Medical Policy


Subject: Eteplirsen (Exondys 51®)
Document #: DRUG.00081 Publish Date:    02/27/2019
Status: Reviewed Last Review Date:    01/24/2019


This document addresses the antisense oligonucleotide drug, eteplirsen (Exondys 51; Sarepta Therapeutics, Inc., Cambridge, MA); an exon-skipping drug intended for the treatment of Duchenne muscular dystrophy (DMD).  Eteplirsen induces skipping of exon 51 which allows for the creation of shorter-than-normal, but partially functional, dystrophin - the muscle protein missing in those diagnosed with DMD.

Position Statement

Medically Necessary:

  1. Initiation of therapy with eteplirsen is considered medically necessary for the treatment of Duchenne muscular dystrophy when all of the following criteria are met:
    1. Individual has a confirmed diagnosis of Duchenne muscular dystrophy; and
    2. Individual must be ambulatory (with or without needing an assistive device, such as a cane or walker); and
    3. Individual has a genetic mutation that is amenable to exon 51 skipping.
  2. Continuation of therapy with eteplirsen, for each 12 month period post initiation of therapy, is considered medically necessary for the treatment of Duchenne muscular dystrophy when the criteria above for initiation of therapy have been met including that the individual remains ambulatory (with or without needing an assistive device, such as a cane or walker).

Investigational and Not Medically Necessary:

Use of eteplirsen is considered investigational and not medically necessary when the criteria above are not met, and for all other indications.


On September 19, 2016, the Food and Drug Administration (FDA) approved eteplirsen (Exondys 51) for the treatment of individuals who have a confirmed mutation of the dystrophin gene that is amenable to exon 51 skipping (Product Information [PI] Label, 2018).  Eteplirsen, which has orphan drug status, was under priority review.  Priority review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists.  Eteplirsen was also granted accelerated approval, which allows a surrogate endpoint to be used for serious diseases in which there exists an unmet need for therapy. 

The FDA approval was based on an unpublished, open-label study of 13 ambulatory boys who were on a stable dose of corticosteroids (≥ 6 months) and who were treated with eteplirsen (30 mg/kg) weekly for 48 weeks (1 subject was unavailable for analysis at 48 weeks).  Muscle biopsies were obtained at both baseline and study end to assess the study’s primary endpoint of dystrophin levels in muscle tissues.  The average age was 8.9 years at enrollment.  Baseline dystrophin levels in study participants averaged 0.16% (± 0.12%) of the dystrophin level in a healthy subject and at study-end, had a statistically significant increase (p=0.008), resulting in an average of 0.44% (± 0.43%) of the level in a healthy subject.  Overall, there was a median increase after 48 weeks of 0.1% in the dystrophin levels after treatment with eteplirsen.  A statistically significant increase in dystrophin was reported (0.22% to 0.32% of normal).  The trial used differing methods of evaluating dystrophin levels (Western blot [percent of normal] and immunofluorescence [percent positive fibers]), variable time points of specimen collection, and from variable muscles.  The aforementioned limitations complicate use of dystrophin levels as a surrogate endpoint for clinical efficacy in DMD (FDA, 2016).  Continued FDA approval is contingent upon the drug’s ability to successfully demonstrate a clinically meaningful benefit.  The most frequently reported adverse events (≥ 35%) across clinical trials, when compared to control groups, were balance disorder and vomiting (FDA PI Label, 2018).

