Last Review Date: 05/02/2024

Date of Origin: 11/22/2016

Dates Reviewed: 11/2016, 10/2017, 08/2018, 10/2018, 08/2019, 02/2020, 08/2020, 08/2021, 08/2022, 08/2023, 05/2024

1. Description of Procedure or Service

Eteplirsen is an antisense oligonucleotide specifically indicated for the treatment of patients with DMD who have a confirmed mutation of the dystrophin gene that makes them more likely to respond to exon 51 skipping. Eteplirsen’s intended mechanism of action is removal of exon 51 of the pre-messenger ribonucleic acid (RNA), thereby restoring the messenger RNA reading frame. This shift would enable the production of a truncated form of the dystrophin protein. By increasing the quantity of an abnormal, but potentially functional, dystrophin protein, the objective is to slow or prevent the progression of DMD. Eteplirsen is the first drug to receive FDA-approval for the treatment of DMD.

2. Policy

Exondys 51 (eteplirsen) is considered not medically necessary for all indications including treatment of Duchenne’s muscular dystrophy.

Note: There is insufficient clinical evidence for demonstrated efficacy. This position statement is consistent with FDA reviewers’ comments and the FDA Advisory Panel’s vote on eteplirsen.

3. Key Points

Duchenne muscular dystrophy (DMD), a form of muscular dystrophy, is a genetic disorder characterized by progressive muscle degeneration and weakness that predominantly affects males. It is the most common and severe form of muscular dystrophy among children and accounts for more than 50% of all cases. DMD is caused by a deficiency of dystrophin, a protein that helps strengthen muscle fibers and protect them from injury.

Prevalence in the United States is not exactly known but is estimated to be approximately 1.0-1.8 per 10,000 males age 5-24 years old. DMD appears typically in boys between ages 3 and 5 and progresses rapidly. Most people with DMD are unable to walk by age 12 and may later need a respirator to breathe. They usually die in their late teens or early 20s from heart trouble, respiratory complications, or infection.

Currently, there is no cure for DMD and therapies are supportive in nature. Physical therapy, occupational therapy, respiratory care, speech therapy, braces/wheelchairs/contractures and glucocorticoid therapy are among the many common therapies. Historically, glucocorticoids were the only pharmacologic treatment for DMD utilized to slow the progression of weakness.

4. Clinical Trials and FDA Review

Eteplirsen was approved through the FDA accelerated approval process.

“For purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure, that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. Depending on the strength of the evidence supporting the ability of a marker to predict clinical benefit, the marker may be a surrogate endpoint that is known to predict clinical benefit (a validated surrogate endpoint that could be used for traditional approval), a surrogate endpoint that is reasonably likely to predict a drug’s intended clinical benefit (and that could therefore be used as a basis for accelerated approval), or a marker for which there is insufficient evidence to support reliance on the marker as either kind of surrogate endpoint (and that therefore cannot be used to support traditional or accelerated approval for a marketing application).”

Much controversy ensued within the FDA surrounding whether the change shown in the surrogate endpoint (an increase in dystrophin) in the clinical studies was “reasonably likely to predict clinical benefit.” Dr. Unger (Director, Office of Drug Evaluation I, CDER) believes that an increase of approximately 10% of normal dystrophin levels (Becker-type: Becker Muscular Dystrophy or BMD is a less severe form of MD and has approximately 10% normal dystrophin levels) would meet criteria that is “reasonably likely to predict clinical benefit,” which would require a substantial increase in dose (approximately a log order).” He believes that the near-zero quantity of dystrophin (0.3%) could produce clinical benefit, but does not reach the threshold of “reasonably likely” to predict clinical benefit. Whereas Dr. Woodcock (Director, CDER) argues that within the BMD phenotype, the relation between disease severity and protein expression is not clear. Protein quality, rather than quantity, may play a key role in determining phenotype of BMD. The minimum quantity of Becker-type dystrophin that will produce a clinical benefit in DMD patients is unknown. Dr. Califf, Commissioner of Food and Drug, sided on behalf of Dr. Woodcock.

