FDA Panel Votes in Favor of Gene Therapy SRP-9001 for Duchenne Muscular Dystrophy In Tight Decision


The FDA is set to make a final decision later this month and, if approved, SRP-9001 would be the first gene therapy specific to treat Duchenne muscular dystrophy.

The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee has voted that the current data on SRP-9001 (Sarepta Therapeutics), an AAV vector-based gene therapy in development for Duchenne muscular dystrophy (DMD), was sufficient enough to warrant potential approval. Submitted under the accelerated approval pathway, the therapy has a scheduled PDUFA date of May 29, 2023.1

Following the discussion topics, the panel was asked to vote on whether SRP-9001 was deserving of accelerated approval, while considering the benefits and risks of the treatment, and using micro-dystrophin expression at week 12 as a surrogate end point. The panel voted 8–6 (8 Yes; 6 No; 0 Abstain) in favor of the agent.

If approved, SRP-9001 would be indicated for the treatment of ambulatory patients with DMD with a confirmed mutation in the DMD gene, and contraindicated in patients with any deletion that fully includes exons 9-13 in the DMD gene. It would not be recommended in patients with elevated anti-AAVrh74 total binding antibody titers greater than 1:400. In its presentation, Sarepta proposed several risk mitigations to potential safety concerns raised, including pre- and post-infusion monitoring of liver enzymes, weekly troponin monitoring during first month following treatment, weekly platelet monitoring during first 2 weeks, and long-term follow-up to better characterize safety concerns.

The committee answered on 4 discussion topics, the first of which asked whether SRP-9001’s impact on microdystrophin, considered a surrogate biomarker, would be reasonably likely to predict clinical benefit. In the second discussion topic, those on the committee commented on the clinical significance of SRP-9001’s impact on certain exploratory subgroups, specifically patients between 4 and 5 years old in Study 102 (NCT03769116), the only randomized, double-blind, placebo-controlled study used to support the therapy. In the final topic, members of the committee discussed the potential benefits, risks, and uncertainties that may be associated with the administration of SRP-9001 in ambulatory patients with DMD with a confirmed mutation in the DMD gene.

Throughout the hearing, the agency brought up several concerns, including the challenges faced to distinguish an effect of SRP-9001 vs standard of care, a lack of clear indication on which patients may benefit from the drug, and no clear association of microdystrophin—a shorted but functional version of the dystrophin protein, whose lack causes DMD—and change in North Star Ambulatory Assessment (NSAA) score—which served the primary end point used in all the supportive studies. Additionally, concerns were raced about the manufacturing and nonclinical studies of the gene therapy. Specifically, they felt results of nonclinical studies were inconsistent, and found limitations in extrapolation from animal models to humans.

As gene therapies are new to neurology, the FDA also brought up safety concerns, and the potential cross–reactivity to future gene therapies. Questions surrounding SRP-9001’s efficacy and safety may be answered in the ongoing phase 3 EMBARK study (NCT05096221), which is set to complete in late 2023 and have data read out in early 2024. This randomized, double-blind, placebo-controlled trial includes 120 individuals with DMD between the ages of 4 to 7 years. Part 1 of the study would serve as a confirmatory study of SRP-9001 receives accelerated approval.

SRP-9001, otherwise known as delandistrogene moxeparvovec, is designed to deliver a copy of a gene encoding microdystrophin to muscle cells using a lab-engineered, harmless virus as a vector. It is prepared as a suspension of concentration of 1.33 x 1013 vg/mL, and is supplied in a single-use, 10 mL vial for a single-dose, intravenous infusion. The biologics license application (BLA) for the agent was submitted using the accelerated approval pathway in September 2022, and accepted months later.

The BLA was supported by positive data from the phase 1/2 Study SRP-9001-101 (NCT03375164), the phase 2 SRP-9001-102 study, and the phase 1 ENDEAVOR study (SRP-9001-103; NCT04626674). To date, SRP-9001 has demonstrated safety and efficacy in over 80 treated patients so far, with follow-up of up to 4 years post-treatment.

