MDedge Neurology

Long COVID can exacerbate existing mental health disorders or cause new-onset psychiatric symptoms, but mental illness does not cause long COVID, experts say.

The consensus guidance statement on the assessment and treatment of mental health symptoms in patients with post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID, was published online in Physical Medicine and Rehabilitation, the journal of the American Academy of Physical Medicine and Rehabilitation (AAPM&R).

The statement was developed by a task force that included experts from physical medicine, neurology, neuropsychiatry, neuropsychology, rehabilitation psychology, and primary care. It is the eighth guidance statement on long COVID published by AAPM&R).

“Many of our patients have reported experiences in which their symptoms of long COVID have been dismissed either by loved ones in the community, or also amongst health care providers, and they’ve been told their symptoms are in their head or due to a mental health condition, but that’s simply not true,” Abby L. Cheng, MD, a physiatrist at Barnes Jewish Hospital in St. Louis and a coauthor of the new guidance, said in a press briefing.

“Long COVID is real, and mental health conditions do not cause long COVID,” Dr. Cheng added.
 

Millions of Americans affected

Anxiety and depression have been reported as the second and third most common symptoms of long COVID, according to the guidance statement.

There is some evidence that the body’s inflammatory response – specifically, circulating cytokines – may contribute to the worsening of mental health symptoms or may bring on new symptoms of anxiety or depression, said Dr. Cheng. Cytokines may also affect levels of brain chemicals, such as serotonin, she said.

Researchers are also exploring whether the persistence of virus in the body, miniature blood clots in the body and brain, and changes to the gut microbiome affect the mental health of people with long COVID.

Some mental health symptoms – such as fatigue, brain fog, sleep disturbances, and tachycardia – can mimic long COVID symptoms, said Dr. Cheng.

The treatment is the same for someone with or without long COVID who has anxiety, depression, posttraumatic stress disorder, or other mental health conditions and includes treatment of coexisting medical conditions, supportive therapy and cognitive-behavioral therapy, and pharmacologic interventions, she said.

“Group therapy may have a particular role in the long COVID population because it really provides that social connection and awareness of additional resources in addition to validation of their experiences,” Dr. Cheng said.

The guidance suggests that primary care practitioners – if it’s within their comfort zone and they have the training – can be the first line for managing mental health symptoms.

But for patients whose symptoms are interfering with functioning and their ability to interact with the community, the guidance urges primary care clinicians to refer the patient to a specialist.

“It leaves the door open to them to practice within their scope but also gives guidance as to how, why, and who should be referred to the next level of care,” said Dr. Cheng.

Coauthor Monica Verduzco-Gutierrez, MD, chair of rehabilitation medicine at UT Health San Antonio, Texas, said that although fewer people are now getting long COVID, “it’s still an impactful number.”

The Centers for Disease Control and Prevention recently estimated that about 7% of American adults (18 million) and 1.3% of children had experienced long COVID.

Dr. Gutierrez said that it’s an evolving number, as some patients who have a second or third or fourth SARS-CoV-2 infection experience exacerbations of previous bouts of long COVID or develop long COVID for the first time.

“We are still getting new patients on a regular basis with long COVID,” said AAPM&R President Steven R. Flanagan, MD, a physical medicine specialist.

“This is a problem that really is not going away. It is still real and still ever-present,” said Dr. Flanagan, chair of rehabilitation medicine at NYU Langone Health.
 

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

Long COVID can exacerbate existing mental health disorders or cause new-onset psychiatric symptoms, but mental illness does not cause long COVID, experts say.

The consensus guidance statement on the assessment and treatment of mental health symptoms in patients with post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID, was published online in Physical Medicine and Rehabilitation, the journal of the American Academy of Physical Medicine and Rehabilitation (AAPM&R).

The statement was developed by a task force that included experts from physical medicine, neurology, neuropsychiatry, neuropsychology, rehabilitation psychology, and primary care. It is the eighth guidance statement on long COVID published by AAPM&R).

“Many of our patients have reported experiences in which their symptoms of long COVID have been dismissed either by loved ones in the community, or also amongst health care providers, and they’ve been told their symptoms are in their head or due to a mental health condition, but that’s simply not true,” Abby L. Cheng, MD, a physiatrist at Barnes Jewish Hospital in St. Louis and a coauthor of the new guidance, said in a press briefing.

“Long COVID is real, and mental health conditions do not cause long COVID,” Dr. Cheng added.
 

Millions of Americans affected

Anxiety and depression have been reported as the second and third most common symptoms of long COVID, according to the guidance statement.

There is some evidence that the body’s inflammatory response – specifically, circulating cytokines – may contribute to the worsening of mental health symptoms or may bring on new symptoms of anxiety or depression, said Dr. Cheng. Cytokines may also affect levels of brain chemicals, such as serotonin, she said.

Researchers are also exploring whether the persistence of virus in the body, miniature blood clots in the body and brain, and changes to the gut microbiome affect the mental health of people with long COVID.

Some mental health symptoms – such as fatigue, brain fog, sleep disturbances, and tachycardia – can mimic long COVID symptoms, said Dr. Cheng.

The treatment is the same for someone with or without long COVID who has anxiety, depression, posttraumatic stress disorder, or other mental health conditions and includes treatment of coexisting medical conditions, supportive therapy and cognitive-behavioral therapy, and pharmacologic interventions, she said.

“Group therapy may have a particular role in the long COVID population because it really provides that social connection and awareness of additional resources in addition to validation of their experiences,” Dr. Cheng said.

The guidance suggests that primary care practitioners – if it’s within their comfort zone and they have the training – can be the first line for managing mental health symptoms.

But for patients whose symptoms are interfering with functioning and their ability to interact with the community, the guidance urges primary care clinicians to refer the patient to a specialist.

“It leaves the door open to them to practice within their scope but also gives guidance as to how, why, and who should be referred to the next level of care,” said Dr. Cheng.

Coauthor Monica Verduzco-Gutierrez, MD, chair of rehabilitation medicine at UT Health San Antonio, Texas, said that although fewer people are now getting long COVID, “it’s still an impactful number.”

The Centers for Disease Control and Prevention recently estimated that about 7% of American adults (18 million) and 1.3% of children had experienced long COVID.

Dr. Gutierrez said that it’s an evolving number, as some patients who have a second or third or fourth SARS-CoV-2 infection experience exacerbations of previous bouts of long COVID or develop long COVID for the first time.

“We are still getting new patients on a regular basis with long COVID,” said AAPM&R President Steven R. Flanagan, MD, a physical medicine specialist.

“This is a problem that really is not going away. It is still real and still ever-present,” said Dr. Flanagan, chair of rehabilitation medicine at NYU Langone Health.
 

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

Long COVID can exacerbate existing mental health disorders or cause new-onset psychiatric symptoms, but mental illness does not cause long COVID, experts say.

The consensus guidance statement on the assessment and treatment of mental health symptoms in patients with post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID, was published online in Physical Medicine and Rehabilitation, the journal of the American Academy of Physical Medicine and Rehabilitation (AAPM&R).

