Riding Momentum in the DMD Space: A New Wave of Progress

Recently, topline results from Part 2 of Sarepta Therapeutics’ EMBARK trial showed significant improvements in motor function among Duchenne muscular dystrophy (DMD) patients who switched from placebo to Elevidys. These findings reinforce the potential of Elevidys to deliver long-term, clinically meaningful benefits and enhance the quality of life for individuals living with DMD.

Over the past decade, eight drugs have been approved for the treatment of DMD, marking significant progress in the field. The DMD treatment landscape is currently undergoing a transformative phase, with companies such as Capricor Therapeutics, Wave Life Sciences, Regenxbio, and others leading the charge through innovative approaches, near-term data readouts, and critical regulatory milestones. Despite these advancements, substantial unmet needs persist, particularly in areas like treatment durability, addressing cardiomyopathy, and enhancing skeletal muscle function. These challenges highlight the ongoing necessity for continued research and development to improve outcomes for individuals living with DMD.

The Science Behind DMD and the Need for Innovation

DMD is caused by mutations in the dystrophin gene, which is essential for maintaining muscle cell integrity. Without functional dystrophin, muscle fibers become damaged during contraction, leading to progressive weakness and degeneration. Historically, treatments like corticosteroids have provided symptomatic relief but failed to address the underlying cause of the disease.

The advent of genetic therapies and other innovative approaches is changing this paradigm. By targeting the root cause of DMD—whether through gene replacement, exon-skipping, or muscle protection—these therapies aim to slow or even halt disease progression, offering the potential for life-changing outcomes.

Companies like Sarepta Therapeutics and Pfizer are at the forefront of this effort. As mentioned above, Sarepta’s Elevidys or SRP-9001 (delandistrogene moxeparvovec), has demonstrated the ability to produce functional dystrophin in patients, potentially slowing disease progression. Similarly, Pfizer’s PF-06939926, another gene therapy candidate, has shown promise in clinical trials.

Another innovative strategy is exon-skipping, a technique that allows cells to “skip over” faulty sections of the dystrophin gene, enabling the production of a partially functional protein. Sarepta Therapeutics has been a leader in this space with its FDA-approved exon-skipping therapies, including Exondys 51 (eteplirsen) for patients with mutations amenable to exon 51 skipping, Vyondys 53 (golodirsen) for exon 53 skipping, and Amondys 45 (casimersen) for exon 45 skipping.

Beyond gene therapy and exon-skipping, other approaches are gaining traction. Antisense oligonucleotides (ASOs), small molecules, and CRISPR-based gene editing are among the technologies being explored to address the root cause of DMD. Nippon Shinyaku has also made significant contributions with its FDA-approved therapy Viltepso (viltolarsen), which uses antisense oligonucleotide to target exon 53. Companies like Wave Life Sciences and Dyne Therapeutics are also actively developing ASO-based therapies, while CRISPR Therapeutics and Editas Medicine are pioneering gene-editing approaches to correct dystrophin mutations.

The DMD community is now looking toward 2025 as a pivotal year, with next-generation therapies expected to bring transformative changes. Here’s a detailed look at the key players and their groundbreaking approaches:

1. Capricor Therapeutics – Deramiocel

Mechanism: Allogeneic cell therapy derived from cardiosphere-derived cells (CDCs) from donor hearts.
Target: DMD-associated cardiomyopathy (a leading cause of death in DMD patients).
Progress:

• • Deramiocel is an off-the-shelf therapy administered via intravenous infusion four times a year. It works by reducing inflammation, modulating the immune system, and promoting muscle repair.
  • Phase II studies have shown that deramiocel slows disease progression in non-ambulatory patients by nearly 50%, as measured by upper limb performance, compared to natural history studies.
  • The therapy also significantly slows the decline in cardiac function, addressing a critical unmet need in DMD.
  • Capricor has submitted a Biologics License Application (BLA) to the FDA, with a potential approval decision expected by Q4 2024. If approved, deramiocel will be the first therapy specifically targeting DMD cardiomyopathy.

Future Plans: Capricor is expanding its manufacturing capabilities to treat thousands of patients, ensuring broad accessibility upon approval.

