Genetic Medicine in DMD: End Points, Assessment, and Approvals


CGTLive takes a look at challenges that have beset the first gene therapy coming close to market for treating Duchenne muscular dystrophy in 2023.

While the field of muscular dystrophy is closer than ever to its first approval of a gene therapy, regulators have struggled to come to a consensus on the validity of microdystrophin as a surrogate end point for clinical benefit in pivotal clinical trials in the accelerated approval pathway. The FDA has previously accepted microdystrophin as a surrogate endpoint in the accelerated approvals of 4 exon-skipping drugs for treating Duchenne muscular dystrophy (DMD): eteplirsen (Exondys 51), golodirsen (Vyondys 53), viltolarsen (Viltepso), and casimersen (Amondys 450).1 Although, discussion has continued to abound around different forms of synthetic microdystrophin as expressed by adeno-associated virus vector (AAV) gene therapies.

The Microdystrophin Problem

“The FDA has been traditionally a little reluctant to just use protein expression as a surrogate end point. They've done it a number of times, they're doing it increasingly often, and even in the case of DMD, they've clearly latched onto that, to approve some of the exon skipping therapies that are out there. Yet, we feel that the microdystrophin [gene] therapies are making more of the protein, they're going to have a greater clinical benefit, and so those same considerations should be applied,” Jeffrey S. Chamberlain, PhD, Professor and McCaw Chair of Muscular Dystrophy and director of the Sen. Paul D. Wellstone Muscular Dystrophy Specialized Research Center at the University of Washington School of Medicine, told CGTLive™.

Chamberlain and colleagues reviewed and advocated for the use of microdystrophin as a surrogate endpoint in DMD gene therapy trials in a paper published in Human Gene Therapy in February 2023. The paper outlined its previous use in approving exon-skipping drugs, the time benefits of using microdystrophin as opposed to clinical end points; preclinical data that demonstrated prevention and restoration of pathology along with increased strength; the most critical elements of the microdystrophin protein in producing this effect; and available clinical data showing the relationship between microdystrophin expression and muscle function.

Hear more in detail from Chamberlain below:

For somewhat slowly progressive diseases like this, it takes a long time to really evaluate efficacy, particularly using traditional methods that the FDA applies with the desire to follow patients for a long time and see a clear clinical benefit. Yet at the same time, they're a little cautious in setting up these trials. Most of the early kids that have been enrolled in these trials are still fairly young. They're not as as weak or severely affected as some of the older boys unfortunately are. So, that complicates waiting for a clear clinical benefit.
— Jeffrey S. Chamberlain, PhD

The microdystrophin-expressing AAV gene therapy closest to the market for treating DMD is Sarepta Therapeutics’ delandistrogene moxeparvovec (SRP-9001), which uses the AAVrh74 recombinant vector. The Prescription Drug User Fee Act action date for the therapy was recently pushed back from May 29, 2023, to June 22, 2023, possibly partially because of the recent discussions on microdystrophin, which may have also prompted the FDA to hold a recent FDA Cellular, Tissue, and Gene Therapies Advisory Committee meeting for the therapy after stating one would not be needed.2,3 The meeting’s presenters were certainly not united in their opinion, and the panel found itself going back and forth on the question of whether or not definitive clinical benefit could be observed with microdystrophin expression as a surrogate end point before finally voting 8–6 (8 Yes; 6 No; 0 Abstain) in support of the therapy’s approval.

“Several new therapies have been approved by the FDA for DMD using the presence of dystrophin as a surrogate end point. With this as established precedent, we expect additional clinical studies, including ongoing gene therapy clinical trials, to rely on dystrophin as a surrogate end point to predict clinical benefit and therefore potentially receive a marketing approval via accelerated approval from the FDA. Confirmatory studies to establish clinical benefit in the previously approved studies are ongoing,” Paul Melmeyer, MPP, the vice president of public policy and advocacy at the Muscular Dystrophy Association (MDA), told CGTLive.