The statement was developed by a task force that included experts from physical medicine, neurology, neuropsychiatry, neuropsychology, rehabilitation psychology, and primary care. It is the eighth guidance statement on long COVID published by AAPM&R).

“Many of our patients have reported experiences in which their symptoms of long COVID have been dismissed either by loved ones in the community, or also amongst health care providers, and they’ve been told their symptoms are in their head or due to a mental health condition, but that’s simply not true,” Abby L. Cheng, MD, a physiatrist at Barnes Jewish Hospital in St. Louis and a coauthor of the new guidance, said in a press briefing.

“Long COVID is real, and mental health conditions do not cause long COVID,” Dr. Cheng added.
 

Millions of Americans affected

Anxiety and depression have been reported as the second and third most common symptoms of long COVID, according to the guidance statement.

There is some evidence that the body’s inflammatory response – specifically, circulating cytokines – may contribute to the worsening of mental health symptoms or may bring on new symptoms of anxiety or depression, said Dr. Cheng. Cytokines may also affect levels of brain chemicals, such as serotonin, she said.

Researchers are also exploring whether the persistence of virus in the body, miniature blood clots in the body and brain, and changes to the gut microbiome affect the mental health of people with long COVID.

Some mental health symptoms – such as fatigue, brain fog, sleep disturbances, and tachycardia – can mimic long COVID symptoms, said Dr. Cheng.

The treatment is the same for someone with or without long COVID who has anxiety, depression, posttraumatic stress disorder, or other mental health conditions and includes treatment of coexisting medical conditions, supportive therapy and cognitive-behavioral therapy, and pharmacologic interventions, she said.

“Group therapy may have a particular role in the long COVID population because it really provides that social connection and awareness of additional resources in addition to validation of their experiences,” Dr. Cheng said.

The guidance suggests that primary care practitioners – if it’s within their comfort zone and they have the training – can be the first line for managing mental health symptoms.

But for patients whose symptoms are interfering with functioning and their ability to interact with the community, the guidance urges primary care clinicians to refer the patient to a specialist.

“It leaves the door open to them to practice within their scope but also gives guidance as to how, why, and who should be referred to the next level of care,” said Dr. Cheng.

Coauthor Monica Verduzco-Gutierrez, MD, chair of rehabilitation medicine at UT Health San Antonio, Texas, said that although fewer people are now getting long COVID, “it’s still an impactful number.”

The Centers for Disease Control and Prevention recently estimated that about 7% of American adults (18 million) and 1.3% of children had experienced long COVID.

Dr. Gutierrez said that it’s an evolving number, as some patients who have a second or third or fourth SARS-CoV-2 infection experience exacerbations of previous bouts of long COVID or develop long COVID for the first time.

“We are still getting new patients on a regular basis with long COVID,” said AAPM&R President Steven R. Flanagan, MD, a physical medicine specialist.

“This is a problem that really is not going away. It is still real and still ever-present,” said Dr. Flanagan, chair of rehabilitation medicine at NYU Langone Health.
 

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

Neurologic music therapy (NMT), a specially designed intervention targeting movement, balance, and cognitive functioning, improves depressive symptoms and increases brain-derived neurotrophic factor (BDNF), early results of a small study suggest.

“We’re really happy with the results,” said lead study author psychotherapist Honey Bryant, a PhD candidate and research assistant at the Centre for Neuroscience Studies, Queen’s University, Kingston, Ont.

“We showed neurologic music therapy improves mental health and increases neuroplasticity, when used in conjunction with stroke rehabilitation.”

The findings were presented at the virtual XXVI World Congress of Neurology.
 

Moving with music

With improved stroke survival rates and longer life expectancy, there’s an increasing need for effective post-stroke interventions for neurocognitive impairments and mood disorders, the authors noted.

NMT is an evidence-based treatment system that uses elements of music such as rhythm, melody, and tempo to treat various brain conditions. A trained NMT therapist uses standardized techniques to address goals in the areas of speech, movement, and cognition.

The intervention is not new – it’s been around for a few decades – but there are “minimal papers on NMT and nothing on stroke rehabilitation used in the way we did it,” said Ms. Bryant.

The study included 57 patients, mean age 75 years, receiving rehabilitation following a stroke who were randomly assigned to NMT or passive music listening.

In the NMT group, a music therapist asked participants to choose music beforehand and integrated this into each session.

“Each day was different,” said Ms. Bryant. “For example, if it involved motor movement, the music therapist would say, ‘When I sing this word, raise your arm up.’ For Johnny Cash’s ‘Ring of Fire,’ we made our arms into a circle.”

She explained that the rhythm and timing of the music can affect the motor system and other areas of the brain.

Those in the passive music group listened to a curated list of calming classical and relaxing spa music.

Both groups were offered five 45-minute sessions per week for 2 weeks.

Among other things, researchers used the Hospital Anxiety and Depression Scale (HADS), administered a semistructured interview, and collected blood samples to determine levels of cortisol and BDNF.

After the 2-week intervention, the researchers found participants in the NMT group had a significant mean decrease in depression.

They also had increased cortisol levels, which is not unexpected after a stroke, especially with increased anxiety linked to financial and other stressors, said Ms. Bryant, adding these levels should decrease with treatment.

Recipients of the NMT had significant increases in BDNF, a neurotrophin that plays an important role in neuronal survival and growth, but only in those who attended several consecutive sessions.
 

Increased plasticity

“We see greater increases in plasticity when the therapy is used intensively, meaning at least four treatments consecutively,” said Ms. Bryant. Participants in the NMT group also reported they “overall felt well,” she added.

She noted NMT can be tailored to individual deficit, “so you can make it solely for motor movement or you can make it solely for language.”

Next steps could include more closely targeting the music to individual preferences and investigating whether the benefits of the intervention extend to other types of brain injury, for example traumatic brain injury, which typically affects younger people, said Ms. Bryant.

“In this study, participants were older and there was an unknown; a lot of them were going back into the community but didn’t know if it was into a retirement home or long-term care.”

It’s unclear if the benefits are sustained after the intervention stops, she said.

There are also the issues of cost and accessibility; in Kingston, there are few music therapists certified in the area of NMT.

Ms. Bryant hopes NMT is eventually included in stroke rehabilitation. “Stroke therapy is typically very intensive on its own; you’re doing it every single day for about a month or 6 weeks,” she said. “It would be interesting to see whether we would see a shorter hospital stay if this is included in stroke rehab.”

Asked to comment, Michael H. Thaut, PhD, professor, faculty of music and faculty of medicine, and Canada research chair in music, neuroscience and health at the University of Toronto, said while these data are preliminary, “they do extend the benefits of NMT in stroke rehabilitation, especially measuring BDNF in addition to having behavioral data.”

However, it’s “unfortunate” the poster didn’t specify which cognitive intervention techniques were used in the study, said Dr. Thaut. “There are nine coded techniques in NMT, including for attention, memory, psychosocial function, and executive function.”