In 2016, an open-label extension study was conducted by Mendell and colleagues to evaluate the long-term efficacy and safety of eteplirsen.  Study enrollees received 30 mg/kg (n=6) or 50 mg/kg (n=6) of IV eteplirsen.  At 36 months of follow-up, a total of 12 individuals had been enrolled and treated with eteplirsen.  Only subjects treated with corticosteroids were included in the analysis due to its previously demonstrated efficacy on slowing disease progression.  Although at 12 months there was no difference between eteplirsen and historical controls on the 6-minute walk test (6MWT) scores, at 3 years the eteplirsen cohort was found to have a 151 m advantage in the 6MWT over the matched historical controls identified from two natural history studies (n=13; p<0.01).  Also at the 3-year follow-up, 16.7% of the treatment cohort (n=2/12) had lost the ability to ambulate while 46.2% of the historical controls had lost ambulation (n=6/13).  A direct comparison of change in pulmonary function was also not possible due to a lack of data from the historical controls.  At study end, the average dystrophin protein levels were 0.93% of the dystrophin level in healthy subjects; baseline measurements were not available.  Over the course of the 3 year study, there were no serious events reported and no reports of systemic reactions.  There were no reported infusion interruptions or dose adjustments.  In 2018, Kinane published long-term pulmonary function data from this cohort compared to historical controls.  Data from 34 boys who participated in the United Dystrophinopathy Project (UDP), who were 7-15 years old, and underwent pulmonary function testing served as a the comparator. Pulmonary function tests included forced vital capacity (FVC), maximum expiratory pressure (MEP), and maximum inspiratory pressure (MIP).  To account for children’s natural increase in these measures due to their growth, measurements over time are calculated using percent predicted (%p) relative to expected measurements in healthy controls.  FVC data was available for comparison from the UDP cohort; however, only published natural history data was available as a comparator for MIP and MEP.  The eteplirsen-treated and UPD cohorts were reasonably comparably matched at baseline.  The UDP cohort was slightly older than the eteplirsen-treated cohort (mean age of 10.1 years vs. 9.0 years, respectively).  While 100% of the eteplirsen-treated cohort was ambulatory at baseline, only 79% (n=29) of the UDP cohort was ambulatory at baseline.  The FVC, of the eteplirsen-treated cohort was lower than the UDP cohort at baseline (1.66 vs. 1.80, respectively).  Age-adjusted mixed-model repeated-measures (MMRM) analysis showed decreases in FVC%p of 2.3% annually for the eteplirsen-treated cohort and a 4.1% annual decline in FVC%p for the UDP cohort.  Similarly, the eteplirsen-cohort experienced a 2.6% annual decline for MEP%p, and an annual increase of 0.6% for MIP%p while the published natural history data reports declines of at least 2.7% and 3.8% for MEP%p and MIP%p, respectively.  Based on this data which suggests that the rate of decline is halved by treatment with eteplirsen, the authors note that treatment with eteplirsen may have a clinically significant, disease-modifying impact on the natural course of DMD amenable to exon 51 skipping in ambulatory individuals.  That said, a number of considerations limit interpretation of this data, including the post-hoc nature of the analysis, difficulty in interpreting modest changes in FVC, which are effort and coaching dependent, the small size of the study, the absence of a placebo group, and methodological assumptions regarding published natural history data.  The association between pulmonary function and other health outcomes should be assessed in ongoing post-approval follow-up data, including rates of hospitalization for respiratory events, risk of postoperative respiratory insufficiency, need for assisted cough techniques, nocturnal ventilation, full-time ventilation, quality of life and mortality data.

Earlier published data includes a double-blind, placebo-controlled study conducted by Mendell and colleagues (2013) to evaluate eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT).  Boys diagnosed with DMD (n=12), aged 7 to 13 years, with confirmed deletions correctable by skipping exon 51, and a stable steroid regimen, were randomized to weekly intravenous (IV) infusions of 30 or 50 mg/kg of eteplirsen or placebo for 24 weeks (n=4 per group).  The placebo group switched to 30 or 50 mg/kg eteplirsen (n=2 per group) at week 25 and treatment became open-label thereafter.  All study enrollees had muscle biopsies at baseline and week 48.  Efficacy measurements included dystrophin-positive fibers from biopsy and distance walked on the 6MWT.  At week 24, the 30 mg/kg eteplirsen group’s percentage of dystrophin-positive fibers had increased to 23% of normal, whereas no increases were found in the placebo group (p≤0.002).  Of the 4 boys who had consistent increases in dystrophin-positive fibers, 2 (50%) concurrently experienced a rapidly progressive decline in motor function (ability to ambulate was lost).  The increases in the treatment group’s dystrophin-positive fibers were greater by week 48 (52% and 43% in the 30 and 50 mg/kg cohorts, respectively).  Boys from the treatment group with evaluable ambulation experienced a 67.3 m benefit compared to the placebo group (p≤0.001); this result includes 4 boys treated with a non FDA-approved dose of 50 mg/kg dose; 2 were treated with the 30 mg/kg dose.  No severe adverse events were reported.  The FDA has recommended retraction of this study due to concerns related to interpretation of its findings.

There is an on-going Phase III confirmatory study on eteplirsen’s efficacy as a treatment for DMD with a target enrollment of 160 subjects (PROMOVI; NCT02255552).  PROMVI is an open-label, multi-center 48 week study.  Boys with DMD that are amenable to skipping exon 51 will be administered 30 mg/kg of eteplirsen IV, weekly.  Boys with DMD not amenable to skipping exon 51 will serve as a concurrent control arm.  Eligibility criteria are similar to the preceding studies conducted investigating the safety and efficacy of eteplirsen and include boys aged 7 to 16 years of age on a stable dose of corticosteroids.  The primary outcome of interest is change in 6MWT from baseline and secondary study objectives include documented changes from baseline in the percent of dystrophin-positive muscle fibers and PFT results.  The estimated primary completion date is January 2019.  There are additional studies being conducted to assess eteplirsen’s efficacy in both early (ages 4-6) and more advanced (ages 7-21) stages of DMD (NCT02286947, NCT02420379).

