Pending Policies - Prescription Drugs
Eteplirsen (Exondys 51)
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Eteplirsen (Exondys 51™) for the treatment of Duchenne muscular dystrophy is considered not medically necessary as a clinical benefit has not been established.
Eteplirsen (Exondys 51™) for the treatment of all other indications is considered experimental, investigational and/or unproven.
Duchenne muscular dystrophy (DMD) is an X-linked, recessive disorder that occurs in approximately 1 in every 3500 to 5000 boys. (1) It primarily affects boys. 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 DMD 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) DMD occurs as a result of mutation(s) in the gene responsible for producing dystrophin, a cohesive protein that is essential for maintaining muscle support and strength. DMD is the longest known human gene and several mutations can cause DMD. Most deletion mutations disrupt the translational reading frame in the dystrophin messenger RNA (mRNA) resulting in an unstable, nonfunctional dystrophin molecule. As a result, there is progressive muscle 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 DMD gene mutation(s) for a definitive diagnosis, even when the absence of dystrophin protein expression has been confirmed by muscle biopsy. There are over 4700 mutations in the Leiden DMD mutation database and the most common mutations are concentrated between exons 45 and 53.
Eteplirsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) class. PMOs are stable oligonucleotide analogues that selectively bind to RNA to alter gene expression. In the case of eteplirsen, the PMO binds to exon 51 of the dystrophin premessenger RNA causing the exon to be skipped and prevents that part of the code from being read during mRNA processing, thereby partially repairing the mutated reading frame in the mRNA coding sequence. As a result, eteplirsen enables the production of an internally truncated, yet functional, dystrophin protein.
The current standard of pharmacotherapy for DMD is corticosteroids for all patients regardless of genetic mutation. 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. (1)
In September 2016, eteplirsen (Exondys 51™; Sarepta Therapeutics) was approved by the U.S. Food and Drug Administration through the orphan drug status process for use in Duchenne muscular dystrophy (DMD) patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication was approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with eteplirsen.
Studies 201 AND 202 (Pivotal Trial)
In single-center, double-blind, placebo-controlled trial, 12 boys ages 7 to 13 years with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping and on stable corticosteroid dose for last 6 months were randomized to eteplirsen (30 or 50 mg/kg/wk) or placebo (4 patients per group). Treatment continued for 24 weeks and then placebo patients switched to eteplirsen 30 or 50 mg/kg (n=2 per group) at week 25. All treatment subsequently became open-label and patients were followed for an additional 24 weeks (48 weeks in total). The primary end point was dystrophin expression. Clinical end points such as 6-minute walk distance (6MWD) were also assessed. 6MWD measures the distance that a patient can walk on a flat, hard surface in 6 minutes. Mean age was 9.4 years and mean 6MWD at baseline was 363 meters. (4, 5)
The primary trial end point was a surrogate measure of change in dystrophin-positive fibers as measured in muscle biopsy tissue using immunohistochemistry. (6) Serial biopsies were performed at 12, 24, and 48 weeks, although biopsies were performed on only half of the treated patients at each of the 12- (only for eteplirsen 50-mg/kg group) and 24- (only for eteplirsen 30-mg/kg group) week periods; all 12 patients were receiving drug treatment by week 48. The results published in 2013 reported a substantial increase (range, 23%-52%) in the percentage of dystrophin-containing fibers in the biopsy specimens at weeks 24 and 48 in the eteplirsen-treated groups. (5) However, immunohistochemistry analysis is not a quantitative measure of dystrophin. This analysis evaluates thin slices of muscle biopsies to assess whether dystrophin is present or absent. Each muscle fiber showing any amount of dystrophin counts as positive, regardless of the actual quantity of dystrophin present. On the other hand, Western blot analyzes how much dystrophin is present in a sample. Results reported in the prescribing label showed the average dystrophin protein level after 180 weeks of treatment with eteplirsen measured by Western blot analysis of biopsy was 0.93% of the dystrophin level in healthy subjects. (4) Further, a more rigorous and fully blinded reanalysis by 3 investigators of the immunohistochemical assay by the Food and Drug Administration (FDA) cast further doubt about the consistency of immunohistochemical analysis because there was little difference in positive fibers between original baseline samples and week 180. (7)
6-Minute Walking Test
The prespecified clinical end points on the 6-minute walk test (6MWT) for study 201 (week 24) and study 202 (week 48) were negative. (7) The published article reported a 67.3-meter benefit in 6MWD at week 48 in ambulation-evaluable eteplirsen-treated patients compared to placebo/delayed patients (p<0.005). (5) However, this was a post hoc analysis because it excluded 2 eteplirsen-treated patients who deteriorated quickly while receiving therapy and lost ambulation at or beyond week 24. The FDA has recommended retraction of the published study due to concerns about interpretation of its findings. (8) Further, in an exploratory analysis, the FDA found no correlation between dystrophin levels and 6MWD.(7) For example, among 4 patients with the most preserved 6MWD, 2 had the lowest and 2 had the highest dystrophin levels using per Western blot. As per the prescribing label, there was no significant difference in change in 6MWD between patients treated with eteplirsen and placebo. While the 6MWT may be an objective test, its results can be influenced by expectation bias, motivation, and coaching especially in the context that patients in the pivotal 201/202 trial were aware of treatment assignment for most the investigation period.
