Exondys (eteplirsen) and Vyondys (golodirsen) for Duchenne Muscular Dystrophy Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM

EFFECTIVE DATE: 10|01|2020 POLICY LAST UPDATED: 07|16|2020

OVERVIEW Duchenne muscular dystrophy is an inherited disorder that results in progressive muscle weakness and loss of muscle mass, primarily affecting males. Duchenne muscular dystrophy is caused by variant(s) in the exon gene responsible for producing dystrophin, a cohesive protein essential for maintaining muscle support and strength. The variant(s) disrupts the translational reading of messenger RNA resulting in an unstable, nonfunctional dystrophin molecule. Eteplirsen and golodirsen are antisense oligonucleotides that induce skipping of exons 51 and 53 respectively and thereby repairing the mutated reading frame. As a result, eteplirsen and golodirsen enable production of an internally truncated, yet functional, dystrophin protein.

MEDICAL CRITERIA Not applicable.

PRIOR AUTHORIZATION
Not applicable.

POLICY STATEMENT Medicare Advantage Plans and Commercial Products The use of eteplirsen or golodirsen are not covered for all indications including treatment of Duchenne muscular dystrophy as the evidence is insufficient to determine the effects of the technology on health outcomes.

COVERAGE Benefits may vary between groups/contracts. Please refer to the appropriate Evidence of Coverage for applicable physician administered drug infusion coverage/benefits.

BACKGROUND Duchenne muscular dystrophy is an X-linked, recessive disorder that occurs in approximately 1 in every 3500 to 5000 males. It primarily affects males. However, a small number of girls are also affected, but they are usually asymptomatic, and even when symptomatic, only present with a mild form of the disease. According to U.S. epidemiologic data, the first signs or symptoms of Duchenne muscular dystrophy are noted at a mean age of 2.5 years (range, 0.2-1 years), and the mean age at definitive diagnosis is 4.9 years (range, 0.3-8.8 years).2, Symptoms include motor difficulties such as running, jumping, walking up stairs, and an unusual waddling gait. Some improvement in symptoms may be seen from 3 to 6 years of age, though gradual deterioration resumes and most patients lose ambulation by age 12 and require noninvasive ventilation by late teenage years. Patients progress from needing noninvasive ventilation only during night sleeping, followed by noninvasive ventilation during day and night sleeping, and then noninvasive ventilation during day and night over the course of 5 to 10 years.

Duchenne muscular dystrophy occurs as a result of variant(s) in the gene responsible for producing dystrophin, a cohesive protein that is essential for maintaining muscle support and strength. Duchenne muscular dystrophy is the longest known human gene, and several variants can cause Duchenne muscular dystrophy. Most deletion variants disrupt the translational reading frame in the dystrophin messenger RNA resulting in an unstable, nonfunctional dystrophin molecule. As a result, there is progressive muscle Medical Coverage Policy | Exondys (eteplirsen) and Vyondys (golodirsen) for Duchenne Muscular Dystrophy

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

degeneration leading to loss of independent ambulation, as well as other complications, including respiratory and cardiac complications.3, Genetic testing is required to determine the specific Duchenne muscular dystrophy gene variant(s) for a definitive diagnosis, even when the absence of dystrophin protein expression has been confirmed by muscle biopsy. There are over 4700 variants in the Leiden Duchenne muscular dystrophy mutation database, and the most common variants are concentrated between exons 45 and 53.

The current standard of pharmacotherapy for DMD is corticosteroids for all patients regardless of genetic variant. Treatment is initiated once patients reach a plateau of motor skill development, generally at ages 4 to 6 years, but prior to onset of motor decline. The goal of corticosteroid therapy is to preserve ambulation and minimize respiratory, cardiac, and orthopedic complications. In addition, muscle weakness and pain, cardiac, pulmonary, orthopedic, and endocrine symptoms should be managed.

Regulatory Status
Eteplirsen
In September 2016, eteplirsen (Exondys 51™; Sarepta Therapeutics) was approved by the U.S. Food and Drug Administration (FDA) after orphan drug designation for Duchenne muscular dystrophy patients who have a confirmed variant of the Duchenne muscular dystrophy gene that is amenable to exon 51 skipping. This indication was approved with a fast track designation based on an increase in dystrophin in skeletal muscle observed in some patients treated with eteplirsen.

The FDA, under the accelerated approval regulations (21 CFR 314.510), requires that Sarepta conduct a confirmatory trial to demonstrate the clinical benefit of eteplirsen. In the preceding 3 years after the FDA approval, there has still been no publication of a trial confirming or refuting a clinical benefit of eteplirsen. The European Medicines Agency rejected marketing approval for eteplirsen in September 2018.