While noted methodological limitations complicate interpretation of clinical trial data, clinical use of eteplirsen as a disease modifying therapy for individuals with DMD amenable to exon 51 skipping is supported by biological plausibility because production of dystrophin at the fiber level may be sufficient to produce a clinical benefit even though the overall average of dystrophin is only minimally increased.  Thus, ongoing observations of preservation of ambulation exceeding the natural, expected course of disease provides support that eteplirsen may delay loss of ambulation in this progressive disease.  There are other outcomes of interest, such as respiratory function (and potential to delay onset of mechanical ventilation) and upper extremity strength (and potential to delay loss of ability to perform activities of daily living) which have not yet been evaluated in the peer reviewed literature.

In a guidance document published in 2018 by the U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), the following direction has been provided for future study of disease-modifying therapies for DMD:

FDA strongly recommends randomized placebo-controlled trials, which generally are the most efficient way to demonstrate efficacy of drugs to treat dystrophinopathies. In some circumstances, however, FDA may consider trials using external controls (historically controlled trials) to be adequate and well controlled studies that may contribute to evidence of efficacy to support approval. However, FDA recognizes that historically controlled trials lack important design features that reduce bias, such as randomization and masking of treatment assignment and generally are persuasive only when drug effects are large on objective endpoints that are less susceptible to bias.


Duchenne Muscular Dystrophy

Muscular dystrophy (MD) refers to a diverse group of genetic diseases (disorders) characterized by a decrease in muscle mass over time, including progressive damage and weakness of facial, limb, breathing, and heart muscles.  Some disorders within this group, referred to as dystrophinopathies, are categorized based on clinical features (such as, the age when signs are first seen), genetic (inheritance) pattern, the muscles affected, and muscle biopsy features.  A major type of MD is DMD, and is the most common form affecting children.

DMD is X-linked recessive and penetrance is complete in males.  The gene that codes for dystrophin is the largest known human gene.  A molecular confirmation of DMD is achieved by confirming the presence of a pathogenic variant in this gene by a number of available assays.  The large size of the dystrophin gene results in a complex mutational spectrum with over 5000 different reported mutations as well as a high spontaneous mutation rate.  The DMD gene is the only gene in which mutations are known to cause DMD and DMD-associated cardiomyopathy.

It is estimated that 9000-12,000 boys in the United States (US) have been diagnosed with DMD.  The disease prevalence for DMD is typically estimated with the prevalence of BMD.  Diagnosis usually occurs around age 6 when symptoms begin to manifest and by the age of 10 most boys have lost the ability to ambulate.  Few individuals survive into their fourth decade of life.  The current standard of care focuses on management of symptoms associated with DMD and includes treatment with steroids to reduce the characteristic loss in muscle function.

Eteplirsen targets exon 51 using a molecule called an antisense oligonucleotide.  It has been estimated that 13% of boys with DMD may benefit from skipping exon 51 (1200-1500 boys in the US).  DMD is caused by a mutation in the gene encoding the protein dystrophin.  Eteplirsen induces skipping of exon 51 in the dystrophin pre-messenger RNA to correct this DMD-related mutation.  The following are genetic mutations that may be found in boys with DMD which are amenable to exon 51 skipping: 45-50 deletion; 48-50 deletion; 49-50 deletion; 50 deletion; 52 deletion.  Eteplirsen is designed to restore the messenger RNA reading frame so that a truncated but partially functional form of the dystrophin protein can be produced by muscle cells; similar truncated dystrophin is found in a less severe form of muscular dystrophy, BMD.

Most common adverse reactions listed on the FDA PI Label (2018) include the following:

Additional considerations and recommendations from the FDA PI Label (2018):


Antisense oligonucleotide: A short strand of deoxyribonucleotide analogue that hybridizes with the complementary messenger ribonucleic acid in a sequence-specific manner via Watson-Crick base pairing.

Cardiomyopathy: A condition in which the heart muscle becomes enlarged, thick, or rigid. In rare cases, the muscle tissue in the heart is replaced with scar tissue.

Exon: Parts of a gene sequence that are expressed in a protein.

Exon 51 skip-amenable Duchenne Muscular Dystrophy: The presence of exon 51 in the dystrophin gene and the deletion of one or more exons contiguous with exon 51, resulting in an out-of-frame deletion in which the reading frame is potentially restorable by the skipping (removing) of exon-51 (e.g., deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63), as confirmed in a Clinical Laboratory Improvement Act-accredited laboratory by any of the peer-reviewed and published methodology that evaluates all exons (including, but not limited to, multiplex ligation-dependent probe, comparative genomic hybridization, and single condition amplification/internal primer analysis).

Pulmonary function tests: A set of non-invasive tests that show how well the lungs are working by measuring lung volume, capacity, rates of flow, and gas exchange.


