the caregiver).
“This is, for our patients, important,” said Dr. Kiritsi, as “it is time that they can spend doing something nice with the family” instead, avoiding the pain and distress associated with frequent dressing changes.
Approved in Europe, not in the United States
Oleogel-S10, classified as an herbal product, contains triterpenes derived from birch bark extract, which have been formulated with sunflower oil to form a gel.
Despite being approved for use in Europe, Oleogel-S10 has not yet been approved to treat EB in the United States. The FDA did not approve Amryt Pharma’s new drug application in February 2022. The application had included data from the EASE trial.
EASE included 223 patients with dystrophic or junctional EB, including 156 children, at 58 sites in 28 countries. As such, this makes it the largest treatment study in this rare genetic disease to date.
The trial had consisted of an initial 90-day, double-blind treatment period, during which time 109 patients had used Oleogel-S10 and 114 had used a control gel. This was followed by a 24-month open-label phase, during which time all remaining patients (n = 205) had used Oleogel-S10 on top of their standard of care.
Dr. Kiritsi summarized the main results of the EASE trial as follows.
- Complete healing of target wounds (primary endpoint) in 41.3% of patients treated with Oleogel-S10 and 28.9% of patients treated with the control gel (P = .013).
- Improved total body wound burden measured by both Epidermolysis Bullosa Disease Activity and Scarring Index and Body Surface Area Percentage scores.
- Reduced frequency of dressing changes (1 less per 2 weeks for Oleogel-S10 versus 0 less per 2 weeks for control gel).
- Improved pain among participants aged 4 years and older while their dressings were being changed.
- Reduced rates of wound infection (0.9% Oleogel-S10 vs. 4.4% control gel).
- Similar rates of treatment-emergent adverse events (24.8% vs. 22.8%, respectively), which were mostly deemed to be mild or moderate.
The EASE study – an important trial for EB
EASE is an important trial for EB, the study’s principal investigator Dédée Murrell, MD, DSc, University of New South Wales, Sydney, has pointed out previously.
“This was the first EB study to meet its primary endpoint and demonstrated a statistically significant acceleration of target wound healing by day 45,” Dr. Murrell said in a press release issued by Amryt Pharma to coincide with the online publication of the trial results.
“In addition, the favorable trends we see with key secondary endpoints such as reduced wound burden, pain, and frequency of dressing changes are considered as being very meaningful for patients,” Dr. Murrell said.
The EASE study was funded by Amryt Research Limited. Dr. Kiritsi reported receiving honoraria or consultation fees from Amryt, RHEACELL GmbH, and Fibrx Derm. She also acknowledged grant or research support from DEBRA International, EB Research Partnership, Fritz-Thyssen Foundation, German Research Foundation, and RHEACELL. Dr. Murrell has ties to Amryt and Amicus and is a co-owner of the patent for topical sirolimus for EB simplex.
A version of this article appeared on Medscape.com.
FROM THE EADV CONGRESS
FDA OKs first ustekinumab biosimilar
The U.S. Food and Drug Administration has approved ustekinumab-auub (Wezlana) as a biosimilar to ustekinumab (Stelara) for the treatment of multiple inflammatory conditions. This is the first approval for a ustekinumab biosimilar in the United States.
Ustekinumab-auub was also granted an interchangeability designation, meaning that, depending on state law, a pharmacist may substitute the biosimilar for the reference product without consulting the prescribing provider.
“Today’s approval exemplifies the FDA’s longstanding commitment to support a competitive marketplace for biological products,” Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval can empower patients by helping to increase access to safe, effective, and high-quality medications at potentially lower cost.”
Ustekinumab, manufactured by Johnson & Johnson, targets interleukin-12 and IL-23 and was first approved in 2009. Ustekinumab-auub was developed by Amgen.
Ustekinumab-auub is approved for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, active psoriatic arthritis, moderate to severely active Crohn’s disease, and moderate to severely active ulcerative colitis. It is also approved for pediatric patients aged 6 years and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and active psoriatic arthritis.
