Medical Policy: 05.02.03 

Original Effective Date: October 2016 

Reviewed: October 2017 

Revised:  

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Exondys 51 (eteplirsen) is indicated for treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. It is administered once weekly as an intravenous (IV) infusion and may be used as monotherapy or in combination with corticosteroids.

 

This indication is approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with Exondys 51. A clinical benefit of Exondys 51 has not been established.

 

Prior Approval:

 

Not applicable

 

Policy:

Exondys 51 (eteplirsen) is considered not medically necessary for all indications, including the treatment for DMD, due to insufficient evidence to demonstrate clinical efficacy. 

Clinical Rationale

Exondys 51 (eteplirsen) was evaluated in three clinical studies in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. The trials were not designed to evaluate long-term safety, and a clinical benefit of Exondys 51 (eteplirsen) has not been established.

 

In Study 1, patients were randomized to receive weekly infusions of eteplirsen (30 mg/kg, n=4); eteplirsen (50 mg/kg, n=4), or placebo (n=4) for 24 weeks. The primary endpoint was dystrophin production; a clinical outcome measure, the 6-minute walk test (6MWT), was also assessed. The 6MWT measures the distance that a patient can walk on a flat, hard surface in a period of 6 minutes. Patients had a mean age of 9.4 years, a mean 6-minute walk distance (6MWD) at baseline of 363 meters, and were on a stable dose of corticosteroids for at least 6 months. There was no significant difference in change in 6MWD between patients treated with eteplirsen and those treated with placebo.

 

All 12 patients who participated in Study 1 continued treatment with open-label eteplirsen weekly for an additional 4 years in Study 2. The 4 patients who had been randomized to placebo were re-randomized 1:1 to eteplirsen 30 or 50 mg/kg/week such that there were 6 patients on each dose. Patients who participated in Study 2 were compared to an external control group. The primary clinical efficacy outcome measure was the 6MWT. Eleven patients in Study 2 had a muscle biopsy after 180 weeks of treatment with eteplirsen, which was analyzed for dystrophin protein level by Western blot. Study 2 failed to provide evidence of a clinical benefit of eteplirsen compared to the external control group. The average dystrophin protein level after 180 weeks of treatment with eteplirsen was 0.93% of the dystrophin level in healthy subjects. Because of insufficient information on dystrophin protein levels before treatment with eteplirsen in Study 1, it is not possible to estimate dystrophin production in response to eteplirsen in Study 1.

 

In Study 3, 13 patients were treated with open-label eteplirsen (30 mg/kg) weekly for 48 weeks and had a muscle biopsy at baseline and after 48 weeks of treatment. Patients had a mean age of 8.9 years and were on a stable dose of corticosteroids for at least 6 months. Dystrophin levels in muscle tissue were assessed by Western blot. In the 12 patients with evaluable results, the pre-treatment dystrophin level was 0.16% ± 0.12% (mean ± standard deviation) of the dystrophin level in a healthy subject and 0.44% ± 0.43% after 48 weeks of treatment with eteplirsen (p < 0.05). The median increase after 48 weeks was 0.1% in the dystrophin levels after treatment with eteplirsen.  A statistically significant, yet marginal, increase in dystrophin was reported (0.22% to 0.32% of normal) but there was no evidence proving that this increase translated to a clinical benefit.

 

A Phase III confirmatory study on eteplirsen's efficacy as a treatment for DMD is currently recruiting participants. The confirmatory study called PROMVI is an open-label, multi-center 48-week study with a target enrollment of 160 subjects.  Boys with DMD that are amenable to skipping exon 51 will be administered a weekly 30 mg/kg IV dose of eteplirsen IV.  Boys with DMD not amenable to skipping exon 51 will serve as a concurrent control arm.  Eligibility criteria include boys aged 7 to 16 years of age on a stable dose of corticosteroids.  The primary outcome measure is change in 6MWT distance from baseline and secondary outcome measures include documented changes from baseline in the percent of dystrophin-positive muscle fibers and inspiratory/expiratory pressure percent predicted. Other outcome measures will include evaluating the long-term effects of eteplirsen up to 96 weeks. The estimated primary completion date is early 2019.  There are additional studies being conducted to assess eteplirsen's efficacy in both early and more advanced stages of DMD (NCT02286947, NCT02420379) with estimated primary completion dates of early 2018.

In summary, the clinical benefit of treatment for DMD with eteplirsen has not been demonstrated.  The establishment of a clinical benefit, including improved motor function, is warranted in on-going clinical trials.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD diagnostic codes.

  • J1428 Injection, eteplirsen, 10mg 
  • J3490 Unclassified drugs [when specified as eteplirsen (Exondys 51)]
  • J3590 Unclassified biologics [when specified as eteplirsen (Exondys 51)]

 

Selected References:

  • Exondys 51 [package insert]. Cambridge, MA: Sarepta Therapeutics, Inc.; September 2016.
  • 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.
  • 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.
  • Mendell JR, Goemans N, Lowes L, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in duchenne muscular dystrophy. Ann Neurol. 2016; 79(2): 257-271.
  • 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.
  • Ricottii V, Ridout DA, Pane M, et al. The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials. J Neurol Neurosurg Psychiatry 2016; 87(2):149-155.
  • 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.
  • Eteplirsen. Food and Drug Administration (FDA) Briefing Document: Peripheral and Central Nervous System Drugs Advisory Committee Meeting. January 22, 2016a. Accessed on October 17, 2016. Sarepta Therapeutics, Inc. Revised September 19, 2016. Accessed on September 20, 2016.
  • Exondys 51 [Product Information]. Cambridge, MA.
  • 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, 2016. Accessed on October 17, 2016.
  • 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 October 03, 2017. Accessed on October 24, 2017.
  • 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 October 04, 2017. Accessed on October 24, 2017.
  • Sarepta Therapeutics. Confirmatory Study of Eteplirsen in DMD Patients (PROMOVI). NLM Identifier: NCT02255552. Last Updated on October 3, 2017. Accessed on October 24, 2017.

 

Policy History:

  • October 2017 - Annual Review, Policy Renewed
  • October 2016 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.