The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:




Injection, eteplirsen, 10 mg [Exondys 51]



ICD-10 Diagnosis




Duchenne or Becker muscular dystrophy


When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other indications.


 Peer Reviewed Publications:

  1. Kinane TB, Mayer OH, Duda PW, et al. Long-term pulmonary function in Duchenne muscular dystrophy: Comparison of eteplirsen-treated patients to natural history. J Neuromuscul Dis. 2018; 5(1):47-58.
  2. Mazzone E, Martinelli D, Berardinelli A, et al. North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant boys with Duchenne muscular dystrophy. Neuromuscul Disord. 2010; 20(11):712-716.
  3. McDonald CM, Henricson EK, Abresch RT, et al. The 6-minute walk test and other clinical endpoints in duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study. Muscle Nerve. 2013; 48(3):357-368.
  4. Mendell JR, Goemans N, Lowes LP, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016; 79(2):257-271.
  5. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al.; Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013; 74(5):637-647.
  6. Randeree L, Eslick GD. Eteplirsen for paediatric patients with Duchenne muscular dystrophy: A pooled-analysis. J Clin Neurosci. 2018; 49:1-6.
  7. Ricotti V, Ridout DA, Pane M, et al. The North Star Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials. J Neurol Neurosurg Psychiatry. 2016; 87(2):149-155.
  8. Voit T, Topaloglu H, Straub V, et al. Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol. 2014; 13(10):987-996.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Bourke JP, Bueser T, Quinlivan R. Interventions for preventing and treating cardiac complications in Duchenne and Becker muscular dystrophy and X-linked dilated cardiomyopathy. Cochrane Database Syst Rev. 2018 Oct 16;10:CD009068.
  2. Eteplirsen: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated August 06, 2018. Available at: Accessed on December 11, 2018.
  3. Eteplirsen. Food and Drug Administration (FDA) Briefing Document: Peripheral and Central Nervous System Drugs Advisory Committee Meeting. January 22, 2016a. Available at:
    . Accessed on December 11, 2018. 
  4. Eteplirsen Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised January 29, 2018. Accessed on December 11, 2018.
  5. Exondys 51 [Product Information]. Cambridge, MA. Sarepta Therapeutics, Inc. Revised October 11, 2018. Available at: Accessed on December 11, 2018.
  6. Food and Drug Administration (FDA) Center for Drug Evaluation and Research. Summary minutes of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting. April 25, 2016b. Available at:
    . Accessed on December 11, 2018.
  7. Sarepta Therapeutics. An open-label, multi-center study to evaluate the safety and tolerability of eteplirsen in early stage Duchenne muscular dystrophy. NLM Identifier: NCT02420379. Last Updated on November 26, 2018. Available at: Accessed on December 11, 2018. 
  8. Sarepta Therapeutics. An open-label, multi-center study to evaluate the safety and tolerability of eteplirsen in patients with advanced stage Duchenne muscular dystrophy. NLM Identifier: NCT02286947. Last Updated on May 11, 2018. Available at: Accessed on December 11, 2018. 
  9. Sarepta Therapeutics. Confirmatory study of eteplirsen in DMD patients (PROMOVI). NLM Identifier: NCT02255552. Last Updated on November 26, 2018. Available at: Accessed on December 11, 2018.  
  10. U.S. Department of Health and Hhuman Services, Food and Drug Andiminstration, Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment Guidance for Industry. February 2018. Available at: Accessed on December 12, 2018. 
Websites for Additional Information
  1. U.S. National Library of Medicine®. Genetics Home Reference. Available at: Accessed on November 28, 2018.
  2. DMD. Last updated February 2017. Available at: Accessed on November 28, 2018.
  3. Duchenne and Becker muscular dystrophy. Last updated November 2016. Available at: Accessed on November 28, 2018.
  4. DMD-associated dilated cardiomyopathy. Last updated February 2017. Available at: Accessed on November 28, 2018.
Document History






Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Title with registered trademark symbol. Updated Rationale, Background/Overview and References sections.



Updated Coding section with 10/01/2018 ICD-10-CM diagnosis code change to G71.01.



MPTAC review. Clarified MN statement. Updated Rationale and References sections. Updated Coding section to remove C9484 deleted 12/31/2017 and NOC codes.



MPTAC review. Updated header language from “Current Effective Date” to “Publish Date.” Revised criteria to include MN statement. Updated Rationale, Background/Overview, References and Websites sections. Updated Coding section to include 01/01/2018 HCPCS changes.



MPTAC review. Updated References and Websites sections.



MPTAC review. Updated Rationale, Background/Overview and References sections. Updated Coding section with 04/01/2017 HCPCS changes.



MPTAC review. Initial document development.