Ahead of the May 29, 2023, action date, the FDA is now seeking to hold an advisory committee meeting on Sarepta’s investigational agent SRP-9001 (also known as delandistrogene moxeparvovec) for the treatment of Duchenne muscular dystrophy.
In advance of the upcoming regulatory action deadline for Sarepta Therapuetics’ investigational gene therapy for the treatment of Duchenne muscular dystrophy (DMD), delandistrogene moxeparvovec (also known as SRP-9001), the FDA has determined it will hold an advisory committee (AdComm) meeting.1 The current Prescription Drug User Fee Act action date for the treatment’s biologics license application (BLA) is set for May 29, 2023.
Doug Ingram, president and chief executive officer of Sarepta, noted in a statement issued by the company that represented a change in plans based on what was communicated at the midcycle meeting.1 On its full-year earnings call in February 2023,2 the company had expressed that the agency would not require such a meeting, and Ingram noted at the time that the FDA had “confirmed they saw no significant safety issues with the program to be able to identify any significant clinical issues or major deficiencies and then determined that they didn't need an AdComm. That's where we are right now.”
Ingram additionally noted the company’s disappointment in need to communicate a change in decision from its prior stance, but that Sarepta had been preparing for the possibility of an AdComm meeting when the BLA was filed in late 2022.3
“FDA leadership has noted publicly that FDA is interested in exploring the use of surrogate endpoints, biomarkers, and innovative approaches like accelerated approval to advance cell and gene therapies, particularly for rare, life-ending degenerative diseases,” Ingram said.1 “It is our understanding that as one of the first gene therapy BLAs founded on a surrogate endpoint, the advisory committee will primarily relate to the totality of evidence supporting the conclusion that the SRP 9001 dystrophin is reasonably likely to predict clinical benefit, the standard for accelerated approval.”
“We will be well prepared, and look forward to presenting the wealth of evidence supporting the transformative potential of SRP-9001. We would like to thank [the Center for Biologics Evaluation and Research] for moving expeditiously to schedule the advisory committee in advance of our May 29, 2023, regulatory action date, once the change in decision was made,” he said.1
The BLA is supported by positive data from the phase 1/2 Study SRP-9001-101 (NCT03375164), the phase 2 SRP-9001-102 study (NCT03769116), and the phase 1 ENDEAVOR study (SRP-9001-103; NCT04626674).4 After 1, 2, and 4 years of treatment with SRP-9001, findings suggest the agent was well-tolerated and yielded clinical improvements and biomarker expression. Sarepta also found evidence of clinical benefit by comparing an integrated analysis across the 3 studies to an external control. The biomarker findings were obtained by western blot and supported by immunofluorescence, while efficacy and clinical benefits were measured by the North Star Ambulatory Assessment (NSAA) and secondary timed tests.
SRP-9001 is also currently being evaluated in the double-blind, randomized, placebo-controlled EMBARK study (Study SRP-9001-301; NCT05096221), which was proposed as the post-marketing confirmatory study to support an accelerated approval. EMBARK is primarily assessing change in NSAA total score from baseline to week 52 compared with placebo, though secondary end points include microdystrophin expression, time to rise from floor, patient-reported outcomes, skills gained, incidence of adverse events, and changes in scores on 100- and 10-meter walk/run, Timed Stair Ascend 4 Steps, and Stride Velocity 95th Centile tests.
Data from the ENDEAVOR study showed with follow-up of up to 4 years post treatment, participants treated with the adeno-associated virus (AAV) therapy demonstrated an improvement of 4 points on the NSAA from pretherapy baselines in 20 participants at 52 weeks, as well as a 3.8-point (unadjusted means) and 3.2-point (least squared means) improvement compared with a propensity-weighted external control group (P <.0001).4
Long-term follow-up data from 4 patients from Study SRP-9001-101 showed a 7-point improvement above pretreatment baselines on the NSAA, a 9.9-point unadjusted means and a 9.4-point least squared means versus a propensity-weighted external control (P = .0125) at the 4-year mark post dosing. An additional integrated analysis of 52 patients across studies SRP-9001-101, SRP-9001-102, and ENDEAVOR also showed that at 1 year, patients treated with SRP-9001 at the target dose improved 3.1 points (unadjusted means) and 2.4 points (least squared means) on NSAA versus propensity-weighted external control (P <.0001).4