Safety Concerns and Promising Developments in Duchenne Muscular Dystrophy Therapies

Recent developments in Duchenne muscular dystrophy (DMD) treatments have brought both excitement and caution to the pharmaceutical industry. While several companies are preparing to submit new therapies for FDA approval, safety concerns have emerged following the death of a patient taking Sarepta's approved gene therapy, Elevidys.

Safety Questions Loom as Companies Prepare for FDA Submissions

The recent death of a patient taking Sarepta's Elevidys has raised important safety questions in the DMD treatment landscape. The patient, who had also tested positive for cytomegalovirus (CMV) infection, died while undergoing treatment with the gene therapy. Sarepta noted that CMV infection, which can damage the liver, may have been a contributing factor to the death.

This incident has highlighted the need for careful patient selection and monitoring in gene therapy treatments. Christiana Bardon, managing partner at MPM BioImpact, emphasized the importance of identifying patients who should not receive gene therapies due to existing infections or other medical issues. She also stressed the need for close post-administration monitoring to detect and address any complications.

Despite these concerns, several companies are moving forward with plans to seek FDA approval for their DMD treatments in 2026. Wave Life Sciences, Dyne Therapeutics, and REGENXBIO are all preparing regulatory submissions based on promising clinical trial results.

Exon Skipping vs. Gene Therapy: Advancements and Comparisons

The DMD treatment landscape is primarily divided between gene therapies and exon-skipping technologies. Recent advancements in both approaches have shown promising results, but experts agree that the heterogeneous nature of DMD requires a variety of treatment options.

Wave Life Sciences recently announced positive data from its Phase II FORWARD-53 trial of WVE-N531, an exon-skipping therapy. The drug demonstrated functional benefits and reversed muscle damage in 11 boys after 48 weeks of treatment. Notably, Wave reported evidence of myofiber regeneration, a finding not previously seen with other exon skippers or gene therapies.

Dyne Therapeutics' exon-skipper DYNE-251 has shown superiority to Sarepta's Exondys 51 in head-to-head comparisons. The company reported more than 10-fold higher dystrophin expression and improvements across multiple functional endpoints. Long-term follow-up data presented at the 2025 Muscular Dystrophy Association conference showed maintained functional benefits through 18 months.

On the gene therapy front, REGENXBIO presented biomarker data from its Phase I/II AFFINITY DUCHENNE trial, demonstrating robust microdystrophin and transduction levels across patients of all ages treated with RGX-202. The company plans to submit a biologics license application to the FDA in mid-2026.

Genethon, a non-profit gene therapy developer, reported positive results for its AAV vector-based gene therapy GNT0004. The treatment showed a 68% reduction in creatine kinase levels over two years and stabilization or improvement in functional outcomes. Genethon believes GNT0004 has the potential to be "best in class" due to its smaller size and lower dosage requirements.

Challenges and Future Directions in DMD Treatment

As the field of DMD therapeutics advances, several challenges remain. Researchers are working to identify better measurements of clinical efficacy, as current assessments like the North Star Ambulatory Assessment (NSAA) can be influenced by factors such as patient growth. Alternative measures, including time-to-rise from the floor and the Stride Velocity 95th Centile (SV95C), are being explored to provide more accurate assessments of treatment efficacy.

Future developments in DMD therapies may include next-generation treatments capable of transducing larger portions of the dystrophin gene using double vectors and potentially gene editing tools. Additionally, addressing muscle fibrosis has been identified as a crucial area for enhancing both muscle function and the effectiveness of gene therapies.

As the industry moves forward, balancing the promise of new treatments with careful consideration of safety concerns will be paramount in bringing effective therapies to DMD patients.