Eteplirsen’s manufacturer reported a gain of 162 meters in 6MWD at 4 years after treatment with eteplirsen in 12 patients in study 202 compared to 13 patients from an external control at the FDA Peripheral and Central Nervous System Drugs Advisory Committee meeting. (6) Results were subsequently published in a peer-reviewed journal. (9) Data for external control were extracted from pooled data from an Italian and Belgian registry by matching corticosteroid use at baseline, availability of longitudinal data for 6MWD, age, and genotype amenable to exon 51 skipping therapy. However, the FDA (10) and others (11) have identified several issues related to the use of an external control such as differences in the use of steroids and physical therapy between the 2 groups. Most importantly, the impact of unknown prognostic factors cannot be ascertained in an externally controlled study. The FDA was unable to draw conclusions from the pivotal trial data about whether eteplirsen increased dystrophin production because quantitative estimates of pretreatment dystrophin levels were not available. In June 2016, the FDA requested that Sarepta submit additional eteplirsen data for review. (12) Sarepta complied with this request, submitting data of 13 patients from the ongoing PROMOVI trial for whom quantitative estimates of dystrophin at baseline and at week 48 were available. PROMOVI is a 96-week, open-label, multicenter, phase 3 study with a planned enrollment of 160 patients with genotype-confirmed DMD; 80 patients amenable to exon 51 skipping will be treated with eteplirsen (30 mg/kg) and compared to 80 untreated patients not amenable to exon 51 skipping. (13) Male ambulatory patients between 7 and 16 years of age who are on stable doses of corticosteroids for at least 6 months and have intact right and left bicep muscles (the preferred biopsy site) or 2 other upper arm muscle groups will be included in the trial. The estimated completion date of this trial is January 2019. Subsequent FDA approval was based on data for these 13 patients (mean age, 8.9 years).4 In the 12 patients with evaluable results, the pretreatment dystrophin level was 0.16%±0.12% of the dystrophin level in a healthy subject and 0.44%±0.43% after 48 weeks of eteplirsen treatment (p<0.05). Median increase after 48 weeks was 0.1%. The clinical benefit of this dystrophin increase is unknown.
Section Summary: Studies 201 and 202
The clinical benefit of DMD treatment with eteplirsen, including improved motor function, has not been demonstrated. Establishing a clinical benefit is necessary in ongoing clinical trials.
The most frequently reported adverse events across the clinical trials were balance disorder, vomiting, and contact dermatitis. (4)
Summary of Evidence
For individuals with confirmed mutation of the Duchenne muscular dystrophy gene that is amenable to exon 51 skipping who receive eteplirsen, the evidence includes 1 randomized controlled trial (RCT) and its open-labelled follow-up study, and interim data from an ongoing RCT. Relevant outcomes are disease-specific survival, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. As per the Food and Drug Administration analysis, the pivotal RCT and its open-labelled follow-up failed to provide evidence of a clinical benefit in terms of 6-minute walk distance. Evidence regarding the impact of eteplirsen treatment on dystrophin levels was inconclusive. Interim results from an ongoing study provided evidence that eteplirsen increased dystrophin levels in skeletal muscle in some patients by a median of 0.1% after 48 weeks of treatment. In summary, the clinical benefit of treatment for Duchenne muscular dystrophy with eteplirsen, including improved motor function, has not been demonstrated. Establishing a clinical benefit is necessary in ongoing clinical trials.