His own study, published in NeuroRehabilitation, focused on training for motor goals in stroke patients. It showed that NMT benefited cognitive functioning and affective responses.

The study was funded by a Queen’s University Research Initiation Grant. Ms. Bryant and Dr. Thaut have not disclosed any relevant financial relationships.

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

Neurologic music therapy (NMT), a specially designed intervention targeting movement, balance, and cognitive functioning, improves depressive symptoms and increases brain-derived neurotrophic factor (BDNF), early results of a small study suggest.

“We’re really happy with the results,” said lead study author psychotherapist Honey Bryant, a PhD candidate and research assistant at the Centre for Neuroscience Studies, Queen’s University, Kingston, Ont.

“We showed neurologic music therapy improves mental health and increases neuroplasticity, when used in conjunction with stroke rehabilitation.”

The findings were presented at the virtual XXVI World Congress of Neurology.
 

Moving with music

With improved stroke survival rates and longer life expectancy, there’s an increasing need for effective post-stroke interventions for neurocognitive impairments and mood disorders, the authors noted.

NMT is an evidence-based treatment system that uses elements of music such as rhythm, melody, and tempo to treat various brain conditions. A trained NMT therapist uses standardized techniques to address goals in the areas of speech, movement, and cognition.

The intervention is not new – it’s been around for a few decades – but there are “minimal papers on NMT and nothing on stroke rehabilitation used in the way we did it,” said Ms. Bryant.

The study included 57 patients, mean age 75 years, receiving rehabilitation following a stroke who were randomly assigned to NMT or passive music listening.

In the NMT group, a music therapist asked participants to choose music beforehand and integrated this into each session.

“Each day was different,” said Ms. Bryant. “For example, if it involved motor movement, the music therapist would say, ‘When I sing this word, raise your arm up.’ For Johnny Cash’s ‘Ring of Fire,’ we made our arms into a circle.”

She explained that the rhythm and timing of the music can affect the motor system and other areas of the brain.

Those in the passive music group listened to a curated list of calming classical and relaxing spa music.

Both groups were offered five 45-minute sessions per week for 2 weeks.

Among other things, researchers used the Hospital Anxiety and Depression Scale (HADS), administered a semistructured interview, and collected blood samples to determine levels of cortisol and BDNF.

After the 2-week intervention, the researchers found participants in the NMT group had a significant mean decrease in depression.

They also had increased cortisol levels, which is not unexpected after a stroke, especially with increased anxiety linked to financial and other stressors, said Ms. Bryant, adding these levels should decrease with treatment.

Recipients of the NMT had significant increases in BDNF, a neurotrophin that plays an important role in neuronal survival and growth, but only in those who attended several consecutive sessions.
 

Increased plasticity

“We see greater increases in plasticity when the therapy is used intensively, meaning at least four treatments consecutively,” said Ms. Bryant. Participants in the NMT group also reported they “overall felt well,” she added.

She noted NMT can be tailored to individual deficit, “so you can make it solely for motor movement or you can make it solely for language.”

Next steps could include more closely targeting the music to individual preferences and investigating whether the benefits of the intervention extend to other types of brain injury, for example traumatic brain injury, which typically affects younger people, said Ms. Bryant.

“In this study, participants were older and there was an unknown; a lot of them were going back into the community but didn’t know if it was into a retirement home or long-term care.”

It’s unclear if the benefits are sustained after the intervention stops, she said.

There are also the issues of cost and accessibility; in Kingston, there are few music therapists certified in the area of NMT.

Ms. Bryant hopes NMT is eventually included in stroke rehabilitation. “Stroke therapy is typically very intensive on its own; you’re doing it every single day for about a month or 6 weeks,” she said. “It would be interesting to see whether we would see a shorter hospital stay if this is included in stroke rehab.”

Asked to comment, Michael H. Thaut, PhD, professor, faculty of music and faculty of medicine, and Canada research chair in music, neuroscience and health at the University of Toronto, said while these data are preliminary, “they do extend the benefits of NMT in stroke rehabilitation, especially measuring BDNF in addition to having behavioral data.”

However, it’s “unfortunate” the poster didn’t specify which cognitive intervention techniques were used in the study, said Dr. Thaut. “There are nine coded techniques in NMT, including for attention, memory, psychosocial function, and executive function.”

His own study, published in NeuroRehabilitation, focused on training for motor goals in stroke patients. It showed that NMT benefited cognitive functioning and affective responses.

The study was funded by a Queen’s University Research Initiation Grant. Ms. Bryant and Dr. Thaut have not disclosed any relevant financial relationships.

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

Neurologic music therapy (NMT), a specially designed intervention targeting movement, balance, and cognitive functioning, improves depressive symptoms and increases brain-derived neurotrophic factor (BDNF), early results of a small study suggest.

“We’re really happy with the results,” said lead study author psychotherapist Honey Bryant, a PhD candidate and research assistant at the Centre for Neuroscience Studies, Queen’s University, Kingston, Ont.

“We showed neurologic music therapy improves mental health and increases neuroplasticity, when used in conjunction with stroke rehabilitation.”

The findings were presented at the virtual XXVI World Congress of Neurology.
 

Moving with music

With improved stroke survival rates and longer life expectancy, there’s an increasing need for effective post-stroke interventions for neurocognitive impairments and mood disorders, the authors noted.

NMT is an evidence-based treatment system that uses elements of music such as rhythm, melody, and tempo to treat various brain conditions. A trained NMT therapist uses standardized techniques to address goals in the areas of speech, movement, and cognition.

The intervention is not new – it’s been around for a few decades – but there are “minimal papers on NMT and nothing on stroke rehabilitation used in the way we did it,” said Ms. Bryant.

The study included 57 patients, mean age 75 years, receiving rehabilitation following a stroke who were randomly assigned to NMT or passive music listening.

In the NMT group, a music therapist asked participants to choose music beforehand and integrated this into each session.

“Each day was different,” said Ms. Bryant. “For example, if it involved motor movement, the music therapist would say, ‘When I sing this word, raise your arm up.’ For Johnny Cash’s ‘Ring of Fire,’ we made our arms into a circle.”

She explained that the rhythm and timing of the music can affect the motor system and other areas of the brain.

Those in the passive music group listened to a curated list of calming classical and relaxing spa music.

Both groups were offered five 45-minute sessions per week for 2 weeks.

Among other things, researchers used the Hospital Anxiety and Depression Scale (HADS), administered a semistructured interview, and collected blood samples to determine levels of cortisol and BDNF.

After the 2-week intervention, the researchers found participants in the NMT group had a significant mean decrease in depression.

They also had increased cortisol levels, which is not unexpected after a stroke, especially with increased anxiety linked to financial and other stressors, said Ms. Bryant, adding these levels should decrease with treatment.

Recipients of the NMT had significant increases in BDNF, a neurotrophin that plays an important role in neuronal survival and growth, but only in those who attended several consecutive sessions.
 

