FDA reviewers said in a published briefing document that clinical studies to date “provided no clear evidence” for SRP-9001 (delandistrogene moxeparvovec), an outpatient-targeted Research Gene Therapy Advisory Committee Meeting for Patients with Duchenne Muscular Dystrophy.
The agency also raised safety concerns about the possibility of ineffective gene therapy.
Duchenne muscular dystrophy is characterized by mutations that cause a lack of dystrophin protein and muscle loss. It affects about 1 in 3,300 boys, and there is no known cure.
SRP-9001 is designed to deliver a gene that encodes a shortened form of dystrophin called microdystrophin to help protect muscles. To qualify for accelerated approval, Sarepta Therapeutics is proposing expression of microdystrophin, a novel engineered protein, as a surrogate endpoint.
On Friday, the FDA’s Cell, Tissue, and Gene Therapy Advisory Committee will meet to discuss whether microdystrophin levels 12 weeks after SRP-9001 treatment can serve as a reasonable predictor of clinical benefit from gene therapy Alternative endpoint.
Corticosteroids are Duchenne’s main medical treatment. In addition, four exon-skipping drugs—including three from Sarepta—have received accelerated FDA approval for patients with specific DMD mutations; their Clinical benefit has not been proven.
SRP-9001 Therapy Aims to Change Disease Trajectory of Duchenne Muscular Dystrophy to Milder Becker Muscular Dystrophy (BMD)-Like Phenotype, FDA the clerk said. But the agency notes that there is currently no epidemiological or pathophysiological evidence for microdystrophin function.
and internally truncated dystrophin expressed by exon-skipping drugs,” wrote the agency’s reviewers. In SRP-9001-transduced cells, instead of Gain insight into the pharmacological effects of biomarkers in disease pathways,” they added.
The brief report evaluated nonclinical data and three clinical studies, including one randomized, placebo-controlled trial. The study failed to demonstrate statistical significance for SRP-9001 treatment, but an exploratory subgroup analysis suggested a possible benefit in outpatients aged 4 to 5 years.
Still, the FDA reviewers said it was difficult “to conclude with reasonable certainty from the data presented by the applicant that SRP-9001 is likely to be effective in younger patients or likely to be effective in older patients or poor functional status.”
In addition, the agency noted that accelerated approval of ineffective gene therapies poses unique risks. Due to immune responses associated with adeno-associated virus (AAV) vector-based therapy, patients receiving SRP-9001 will not be able to receive a second dose if needed, or follow-up with another AAV vector-based gene therapy in the future.
FDA filings reveal a long history of regulatory interactions regarding SRP-9001, with the agency saying as early as 2018 that it did not believe microdystrophin was a good endpoint for accelerated approval. The report also The SRP-9001 trial was put on clinical hold in 2021 after a debilitating adverse event in a 9-year-old patient who required hospitalization and respiratory support, the report showed.
SRP-9001 is currently being studied in the randomized, double-blind, placebo-controlled EMBARK trial of 125 Duchenne patients aged 4 to 7 years. Sarepta is proposing EMBARK as a postmarketing validation trial for SRP-9001. Other companies are also developing AAV gene therapies for Duchenne.
On Friday, an FDA advisory committee will discuss the clinical implications of Sarepta’s findings to date, as well as potential risks, benefits and uncertainties surrounding accelerated approval of SRP-9001.
FDA plans to decide by May 29 whether to approve SRP-9001. The agency is not required to follow the advice of its advisory committee, but usually does.
Judy George covers neurology and neuroscience news for MedPage Today, writing on brain aging, Alzheimer’s Articles on Haimer’s, Dementia, Multiple Sclerosis, Rare Diseases, Epilepsy, Autism, Headaches, Stroke, Parkinson’s, ALS, Concussions, CTE, Sleep, Pain, and more. Follow