The approval was based on “comprehensive review of scientific evidence,” including “comparisons of the products on an analytical level using an extensive battery of chemical and biological tests and biological assays that confirmed similarity in the structural and functional features of Wezlana and Stelara (including those known to impact safety and efficacy), and comparative human pharmacokinetic data, clinical immunogenicity data, and other clinical safety and effectiveness data,” the FDA said.
Some common side effects of ustekinumab-auub include nasopharyngitis, upper respiratory tract infection, headache, fatigue, and nausea. The most severe side effect of the biosimilar, as with the reference drug ustekinumab, is infection.
The product launch of ustekinumab-auub will be delayed as a part of a settlement of Johnson & Johnson’s lawsuit against Amgen, according to Reuters. The details of the settlement are confidential, but it was stated that the biosimilar would be available by Jan. 1, 2025.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved ustekinumab-auub (Wezlana) as a biosimilar to ustekinumab (Stelara) for the treatment of multiple inflammatory conditions. This is the first approval for a ustekinumab biosimilar in the United States.
Ustekinumab-auub was also granted an interchangeability designation, meaning that, depending on state law, a pharmacist may substitute the biosimilar for the reference product without consulting the prescribing provider.
“Today’s approval exemplifies the FDA’s longstanding commitment to support a competitive marketplace for biological products,” Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval can empower patients by helping to increase access to safe, effective, and high-quality medications at potentially lower cost.”
Ustekinumab, manufactured by Johnson & Johnson, targets interleukin-12 and IL-23 and was first approved in 2009. Ustekinumab-auub was developed by Amgen.
Ustekinumab-auub is approved for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, active psoriatic arthritis, moderate to severely active Crohn’s disease, and moderate to severely active ulcerative colitis. It is also approved for pediatric patients aged 6 years and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and active psoriatic arthritis.
The approval was based on “comprehensive review of scientific evidence,” including “comparisons of the products on an analytical level using an extensive battery of chemical and biological tests and biological assays that confirmed similarity in the structural and functional features of Wezlana and Stelara (including those known to impact safety and efficacy), and comparative human pharmacokinetic data, clinical immunogenicity data, and other clinical safety and effectiveness data,” the FDA said.
Some common side effects of ustekinumab-auub include nasopharyngitis, upper respiratory tract infection, headache, fatigue, and nausea. The most severe side effect of the biosimilar, as with the reference drug ustekinumab, is infection.
The product launch of ustekinumab-auub will be delayed as a part of a settlement of Johnson & Johnson’s lawsuit against Amgen, according to Reuters. The details of the settlement are confidential, but it was stated that the biosimilar would be available by Jan. 1, 2025.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved ustekinumab-auub (Wezlana) as a biosimilar to ustekinumab (Stelara) for the treatment of multiple inflammatory conditions. This is the first approval for a ustekinumab biosimilar in the United States.
Ustekinumab-auub was also granted an interchangeability designation, meaning that, depending on state law, a pharmacist may substitute the biosimilar for the reference product without consulting the prescribing provider.
“Today’s approval exemplifies the FDA’s longstanding commitment to support a competitive marketplace for biological products,” Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval can empower patients by helping to increase access to safe, effective, and high-quality medications at potentially lower cost.”
Ustekinumab, manufactured by Johnson & Johnson, targets interleukin-12 and IL-23 and was first approved in 2009. Ustekinumab-auub was developed by Amgen.
Ustekinumab-auub is approved for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, active psoriatic arthritis, moderate to severely active Crohn’s disease, and moderate to severely active ulcerative colitis. It is also approved for pediatric patients aged 6 years and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and active psoriatic arthritis.
The approval was based on “comprehensive review of scientific evidence,” including “comparisons of the products on an analytical level using an extensive battery of chemical and biological tests and biological assays that confirmed similarity in the structural and functional features of Wezlana and Stelara (including those known to impact safety and efficacy), and comparative human pharmacokinetic data, clinical immunogenicity data, and other clinical safety and effectiveness data,” the FDA said.
