Elevidys is the first gene therapy approved for the treatment of certain patients with Duchenne muscular dystrophy (DMD) 

The U.S. Food and Drug Administration (FDA) has approved Sarepta’s Elevidys (delandistrogene moxeparvovec) for the treatment of ambulant pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.¹ DMD occurs in approximately one in every 3,500 to 5,000 newborn males worldwide or about 400 to 600 boys per year in the U.S.

Drug name:           Elevidys (delandistrogene moxeparvovec)
Manufacturer:       Sarepta
Condition:             Duchenne muscular dystrophy (DMD)

Condition overview:^1-4

DMD is a rare, fatal, X-linked neuromuscular disease caused by mutations in the dystrophin gene. Dystrophin plays an essential role in the organization and coordination of structural proteins that execute the functions of skeletal muscle. Loss of expression of the dystrophin protein results in inflammation, replacement of muscle with fibrotic fat tissue, and muscle degeneration leading to loss of ambulation, decreased respiratory function and heart failure. As a result of this genetic defect, individuals with DMD may have symptoms such as trouble walking and running, falling frequently, fatigue, learning disabilities/difficulties, heart issues as a result of impact on heart muscle functioning, and breathing problems due to weakening of respiratory muscles involved in lung function.

Symptoms of muscle weakness associated with DMD typically begin in childhood, often between 3 to 6 years of age.  As the disease progresses, life-threatening heart and respiratory problems can occur. Although disease severity and life expectancy vary, patients often succumb to the disease in their 20s or 30s because of heart and/or respiratory failure.

Current treatment options:^3,4

Most current treatment approaches address the symptoms of the disease, but not its underlying genetic cause.‘

Supportive care and medications including corticosteroids and exon-skipping therapies are used to treat DMD. The mainstay of drug therapy in DMD is corticosteroids, including prednisone. Corticosteroids have been shown to slow disease progression and extend life expectancy.

In DMD, an exon or exons have mutations which result in non-functional dystrophin protein.  Exon-skipping therapies use small pieces of DNA  called antisense oligonucleotides to help cells skip over a specific exon during dystrophin production.  Skipping mutated exons results in restoration of small amounts of dystrophin that may slow progression of the disease; however, this has not yet been established.

Exon-skipping therapies, are FDA approved for the treatment of DMD through the accelerated approval pathway. Continued approval may be contingent upon verification of a clinical benefit in confirmatory trials.

FDA-Approved Drugs for DMD^3,4,7

Drug	Manufacturer	Drug class	ROA	Indication
Emflaza® (deflazacort)	PTC Therapeutics	Corticosteroid	Oral	People with DMD aged 2 years and older
Amondys 45 (casimersen)	Sarepta Therapeutics	Antisense oligonucleotide	IV	People with DMD with mutations amenable to exon 45 skipping
Exondys 51  (eteplirsen)	Sarepta Therapeutics	Antisense oligonucleotide	IV	People with DMD with mutations amenable to exon 51 skipping
Vyondys 53 (golodirsen)	Sarepta Therapeutics	Antisense oligonucleotide	IV	People with DMD with mutations amenable to exon 53 skipping
Viltepso (viltolarsen)	Nippon Shinyaku	Antisense oligonucleotide	IV	People with DMD with mutations

ROA=route of administration; IV=intravenous

Elevidys overview ^1,5,8-14

Individuals with DMD fail to make functional dystrophin, leading to a progressive loss of muscle strength. Elevidys is a one-time gene therapy. The gene therapy uses an adeno-associated virus (AAV) that delivers an Elevidys dystrophin-encoding gene to muscle tissue to produce Elevidys micro-dystrophin.

Mechanism of action:¹ Elevidys is designed to deliver a gene coding for Elevidys micro-dystrophin which works similar to dystrophin but is smaller in size. It also delivers a muscle-specific promoter, a DNA element that controls the activity of the MHCK7 gene to enhance the gene’s activity in cardiac and skeletal muscles.

Prime’s forecast assumes Elevidys will be a one-time infusion with a wholesale acquisition cost (WAC) of $3.2 million per treated member.

