FDA Grants Traditional Approval to Elevidys Gene Therapy for Ambulatory DMD, Accelerated Approval for Nonambulatory Patients
The AAV vector-based gene therapy originally received FDA approval for treating ambulatory pediatric patients aged 4 to 5 years with Duchenne under the accelerated approval pathway.
Debra Miller
Months after the FDA accepted and filed Sarepta Therapeutics’ efficacy supplement to the biologics license application for SRP-9001 (Elevidys), otherwise known as delandistrogene moxeparvovec-rokl, the agency has granted it traditional approval for ambulatory patients with Duchenne muscular dystrophy (DMD). With traditional approval, SRP-9001's indication has been expanded to include patients aged 4 years and older with DMD who have a confirmed mutation in the DMD gene.1
The company announced that this agency decision also includes an accelerated approval for nonambulatory patients, continued approval for which may be contingent upon verification of clinical benefit in a confirmatory trial. The gene therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9.
“We are delighted that the FDA has expanded the label for Elevidys, Sarepta’s gene therapy for DMD to include ambulatory and non-ambulatory Duchenne patients who are older than 4 years of age," Debra Miller, founder and CEO of CureDuchenne, told NeurologyLive®. "Families facing Duchenne have an urgent need for treatments that will delay the progression of the disease and this represents a significant treatment option for many boys and young men with Duchenne. We are grateful to Sarepta Therapeutics, the FDA, and of course the many families who have participated in clinical trials to advance this critical research.
"Duchenne is a complex disease and we recognize that our work is not done to ensure everyone with Duchenne has transformative treatment. For this reason, we must continue to support and invest in a diverse array of promising research to bring solutions to everyone living with Duchenne," Miller said.
Originally known as SRP-9001, the AAV vector-based gene therapy received FDA approval under the accelerated approval pathway in June 2023. The decision came months after the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted that the data on the agent at the time was sufficient enough to warrant approval. The committee answered 4 discussion topics, the first of which asked whether the agent’s impact on microdystrophin, considered a surrogate biomarker, would be reasonably likely to predict clinical benefit.
In the hearing, panelists weighed in on data from the biologics license application of SRP-9001, which was comprised of the 3 clinical trials. These trials included the phase 1/2 SRP-9001-101 (NCT03375164) study, the phase 2 SRP-9001-102 study, and the phase 1 ENDEAVOR study (SRP-9001-103; NCT04626674). Overall, the treatment was approved based on changes in a surrogate end point—the expression of microdystrophin—from several different trials.2
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 North Star Ambulatory Assessment (NSAA) compared with a propensity-weighted external control group (P <.0001) over a 1-year period. These patients demonstrated a 3.8-point (unadjusted mean) and 3.2-point (least-squares mean) improvement that diverged from the natural history of DMD over time.2
Jerry Mendell, MD
“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, [PhD] a nearly 20-year effort to optimize and develop a gene therapy that could be safely and effectively delivered to muscle,” Jerry Mendell, MD, coinventor of the treatment and a senior advisor of Medical Affairs with Sarepta, said in a statement. “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.”
Presented at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, results from part 1 of the phase 3 EMBARK study (NCT05096221) assessing SRP-9001 showed that the agent failed to meet its primary end point in change among patients with DMD; however, did demonstrate several benefits on other secondary analyses.3 Treatment with the agent resulted in a nominal difference in change on NSAA total score vs placebo over 52 weeks (SRP-9001 change: 2.6; n = 63; placebo: 1.9; n = 61). Using a cohort of ambulatory patients aged between 4 and 8 years with a confirmed DMD mutation within exons 18-79, there were no identified new safety signals, reinforcing the favorable safety profile observed to date.
Led by Mendell, who is also an advisor to the Center for Gene Therapy in the Abigail Wexner Research Institute at Nationwide Children’s and emeritus professor of pediatrics at The Ohio State University, the trial included individuals who had NSAA scores between 16 and 29 at screening, had recombinant adeno-associated virus serotype rh74 (AAVrh74) antibody titer less than 1:400, and were on a stable daily dose of oral corticosteroids for at least 12 weeks prior to the trial beginning. The study includes 2 parts, both of which are 52 weeks in length. In part 1, patients were randomly assigned 1:1 to either SRP-9001 or placebo, according to age at randomization and baseline NSAA. For the SRP-9001 group, a single, intravenous 1.33x1014 vg/kg linear standard dose was used.
At week 52, key secondary end points, which included time to rise, micro-dystrophin expression, and 10-meter walk/run demonstrated treatment benefit in both age groups (4-5 and 6-7 years; P <.005). In addition, stride velocity 95th centile and time to ascend 4-steps showed benefit that was similar in magnitude and significant in the overall population (P <.005). "Based on the totality of functional assessments including the timed function tests, treatment with delandistrogene moxeparvovec indicates beneficial modification of disease trajectory," the study authors concluded.3
Doug Ingram, president and chief executive officer of Sarepta, said in a statement that this expansion “represent[s] many years of dedicated research, development, investment and creative energy" and that it "is a defining moment for the Duchenne community. Today also stands as a watershed occasion for the promise of gene therapy and a win for science."
“At this pivotal moment, I want to give warm thanks to Drs. Jerry Mendell and Louise Rodino-Klapac for their dogged, 20-year pursuit of a gene therapy to treat this ruthless and life-robbing disease, to the FDA for following the scientific evidence to speed delivery of a therapy for a life-threatening rare disease to waiting patients, and to the many clinical investigators and courageous Duchenne families who have participated in the multiple studies that led to this important day," Ingram said.
In October 2023, the company announced topline data from EMBARK which showed that patients with DMD aged 4 to 7 years old improved 2.6 points on the NSAA total score, the primary end point, 52 weeks after treatment started. In comparison, those on placebo improved 1.9 points, a difference of 0.65 points that was not statistically significant between groups (P = .24). In addition, treatment with the therapy resulted in robust changes on all key pre-specified functional secondary end points over the treatment period.4
Across secondary end points, investigators recorded a least square mean (LSM) difference of –0.64 (P = .0025) in change on time to rise (TTR) for SRP-9001-treated patients vs placebo. The effects of the agent were more pronounced among 6- and 7-year-old treated patients (LSM change vs placebo, –0.78; P = .0291) than among patients aged 4-5 (LSM change vs placebo, –.50; P = .0177). Similarly, the agent resulted in clinically meaningful treatment effects on 10-meter walk test (LSM change vs placebo, –0.42; P = .0048), with higher impacts observed among those aged 6-7 years old (LSM change vs placebo, –0.52; P = .0363) than those aged 4-5 years old (LSM change vs placebo, –0.33; P = .0319).
