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“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”
DMD: Current and emerging therapies
DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.
FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.
AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.
The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.3 The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.
Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.
Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.
Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:
ENTR-601-44 is another exon 44–skipping therapy in the pipeline.
On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.
Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.
Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.
Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.
“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
FSHD: Emerging therapies
The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.1 An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.4 The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.
AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.5 The trial began in April 2023; estimated completion date is September 2025.
As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.
“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
Neonatal screening and early diagnosis: Imperative for improving outcomes
Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.
DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.
In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.
Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.
“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”
Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
DMD therapies carry a hefty price
Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.
Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.6,7
‘It takes a village’: Comprehensive care requires a multidisciplinary team
Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.
A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.
“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”
“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”
Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.
Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
References
1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.
2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.
3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.
4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.
5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.
6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.
7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.
“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”
DMD: Current and emerging therapies
DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.
FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.
AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.
The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.3 The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.
Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.
Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.
Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:
ENTR-601-44 is another exon 44–skipping therapy in the pipeline.
On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.
Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.
Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.
Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.
“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
FSHD: Emerging therapies
The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.1 An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.4 The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.
AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.5 The trial began in April 2023; estimated completion date is September 2025.
As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.
“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
Neonatal screening and early diagnosis: Imperative for improving outcomes
Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.
DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.
In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.
Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.
“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”
Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
DMD therapies carry a hefty price
Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.
Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.6,7
‘It takes a village’: Comprehensive care requires a multidisciplinary team
Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.
A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.
“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”
“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”
Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.
Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
References
1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.
2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.
3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.
4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.
5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.
6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.
7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.
“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”
DMD: Current and emerging therapies
DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.
FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.
AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.
The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.3 The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.
Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.
Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.
Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:
ENTR-601-44 is another exon 44–skipping therapy in the pipeline.
On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.
Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.
Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.
Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.
“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
FSHD: Emerging therapies
The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.1 An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.4 The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.
AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.5 The trial began in April 2023; estimated completion date is September 2025.
As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.
“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
Neonatal screening and early diagnosis: Imperative for improving outcomes
Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.
DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.
In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.
Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.
“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”
Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
DMD therapies carry a hefty price
Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.
Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.6,7
‘It takes a village’: Comprehensive care requires a multidisciplinary team
Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.
A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.
“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”
“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”
Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.
Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
References
1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.
2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.
3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.
4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.
5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.
6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.
7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.