For individuals with a confirmed variant of the Duchenne muscular dystrophy gene that is amenable to exon 51 skipping who receive eteplirsen, the evidence includes 1 randomized controlled trial (RCT), 1 ongoing prospective open-label trial with a concurrent untreated control arm and multiple post-hoc studies with historical control. Relevant outcomes are disease-specific survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. For the single pivotal RCT, no formal sample size calculations were conducted. A sample size of 12 total patients was selected with 4 patients in 3 treatment groups. There was no statistically significant difference either in the mean change from baseline in the 6-minute walk test distance or change in the North Star Ambulatory Assessment total score between eteplirsen treated patients and placebo-treated patients at week 48. While eteplirsen treatment resulted in dystrophin detection in muscle biopsies suggesting the production of (truncated) dystrophin, the amount of protein produced was very limited according to the Western blot results (0.44% of normal dystrophin at week 48 [Study 301]; 0.93% at week 180 [Study 201/202]). There are no satisfactory data, clearly establishing the effectiveness of the truncated dystrophin. Further, the minimum beneficial amount of dystrophin expression to be translated into a clinical benefit has yet to be established. In the absence of clinical data convincingly demonstrating a clinical effect, it cannot be concluded that the amount of dystrophin expressed with eteplirsen will translate into a clinical benefit to patients. Multiple analysis of long-term follow-up data from study 201/202 and 301 on functional outcome measures such as 6- minute walk test and pulmonary function suggest that the rate of decline in eteplirsen treated patients was less as compared to historical controls. However, the post-hoc nature of the analysis and the fact that the cohorts were retrospectively identified within the untreated group of patients is of serious concern (potential selection bias) and undermines the robustness of the data. Particularly, the 6-minute walk test is subject to inter- and intra-subject variability and is influenced by training and motivation making it a less suitable outcome measure for external control group comparison. Thus the clinical benefit of treating Duchenne muscular dystrophy with eteplirsen, including improved motor function and pulmonary function, has not been demonstrated. A confirmatory, prospective and adequately powered trial is necessary to assess the net health benefit of eteplirsen in patients with Duchenne muscular dystrophy amenable to 51 skipping. The evidence is insufficient to determine the effects of the technology on health outcomes.

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM

Golodirsen
In December 2019, golodirsen (Vyondys 53™; Sarepta Therapeutics) was approved by the FDA after orphan drug designation for Duchenne muscular dystrophy patients who have a confirmed variant of the Duchenne muscular dystrophy gene that is amenable to exon 53 skipping. This indication was approved with a fast track designation based on an increase in dystrophin in skeletal muscle observed in some patients treated with golodirsen.

The FDA, under the accelerated approval regulations (21 CFR 314.510), requires that Sarepta conduct a randomized double-blind, placebo-controlled trial of 96 weeks with an open-label extension to 144 weeks to verify the clinical benefit of golodirsen with the primary endpoint of 6-minute walk test. The expected date of trial completion is April 2024 and final report submission to the FDA by October 2024.

For individuals with a confirmed variant of the Duchenne muscular dystrophy gene that is amenable to exon 53 skipping who receive golodirsen, the evidence includes a 2-part multicenter study which consists of a part 1 randomized, double-blind safety and tolerability study and a part 2 open-label efficacy and safety study. Relevant outcomes are disease-specific survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. Results of interim analysis were based on 25 patients who received a weekly intravenous infusion of golodirsen 30 mg/kg. At week 48, the mean change in dystrophin protein levels was 0.924% increase from the baseline (1.019% vs. 0.095%; P <0.001). There are no satisfactory data, clearly establishing the effectiveness of the truncated dystrophin. Further, the minimum beneficial amount of dystrophin expression to be translated into a clinical benefit has yet to be established. In the absence of clinical data convincingly demonstrating a clinical effect, it cannot be concluded that the amount of dystrophin expressed with golodirsen will translate into a clinical benefit to patients. A confirmatory, prospective and adequately powered trial is necessary to assess the net health benefit of eteplirsen in patients with Duchenne muscular dystrophy amenable to 51 skipping. The evidence is insufficient to determine the effects of the technology on health outcomes.

CODING Medicare Advantage Plans and Commercial Products The following HCPCS codes are not covered:
J1428 Injection, eteplirsen, 10 mg
J1429 Injection, golodirsen, 10 mg J1426 Injection, casimersen, 10 mg

RELATED POLICIES Not applicable.

PUBLISHED Provider Update, September 2021 Provider Update, October 2020
Provider Update, July 2019
Provider Update, June 2018
Provider Update, June 2017

REFERENCES

1. Center for Disease Control and Prevention. Muscular Dystrophy: MD STARnet Data and Statistics. 2016; http://www.cdc.gov/ncbddd/musculardystrophy/data.html. Accessed February 19, 2020.
2. Falzarano MS, Scotton C, Passarelli C, et al. Duchenne muscular dystrophy: from diagnosis to therapy. Molecules. Oct 07 2015;20(10):18168-18184. PMID 26457695
3. 3. Committee for Medicinal Products for Human Use (CHMP) Assessment Report: Exondys. Published September 20, 2018, Available at

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 4 (401) 274-4848 WWW.BCBSRI.COM

https://www.ema.europa.eu/en/documents/assessmentreport/exondys-epar-refusal-public- assessment-report_en.pdf. Accessed February 19, 2020.

