FDA Approves Sarepta's Landmark DMD Gene Therapy Elevidys

The FDA has approved Sarepta Therapeutics’ delandistrogene moxeparvovec (SRP-9001) for treating ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) and a confirmed mutation in the DMD gene, excluding patients with any deletion in exon 8 and/or exon 9, to be marketed under the name Elevidys.¹

"It is gratifying and a relief to finally have an approved gene therapy for DMD. This drug is likely to be the most potent treatment method available today, although it is not as robust as many had hoped. Nonetheless, approval sets the stage for intensive analysis of the long-term effects of this gene therapy, and will hopefully spur increased research and testing of improved next generation gene therapies," Jeffrey Chamberlain, PhD, professor and director, Sen. Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine, told CGTLive.

“Duchenne is a relentlessly progressive, degenerative disease, robbing children of muscle function,” Jerry Mendell, MD, pediatric neurologist and principal investigator, Center for Gene Therapy, Nationwide Children’s Hospital, said in a statement.¹ “The increases in ELEVIDYS dystrophin expression and the functional results that we see can make a difference in the lives of our patients.”

The FDA previously pushed back the Prescription Drug User Fee Act action date for the therapy from May 29, 2023, to June 22, 2023, possibly partially because of recent discussions on microdystrophin, which may have also prompted the FDA to hold a recent FDA Cellular, Tissue, and Gene Therapies Advisory Committee meeting for the therapy after previously stating one would not be needed.^2,3 Although split, the committee eventually voted 8–6 (8 Yes; 6 No; 0 Abstain) in support of the therapy’s approval to the question of whether or not definitive clinical benefit could be observed with microdystrophin expression as a surrogate end point.

"Having been working for more than 30 years in my own lab on gene therapy for DMD, including the initial design of Sarepta’s micro-dystrophin and the promoter that regulates its production, it is very exciting to finally see an approved product. However, the work is not finished and will continue until we have a full cure," Chamberlain said.

Delandistrogene moxeparvovec uses the AAVrh74 recombinant vector to express microdystrophin. Based on the BLA data, the FDA concluded that the increase in the microdystrophin surrogate endpoint is reasonably likely to predict clinical benefit in individuals 4 to 5 years of age with DMD who do not have significant pre-existing antibody titers against the vector or have other contraindications.⁴

“Today’s approval addresses an urgent unmet medical need and is an important advancement in the treatment of DMD, a devastating condition with limited treatment options, that leads to a progressive deterioration of an individual’s health over time,” Peter Marks, MD, PhD, director, Center for Biologics Evaluation and Research, FDA, said in an FDA statement.⁴ “The FDA remains committed to facilitating the development of innovative new therapies to reduce the impact of debilitating diseases and to improve outcomes and quality of life for those affected.”

READ MORE: Genetic Medicine in DMD: End Points, Assessment, and Approvals 

The BLA is supported by data from the global, randomized, double-blind, placebo-controlled phase 3 EMBARK clinical trial (NCT05096221). The FDA has noted that it may consider a non–age-restricted expansion of the therapy’s label if EMBARK ultimately meets its objectives. EMBARK is currently expected to be completed later in 2023, with data read out in Q4. 

“The approval of ELEVIDYS is a watershed moment for the treatment of Duchenne. ELEVIDYS is the first and only gene therapy approved for Duchenne, and this approval brings us closer to our goal of bringing forward a treatment that provides the potential to alter the trajectory of this degenerative disease,” Doug Ingram, president and chief executive officer, Sarepta, added.¹ “As we prepare to launch ELEVIDYS, we should acknowledge and celebrate the decades of dedication and work from the patient community, families, clinicians, and our Sarepta colleagues that resulted in today’s approval. Our confirmatory trial, EMBARK, should read out in the fourth quarter of this year. If EMBARK confirms the benefits seen in our prior trials, Sarepta will move rapidly to submit a BLA supplement to expand the approved label as broadly as good science permits.”

The most recent data reported on delandistrogene moxeparvovec were 4-year data from the phase 1/2 Study 101 (NCT03375164) presented at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California. These data showed a mean improvement in North Star Ambulatory Assessment (NSAA) total scores of 7.0 (SD, 2.9) from baseline to 4 years posttreatment in patients who had a mean age of 5.1 years at baseline in contrast to the decline typically expected in this age range for patients with DMD.⁵ Improvements were also observed from baseline to 4 years posttreatment in the patients’ mean scores for other functional tests including Mean Time to Rise, Mean 4-stair Climb, Mean 100 Meter Walk/Run (MWR), and Mean 10MWR. There were no serious adverse events (AEs) reported and no patients discontinued from the study.

“Today’s decision marks an important moment in gene therapy for patients living with Duchenne,” Pat Furlong, founding president and chief executive officer, Parent Project Muscular Dystrophy, added.¹ “It’s been the lifelong work of so many in the Duchenne community. Our work continues until all patients in our community have access to therapy."

REFERENCES

1.Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy. News release. Sarepta Therapeutics. June 22, 2023.
2. Sarepta Therapeutics Announces Update on Regulatory Review of SRP-9001. News release. Sarepta Therapeutics. May 24, 2023. Accessed May 24, 2023. https://www.businesswire.com/news/home/20230523006142/en/
3. 74th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. May 12, 2023. Accessed May 24, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-may-12-2023-meeting-announcement-05122023
4. FDA Approves First Gene Therapy for Treatment of Certain Patients with Duchenne Muscular Dystrophy. News release. FDA. June 22, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy
5. D’Ambrosio E. Phase 1/2a trial of delandistrogene moxeparvovec in patients with DMD: 4-year update. Presented at: American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. May 16-20, 2023; Los Angeles, CA. Oral abstract session.