Part of the committee's concerns were that, unlike exon-skipping approaches allowing the body to produce a shortened form of microdystrophin that is normally naturally found there, Sarepta’s gene therapy is designed to express a synthetic microdystrophin protein. Most of the data on delandistrogene moxaparvovec are from Study 102 (NCT03769116), whereas a different process producing a “less pure” product would be commercially available and is being studied in the ongoing studies 301 (EMBARK; NCT05096221) and 103 (ENDEAVOR; NCT04626674). Moreover, Study-102 did not meet its primary end point, although further analyses have demonstrated clinical benefit, most strongly in boys aged 4 to 5 years. Sarepta has said that the initial lack of positive data was because of the internal control group not being well-matched to the treated group, further showcasing difficulties in enrolling and evaluating clinical trials in rare, progressive diseases like DMD.

“Enrollment in any rare disease clinical trial is inherently difficult due to the small patient populations and often limited inclusion criteria. Within DMD clinical trials—particularly for gene therapies—this is no different as many individuals with DMD may be excluded due to their age, the progression of their DMD, their specific genetic mutation, or their previous exposure to the viral vector. Consequently, we understand that enrolling gene therapy clinical trials for DMD is a challenge,” Melmeyer told CGTLive. “However, we also know that the community is eager to move these technologies forward, hopefully resulting in an FDA approval. Individuals with DMD participating in these clinical trials are true medical pioneers, and they deserve everyone’s gratitude.”

As required under law, any product approved by the FDA via accelerated approval must confirm clinical effectiveness in subsequent confirmatory trials. We expect all DMD products approved via accelerated approval to similarly meet this statutory requirement."
— Paul Melmeyer, MPP

Another confounding factor in seeing clear benefit with gene therapy is the heterogeneous disease course and fast deterioration in patients with DMD—in such a time-sensitive disease, a faster measure of efficacy, like microdystrophin expression, is needed when clinical end points may take over a decade to measure. Confirmatory studies are mandatory after accelerated approvals, and the committee doubted Sarepta’s follow-through on conducting one such trial for delandistrogene moxaparvovec, considering the confirmatory trials for its exon-skipping drugs (eteplirsen, golodirsen, and casimersen) are still ongoing after much delay.

Federal Cooperation for Access

Earlier this year, the Secretary of the Department of Health and Human Services (HHS) selected 3 new models by the Centers for Medicaid & Medicare Services (CMS) for testing, 2 of which directly affect cell and gene therapies, to help lower costs and improve access to novel therapies.4 One model is the Accelerating Clinical Evidence Model, which will seek to develop payment methods for drugs approved under the accelerated approval pathway. The HHS hopes the model will encourage confirmatory trials to complete in a timely fashion and to establish postmarket safety and efficacy data to reduce spending on drugs with no confirmed clinical benefit. (FIGURE 1).

2023 Discussions on Accelerated Approval

(Click to enlarge)

“We are encouraged by the CMS's recent announcement of a pilot project to test CMS serving as a central negotiator and facilitator for state Medicaid programs on outcomes-based payment agreements for gene therapies. We are hopeful that such an innovative approach could relieve some of the burdens state Medicaid agencies face when covering highly expensive, single-administration gene therapies such as some available or under development for neuromuscular diseases, ultimately resulting in greater access to gene therapies for our community. We understand that this pilot may not launch until 2026, meaning it will not have a substantial impact on access to the potential DMD gene therapy approvals this year,” Melmeyer added.

The most recent data on delandistrogene moxaparvovec were 4-year follow-up data from Study 101 (NCT03375164) presented at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California.5 There were no serious adverse events observed and patients showed a mean improvement in North Star Ambulatory Assessment (NSAA) total scores of 7.0 (SD, 2.9) from baseline to 4 years posttreatment. This improvement stands in contrast to the decline typically expected in this age range for patients with DMD. Improvements were also observed from baseline to 4 years posttreatment in the patients’ mean scores for other functional tests including Mean Time to Rise, Mean 4-stair Climb, Mean 100 Meter Walk/Run (MWR), and Mean 10MWR.

