Last Review Date: 05/02/2024

Date of Origin: 01/06/2020

Dates Reviewed: 01/2020, 08/2020, 09/2020, 08/2021, 08/2022, 08/2023, 05/2024

1. Description of Procedure or Service

Golodirsen (formerly SRP-4053) is an antisense oligonucleotide designed to bind to exon 53 of dystrophin pre-mRNA. This results in the exclusion or skipping of exon 53 which allows for production of dystrophin that is truncated, but still partially functional. It is estimated that approximately 8% of patients may be amenable to exon 53 skipping. Dystrophin is the protein that is absent in patients with Duchenne Muscular Dystrophy (DMD) which results in muscle damage and progressive dysfunction.

2. Policy

Vyondys 53 (golodirsen) 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 ^1-5

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.

In much the same way as eteplirsen, golodirsen 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) of dystrophin increase in skeletal muscle observed in patients. Initially, in August of 2019, the FDA voted against approval based on risk of infections related to intravenous infusion ports and renal toxicity seen in pre-clinical models of golodirsen and observed following administration of other antisense oligonucleotides. Sarepta appealed this decision and FDA approval was granted December 12, 2019. Whether the small increase in truncated dystrophin level seen in the trial 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 golodirsen treatment.

4. Clinical Trials and FDA Review ^1-5

Study 4053-101 (NCT02310906)

Patients were required to have a mutation in the DMD gene amenable to exon 53 skipping. Part 1 was a double-blind, placebo-controlled, dose-titration study in 12 DMD patients randomized 2:1 to golodirsen, in four escalating dose levels, or placebo. Part 2 was a 168-week, open-label study at a dose of 30 mg/kg/week which included the 12 patients from Part 1 plus an additional 13 patients with DMD. Patients had a median age of 8 years and were on a stable dose of corticosteroids for at least 6 months. Muscle biopsies were obtained from all patients at baseline prior to treatment and at Week 48 of Part 2 and were analyzed using Western blot for dystrophin level (primary endpoint). Mean dystrophin levels increased from 0.095% (SD 0.07) of normal at baseline to 1.019% (SD 1.03) of normal by Week 48 of Study 1 Part 2, with a mean change in dystrophin of 0.924% (SD 1.01) of normal levels (p<0.001).

ESSENCE study (4045-301; NCT02500381)

An ongoing, currently recruiting, double-blind, placebo-controlled, multi-center, Phase 3 study to evaluate the efficacy of SRP-4045 and SRP-4053 for up to 96 weeks which will be followed by an open label extension period in which all patients will receive open-label active treatment for 48 weeks in patients with DMD amenable to skipping exon 45 and exon 53 respectively. Twice as many patients will receive active treatment as will receive placebo (2:1). Target estimated enrollment of 222 subjects, males aged 7-13 years. Clinical efficacy will be assessed via six-minute walk test. All patients will undergo a muscle biopsy at baseline and a second muscle biopsy either at Week 48 or Week 96. The estimated primary completion date is May 2023.

NCT03532542

A Phase 3 open-label interventional extension study to evaluate the safety and tolerability of long-term treatment with casimersen or golodirsen in patients with DMD. Target estimated enrollment, by invitation, of 260 subjects (males between the ages of 7 to 23 years). The estimated primary completion date is August 2026.

5. Billing Code/Availability Information

HCPCS Code:

• J1429 – Injection, golodirsen, 10 mg; 1 billable unit = 10 mg

NDC:

• Vyondys 53 100 mg/2 mL single-dose vial: 60923-0465-xx

6. Billing Code/Availability Information

HCPCS Code:

• J1429 – Injection, golodirsen, 10 mg; 1 billable unit = 10 mg

NDC:

• Vyondys 53 100 mg/2 mL single-dose vial: 60923-0465-xx

7. References

1. Vyondys 53 [package insert]. Cambridge, MA; Sarepta Therapeutics, Inc.; February 2021. Accessed March 2024.
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. Kinane TB, Mayer OH, Duda PW, et al. Long-Term Pulmonary Function in Duchenne Muscular Dystrophy: Comparison of Eteplirsen-Treated Patients to Natural History. Journal of Neuromuscular Diseases 5 (2018) 47–58.
6. Muntoni F, Frank D, Sardone V, et al. Golodirsen Induces Exon Skipping Leading to Sarcolemmal Dystrophin Expression in Duchenne Muscular Dystrophy Patients With Mutations Amenable to Exon 53 Skipping (S22.001). Neurology Apr 2018, 90 (15 Supplement) S22.001
7. Institute for Clinical and Economic Review. Deflazacort, Eteplirsen, and Golodirsen for Duchenne Muscular Dystrophy: Effectiveness and Value. Final Evidence Report. August 15, 2019 https://icer.org/wp-content/uploads/2020/10/ICER_DMD-Final-Report_081519-2-1.pdf. Accessed March 2024.
8. Khan N, Eliopoulos H, et al on behalf of the Eteplirsen Investigators and the CINRG DNHS Investigators. Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy. J. Neuromuscular Dis, vol. 6, no. 2, pp. 213-225, 2019.
9. Frank DE, Schnell FJ, Akana C, et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020 May 26;94(21):e2270-e2282. doi: 10.1212/WNL.0000000000009233. Epub 2020 Mar 5
10. 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.
11. 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.
12. Servais L, Mercuri E, Straub V, et al.; SKIP-NMD Study Group. Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial. Nucleic Acid Ther. 2022 Feb;32(1):29-39. doi: 10.1089/nat.2021.0043. Epub 2021 Nov 17.
13. 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.
14. Gloss D, Moxley RT 3^rd, Ashwal S, Oskoui M. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016 Feb 2;86(5):465-72. Doi: 10.1212/WNL.0000000000002337. Reaffirmed on January 22, 2022.
15. Darras BT, Urion DK, Ghosh PS. Dystrophinopathies. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1119/. Initial Posting: September 5, 2000; Last Revision: January 20, 2022. Accessed on March 29, 2024.
16. Childs, AM, Turner, C, Astin, R, et al. (2023). Development of respiratory care guidelines for Duchenne muscular dystrophy in the UK: key recommendations for clinical practice. thorax.
17. Landfeldt, Erik. Measuring health-related quality of life in Duchenne muscular dystrophy: Current perspectives and recommendations. Journal of the Neurological Sciences 446 (2023).

Appendix 1 – Covered Diagnosis Codes

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

The preceding information is intended for non-Medicare coverage determinations. 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 Determinations (NCDs) and/or Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. Local Coverage Articles (LCAs) may also exist for claims payment purposes or to clarify benefit eligibility under Part B for drugs which may be self-administered. The following link may be used to search for NCD, LCD, or LCA documents: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications, including any preceding information, may be applied at the discretion of the health plan.

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