Practice Guidelines and Position Statements
The U.S. Centers for Disease Control and Prevention (CDC) has developed care recommendations. (1, 14) They focus on the overall perspective on care, pharmacologic treatment, psychosocial management, rehabilitation, orthopedic, respiratory, cardiovascular, gastroenterology and nutrition, and pain issues, as well as general surgical and emergency room precautions. CDC recommended use of corticosteroids to slow the decline in muscle strength and function in Duchenne muscular dystrophy (DMD). CDC did not make recommendations on the use of any other drugs or dietary supplements and did not mention eteplirsen in the recommendations.
Ongoing and Unpublished Clinical Trials
There is an ongoing Phase III confirmatory trial NCT02255552 evaluating the efficacy of eteplirsen in DMD with a target enrollment of 160 patients. Per clinicaltrials.gov this study is currently recruiting patients. The main objective of this study is to provide confirmatory evidence of efficacy of eteplirsen (AVI-4658) in Duchenne muscular dystrophy (DMD) patients that are amenable to skipping exon 51. Additional objectives include evaluation of safety, biomarkers and the long-term effects of eteplirsen up to 96 weeks, followed by a safety extension (not to exceed 48 weeks). The estimated completion date is January 2019.
The Food and Drug Administration (FDA)
The FDA, under the accelerated approval regulations (21 CFR 314.510), requires that Sarepta conduct a 2-year randomized, double-blind, controlled trial of eteplirsen in patients with a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. Patients should be randomized to the approved dosage of eteplirsen (30 mg/kg/wk) or to a dosage that provides significantly higher exposure (e.g., 30 mg/kg/d). The primary end point will be the North Star Ambulatory Assessment. (15)
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Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
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The following codes may be applicable to this Medical policy and may not be all inclusive.
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1. 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. Jan 2010; 9(1):77-93. PMID 19945913
2. MD STARnet Data and Statistics. Available at: <http://www.cdc.gov>. Accessed November, 2016.
3. 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
4. Prescribing Label: EXONDYS 51 (eteplirsen) injection, for intravenous use. Sarepta Therapeutics, Inc. Available at: <http://www.accessdata.fda.gov>. Accessed November 2016.
5. 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
6. Sarepta Presentations for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Available at: <http://www.fda.gov>. Accessed November 2016, 2016.
7. FDA Presentations for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. Available at: <http://www.fda.gov>. Accessed November, 2016
8. Center for Drug Evaluation and Research. Application Number: 206488orig1s000: Summary Review. 2016, September 16; Available at: <http://www.accessdata.fda.gov>. Accessed November, 2016.
9. 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
10. FDA Briefing Information for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Available at: <http://www.fda.gov>. Accessed November 2016.
11. Kesselheim AS, Avorn J. Approving a Problematic Muscular Dystrophy Drug: Implications for FDA Policy. JAMA. Oct 24 2016. PMID 27775756
12. Sarepta Therapeutics Announces FDA Request for Dystrophin Data Prior to Making a Decision on Eteplirsen NDA. Available at: <http://investorrelations.sarepta.com> Accessed November, 2016.
13. Confirmatory Study of Eteplirsen in DMD Patients (PROMOVI). Available at: <https://www.clinicaltrials.gov>. Accessed November, 2016.
14. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. Feb 2010; 9(2):177-189. PMID 19945914
15. Accelerated Approval Letter to Sarepta Therapeutics: NDA 206488. 2016, September 19; Available at: <https://www.accessdata.fda.gov>. Accessed November, 2016.
16. Eteplirsen for Duchenne Muscular Dystrophy. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (December 2016) Surgery 5.01.27
|4/15/2018||Reviewed. No changes.|
|6/15/2017||New medical document. Eteplirsen (Exondys 51™) for the treatment of Duchenne muscular dystrophy is considered not medically necessary as a clinical benefit has not been established. Eteplirsen (Exondys 51™) for the treatment of all other indications is considered experimental, investigational and/or unproven.|
|Title:||Effective Date:||End Date:|
|Eteplirsen (Exondys 51)||06-15-2017||04-14-2018|