FDA Grants 2 Approvals to Delandistrogene Moxeparvovec for DMD

This article has been updated.

The FDA has expanded its approval of delandistrogene moxeparvovec-rokl (Elevidys; Sarepta Therapeutics) to treat Duchenne muscular dystrophy (DMD) to now include patients 4 years and older. This expansion includes traditional approval for patients who are ambulatory and accelerated approval for patients who are nonambulatory.¹

The gene therapy is also the first gene therapy approved to treat DMD. It previously received an accelerated approval to treat children aged 4 to 5 years, which was granted in June of 2023 over objections from some.^2-4

With this approval, delandistrogene moxeparvovec is now approved to treat DMD in patients 4 years and older regardless of ambulatory status | Image Credit: argus - stock.adobe.com

The objections to that accelerated approval, filed under BLA 125781, encompassed issues of manufacturing quality, safety, and efficacy, but the approval was pushed through anyway by Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, who noted, “The data and information in BLA125781, including data from the submitted randomized clinical trial (Study 102), provide substantial evidence of effectiveness of Elevidys by demonstrating an effect on a surrogate end point—expression of Elevidys micro-dystrophin protein at week 12 following administration of Elevidys—that is reasonably likely to predict clinical benefit in this specific population for a serious disease with high unmet medical need.”⁵

To receive the traditional approval, Sarepta submitted its request to the FDA in December, which encompassed an efficacy supplement to BLA 125781 and a request for a priority review. Results from the EMBARK trial (NCT05096221), a phase 3 multinational, randomized, double-blind, placebo-controlled trial of patients with DMD aged 4 to 7 years, and ENDEAVOR (NCT04626674), a phase 1 open-label trial in patients 2 years and older, supported Sarepta’s request.^6,7 This request was accepted by the FDA in February.⁸

The global, randomized, double-blind, placebo-controlled, phase 3 ENVISION trial (NCT05881408) is Sarepta's confirmatory trial to fulfill the postmarketing requirement from the FDA. This trial is ongoing among nonambulatory patients and older ambulatory patients,⁹ with the press release noting that ongoing use of delandistrogene moxeparvovec in nonambulatory patients may be contingent on the trial's results.¹

“Today’s expansion of the Elevidys label represents the culmination of my 50-year pursuit of a treatment for Duchenne patients and, along with my colleague Dr. Louise Rodino-Klapac, a nearly 20-year effort to optimize and develop a gene therapy that could be safely and effectively delivered to muscle,” said Jerry Mendell, MD, co-inventor of Elevidys and senior advisor, Medical Affairs, Sarepta, in the press release announcing the approval. “The initial approval of Elevidys was a significant milestone, and the expanded indication means clinicians now have a treatment option for the great majority of boys and young men living with Duchenne. This expansion speaks to the success of the science, the evidence, and the improvements in the trajectory of the disease we have seen to date across studies.”

DMD is typically diagnosed between ages 4 and 5 years, although experts note that muscle degeneration begins at birth. Therefore, when developmental delays are noticed, clinicians should initiate creatine kinase level testing for the presence of neuromuscular disorders. The earlier the diagnosis, the sooner patients can access treatment options that include clinical trials and genetic counseling.¹⁰

Treatment with delandistrogene moxeparvovec-rokl encompasses a single-dose infusion. To be eligible for the gene therapy, patients must have a confirmed DMD gene mutation, nonelevated antibodies against anti–AAV-associated rhesus isolate serotype 74 (or AAVrh74), and vaccinations that are up to date and completed at least 4 weeks before the pretreatment oral corticosteroid regimen, which is meant to reduce the immune system’s response to delandistrogene moxeparvovec-rokl, and should continue for up to 60 days after infusion. Candidates cannot have deletion in exon 8 and/or exon 9 in the DMD gene.¹¹