The Biologics License Application (BLA) was supported from three studies with more than 80 patients treated with Elevidys. In these trials, Elevidys increased micro-dystrophin expression in skeletal muscle which is considered a surrogate endpoint. Continued approval may be contingent upon verification of clinical benefit in a confirmatory trial. The confirmatory trial, EMBARK, is expected to read out in the fourth quarter of 2023.

On May 16, 2023, the FDA Cellular, Tissue and Gene Therapies Advisory Committee voted 8 to 6 in support of accelerated approval of Elevidys for the treatment of ambulatory patients with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.

DMD Gene Therapy Pipeline¹⁵

Multiple manufacturers are working on gene therapies for the treatment of DMD including fordadistrogene movaparvovec (Pfizer). This product in development utilizes a recombinant adeno-associated viral vector serotype 9 (AAV9) administered as a one-time intravenous infusion to deliver a functional minidystrophin gene in people with DMD. Pfizer may file for approval of this gene therapy product in late 2023.

Date approved:   June 22, 2023
Benefit/ROA:       Medical benefit/Intravenous infusion

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References

1. Sarepta Therapeutics. Sarepta Therapeutics announces that U.S. FDA has accepted for filing and granted Priority Review for the Biologics License Application for SRP-9001, Sarepta’s gene therapy for the treatment of ambulant individuals with Duchenne muscular dystrophy.  Accessed in February 2023 at: Sarepta Therapeutics Announces That U.S. FDA has Accepted for Filing and Granted Priority Review for the Biologics License Application for SRP-9001, Sarepta’s Gene Therapy for the Treatment of Ambulant Individuals with Duchenne Muscular Dystrophy | Sarepta Therapeutics, Inc.
2. net Duchenne muscular dystrophy. Accessed in February 2023 at: Orphanet: Duchenne muscular dystrophy
3. org Deflazacort, eteplirsen and golodirsen for Duchenne muscular dystrophy: effectiveness and value. Evidence Report. July 11, 2019.  Accessed in February 2023 at: ICER_DMD_Evidence-Report_071619.pdf
4. Search terms included: DMD.  Accessed February 2023.
5. IPD analytics.com Search terms included: antisense oligonucleotide and corticosteroids.  Accessed in February 2023.
6. com Sarepta Therapeutics’ investigational gene therapy SRP-9001 for Duchenne muscular dystrophy demonstrates significant functional improvements across multiple studies. Accessed in February 2023 at: https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-investigational-gene-therapy-srp-9001
7. com Sarepta Therapeutics. Accessed in February 2023 at: PowerPoint Presentation (sarepta.com)
8. com Accessed in March 2023 at: Sarepta Therapeutics’ Investigational Gene Therapy SRP-9001 for Duchenne Muscular Dystrophy Demonstrates Significant Functional Improvements Across Multiple Studies | Sarepta Therapeutics, Inc.
9. com Accessed in March 2023: 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 | Sarepta Therapeutics, Inc.
10. com Accessed in March 2023: Sarepta Therapeutics gene therapy SRP-9001 shows statistically significant functional improvements compared to pre-specified matched external control in Part 2 study SRP-9001-102 for the treatment of Duchenne muscular dystrophy.
11. SRP-9001: New clinical data and integrated analysis. Accessed in March 2023 at:https://investorrelations.sarepta.com/static-files/b58a68ba-d97a-4505-9929-a097a12006e8
12. com Accessed in March 2023 at: Sarepta Therapeutics Announces Advisory Committee Meeting will be Held for SRP-9001 | Sarepta Therapeutics, Inc.
13. Search terms: DMD and gene therapy.  Accessed in March 2023.
14. FDA Approves First Gene Therapy for Treatment of Certain Patients with Duchenne Muscular Dystrophy, June 22, 2023. FDA.gov. Accessed at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy
15. Prescribing information. Accessed at: PI (elevidys.com)
16. Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy | Sarepta Therapeutics, Inc. Sarepta Therapeutics. June 22, 2023. Accessed at: https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-elevidys-first-gene