Increased plasticity

“We see greater increases in plasticity when the therapy is used intensively, meaning at least four treatments consecutively,” said Ms. Bryant. Participants in the NMT group also reported they “overall felt well,” she added.

She noted NMT can be tailored to individual deficit, “so you can make it solely for motor movement or you can make it solely for language.”

Next steps could include more closely targeting the music to individual preferences and investigating whether the benefits of the intervention extend to other types of brain injury, for example traumatic brain injury, which typically affects younger people, said Ms. Bryant.

“In this study, participants were older and there was an unknown; a lot of them were going back into the community but didn’t know if it was into a retirement home or long-term care.”

It’s unclear if the benefits are sustained after the intervention stops, she said.

There are also the issues of cost and accessibility; in Kingston, there are few music therapists certified in the area of NMT.

Ms. Bryant hopes NMT is eventually included in stroke rehabilitation. “Stroke therapy is typically very intensive on its own; you’re doing it every single day for about a month or 6 weeks,” she said. “It would be interesting to see whether we would see a shorter hospital stay if this is included in stroke rehab.”

Asked to comment, Michael H. Thaut, PhD, professor, faculty of music and faculty of medicine, and Canada research chair in music, neuroscience and health at the University of Toronto, said while these data are preliminary, “they do extend the benefits of NMT in stroke rehabilitation, especially measuring BDNF in addition to having behavioral data.”

However, it’s “unfortunate” the poster didn’t specify which cognitive intervention techniques were used in the study, said Dr. Thaut. “There are nine coded techniques in NMT, including for attention, memory, psychosocial function, and executive function.”

His own study, published in NeuroRehabilitation, focused on training for motor goals in stroke patients. It showed that NMT benefited cognitive functioning and affective responses.

The study was funded by a Queen’s University Research Initiation Grant. Ms. Bryant and Dr. Thaut have not disclosed any relevant financial relationships.

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

The American Heart Association (AHA) has now formally voted to join several other cardiovascular societies to form a new professional certification board for cardiovascular medicine, to be known as the American Board of Cardiovascular Medicine (ABCVM).  

The ABCVM would be independent of the American Board of Internal Medicine (ABIM), the current organization providing maintenance of certification for cardiologists along with 20 other internal medicine subspecialties. The ABIM’s maintenance of certification process has been widely criticized for many years and has been described as “needlessly burdensome and expensive.”

The AHA will be joining the American College of Cardiology (ACC), Heart Failure Society of America (HFSA), Heart Rhythm Society (HRS), and Society for Cardiovascular Angiography & Interventions (SCAI) in forming the ABCVM. 

These four other societies issued a joint statement in September saying that they will apply to the American Board of Medical Specialties (ABMS) to request an independent cardiology board that follows a “new competency-based approach to continuous certification — one that harnesses the knowledge, skills, and attitudes required to sustain professional excellence and care for cardiovascular patients effectively.”

The new board requirements will “de-emphasize timed, high stakes performance exams in the continuous certification process and instead will focus on learning assessments to identify gaps in current knowledge or skills,” the statement noted.

At the time the September statement was issued, the AHA was said to be supportive of the move but was waiting for formal endorsement to join the effort by its board of directors.

That has now happened, with the AHA’s national board of directors voting to provide “full support” for the creation of the proposed ABCVM.

“We enthusiastically join with our colleagues in proposing a new professional certification body to accredit cardiovascular professionals called the American Board of Cardiovascular Medicine,” said the association’s volunteer president Joseph C. Wu, MD. “The new ABCVM will be independent of the ABIM and focus on the specific competency-based trainings and appropriate ongoing certifications that align with and strengthen skills for cardiovascular physicians and enhance quality of care for people with cardiovascular disease,” Wu said.

“The AHA joins the consortium to submit the application to the American Board of Medical Specialties (ABMS) requesting an independent medical board for cardiovascular medicine. The consortium’s robust proposal harnesses the knowledge, skills, and benchmarks appropriate for professional excellence and delivery of effective, high-quality cardiovascular care,” Wu added.

The leaders of the ABCVM will include professional representatives from the consortium of member organizations, with a specific focus on relevant education, trainings, and supports that recognize the increasing specialization in cardiology and the latest advances in the various subspecialties of cardiovascular medicine, the AHA notes in a statement.

Professional certification by ABIM is a condition of employment for physicians practicing in large hospitals or health systems. A dedicated certification board separate from ABIM will help to ensure that cardiovascular professionals are maintaining the expertise appropriate to high-quality care and improved outcomes for their patients, the AHA said.

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

The American Heart Association (AHA) has now formally voted to join several other cardiovascular societies to form a new professional certification board for cardiovascular medicine, to be known as the American Board of Cardiovascular Medicine (ABCVM).  

The ABCVM would be independent of the American Board of Internal Medicine (ABIM), the current organization providing maintenance of certification for cardiologists along with 20 other internal medicine subspecialties. The ABIM’s maintenance of certification process has been widely criticized for many years and has been described as “needlessly burdensome and expensive.”

The AHA will be joining the American College of Cardiology (ACC), Heart Failure Society of America (HFSA), Heart Rhythm Society (HRS), and Society for Cardiovascular Angiography & Interventions (SCAI) in forming the ABCVM. 

These four other societies issued a joint statement in September saying that they will apply to the American Board of Medical Specialties (ABMS) to request an independent cardiology board that follows a “new competency-based approach to continuous certification — one that harnesses the knowledge, skills, and attitudes required to sustain professional excellence and care for cardiovascular patients effectively.”

The new board requirements will “de-emphasize timed, high stakes performance exams in the continuous certification process and instead will focus on learning assessments to identify gaps in current knowledge or skills,” the statement noted.

At the time the September statement was issued, the AHA was said to be supportive of the move but was waiting for formal endorsement to join the effort by its board of directors.

That has now happened, with the AHA’s national board of directors voting to provide “full support” for the creation of the proposed ABCVM.

“We enthusiastically join with our colleagues in proposing a new professional certification body to accredit cardiovascular professionals called the American Board of Cardiovascular Medicine,” said the association’s volunteer president Joseph C. Wu, MD. “The new ABCVM will be independent of the ABIM and focus on the specific competency-based trainings and appropriate ongoing certifications that align with and strengthen skills for cardiovascular physicians and enhance quality of care for people with cardiovascular disease,” Wu said.

“The AHA joins the consortium to submit the application to the American Board of Medical Specialties (ABMS) requesting an independent medical board for cardiovascular medicine. The consortium’s robust proposal harnesses the knowledge, skills, and benchmarks appropriate for professional excellence and delivery of effective, high-quality cardiovascular care,” Wu added.

The leaders of the ABCVM will include professional representatives from the consortium of member organizations, with a specific focus on relevant education, trainings, and supports that recognize the increasing specialization in cardiology and the latest advances in the various subspecialties of cardiovascular medicine, the AHA notes in a statement.