The treatment aims to deliver a shortened and functional form of the dystrophin protein, the lack of which is caused by the mutated dystrophin gene and results in loss of shock absorbers at the muscle membrane. DMD is a fatal disease, and its current standard treatment is corticosteroids. Potential adverse reactions include infusion-related reactions, acute serious liver injury, immune-mediated myositis, and myocarditis.¹

Sarepta has previously priced delandistrogene moxeparvovec-rokl at $3.2 million, making it the second most expensive gene therapy approved by the FDA behind etranacogene dezaparvovec (Hemgenix; CSL Behring), priced at $3.5 million.¹²

Sarepta and Roche are collaborating to bring the treatment to a global patient population; Sarepta is tasked with regulatory approval, commercialization, and manufacturing in the US and Roche, the rest of the world.

This most recent approval was again made over objections claiming Sarepta's data "cast significant uncertainty regarding the benefits of the treatment."¹³

References

1. Sarepta Therapeutics announces expanded US FDA approval of Elevidys to Duchenne muscular dystrophy patients ages 4 and above. News release. Sarepta Therapeutics. June 20, 2024. Accessed June 20, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-expanded-us-fda-approval-elevidys

2. Mullard A. FDA approves first gene therapy for Duchenne muscular dystrophy, despite internal objection. Nat Rev Drug Discov. 2023;22:610-611. https://tinyurl.com/yspmapws

3. Caffrey M. FDA approves delandistrogene moxeparvovec, first gene therapy to treat Duchenne muscular dystrophy. The American Journal of Managed Care®. June 22, 2023. Accessed June 18, 2024. https://www.ajmc.com/view/fda-approves-delandistrogene-moxeparvovec-first-gene-therapy-to-treat-duchenne-muscular-dystrophy

4. FDA's drug review process: continued. FDA. Updated August 24, Accessed June 18, 2024. http://tinyurl.com/26vcafun

5. Center director decisional memo. FDA. Accessed June 18, 2024. https://www.fda.gov/media/169707/download

6. Sarepta Therapeutics submits efficacy supplement to expand the Elevidys label to include Duchenne muscular dystrophy patients without restriction to age or ambulatory status. News release. Sarepta Therapeutics. December 22, 2023. Accessed June 18, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-submits-efficacy-supplement-expand-elevidys

7. Shaw M. Sarepta Therapeutics seeks to expand delandistrogene moxeparvovec indications. AJMC®. January 5, 2024. Accessed June 19, 2024. https://www.ajmc.com/view/sarepta-therapeutic-seeks-to-expand-delandistrogene-moxeparvovec-indications

8. Sarepta Therapeutics announces U.S. FDA acceptance of an efficacy supplement to expand the ELEVIDYS indication. News release. Sarepta Therapeutics. February 16, 2024. Accessed June 19, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-us-fda-acceptance-efficacy

9. A gene transfer therapy study to evaluate the safety and efficacy of delandistrogene moxeparvovec (SRP-9001) in non-ambulatory and ambulatory participants With Duchenne muscular dystrophy (DMD) (ENVISION). ClinicalTrials.gov. Updated May 10, 2024. Accessed June 20, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05881408

10. Importance of early diagnosis. Duchenne.com. Accessed June 19, 2024. https://www.duchenne.com/hcp/identifying-dmd/importance-early-diagnosis

11. Elevidys. Prescribing information. Sarepta Therapeutics; 2024. Accessed June 19, 2024. https://www.elevidys.com/#:~:text=THE%20ONLY%20GENE%20THERAPY,mutation%20in%20the%20dystrophin%20gene

12. The Top 5 most expensive FDA-approved gene therapies. Lifesciences Intelligence. May 24, 2023. Accessed June 19, 2024. https://lifesciencesintelligence.com/features/the-top-5-most-expensive-fda-approved-gene-therapies

13. Mast J,l Herper M. Top FDA official Peter Marks overruled staff, review team to approve Sarepta gene therapy. Stat. June 20, 2024. Accessed June 21, 2024. https://tinyurl.com/ccpa77n7