4. 4. Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment Guidance for Industry. Published February 2018. https://www.fda.gov/media/92233/download, Accessed February 19, 2020.
5. McDonald CM, Henricson EK, Abresch RT et al. The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. Muscle Nerve. 2013 Sep;48(3). PMID 23681930
6. Henricson E, Abresch R, Han JJ, et al. The 6-Minute Walk Test and Person-Reported Outcomes in Boys with Duchenne Muscular Dystrophy and Typically Developing Controls: Longitudinal Comparisons and Clinically-Meaningful Changes Over One Year. PLoS Curr. 2013 Jul;5: NA. PMID 23867975
7. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. Nov 2013;74(5):637-647. PMID 23907995
8. Mendell JR, Goemans N, Lowes LP, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. Feb 2016;79(2):257-271. PMID 26573217
9. Khan N, Eliopoulos H, Han L, et al. Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy. J Neuromuscul Dis, 2019 Mar 12;6(2). PMID 30856119
10. Food and Drug Administration. FDA Briefing Document: Peripheral and Central Nervous System Drugs Advisory Committee Meeting, April 25, 2016. NDA 206488. Eteplirsen. 2016; https://www.fda.gov/media/97306/download. Accessed March 4, 2020.
11. Woodcock J, Dunn B. FDA Presentations for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. 2016; https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Perip heralandCentralNervousSystemDrugsAdvisoryCommittee/UCM500821.pdf. Accessed February 19,
13. Center for Drug Evaluation and Research. Application Number: 206488orig1s000. Summary Review. 2016; http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206488_summary%20review_Redacted. pdf. Accessed February 19, 2020.
14. Kesselheim AS, Avorn J. Approving a problematic muscular dystrophy drug: implications for FDA policy. JAMA. Dec 13 2016;316(22):2357-2358. PMID 27775756
15. Business Wire. Sarepta Therapeutics Announces FDA Request for Dystrophin Data Prior to Making a Decision on Eteplirsen NDA. 2016, June 6; http://www.businesswire.com/news/home/20160606006534/en/Sarepta-Therapeutics-Announces- FDA-Request-Dystrophin-Data. Accessed February 19, 2020.
16. Deflazacort, Eteplirsen, and Golodirsen for Duchenne Muscular Dystrophy: Effectiveness and Value. Institute for Clinical and Economic Review. https://icer-review.org/wp- content/uploads/2018/12/ICERDMD-Final-Report081519-1.pdf. Accessed February 18, 2020.
17. McDonald CM, Henricson EK, Abresch RT, et al. Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study. Lancet, 2017 Nov 28;391(10119). PMID 29174484.
18. Kinane TB, Mayer OH, Duda PW, Lowes LP, Moody SL, Mendell JR. Long-Term Pulmonary Function in Duchenne Muscular Dystrophy: Comparison of Eteplirsen-Treated Patients to Natural History. J Neuromuscul Dis. 2018;5(1):47-58. PMID 29278896

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 5 (401) 274-4848 WWW.BCBSRI.COM

18. Alfano LN, Charleston JS, Connolly AM, et al. Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy. Medicine (Baltimore), 2019 Jul 3;98(26). PMID 31261494
19. Prescribing Label: VYONDYS 53 (golodirsen) injection, for intravenous use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211970s000lbl.pdf. Accessed February 19, 2020.
20. 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. Mar 2018;17(3):251-267. PMID 29395989
21. 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. Apr 2018;17(4):347-361. PMID 29395990
22. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Lancet Neurol. May 2018;17(5):445-455. PMID 29398641
23. Feingold B, Mahle WT, Auerbach S, et al. Management of cardiac involvement associated with neuromuscular diseases: a scientific statement from the American Heart Association. Circulation. Sep 26 2017;136(13):e200-e231. PMID 28838934
24. Gloss D, Moxley RT, 3rd, 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. Feb 2 2016;86(5):465-472. PMID 26833937

25. Julie Kanter, John F. Tisdale, Markus Y. Mapara, Janet L. Kwiatkowski, Lakshmanan Krishnamurti, Manfred Schmidt, Alexandra L. Miller, Francis J. Pierciey, Wenmei Huang, Jean-Antoine Ribeil, Alexis A. Thompson, Mark C. Walters; Resolution of Sickle Cell Disease Manifestations in Patients Treated with Lentiglobin Gene Therapy: Updated Results from the Phase 1/2 Hgb-206 Group C Study. Blood 2019; 134 (Supplement_1): 990. doi: https://doi.org/10.1182/blood-2019-128894

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