Medical Policy: 05.02.03
Original Effective Date: October 2016
Reviewed: September 2018
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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.
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.
Exondys 51 (eteplirsen) is considered not medically necessary for all indications, including the treatment for DMD, due to insufficient evidence to demonstrate clinical efficacy.
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.
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