“It's not like with an infectious disease: if you have a new antibiotic you may know in a week or so whether it worked or not. Unfortunately, with a lot of these genetic developmental disorders, where you have slow progression, it's a slower process to follow that. Yet, I think a lot of that work that came out of the preclinical studies and the development of these technologies over the last 20 to 25 years have shown an absolute clear relationship between production of this missing protein and benefit down the road, but it can take a while to measure that.”
— Jeffrey S. Chamberlain, MD, PhD

Other Approaches to DMD

Although Sarepta’s gene therapy leads the pack in microdystrophin-expressing AAV gene therapies being put forward to the FDA for approval, other similar therapies are not too far behind. Also presented at ASGCT 2023 were follow-up data from Pfizer’s phase 1 study (NCT03362502) on fordadistrogene movaparvovec (PF-06939926), an AAV9 gene therapy expressing what Pfizer calls “minidystrophin”. (FIGURE 2).

Novel Therapies in Development for DMD

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Compared with external controls, trial participants had a 2.4-point difference (95% CI, –0.6 to 5.4) in NSAA scores after 2 years.6 When stratifying by age, the patients aged 6 to 7 years showed a 2.5-point difference (95% CI, 0.4-4.7) on NSAA scores and the patients aged 8 to 12 years showed a 2.3-point difference (95% CI, –2.0 to 6.5) on NSAA scores after 2 years. The therapy had a safety profile fairly consistent to other gene therapies in development, but a couple of previously disclosed serious and transient related adverse events did occur, including dehydration, acute kidney injury, and thrombocytopenia. Fordadistrogene movaparvovec is also being evaluated in the phase 3 CIFFREO study (NCT04281485), which was cleared to proceed after a clinical hold in 2022. Lagging further behind is Solid Biosciences’ SGT-003 AAV9 gene therapy, which the company decided to prioritize over its clinical-stage, first-generation SGT-001 generation in 2022, and is not yet in clinical studies.7 The company plans to submit an investigational new drug application for SGT-003 in the fourth quarter of 2023.8

Other companies are moving away from microdystrophin, and gene therapy in general, in the pursuit of treating DMD. Both Capricor Therapeutics and ENCell are developing cell therapies for the indication, CAP-1002 and EN001, respectively. Capricor’s program, unique for evaluating a nonambulatory population, most recently released data from the open-label extension (NCT04428476) of the phase 2 HOPE-2 trial (NCT03406780) that showed that the previous significantly slowed decline in Performance of Upper Limb was maintained for around 3.5 years, which suggests a disease-modification effect.9 This month, the company announced a Type B clinical meeting with FDA to occur in the third quarter of 2023 to discuss its path to a biologics license application for CAP-1002, which is currently being evaluated in the phase 3 HOPE-3 trial (NCT05126758).10

MDA, CureDuchenne, PPMD Fund Study on Reducing AAV Antibodies to Enable Gene Therapy

CureDuchenne, MDA, and Parent Project Muscular Dystrophy (PPMD) have just announced their collaboration on a clinical trial grant to investigate redosing of AAV gene therapies in patients with DMD.

Each organization is granting $100,000 for the 1-year clinical trial at University of Florida (UF) to be led by Barry Byrne, MD, PhD, chief medical advisor, MDA, and associate chair, pediatrics and director, Powell Gene Therapy Center, UF. The open-label, single center, multi-arm, phase 2 trial will assess the safety and efficacy of efgartigimod alfa-fcab (Vyvgart) to lower AAV antibodies in 12 patients with DMD that have pre-existing AAV antibodies from natural infections currently ineligible for gene therapy (n = 6) as well as in patients that have AAV antibodies from previous gene therapies (n = 6) for potential redosing. Vyvgart is currently FDA-approved to treat autoimmune diseases and reduces overall levels of circulating IgG antibodies.

CureDuchenne, Muscular Dystrophy Association, and Parent Project Muscular Dystrophy announce collaborative project to focus on re-dosing gene therapy in Duchenne Muscular Dystrophy. News release. Muscular Dystrophy Association. June 15, 2023.