It was found by the FDA that the Western blots submitted by the applicant for Study 201 were “oversaturated, unreliable, and uninterpretable.” Additionally, there was a lack of agreement between the immunohistochemistry results and Western blot methods from the same laboratory (a lack of internal consistency). With the FDA’s assistance, repeat biopsies were performed on 11 of 12 patients in study 201/202 patients at Week 180 and were compared to the stored baseline samples. However, evaluable tissue was available for only 3 of the 11 patients. Most of the baseline biopsies were obtained from subjects external to Study 201/202, who could differ in unknown ways from subjects in Study 201/202. For all patients, the Week 180 biopsies were obtained from different muscles than the baseline biopsies (dystrophin levels vary among muscles). There was also concern that baseline biopsies for the 3 subjects with Week 180 data had been stored for several years and the protein may have degraded, leading to falsely low baseline values and a greater apparent increase from baseline, accordingly. Of note, Study 201 and 202 failed to show a change in 6-minute walk distance.

The FDA review comments on the development program indicate that the development program for eteplirsen was seriously deficient in a number of aspects including a lack of robust and high-quality assays and inaccurate conclusions from those assays leading to a flawed development program. Additionally, the FDA comments that there should not have been an “exploratory study” for this serious, life-threatening illness without therapeutic options. Randomization should have been performed very early in the development program, and open-label studies should have been avoided. The results of Study 201 were published in Ann Neurol 2013; 74:637-47, which now is known to be misleading, has been called to be retracted by its authors. The publication of the paper was subsequently followed by a Sarepta press release that claimed a remarkable treatment effect from eteplirsen. Subsequently expectations in the DMD community were raised which led Sarepta to declare that a placebo-controlled study was no longer feasible. The FDA review states that this created even more flaws in the development program.

The FDA does agree that there is evidence from a single, adequate, and well controlled study that demonstrates that eteplirsen induces dystrophin production in muscle cells (Study 301/PROMOVl which is ongoing; Western blot analysis was utilized). The primary endpoint for this ongoing study is change in 6-Minute Walk Test (6MWT) distance from baseline with secondary measures of % of dystrophin-positive fibers and maximum inspiratory/expiratory pressure percent predicted (MIP/MEP % predicted). Patients were genotypically confirmed and had been on a stable dose of corticosteroids for at least 6 months. Of the 12 patients in the study, 8 had a change of 0.25% or less and 1 patient (8%) had a change of greater than 1% at 12 months. It has been noted that the 30 mg/kg/week dose is sub-therapeutic due to the fact that the patients who have received the dose for 3.5 years have been progressing at a rate that is similar to that expected, based on the natural history of the disease. It is suggested that confirmatory trials are dose-comparative (aggressively pursuing higher dosing) and need to demonstrate clinical benefit.

Summary

In summary, eteplirsen was approved in September 2016 under an accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with eteplirsen. This approval was based on the surrogate endpoint of increased dystrophin production in skeletal muscle. However, small clinical trials failed to demonstrate statistically significant clinical benefit compared to placebo, and the amount of protein produced was only a small fraction of the normal level.

Much controversy ensued within the FDA surrounding whether the change shown in the surrogate endpoint (an increase in dystrophin) in the clinical studies was “reasonably likely to predict clinical benefit.” Prior to FDA approval, the Peripheral and Central Nervous System Drugs Advisory Committee of the FDA held a meeting and voted against approval of Eteplirsen as treatment for DMD. Uncertainty still exists regarding whether the small observed increase in dystrophin will translate to a clinical benefit. This is also noted in the product labeling, “A clinical benefit of EXONDYS 51 has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.”

5. Billing Code/Availability Information

HCPCS Code:

• J1428 – Injection, eteplirsen, 10 mg; 1 billable unit = 10 mg

NDC(s):

• 100 mg/2 mL single-dose vial: 60923-0363-xx
• 500 mg/10 mL single-dose vial: 60923-0284-xx

6. References

1. Exondys 51 [package insert]. Cambridge, MA; Sarepta Therapeutics, Inc.; January 2022. Accessed March 2024.
2. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013 Nov;74(5):637-47. doi: 10.1002/ana.23982.
3. Mendell JR, Goemans N, Lowes LP, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016 Feb;79(2):257-71. doi: 10.1002/ana.24555.
4. Alfano LN, Charleston JS, Connolly AM, et al. Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy. Medicine (Baltimore). 2019 Jun;98(26):e15858. doi: 10.1097/MD.0000000000015858.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
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 28, 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