Sarepta files Duchenne muscular dystrophy gene therapy with FDA


Sarepta Therapeutics has followed through on its promise to file for accelerated approval  of its gene therapy SRP-9001 for Duchenne muscular dystrophy (DMD), as it aims for a launch in the middle of 2023.

Roche-partnered SRP-9001 (delandistrogene moxeparvovec) has been submitted for approval to treat ambulatory (walking) patients with DMD, a genetic disorder characterised by progressive muscle degeneration due to alterations in a protein called dystrophin that helps keep muscle cells intact.

The one-dose gene therapy – much like rivals from Pfizer and Solid Biosciences – codes for a shortened form of dystrophin that is deficient in patients with the X-linked muscle-wasting disease, which occurs primarily in males. It is administered as a single intravenous dose and uses an adeno-associated virus (AAV) vector to deliver the gene into muscle cells.

Sarepta is seeking accelerated approval for SRP-9001 based on three early-stage studies – studies 101, 102, and 103 (ENDEAVOR) – while it waits for confirmatory results from the phase 3 EMBARK study, which aims to enrol 120 boys with DMD aged four to seven and is due to read out in the latter half of 2023.

The company says its filing is based on "positive preclinical, biomarker, and clinical functional results" at various timepoints, including one, two, and four years after treatment, in addition to a consistent safety profile.

It is going for early approval based on the totality of the clinical data. Last year, the filing looked like a long shot when study 102 – a phase 2 trial – showed no difference between SRP-9001 and placebo on its main endpoint, the North Star Ambulatory Assessment (NSAA) score, at 48 weeks.

The outlook for the programme firmed up earlier this year, however, when updated results from study 102 from patients who crossed over from placebo to SRP-9001 showed an improved performance – a 1.3-point NSAA improvement versus a 0.7-point decline – that was statistically significant.

Then, the open-label ENDEAVOR study showed an improvement on the NSAA scale at one year compared to a matched control group, accompanied by improvements in clinical measures of physical ability, although a serious case of myocarditis in once of the subjects raised a red flag.

Sarepta's chief executive Doug Ingram has been increasingly positive on the prospects for the therapy, and said today that the FDA filing "is a significant milestone in our quest to intervene with urgency on behalf of the children we serve."

The primary endpoint for EMBARK is the assessment of the change in NSAA score from baseline to week 52 compared to placebo, and if the trial is positive it could provide a quick route to converting an accelerated clearance – if forthcoming – to a full approval.

Sarepta already markets three exon-skipping drugs for DMD that have to be taken chronically, but SRP-9001 offers the possibility of a one-shot therapy for the disease. Roche has exclusive rights to the therapy outside the US.

The ambulatory population of DMD patients represents around 50% of all patients, and Sarepta has been planning a study in non-ambulatory patients – called ENVISION – that is due to start this year.

It's the second piece of encouraging DMD news for Sarepta this month, coming after the FDA lifted a clinical hold on SRP-5051 (vesleteplirsen), its new exon-skipping therapy for the disease.

Photo by Markus Spiske on Unsplash