Last Review Date: 07/05/2023

Date of Origin: 07/05/2023

Dates Reviewed: 07/2023

1. Description of Procedure or Service ¹

Elevidys is the recombinant gene therapy product that is comprised of a non-replicating, recombinant, adeno-associated virus (AAV) serotype rh74 (AAVrh74) capsid and a ssDNA expression cassette flanked by inverted terminal repeats (ITRs) derived from AAV2. DMD is caused by a mutation in the DMD gene resulting in lack of functional dystrophin protein. Elevidys carries a transgene encoding a micro-dystrophin protein consisting of selected domains of dystrophin expressed in normal muscle cells. Dystrophin is the protein that is absent in patients with Duchenne Muscular Dystrophy (DMD) which results in muscle damage and progressive dysfunction. Elevidys micro-dystrophin has been demonstrated to localize to the sarcolemma.

2. Policy

Elevidys® (delandistrogene moxeparvovec-rokl) suspension is considered not medically necessary for all indications including treatment of Duchenne’s muscular dystrophy.

Note: There is insufficient clinical evidence for demonstrated efficacy.

3. Key Points

Current treatment options for DMD focus on symptomatic management and prevention of complications. The mainstay of treatment is to offer patients glucocorticoids which have been confirmed to improve motor strength and function, pulmonary function, reduce the risk of scoliosis, and may delay the onset of cardiomyopathy. Current guidelines recommend initiation of glucocorticoids (such as prednisone) once patients reach a plateau of motor skill development, generally at age 4-6 years, but prior to onset of motor decline. Other therapies include ACE-inhibitors or Beta-blockers for cardiac disease, immunizations, pain management, respiratory support, and comorbidity surveillance. Eteplirsen was approved September of 2016 for the treatment of DMD in patients with a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. Golodirsen and viltolarsen were approved (December 2019 and August 2020 respectively) for the treatment of DMD in patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Casimersen was approved February 2021 for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene that is amenable to exon 45 skipping.

In much the same way as the exon-skipping therapies, delandistrogene moxeparvovec, the first gene therapy approval, occurred following priority review as an accelerated approval allowing for use of a surrogate endpoint (contingent upon verification of a clinical benefit in ongoing confirmatory clinical trials). Approval for the DMD indication was based on expression of micro-dystrophin observed in patients treated with Elevidys. Whether this expression of micro-dystrophin seen in the trials is reasonably likely to confer a clinical benefit remains to be elucidated. The below excerpts from the clinical studies elaborate upon the question of clinical benefit posited with delandistrogene treatment.

4. Clinical Trials and FDA Review ^11,12

Elevidys’ safety and efficacy was evaluated in three on-going clinical studies, the SRP-9001 101, 102 and 103 trials. The accelerated approval was primarily based on data from the 102 and 103 studies (ClinicalTrials.gov Identifier: NCT03769116, NCT04626674, respectively). Elevidys is also being studied in the pivotal study SRP-9001-301 or EMBARK, (ClinicalTrials.gov Identifier: NCT05096221) a randomized, double-blind, placebo-controlled phase 3 clinical trial in 126 participants with DMD between the ages of 4 to 7 years. The EMBARK study is expected to serve as the post-marketing confirmatory trial.

SRP-9001-102 included 41 male ambulatory DMD patients aged 4 to 7 years with either a confirmed frameshift mutation, or a premature stop codon mutation between exons 18 to 58 in the DMD gene. In part 1 of the study, patients were randomly assigned to receive Elevidys or placebo and were followed for 48 weeks. In part 2, patients who received placebo during part 1 were treated with Elevidys and those treated with Elevidys during part 1 received placebo; all patients were followed for an additional 48 weeks.

SRP-9001-103 included a cohort of 20 ambulatory male DMD patients aged 4 to 7 years with a confirmed frameshift mutation, canonical splice site mutation, or premature stop codon mutation in the DMD gene.

To support the application for the accelerated approval, Sarepta used the surrogate endpoint of expression of Elevidys micro-dystrophin protein in muscle biopsy tissue samples at Week 12. Correlation analysis was used to assess whether it is “reasonably likely to predict clinical benefit” by correlating it with the change in the North Star Ambulatory Assessment (NSAA) Total Score at Year 1.

Based on the results which were adjusted for baseline age and NSAA Total Score), the Study 102 Part 1 data showed no clear association between expression of Elevidys micro-dystrophin and change in NSAA Total Score. “Correlation analysis at the age group level also did not suggest clear association between Elevidys micro-dystrophin expression and change in NSAA Total Score, based on limited data. However, improved NSAA Total Score with increased Elevidys micro-dystrophin expression was observed in younger subjects (aged 4-5 years), but not in those aged 6 years and older. Because of the very limited data and exploratory nature of the NSAA assessment, these results in subjects aged 4 to 5 years must be interpreted with caution.” ¹¹

The FDA Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) met on May 12, 2023 and were asked to discuss, then vote regarding the following: Do the overall considerations of benefit and risk, taking into account the existing uncertainties, support Accelerated Approval of SRP-9001—using as a surrogate endpoint, expression of Elevidys microdystrophin at Week 12 after administration of Elevidys—for the treatment of ambulatory patients with DMD with a confirmed mutation in the DMD gene.  The committee voted 8 to 6 in favor of Accelerated Approval of Elevidys.  Several committee members who voted in favor of Accelerated Approval did so despite reservations about the clinical study results and use of Elevidys microdystrophin as a surrogate endpoint “reasonably likely to predict clinical benefit.” ¹¹

5. Billing Code/Availability Information

HCPCS code:

• J3590 – Unclassified biologics (Discontinue use on 01/01/2024)
• J1413 – Injection, delandistrogene moxeparvovec-rokl, per therapeutic dose; 1 billable unit = 1 therapeutic dose (Effective 01/01/2024)

NDC:

Elevidys kit sizes:

6. References

1. Elevidys [package insert]. Cambridge, MA; Sarepta Therapeutics, Inc.; June 2023. Accessed June 2023.
2. Topaloglu H, Gloss D, Moxley RT 3^rd, et al. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016 Jul 12;87(2):238.
3. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol; 2010 Jan; 9(1):77‑93.
4. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol; 2010 Jan; 9(2):177-189.
5. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol 2018; 17:251.
6. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol 2018; 17:347.
7. Moxley RT 3rd, Ashwal S, Pandya S, et al. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2005;64:13–20.
8. Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford Progeria Syndrome. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1121/ (Accessed on November 25, 2020).
9. Scott E, Eagle M, Mayhew A, et al. Development of a Functional Assessment Scale for Ambulatory Boys with Duchenne Muscular Dystrophy. Physiother. Res. Int. 17 (2012) 101–109.
10. Mercuri E, Coratti G, Messina S. et al. Revised North Star Ambulatory Assessment for Young Boys with Duchenne Muscular Dystrophy. PLoS ONE, 11(8), e0160195.
11. FDA Summary Basis for Regulatory Action. June 21, 2023. Available at: June 21, 2023 Summary Basis for Regulatory Action - ELEVIDYS (fda.gov).
12. FDA Center Director Decisional Memo – BLA 125781. Available at: Center Director Decisional Memo - ELEVIDYS (fda.gov)

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Articles (LCAs) and Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. They can be found at: http://www.cms.gov/medicare-coverage-database/ search.aspx. Additional indications may be covered at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCA/LCD): N/A