FDA grants accelerated approval for SRP-9001 as the first ever gene therapy for Duchenne muscular dystrophy

On 22^nd June, 2023, the U.S Food and Drug Administration (FDA) granted accelerated approval to Sarepta Therapeutics’ SRP-9001 (ELEVIDYS, delandistrogene moxeparvovec-rokl) for the treatment of ambulatory pediatric patients aged 4 to 5 years with Duchenne muscular dystrophy (DMD), with a confirmed mutation in the DMD gene. It is the first disease-modifying gene therapy for DMD to be authorized for commercial use.¹

DMD is an X-linked, progressive, neuromuscular disease caused by mutations in the DMD gene that disrupts the production of functional dystrophin, an essential protein in muscles.^2,3,4 Deficiency of dystrophin leads to the disruption of the dystrophin-associated protein complex (DAPC), which is required to stabilize muscle cell membranes during muscle contraction and prevent damage to muscle fibers.^3,4 Without functional dystrophin and DAPC, muscle fibers are prone to injury and develop fibrosis, causing progressive muscle degeneration and loss of function.^3,4 Most patients become wheelchair dependent and require respiratory support; eventually, death can occur from cardiac or respiratory failure.^3,4

Management of DMD remains challenging due to limited treatment options and no available cure.^2,3,4 Symptoms can only be managed through a multidisciplinary medical and rehabilitative approach to improve quality of life and longevity.⁴ Assisted ventilation and mobility assistance are commonly provided to patients as their disease progresses.⁴ Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers can be given to manage the cardiac manifestations of DMD.⁴ The use of glucocorticosteroids is recommended when motor development begins to decline, which requires continuous treatment.^3,4 Orthopedic interventions involving physiotherapy focus on preserving weakened muscle function and to prevent the development of limb muscle contractures and scoliosis.⁴ Given the causative nature of mutations in DMD, the promise of gene therapy as a disease modifying approach has been under significant investigation in recent years.

SRP-9001 (ELEVIDYS, delandistrogene moxeparvovec-rokl) is an adeno-associated virus (AAV)-based gene therapy.^1,2 It uses an AAV serotype rh74 (AAVrh74) vector to deliver a gene that encodes for a shortened form of dystrophin called micro-dystrophin, under the control of a muscle-specific promotor, MHCK7, to enhance specificity and expression in the heart and skeletal muscles.^2,3 This gene therapy aims to address the underlying cause of DMD by enabling the production of shortened functional dystrophin protein and, thus, maintaining muscle function and delaying progression.³

The approval of SRP-9001 was based on efficacy and safety data from three Phase I and II studies: SRP-9001-101 (NCT03375164), SRP-9001-102 (NCT03769116), and SRP-9001-103 (ENDEAVOR; NCT04626674).1 Study 101 was a completed Phase I/II trial that enrolled 4 male participants aged 4 to 7 years that were treated with a single infusion of SRP-9001.⁵ The North Star Ambulatory Assessment (NSSA) was used as a standard measurement of motor function. Long-term results showed a positive mean +7.0-point difference above their pre-treatment NSAA baseline scores.⁵ Total NSAA scores for patients treated with SRP-9001 were 9.9 points (unadjusted means) and 9.4 points (least square means) greater compared to a propensity-weighted external control group (p=0.0125).⁵

Study 102 is a Phase II trial that enrolled 41 male patients with DMD.^5,6 The first part of the study evaluated the safety and expression of micro-dystrophin.  The study achieved its primary biological endpoint of increases in micro-dystrophin expression after 12 weeks.⁶ Treatment-emergent adverse events (TEAEs) were transient and manageable, with 82% of patients experiencing mild or moderate TEAEs.⁶ Although patients treated with SRP-9001 did not show a statistically significant increase in total NSAA score (p=0.37) compared to placebo, they outperformed the placebo group at every time point measured and showed a statistically significant improvement in scores from baseline to 48 weeks (p=0.009).⁶ There was also a statistically significant improvement in NSSA scores at 48 weeks within a subgroup analysis of patients aged 4 to 5 years, compared to the placebo group (+4.3 points versus +1.9 points, respectively; p=0.0172).⁶ Part 2 of the study was a cross-over phase, where patients originally assigned to placebo received an SRP-9001 infusion. After 48 weeks, SRP-9001-treated patients scored a mean 2 points higher on the NSAA than the external controls, a statistically significant difference (p=0.0009).⁷ Follow-up is ongoing.