Some common side effects of ustekinumab-auub include nasopharyngitis, upper respiratory tract infection, headache, fatigue, and nausea. The most severe side effect of the biosimilar, as with the reference drug ustekinumab, is infection.
The product launch of ustekinumab-auub will be delayed as a part of a settlement of Johnson & Johnson’s lawsuit against Amgen, according to Reuters. The details of the settlement are confidential, but it was stated that the biosimilar would be available by Jan. 1, 2025.
A version of this article first appeared on Medscape.com.
FDA okays drug for Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) in patients as young as age 2 years, the company has announced Vamorolone is a structurally unique steroidal anti-inflammatory drug that potently inhibits proinflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor.
“Corticosteroids have been a first line treatment for DMD for many years, but their utility has always been limited by the side effect profile, which includes weight gain, short stature, and decreased bone density, among others,” Sharon Hesterlee, PhD, chief research officer for the Muscular Dystrophy Association, said in a statement.
The approval of vamorolone “provides people living with Duchenne, and their families, a powerful tool to treat the disease, while limiting some negative side effects associated with corticosteroids,” Dr. Hesterlee added.
The approval was based on data from the phase 2b VISION-DMD study, supplemented with safety information collected from three open-label studies.
Vamorolone was administered at doses ranging from 2-6 mg/kg/d for a period of up to 48 months.
Vamorolone demonstrated efficacy similar to that of traditional corticosteroids, with data suggesting a reduction in adverse events – notably related to bone health, growth trajectory, and behavior.
Vamorolone had received orphan drug status for DMD, as well as fast track and rare pediatric disease designations. It will be made available in the United States by Catalyst Pharmaceuticals.
A version of this article first appeared on Medscape.com .
Duchenne muscular dystrophy (DMD) in patients as young as age 2 years, the company has announced Vamorolone is a structurally unique steroidal anti-inflammatory drug that potently inhibits proinflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor.
“Corticosteroids have been a first line treatment for DMD for many years, but their utility has always been limited by the side effect profile, which includes weight gain, short stature, and decreased bone density, among others,” Sharon Hesterlee, PhD, chief research officer for the Muscular Dystrophy Association, said in a statement.
The approval of vamorolone “provides people living with Duchenne, and their families, a powerful tool to treat the disease, while limiting some negative side effects associated with corticosteroids,” Dr. Hesterlee added.
The approval was based on data from the phase 2b VISION-DMD study, supplemented with safety information collected from three open-label studies.
Vamorolone was administered at doses ranging from 2-6 mg/kg/d for a period of up to 48 months.
Vamorolone demonstrated efficacy similar to that of traditional corticosteroids, with data suggesting a reduction in adverse events – notably related to bone health, growth trajectory, and behavior.
Vamorolone had received orphan drug status for DMD, as well as fast track and rare pediatric disease designations. It will be made available in the United States by Catalyst Pharmaceuticals.
A version of this article first appeared on Medscape.com .
Duchenne muscular dystrophy (DMD) in patients as young as age 2 years, the company has announced Vamorolone is a structurally unique steroidal anti-inflammatory drug that potently inhibits proinflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor.
“Corticosteroids have been a first line treatment for DMD for many years, but their utility has always been limited by the side effect profile, which includes weight gain, short stature, and decreased bone density, among others,” Sharon Hesterlee, PhD, chief research officer for the Muscular Dystrophy Association, said in a statement.
The approval of vamorolone “provides people living with Duchenne, and their families, a powerful tool to treat the disease, while limiting some negative side effects associated with corticosteroids,” Dr. Hesterlee added.
The approval was based on data from the phase 2b VISION-DMD study, supplemented with safety information collected from three open-label studies.
Vamorolone was administered at doses ranging from 2-6 mg/kg/d for a period of up to 48 months.
Vamorolone demonstrated efficacy similar to that of traditional corticosteroids, with data suggesting a reduction in adverse events – notably related to bone health, growth trajectory, and behavior.
Vamorolone had received orphan drug status for DMD, as well as fast track and rare pediatric disease designations. It will be made available in the United States by Catalyst Pharmaceuticals.
A version of this article first appeared on Medscape.com .