Professional certification by ABIM is a condition of employment for physicians practicing in large hospitals or health systems. A dedicated certification board separate from ABIM will help to ensure that cardiovascular professionals are maintaining the expertise appropriate to high-quality care and improved outcomes for their patients, the AHA said.

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

The American Heart Association (AHA) has now formally voted to join several other cardiovascular societies to form a new professional certification board for cardiovascular medicine, to be known as the American Board of Cardiovascular Medicine (ABCVM).  

The ABCVM would be independent of the American Board of Internal Medicine (ABIM), the current organization providing maintenance of certification for cardiologists along with 20 other internal medicine subspecialties. The ABIM’s maintenance of certification process has been widely criticized for many years and has been described as “needlessly burdensome and expensive.”

The AHA will be joining the American College of Cardiology (ACC), Heart Failure Society of America (HFSA), Heart Rhythm Society (HRS), and Society for Cardiovascular Angiography & Interventions (SCAI) in forming the ABCVM. 

These four other societies issued a joint statement in September saying that they will apply to the American Board of Medical Specialties (ABMS) to request an independent cardiology board that follows a “new competency-based approach to continuous certification — one that harnesses the knowledge, skills, and attitudes required to sustain professional excellence and care for cardiovascular patients effectively.”

The new board requirements will “de-emphasize timed, high stakes performance exams in the continuous certification process and instead will focus on learning assessments to identify gaps in current knowledge or skills,” the statement noted.

At the time the September statement was issued, the AHA was said to be supportive of the move but was waiting for formal endorsement to join the effort by its board of directors.

That has now happened, with the AHA’s national board of directors voting to provide “full support” for the creation of the proposed ABCVM.

“We enthusiastically join with our colleagues in proposing a new professional certification body to accredit cardiovascular professionals called the American Board of Cardiovascular Medicine,” said the association’s volunteer president Joseph C. Wu, MD. “The new ABCVM will be independent of the ABIM and focus on the specific competency-based trainings and appropriate ongoing certifications that align with and strengthen skills for cardiovascular physicians and enhance quality of care for people with cardiovascular disease,” Wu said.

“The AHA joins the consortium to submit the application to the American Board of Medical Specialties (ABMS) requesting an independent medical board for cardiovascular medicine. The consortium’s robust proposal harnesses the knowledge, skills, and benchmarks appropriate for professional excellence and delivery of effective, high-quality cardiovascular care,” Wu added.

The leaders of the ABCVM will include professional representatives from the consortium of member organizations, with a specific focus on relevant education, trainings, and supports that recognize the increasing specialization in cardiology and the latest advances in the various subspecialties of cardiovascular medicine, the AHA notes in a statement.

Professional certification by ABIM is a condition of employment for physicians practicing in large hospitals or health systems. A dedicated certification board separate from ABIM will help to ensure that cardiovascular professionals are maintaining the expertise appropriate to high-quality care and improved outcomes for their patients, the AHA said.

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

PHOENIX – The prevalence of myasthenia gravis is about 0.13% among U.S. adults, and the condition is more common in Whites than in African Americans, according to a new analysis of the National Institutes of Health All of Us database. 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 of myasthenia gravis is about 0.13% among U.S. adults, and the condition is more common in Whites than in African Americans, according to a new analysis of the National Institutes of Health All of Us database. 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 of myasthenia gravis is about 0.13% among U.S. adults, and the condition is more common in Whites than in African Americans, according to a new analysis of the National Institutes of Health All of Us database. 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.

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.

“We now have the potential to change the way genetic epilepsies are treated by addressing the underlying genetic cause of the disease instead of just the seizures,” 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.

“We now have the potential to change the way genetic epilepsies are treated by addressing the underlying genetic cause of the disease instead of just the seizures,” 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.

“We now have the potential to change the way genetic epilepsies are treated by addressing the underlying genetic cause of the disease instead of just the seizures,” 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.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. 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).

Children’s Hospital of Richmond at Virginia Commonwealth University

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.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. 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).

Children’s Hospital of Richmond at Virginia Commonwealth University

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.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. 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).

Children’s Hospital of Richmond at Virginia Commonwealth University

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.

PHOENIX – Subcutaneous efgartigimod PH20 SC shows efficacy and tolerability in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), providing a convenient alternative to intravenous and other older treatments for this rare disease.

“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 – Subcutaneous efgartigimod PH20 SC shows efficacy and tolerability in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), providing a convenient alternative to intravenous and other older treatments for this rare disease.

“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 – Subcutaneous efgartigimod PH20 SC shows efficacy and tolerability in the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), providing a convenient alternative to intravenous and other older treatments for this rare disease.

“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.

Could antidepressants hold the key to treating long COVID? University of Pennsylvania researchers have uncovered a link between long COVID and levels of serotonin in the body that may offer a new explanation for the condition. The study even points to a possible treatment.

Serotonin is a neurotransmitter that has many functions in the body and is targeted by the most commonly prescribed antidepressants – the selective serotonin reuptake inhibitors.

Serotonin is widely studied for its effects on the brain – it regulates the messaging between neurons, affecting sleep, mood, and memory. It is present in the gut, is found in cells along the gastrointestinal tract, and is absorbed by blood platelets. Gut serotonin, known as circulating serotonin, is responsible for a host of other functions, including the regulation of blood flow, body temperature, and digestion.

Low levels of serotonin could result in any number of seemingly unrelated symptoms, as in the case of long COVID, experts say. The condition affects about 7% of Americans and is associated with a wide range of health problems, including fatigue, shortness of breath, neurological symptoms, joint pain, blood clots, heart palpitations, and digestive problems.

Long COVID is difficult to treat because researchers haven’t been able to pinpoint the underlying mechanisms that cause prolonged illness after a SARS-CoV-2 infection, said study author Christoph A. Thaiss, PhD, an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

The hope is that this study could have implications for new treatments, he said.

“Long COVID can have manifestations not only in the brain but in many different parts of the body, so it’s possible that serotonin reductions are involved in many different aspects of the disease,” said Dr. Thaiss.

Dr. Thaiss’s study, published in the journal Cell, found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but who fully recovered.

His team found that reductions in serotonin were driven by low levels of circulating SARS-CoV-2 virus that caused persistent inflammation as well as an inability of the body to absorb tryptophan, an amino acid that’s a precursor to serotonin. Overactive blood platelets were also shown to play a role; they serve as the primary means of serotonin absorption.

The study doesn’t make any recommendations for treatment, but understanding the role of serotonin in long COVID opens the door to a host of novel ideas that could set the stage for clinical trials and affect care.

“The study gives us a few possible targets that could be used in future clinical studies,” Dr. Thaiss said.

Persistent circulating virus is one of the drivers of low serotonin levels, said study author Michael Peluso, MD, an assistant research professor of infectious medicine at the University of California, San Francisco, School of Medicine. This points to the need to reduce viral load using antiviral medications like nirmatrelvir/ritonavir (Paxlovid), which is approved by the U.S. Food and Drug Administration for the treatment of COVID-19, and VV116, which has not yet been approved for use against COVID.

