Sarepta Pushes Forward with Gene Therapy for LGMD Despite Regulatory Hurdles

Sarepta Therapeutics, a company known for its gene therapy developments, is continuing to pursue its investigational treatment for limb-girdle muscular dystrophy (LGMD) despite recent setbacks and a strategic pivot towards siRNA therapies. The company's perseverance with SRP-9003, its LGMD gene therapy candidate, comes amid significant regulatory challenges and safety concerns that have shaken the biotech's gene therapy platform.

Promising Data Amidst Safety Concerns

At the 30th annual International Congress of the World Muscle Society (WMS) in Vienna, Sarepta presented late-stage data for SRP-9003 that showed promise. The Phase III EMERGENE study, which included 17 LGMD patients, demonstrated that the gene therapy met its primary endpoint. Non-ambulatory patients experienced a 23.9% average increase in beta-sarcoglycan protein expression, while ambulatory patients saw a 43.4% increase. This protein is crucial for muscle structure and function.

Safety was a key focus at the WMS meeting, given the recent patient deaths associated with Sarepta's gene therapies. While over 40% of patients in the EMERGENE study experienced adverse events indicative of acute liver injury, none were deemed related to SRP-9003. This data provides some reassurance, although regulatory scrutiny remains high.

Regulatory Challenges and Strategic Decisions

The FDA has placed a clinical hold on all of Sarepta's gene therapy programs for LGMD, including SRP-9003, citing "unreasonable and significant risk of illness or injury" to study participants. This decision came after three patient deaths linked to Sarepta's gene therapy platform, including its Duchenne muscular dystrophy treatment, Elevidys.

Despite these setbacks, Sarepta is pushing forward with SRP-9003. The company's decision is based on several factors:

1. Positive net present value (NPV) analysis, according to Uy Ear, VP of U.S. Healthcare-Biotechnology at Mizuho Securities.
2. SRP-9003's advanced stage of development compared to other LGMD programs.
3. A sense of duty to the LGMD patient community, particularly those with the severe LGMD 2E subtype.

However, analysts remain cautious. Andrew Tsai from Jefferies notes that the probability of success for SRP-9003 has declined due to FDA dynamics, while Andy Chen from Wolfe Research assigns no value to the therapy in their model due to "extreme FDA uncertainty."

Potential Path Forward

Sarepta is exploring ways to address safety concerns and regain FDA confidence. One proposed strategy involves using the immunosuppressant sirolimus as a prophylactic measure to prevent liver damage. An independent abstract presented at the WMS meeting showed some promise for this approach when used with Elevidys, though results were not statistically significant.

Louise Rodino-Klapac, VP of R&D and technical operations at Sarepta, stated that the company's immediate focus is on completing regulatory interactions and submitting a biologics license application (BLA) for SRP-9003 as soon as possible.

As Sarepta navigates these challenges, the outcome of SRP-9003 could have significant implications not only for LGMD patients but also for the company's financial future and the broader field of gene therapy development.