Study 103 (ENDEAVOR) is a Phase Ib trial that assessed the safety and expression of commercially representative SRP-9001 in four cohorts of male patients with DMD.⁵ The 1-year safety findings were consistent with previous clinical studies with similar reported TEAEs.⁵ Gene expression data, measured by western blot at 12 weeks, demonstrated successful delivery of SRP-9001 to target cells and an increase in micro-dystrophin levels from baseline.⁵ Functional results showed improvements in motor function compared to an external control group, assessed by NSAA and timed function tests (TFTs).⁵

“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, JD, President and Chief Executive Officer of Sarepta Therapeutics, Cambridge, MA¹

SRP-9001 is the first and only approved disease-modifying gene therapy for DMD to be authorized for commercial use. The therapy is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.¹ Its approval will be verified based on the findings of the post-marketing confirmatory Phase III trial, EMBARK (NCT05096221).¹ If the findings are positive, the FDA will consider a non-age restricted label expansion of SRP-9001.⁸ Another ongoing Phase III trial, ENVISION (NCT05881408), intends to support its globally regulatory approval in non-ambulatory and older ambulatory (aged 8-18 years) patients with DMD.⁹ Early cost-effectiveness analysis for SRP-9001 revealed it has the potential to be a transformative treatment that prolongs survival for patients with DMD with a substantial increase in overall QALYs (quality-adjusted life years) compared to the current standard of care.³ Other pharmaceutical companies are developing similar gene therapies for DMD and are looking for ways to improve AAV vectors and dosages.² The approval of SRP-9001 represents a significant milestone advancement in the treatment landscape for DMD.

Written by Lemuel Fulgencio

Reviewed by Juliet Lawrence

References:

1. Sarepta Therapeutics. Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy. [Press Release]. 22 Jun 2023. Accessed 28^th June 2023.
2. Deng J, Zhang J, Shi K, et al. Drug development progress in duchenne muscular dystrophy. Front Pharmacol. Jul 2022; 13:950651.
3. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. May 2023; 11(1):2216518.
4. Duan D, Goemans N, Takeda S, et al. Duchenne muscular dystrophy. Nat Rev Dis Primers. Feb 2021; 7:13.
5. Sarepta Therapeutics. Sarepta Therapeutics’ Investigational Gene Therapy SRP-9001 for Duchenne Muscular Dystrophy Demonstrates Significant Functional Improvements Across Multiple Studies. [Press Release]. 06 Jul 2023. Accessed 28^th June 2023.
6. Sarepta Therapeutics. Sarepta Therapeutics Announces Top-line Results for Part 1 of Study 102 Evaluating SRP-9001, its Investigational Gene Therapy for the Treatment of Duchenne Muscular Dystrophy. [Press Release]. 07 Jan 2021. Accessed 28^th June 2023.
7. Sarepta Therapeutics. Sarepta Therapeutics’ Gene Therapy SRP-9001 Shows Statistically Significant Functional Improvements Compared to Pre-specified Matched External Control in Part 2 of Study SRP-9001-102 for the Treatment of Duchenne Muscular Dystrophy. [Press Release]. 01 Oct 2022. Accessed 28^th June 2023.
8. Sarepta Therapeutics. Sarepta Therapeutics Announces Update on Regulatory Review of SRP-9001. [Press Release]. 24 May 2023. Accessed 28^th June 2023.
9. Sarepta Therapeutics. SRP-9001-303: ENVISION study enrollment in U.S. [Press Release]. 08 Jun 2023. Accessed 28^th June 2023.