Research published in the New England Journal of Medicine found that the oral antiviral agent VV116 was as effective as nirmatrelvir/ritonavir in reducing the body’s viral load and aiding recovery from SARS-CoV-2 infection. Paxlovid has also been shown to reduce the likelihood of getting long COVID after an acute SARS-CoV-2 infection.

Researchers are investigating ways to target serotonin levels directly, potentially using SSRIs. But first they need to study whether improvement in serotonin level makes a difference.

“What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief,” Dr. Peluso said.

Indeed, the research did show that the SSRI fluoxetine, as well as a glycine-tryptophan supplement, improved cognitive function in SARS-CoV-2-infected rodent models, which were used in a portion of the study.

David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City, said the research is helping “to paint a biological picture” that’s in line with other research on the mechanisms that cause long COVID symptoms.

But Dr. Putrino, who was not involved in the study, cautions against treating long COVID patients with SSRIs or any other treatment that increases serotonin before testing patients to determine whether their serotonin levels are actually lower than those of healthy persons.

“We don’t want to assume that every patient with long COVID is going to have lower serotonin levels,” said Dr. Putrino.

What’s more, researchers need to investigate whether SSRIs increase levels of circulating serotonin. It’s important to note that researchers found lower levels of circulating serotonin but that serotonin levels in the brain remained normal.

Traditionally, SSRIs are used clinically for increasing the levels of serotonin in the brain, not the body.

“Whether that’s going to contribute to an increase in systemic levels of serotonin, that’s something that needs to be tested,” said Akiko Iwasaki, PhD, co-lead investigator of the Yale School of Medicine, New Haven, Conn., COVID-19 Recovery Study, who was not involved in the research.

Thus far, investigators have not identified one unifying biomarker that seems to cause long COVID in all patients, said Dr. Iwasaki. Some research has found higher levels of certain immune cells and biomarkers: for example, monocytes and activated B lymphocytes, indicating a stronger and ongoing antibody response to the virus. Other recent research conducted by Dr. Iwasaki, Dr. Putrino, and others, published in the journal Nature, showed that long COVID patients tend to have lower levels of cortisol, which could be a factor in the extreme fatigue experienced by many who suffer from the condition.

The findings in the study in The Cell are promising, but they need to be replicated in more people, said Dr. Iwasaki. And even if they’re replicated in a larger study population, this would still be just one biomarker that is associated with one subtype of the disease. There is a need to better understand which biomarkers go with which symptoms so that the most effective treatments can be identified, she said.

Both Dr. Putrino and Dr. Iwasaki contended that there isn’t a single factor that can explain all of long COVID. It’s a complex disease caused by a host of different mechanisms.

Still, low levels of serotonin could be an important piece of the puzzle. The next step, said Dr. Iwasaki, is to uncover how many of the millions of Americans with long COVID have this biomarker.

“People working in the field of long COVID should now be considering this pathway and thinking of ways to measure serotonin in their patients.”

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

Could antidepressants hold the key to treating long COVID? University of Pennsylvania researchers have uncovered a link between long COVID and levels of serotonin in the body that may offer a new explanation for the condition. The study even points to a possible treatment.

Serotonin is a neurotransmitter that has many functions in the body and is targeted by the most commonly prescribed antidepressants – the selective serotonin reuptake inhibitors.

Serotonin is widely studied for its effects on the brain – it regulates the messaging between neurons, affecting sleep, mood, and memory. It is present in the gut, is found in cells along the gastrointestinal tract, and is absorbed by blood platelets. Gut serotonin, known as circulating serotonin, is responsible for a host of other functions, including the regulation of blood flow, body temperature, and digestion.

Low levels of serotonin could result in any number of seemingly unrelated symptoms, as in the case of long COVID, experts say. The condition affects about 7% of Americans and is associated with a wide range of health problems, including fatigue, shortness of breath, neurological symptoms, joint pain, blood clots, heart palpitations, and digestive problems.

Long COVID is difficult to treat because researchers haven’t been able to pinpoint the underlying mechanisms that cause prolonged illness after a SARS-CoV-2 infection, said study author Christoph A. Thaiss, PhD, an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

The hope is that this study could have implications for new treatments, he said.

“Long COVID can have manifestations not only in the brain but in many different parts of the body, so it’s possible that serotonin reductions are involved in many different aspects of the disease,” said Dr. Thaiss.

Dr. Thaiss’s study, published in the journal Cell, found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but who fully recovered.

His team found that reductions in serotonin were driven by low levels of circulating SARS-CoV-2 virus that caused persistent inflammation as well as an inability of the body to absorb tryptophan, an amino acid that’s a precursor to serotonin. Overactive blood platelets were also shown to play a role; they serve as the primary means of serotonin absorption.

The study doesn’t make any recommendations for treatment, but understanding the role of serotonin in long COVID opens the door to a host of novel ideas that could set the stage for clinical trials and affect care.

“The study gives us a few possible targets that could be used in future clinical studies,” Dr. Thaiss said.

Persistent circulating virus is one of the drivers of low serotonin levels, said study author Michael Peluso, MD, an assistant research professor of infectious medicine at the University of California, San Francisco, School of Medicine. This points to the need to reduce viral load using antiviral medications like nirmatrelvir/ritonavir (Paxlovid), which is approved by the U.S. Food and Drug Administration for the treatment of COVID-19, and VV116, which has not yet been approved for use against COVID.

Research published in the New England Journal of Medicine found that the oral antiviral agent VV116 was as effective as nirmatrelvir/ritonavir in reducing the body’s viral load and aiding recovery from SARS-CoV-2 infection. Paxlovid has also been shown to reduce the likelihood of getting long COVID after an acute SARS-CoV-2 infection.

Researchers are investigating ways to target serotonin levels directly, potentially using SSRIs. But first they need to study whether improvement in serotonin level makes a difference.

“What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief,” Dr. Peluso said.

Indeed, the research did show that the SSRI fluoxetine, as well as a glycine-tryptophan supplement, improved cognitive function in SARS-CoV-2-infected rodent models, which were used in a portion of the study.

David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City, said the research is helping “to paint a biological picture” that’s in line with other research on the mechanisms that cause long COVID symptoms.

But Dr. Putrino, who was not involved in the study, cautions against treating long COVID patients with SSRIs or any other treatment that increases serotonin before testing patients to determine whether their serotonin levels are actually lower than those of healthy persons.

“We don’t want to assume that every patient with long COVID is going to have lower serotonin levels,” said Dr. Putrino.

What’s more, researchers need to investigate whether SSRIs increase levels of circulating serotonin. It’s important to note that researchers found lower levels of circulating serotonin but that serotonin levels in the brain remained normal.

Traditionally, SSRIs are used clinically for increasing the levels of serotonin in the brain, not the body.

“Whether that’s going to contribute to an increase in systemic levels of serotonin, that’s something that needs to be tested,” said Akiko Iwasaki, PhD, co-lead investigator of the Yale School of Medicine, New Haven, Conn., COVID-19 Recovery Study, who was not involved in the research.