In a much earlier investigation, ENCell’s phase 1 clinical trial (NCT05338099) showed that 1 patient showed an improvement of 1 point from baseline on their NSAA total score and another patient maintained a stable NSAA total score.11 The other 4 patients showed a decline of 3 to 8 points in NSAA total score.

Though it is easy to pit the different trials against each other, patient advocates and advocacy groups, such as MDA, are quick to stress the collaboration needed to bring a gene or cell therapy to the finish line and to hopefully, open the gates for other disease-modifying therapies to become available for patients with DMD. Collboration is also strong between advocacy groups, with MDA, CureDuchenne, Parent Project Muscular Dystrophy (PPMD) just recently announcing a collaborative grant to investigate depleting anti-AAV antibodies to enable gene therapy treatment (see sidebar).

“MDA routinely collaborates with fellow organizations on advocacy issues, including improving clinical trials. Specifically, MDA leads a group called the Neuromuscular Advocacy Collaborative, which consists of condition-specific organizations all working together to advocate for policies that will help the entire neuromuscular community, including clinical trial reforms. This group was crucial in passing key reforms in 2022 during FDA User Fee Reauthorization,” Mark Fisher, the director ofadvocacy engagement at MDA, told CGTLive. “MDA has a robust grassroots network, whose advocates actively raise their voices and urge decisionmakers to support policies to improve clinical trials. This group consists of those living with neuromuscular diseases, family members, caregivers, and medical professionals. In 2022, MDA grassroots advocates were crucial in getting key reforms passed during the FDA User Fee Reauthorization.”

1. Chamberlain J, Robb M, Braun S, et al. Micro-dystrophin expression as a surrogate end point for Duchenne muscular dystrophy clinical trials. Human Gene Therapy. 2023(34): 9-10, p 404-415. doi: 10.1089/hum.2022.190
2. Sarepta Therapeutics Announces Update on Regulatory Review of SRP-9001. News release. Sarepta Therapeutics. May 24, 2023. Accessed June 15, 2023.
3. 74th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. May 12, 2023.
4. HHS Secretary Responds to the President’s Executive Order on Drug Prices. News release. Centers for Medicaid & Medicare Services. February 14, 2023. Accessed June 15, 2023.
5. D’Ambrosio E. Phase 1/2a trial of delandistrogene moxeparvovec in patients with DMD: 4-year update. Presented at: American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. May 16-20, 2023; Los Angeles, CA. Oral abstract session.
6. Shieh PB, Butterfield RJ, Munotni F, et al. Two-year clinical outcomes with fordadistrogene movaparvovec for Duchenne muscular dystrophy (DMD) and contextualization with external controls. Presented at: ASGCT 2023 Annual Meeting; May 16-20; Los Angeles, California.
7. Solid Biosciences Announces Updated Corporate Strategy to Develop SGT-001 and SGT-003 Pipeline Programs for Patients with Duchenne Muscular Dystrophy. News release. Solid Biosciences. April 27, 2022. Accessed June 15, 2023.
8. Solid Biosciences provides first quarter business update and financial results. News release. Solid Biosciences. May 11, 2023. Accessed June 15, 2023.
9. Marban L, McDonald CM, Hendrix S, et al. Late breaking: CAP-1002, an allogeneic cell therapy demonstrates disease modification in later-stage DMD patients: 18-month results from the HOPE-2-open label extens. Presented at: 2023 MDA Conference, March 19-22; Dallas, Texas. Poster #163
10. Capricor Therapeutics announces follow-up Type-B clinical meeting with the FDA for CAP-1002 for the treatment of Duchenne muscular dystrophy. News release. Capricor Therapeutics. June 7, 2023. Accessed June 15, 2023.
11. Lee J, Lee J, Kim M, Jeon HB, Chang JW. An open-label, dose-escalation, phase 1a study to evaluate safety, tolerability, and exploratory efficacy of intravenous injection of allogenic early-passage mesenchymal stem cells (MSCs), derived from Wharton’s jelly in the umbilical cord, in patients with Duchenne muscular dystrophy. Presented at: American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. May 16-20, 2023; Los Angeles, CA. Poster #952.
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