In the 20-patient cohort 1 of ENDEAVOR, announced in July 2022, findings showed that SRP-9001-treated patients improved 4 points from their pre-therapy baselines on the NSAA compared with a propensity-weighted external control group (P <.0001) over a 4-year period. These patients demonstrated a 3.8-point (unadjusted means) and 3.2-point (least squared means) improvement that diverged from the natural history of DMD over time.2

Announced at the same time, longer follow-up data from 4 patients in Study 101 demonstrated a 7-point improvement above pretreatment baselines on the NSAA, a 9.9-point unadjusted means and a 9.4-point least squared means vs a propensity weighted external control (P = .0125) at 4 years. An integrated analysis of 52 patients across all 3 studies also showed that at 1 year, patients treated with the gene therapy at the target dose improved 3.1 points (unadjusted means) and 2.4 points (least squared means) on NSAA versus propensity-weighted external controls (P <.0001).

The safety and tolerability profile of SRP-9001 was comparable across all studies, with vomiting as the most common treatment-related adverse event (AE). Sarepta provided an overview of the AEs observed, which compiled 183 patient-years of exposure, and a mean follow-up time of 2.2 years. In total, 1,230 treatment-emergent AEs were recorded; however, 98.5% of them were mild to moderate in severity. Furthermore, 95% of treatment-emergent AEs occurred within the first 90 days of SRP-9001 infusion.

Acute liver injury (ALI) was found in 36.5% (n = 31) of all patients across the studies, although there was no acute liver failure and no elevation in international normalized ratio. All patients in the studies recovered to baseline spontaneously or with corticosteroid treatment. Risk mitigation for ALI is planned pre- and post-infusion for patients on SRP-9001.1

In Study 9001-103, there was 1 new serious AE of myocarditis in Cohort 2, which included older ambulatory patients aged 8 years and older. The patient demonstrated no signs or symptoms or systolic dysfunction and received IV methyl-prednisolone and additional chronic cardiac medications added post-event. A cardiac MRI taken 1 month showed normal function and partial resolution of myocarditic changes, and ECHO at 4 months showed normal systolic function.

At the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, a Delphi panel reviewed data from the 3 clinical trials and established a set of consensus considerations for the management of AEs related to the use of SRP-9001. The considerations were for a set of occurring AEs: vomiting, myocarditis, acute liver injury, and immune-mediated myositis. For vomiting, which was the most commonly occurring AE (reported in 61.2% of patients), the Delphi panel offered those patients and caregivers should provide immediate follow-up if posttreatment vomiting occurs, while physicians should offer antiemetics as needed, with a recommended switch to intravenous (IV) steroids if oral administration is not able to be tolerated or retained.3

Acute liver injury occurred in 36.5% of those in the utilized data, with most cases occurring within 4 to 8 weeks post infusion. The observed cases generally resolved within 2 months of onset. The Delphi panel offered considerations for patients and caregivers to provide immediate follow-up upon onset of symptoms such as jaundice or abdominal pain, and that close monitoring of liver function should be initiated, to be increased as clinically indicated.

For immune-mediated myositis, which also occurred in 1 patient (1.2%), the panel recommended patient-caregiver follow-up when experiencing severe muscle weakness, hypophonia, dysphasia, and/or dyspnea. Physical and laboratory monitoring of these symptoms should also be considered. Treatment for this AE may include targeted immunosuppressant therapy, steroid optimization, and other interventions when deemed clinically appropriate. In instances of immune-mediated myositis, a consultation with an immunologist was also recommended by the group.

1. FDA Peripheral and Central Nervous System Drugs Advisory Committee Meeting. May 12, 2023. Accessed May 12, 2023.
2. Sarepta Therapeutics’ investigational gene therapy SRP-9001 for Duchenne muscular dystrophy demonstrates significant functional improvements across multiple studies. News release. Sarepta Therapeutics, Inc. July 6, 2022. Accessed May 12, 2023 https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-investigational-gene-therapy-srp-9001
3. Goedecker N. Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy in Patients with DMD: Delphi Consensus Guidance. Presented at: MDA Clinical & Scientific Conference; March 19-22, 2023; Dallas, TX. Late-breaking session.
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