Thus far, investigators have not identified one unifying biomarker that seems to cause long COVID in all patients, said Dr. Iwasaki. Some research has found higher levels of certain immune cells and biomarkers: for example, monocytes and activated B lymphocytes, indicating a stronger and ongoing antibody response to the virus. Other recent research conducted by Dr. Iwasaki, Dr. Putrino, and others, published in the journal Nature, showed that long COVID patients tend to have lower levels of cortisol, which could be a factor in the extreme fatigue experienced by many who suffer from the condition.

The findings in the study in The Cell are promising, but they need to be replicated in more people, said Dr. Iwasaki. And even if they’re replicated in a larger study population, this would still be just one biomarker that is associated with one subtype of the disease. There is a need to better understand which biomarkers go with which symptoms so that the most effective treatments can be identified, she said.

Both Dr. Putrino and Dr. Iwasaki contended that there isn’t a single factor that can explain all of long COVID. It’s a complex disease caused by a host of different mechanisms.

Still, low levels of serotonin could be an important piece of the puzzle. The next step, said Dr. Iwasaki, is to uncover how many of the millions of Americans with long COVID have this biomarker.

“People working in the field of long COVID should now be considering this pathway and thinking of ways to measure serotonin in their patients.”

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

Could antidepressants hold the key to treating long COVID? University of Pennsylvania researchers have uncovered a link between long COVID and levels of serotonin in the body that may offer a new explanation for the condition. The study even points to a possible treatment.

Serotonin is a neurotransmitter that has many functions in the body and is targeted by the most commonly prescribed antidepressants – the selective serotonin reuptake inhibitors.

Serotonin is widely studied for its effects on the brain – it regulates the messaging between neurons, affecting sleep, mood, and memory. It is present in the gut, is found in cells along the gastrointestinal tract, and is absorbed by blood platelets. Gut serotonin, known as circulating serotonin, is responsible for a host of other functions, including the regulation of blood flow, body temperature, and digestion.

Low levels of serotonin could result in any number of seemingly unrelated symptoms, as in the case of long COVID, experts say. The condition affects about 7% of Americans and is associated with a wide range of health problems, including fatigue, shortness of breath, neurological symptoms, joint pain, blood clots, heart palpitations, and digestive problems.

Long COVID is difficult to treat because researchers haven’t been able to pinpoint the underlying mechanisms that cause prolonged illness after a SARS-CoV-2 infection, said study author Christoph A. Thaiss, PhD, an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

The hope is that this study could have implications for new treatments, he said.

“Long COVID can have manifestations not only in the brain but in many different parts of the body, so it’s possible that serotonin reductions are involved in many different aspects of the disease,” said Dr. Thaiss.

Dr. Thaiss’s study, published in the journal Cell, found lower serotonin levels in long COVID patients, compared with patients who were diagnosed with acute COVID-19 but who fully recovered.

His team found that reductions in serotonin were driven by low levels of circulating SARS-CoV-2 virus that caused persistent inflammation as well as an inability of the body to absorb tryptophan, an amino acid that’s a precursor to serotonin. Overactive blood platelets were also shown to play a role; they serve as the primary means of serotonin absorption.

The study doesn’t make any recommendations for treatment, but understanding the role of serotonin in long COVID opens the door to a host of novel ideas that could set the stage for clinical trials and affect care.

“The study gives us a few possible targets that could be used in future clinical studies,” Dr. Thaiss said.

Persistent circulating virus is one of the drivers of low serotonin levels, said study author Michael Peluso, MD, an assistant research professor of infectious medicine at the University of California, San Francisco, School of Medicine. This points to the need to reduce viral load using antiviral medications like nirmatrelvir/ritonavir (Paxlovid), which is approved by the U.S. Food and Drug Administration for the treatment of COVID-19, and VV116, which has not yet been approved for use against COVID.

Research published in the New England Journal of Medicine found that the oral antiviral agent VV116 was as effective as nirmatrelvir/ritonavir in reducing the body’s viral load and aiding recovery from SARS-CoV-2 infection. Paxlovid has also been shown to reduce the likelihood of getting long COVID after an acute SARS-CoV-2 infection.

Researchers are investigating ways to target serotonin levels directly, potentially using SSRIs. But first they need to study whether improvement in serotonin level makes a difference.

“What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief,” Dr. Peluso said.

Indeed, the research did show that the SSRI fluoxetine, as well as a glycine-tryptophan supplement, improved cognitive function in SARS-CoV-2-infected rodent models, which were used in a portion of the study.

David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City, said the research is helping “to paint a biological picture” that’s in line with other research on the mechanisms that cause long COVID symptoms.

But Dr. Putrino, who was not involved in the study, cautions against treating long COVID patients with SSRIs or any other treatment that increases serotonin before testing patients to determine whether their serotonin levels are actually lower than those of healthy persons.

“We don’t want to assume that every patient with long COVID is going to have lower serotonin levels,” said Dr. Putrino.

What’s more, researchers need to investigate whether SSRIs increase levels of circulating serotonin. It’s important to note that researchers found lower levels of circulating serotonin but that serotonin levels in the brain remained normal.

Traditionally, SSRIs are used clinically for increasing the levels of serotonin in the brain, not the body.

“Whether that’s going to contribute to an increase in systemic levels of serotonin, that’s something that needs to be tested,” said Akiko Iwasaki, PhD, co-lead investigator of the Yale School of Medicine, New Haven, Conn., COVID-19 Recovery Study, who was not involved in the research.

Thus far, investigators have not identified one unifying biomarker that seems to cause long COVID in all patients, said Dr. Iwasaki. Some research has found higher levels of certain immune cells and biomarkers: for example, monocytes and activated B lymphocytes, indicating a stronger and ongoing antibody response to the virus. Other recent research conducted by Dr. Iwasaki, Dr. Putrino, and others, published in the journal Nature, showed that long COVID patients tend to have lower levels of cortisol, which could be a factor in the extreme fatigue experienced by many who suffer from the condition.

The findings in the study in The Cell are promising, but they need to be replicated in more people, said Dr. Iwasaki. And even if they’re replicated in a larger study population, this would still be just one biomarker that is associated with one subtype of the disease. There is a need to better understand which biomarkers go with which symptoms so that the most effective treatments can be identified, she said.

Both Dr. Putrino and Dr. Iwasaki contended that there isn’t a single factor that can explain all of long COVID. It’s a complex disease caused by a host of different mechanisms.

Still, low levels of serotonin could be an important piece of the puzzle. The next step, said Dr. Iwasaki, is to uncover how many of the millions of Americans with long COVID have this biomarker.

“People working in the field of long COVID should now be considering this pathway and thinking of ways to measure serotonin in their patients.”

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

As I noted in my last column, I recently had a generic cold.

One of the more irritating aspects is that I usually get a cough that lasts a few weeks afterwards, and, like most people, I try to do something about it. So I load up on various over-the-counter remedies.