2. Dyne Therapeutics – Dyne-251

Mechanism: Next-generation exon 51 skipping therapy using a proprietary FORCE™ platform for enhanced delivery.
Target: DMD patients with mutations amenable to exon 51 skipping.
Progress:

• • Dyne-251 is designed to address the limitations of first-generation exon skippers like Sarepta’s Exondys 51, which struggle with cell penetration and low dystrophin expression.
  • Phase I/II data showed that Dyne-251 achieved >10x higher dystrophin expression compared to Exondys 51, with nearly 9% mean absolute dystrophin levels when adjusted for muscle content.
  • The therapy also demonstrated improvements in functional endpoints and a favorable safety profile, with no serious adverse events reported.
  • Dyne is currently recruiting for a pivotal trial and plans to pursue accelerated approval based on dystrophin expression as a surrogate endpoint.

Future Plans: DYNE-251 demonstrated a favorable safety profile, and the majority of treatment emergent adverse events were mild or moderate, paving the way for potential approval in 2025.

3. Wave Life Sciences – WVE-N531

Mechanism: Exon 53 skipping therapy with improved cell delivery for consistent dystrophin expression.
Target: DMD patients with mutations amenable to exon 53 skipping (8-10% of the DMD population).
Progress:

• • At the six-month interim analysis of a Phase II study, WVE-N531 demonstrated 9% dystrophin expression consistently across patients, along with reduced levels of creatine kinase (a biomarker for muscle damage).
  • The therapy also showed healthier muscle tissue in biopsies, indicating functional improvements.
  • Wave Life Sciences expects to report full 48-week data in Q1 2025, including clinical measurements of efficacy.

Future Plans: Wave is also developing therapies targeting other exons (51, 52, 45, and 44), aiming to expand treatment options for a broader range of DMD patients.

4. Avidity Biosciences – Delpacibart Zotadirsen (Del-zota)

Mechanism: Exon 44 skipping therapy using a proprietary AOC® (Antibody Oligonucleotide Conjugate) platform.
Target: DMD patients with mutations amenable to exon 44 skipping (approximately 6% of the DMD population).
Progress:

• • Del-zota has shown 25% dystrophin production in Phase I/II trials, some of the highest levels observed in exon-skipping therapies.
  • The therapy also reduced creatine kinase levels to near-normal ranges, indicating significant muscle protection.
  • Avidity is conducting the Explore44 open-label extension study, with additional data expected in 2024.
  • The company plans to submit a BLA by mid-2026, supported by the FDA’s orphan drug designation and fast-track status.

Future Plans: Del-zota could become the first approved therapy for exon 44 skipping, addressing a previously untreated subset of DMD patients.

5. Regenxbio – RGX-202

Mechanism: Gene therapy delivering a slightly larger dystrophin gene construct using the NAV® AAV8 vector.
Target: DMD patients aged 1 year and older.
Progress:

• • RGX-202 is designed to address the limitations of current gene therapies, which use truncated dystrophin genes due to size constraints of AAV vectors.
  • Early Phase II data from a small patient cohort showed strong safety and functional improvements, including better strength and time function tests.
  • Regenxbio is enrolling 30 patients in a pivotal Phase II trial, with a BLA submission planned for 2026.

Future Plans: If approved, RGX-202 will provide another gene therapy option for DMD patients, particularly for younger children who may benefit most from early intervention.

Challenges and Opportunities in the DMD Space

While the progress in DMD treatment is remarkable, several challenges remain:

1. Durability of Therapies: Long-term data is needed to confirm the sustained benefits of gene therapies and exon-skipping drugs.
2. Accessibility and Cost: High treatment costs, particularly for gene therapies, raise concerns about equitable access for all patients.
3. Cardiomyopathy: Addressing heart complications, a leading cause of death in DMD, remains a critical unmet need.
4. Regulatory Pathways: Companies are navigating accelerated approval pathways, relying on surrogate endpoints like dystrophin expression to bring therapies to market faster.

A Hopeful Future

Despite these challenges, the DMD community is optimistic. For patients and families affected by DMD, the advancements in drug development represent a beacon of hope. Collaboration among biotech companies, regulators, and patient advocacy groups has accelerated innovation, and the pipeline of next-generation therapies offers hope for improved outcomes. As mentioned, the DMD space could see the approval this year and commercialization of multiple therapies that address the disease in fundamentally new ways, offering the potential for improved quality of life and longer survival for patients. As the it continues to evolve, the dream of effective, life-changing DMD therapies is becoming a reality.

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