I have no idea if they work, or if I’m shelling out for a placebo. I’m not alone in buying these, or they wouldn’t be on the market, or making money, at all.

But the placebo effect is pretty strong. Phenylephrine has been around since 1938. It’s sold on its own and is an ingredient in almost every anti-cough/cold combination medication out there (NyQuil, DayQuil, Robitussin Multi-Symptom, and their many generic store brands). Millions of people use it every year.

Yet, after sifting through piles of accumulated data, the Food and Drug Administration announced earlier this year that phenylephrine ... doesn’t do anything. Zip. Zero. Nada. When compared with a placebo in controlled trials, you couldn’t tell the difference between them. So now the use of it is being questioned. CVS has started pulling it off their shelves, and I suspect other pharmacies will follow.

But back to my cough. A time-honored tradition in American childhood is having to cram down Robitussin and gagging from its nasty taste (the cherry and orange flavoring don’t make a difference, it tastes terrible no matter what you do). So that gets ingrained into us, and to this day I, and most adults, reach for a bottle of dextromethorphan when they have a cough.

But the evidence for that is spotty, too. Several studies have shown equivocal, if any, evidence to suggest it helps with coughs, though others have shown some. Nothing really amazing though.

But we still buy it by the gallon when we’re sick, because we want something, anything, that will make us better. Even if we’re doing so more from hope than conviction.

There’s also the old standby of cough drops, which have been used for more than 3,000 years. Ingredients vary, but menthol is probably the most common one. I go through those, too. I keep a bag in my desk at work. In medical school, during cold season, it was in my backpack. I remember sitting in the Creighton library to study, quietly sucking on a lozenge to keep my cough from disturbing other students.

But even then, the evidence is iffy as to whether they do anything. In fact, one interesting (though small) study in 2018 suggested they may actually prolong coughs.

The fact is that we are all susceptible to the placebo effect, regardless of how much we know about illness and medication. Maybe these things work, maybe they don’t, but it’s a valid question. How often do we let wishful thinking beat objective data?

Probably more often than we want to admit.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

As I noted in my last column, I recently had a generic cold.

One of the more irritating aspects is that I usually get a cough that lasts a few weeks afterwards, and, like most people, I try to do something about it. So I load up on various over-the-counter remedies.

I have no idea if they work, or if I’m shelling out for a placebo. I’m not alone in buying these, or they wouldn’t be on the market, or making money, at all.

But the placebo effect is pretty strong. Phenylephrine has been around since 1938. It’s sold on its own and is an ingredient in almost every anti-cough/cold combination medication out there (NyQuil, DayQuil, Robitussin Multi-Symptom, and their many generic store brands). Millions of people use it every year.

Yet, after sifting through piles of accumulated data, the Food and Drug Administration announced earlier this year that phenylephrine ... doesn’t do anything. Zip. Zero. Nada. When compared with a placebo in controlled trials, you couldn’t tell the difference between them. So now the use of it is being questioned. CVS has started pulling it off their shelves, and I suspect other pharmacies will follow.

But back to my cough. A time-honored tradition in American childhood is having to cram down Robitussin and gagging from its nasty taste (the cherry and orange flavoring don’t make a difference, it tastes terrible no matter what you do). So that gets ingrained into us, and to this day I, and most adults, reach for a bottle of dextromethorphan when they have a cough.

But the evidence for that is spotty, too. Several studies have shown equivocal, if any, evidence to suggest it helps with coughs, though others have shown some. Nothing really amazing though.

But we still buy it by the gallon when we’re sick, because we want something, anything, that will make us better. Even if we’re doing so more from hope than conviction.

There’s also the old standby of cough drops, which have been used for more than 3,000 years. Ingredients vary, but menthol is probably the most common one. I go through those, too. I keep a bag in my desk at work. In medical school, during cold season, it was in my backpack. I remember sitting in the Creighton library to study, quietly sucking on a lozenge to keep my cough from disturbing other students.

But even then, the evidence is iffy as to whether they do anything. In fact, one interesting (though small) study in 2018 suggested they may actually prolong coughs.

The fact is that we are all susceptible to the placebo effect, regardless of how much we know about illness and medication. Maybe these things work, maybe they don’t, but it’s a valid question. How often do we let wishful thinking beat objective data?

Probably more often than we want to admit.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

As I noted in my last column, I recently had a generic cold.

One of the more irritating aspects is that I usually get a cough that lasts a few weeks afterwards, and, like most people, I try to do something about it. So I load up on various over-the-counter remedies.

I have no idea if they work, or if I’m shelling out for a placebo. I’m not alone in buying these, or they wouldn’t be on the market, or making money, at all.

But the placebo effect is pretty strong. Phenylephrine has been around since 1938. It’s sold on its own and is an ingredient in almost every anti-cough/cold combination medication out there (NyQuil, DayQuil, Robitussin Multi-Symptom, and their many generic store brands). Millions of people use it every year.

Yet, after sifting through piles of accumulated data, the Food and Drug Administration announced earlier this year that phenylephrine ... doesn’t do anything. Zip. Zero. Nada. When compared with a placebo in controlled trials, you couldn’t tell the difference between them. So now the use of it is being questioned. CVS has started pulling it off their shelves, and I suspect other pharmacies will follow.

But back to my cough. A time-honored tradition in American childhood is having to cram down Robitussin and gagging from its nasty taste (the cherry and orange flavoring don’t make a difference, it tastes terrible no matter what you do). So that gets ingrained into us, and to this day I, and most adults, reach for a bottle of dextromethorphan when they have a cough.

But the evidence for that is spotty, too. Several studies have shown equivocal, if any, evidence to suggest it helps with coughs, though others have shown some. Nothing really amazing though.

But we still buy it by the gallon when we’re sick, because we want something, anything, that will make us better. Even if we’re doing so more from hope than conviction.

There’s also the old standby of cough drops, which have been used for more than 3,000 years. Ingredients vary, but menthol is probably the most common one. I go through those, too. I keep a bag in my desk at work. In medical school, during cold season, it was in my backpack. I remember sitting in the Creighton library to study, quietly sucking on a lozenge to keep my cough from disturbing other students.

But even then, the evidence is iffy as to whether they do anything. In fact, one interesting (though small) study in 2018 suggested they may actually prolong coughs.

The fact is that we are all susceptible to the placebo effect, regardless of how much we know about illness and medication. Maybe these things work, maybe they don’t, but it’s a valid question. How often do we let wishful thinking beat objective data?

Probably more often than we want to admit.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

PHOENIX – Children with Duchenne muscular dystrophy (DMD) treated with the only gene therapy to date to be approved for treatment of disease in the United States show sustained maintenance of motor function after 4 years, 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 – Children with Duchenne muscular dystrophy (DMD) treated with the only gene therapy to date to be approved for treatment of disease in the United States show sustained maintenance of motor function after 4 years, 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 – Children with Duchenne muscular dystrophy (DMD) treated with the only gene therapy to date to be approved for treatment of disease in the United States show sustained maintenance of motor function after 4 years, 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.