Eteplirsen (Exondys 51)

Number: 0911

Policy

Notes: REQUIRES PRECERTIFICATION.Footnotes for Precertification of eteplirsen^*

Site of Care Utilization Management Policy applies.  For information on site of service for Exondys 51 infusions, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

Aetna considers eteplirsen (Exondys 51) injection medically necessary for the treatment of individuals with a documented diagnosis of Duchenne muscular dystrophy (DMD) when the following criteria are met:

1. Member has a confirmed mutation of the DMD gene amenable to exon 51 skipping; and
2. Eteplirsen has been initiated in childhood (before 14 years of age); and
3. Member is able to achieve an average distance of at least 180m while walking independently over six minutes; and
4. Medication is prescribed by or in consultation with a physician who specializes in treatment of Duchenne muscular dystrophy.  

Aetna considers continued use of eteplirsen medically necessary for members who have demonstrated a response to therapy as evidenced by remaining ambulatory (e.g. able to walk with or without assistance, not wheelchair dependent).

Aetna considers eteplirsen (Exondys 51) injection experimental and investigational for all other indications.

The medically necessary dosage of eteplirsen is 30 mg/kg body weight once-weekly.

Note: Lab results from genetic testing are a required component of clinical documentation for precertification review.

Footnotes^* Precertification of eteplirsen is required of all Aetna participating providers and members in applicable plan designs.  For precertification of eteplirsen, call (866) 503-0857, or fax (866) 267-3277.

Background

Duchenne muscular dystrophy (DMD) is caused mainly by internal deletions in the gene for dystrophin, a protein essential for maintaining muscle cell membrane integrity. These deletions abrogate the reading frame and the lack of dystrophin results in progressive muscle deterioration.  Patients with DMD experience progressive loss of ambulation, followed by a need for assisted ventilation, and eventual death in mid-20s.  By the method of exon skipping in dystrophin pre-mRNA the reading frame is restored and the internally deleted but functional dystrophin is produced.  Two oligonucleotide drugs (drisapersen and eteplirsen) that induce desired exon skipping are currently in advanced clinical trials (Kole and Krieg, 2015).

Mendell and colleagues (2013) noted that in prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in DMD with genetic mutations amenable to skipping exon 51. The present study used a double-blind, placebo-controlled protocol to examine eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT).  Boys with DMD aged 7 to 13 years, with confirmed deletions correctable by skipping exon 51 and ability to walk 200 to 400 m on 6 MWT, were randomized to weekly intravenous infusions of 30 or 50 mg/kg/week eteplirsen or placebo for 24 weeks (n = 4/group).  Placebo patients switched to 30 or 50 mg/kg eteplirsen (n = 2/group) at week 25; treatment was open label thereafter.  All patients had muscle biopsies at baseline and week 48; effectiveness included dystrophin-positive fibers and distance walked on the 6MWT.  At week 24, the 30 mg/kg eteplirsen patients were biopsied, and percentage of dystrophin-positive fibers was increased to 23 % of normal; no increases were detected in placebo-treated patients (p ≤ 0.002).  Even greater increases occurred at week 48 (52 % and 43 % in the 30 and 50 mg/kg cohorts, respectively), suggesting that dystrophin increases with longer treatment.  Restoration of functional dystrophin was confirmed by detection of sarcoglycans and neuronal nitric oxide synthase at the sarcolemma.  Ambulation-evaluable eteplirsen-treated patients experienced a 67.3 m benefit compared to placebo/delayed patients (p ≤ 0.001).  The authors concluded that eteplirsen restored dystrophin in the 30 and 50 mg/kg/week cohorts, and in subsequently treated, placebo-controlled subjects.  Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability.  No severe adverse events (AEs) were encountered.

Mendell and associates (2016) continued evaluation of the long-term safety and effectiveness of eteplirsen in patients with DMD: 3-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). Ambulatory DMD patients who were greater than or equal to 7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks.  Thereafter, all received eteplirsen on an open-label basis.  The primary functional assessment in this study was the 6MWT.  Respiratory muscle function was assessed by pulmonary function testing (PFT).  Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36.  Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype.  At 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151 m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping.  Results  of PFT remained relatively stable in eteplirsen-treated patients.  Eteplirsen was well-tolerated.  Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable.  The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping.  The authors concluded that over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC.

An UpToDate review on “Treatment of Duchenne and Becker muscular dystrophy” (Darras, 2016) states that “Results from small clinical studies in humans suggest the promise of this approach [gene therapy]. A small open-label study found that weekly intravenous administration of the exon 51 skipping drug eteplirsen induced a dose-related increase in dystrophin production without drug-related adverse effects.  In a 24-week placebo-controlled trial with 12 patients, those assigned to the higher dose drug eteplirsen (50 mg/kg daily intravenously) showed a statistically significant improvement in the six-minute walk test.  Findings from an open-label extension phase of the study through 36 months suggested that, compared with historical controls, eteplirsen-treated patients had continued benefit on the six-minute walk test and a lower rate of loss of ambulation”.

On September 19, 2016, the Food and Drug Administration (FDA) granted accelerated approval to Exondys 51 (eteplirsen) injection -- the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 % of the population with DMD. The pivotal clinical trial of eteplirsen for FDA approval included children under 14 years of age at study entry. The accelerated approval of Exondys 51 was based on the surrogate end-point of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients.  The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.  The most common AEs reported by subjects taking Exondys 51 in the clinical trials were balance disorder and vomiting.  A clinical benefit of Exondys 51, including improved motor function, has not been established.  In making the decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.  Under the accelerated approval provisions, the FDA is requiring Sarepta Therapeutics to conduct a clinical trial  to confirm the drug’s clinical benefit.  The required study is designed to examine if Exondys 51 improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.  If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

In a pooled analysis, Randeree and Eslick (2018) analyzed the results of previous studies to evaluate the safety and efficacy of eteplirsen.  A literature search of electronic databases was performed.  Only human studies using eteplirsen were eligible.  A total of 4 relevant clinical studies were identified.  A pooled-analysis was performed using data relating to percentage dystrophin-positive fibers obtained from muscle biopsy, and the 6 MWT.  The average increase in percentage dystrophin-positive fibers after treatment with eteplirsen was 24.23 % (range of -4 to 78; SD 24.44 %).  The average rate of decline in distance walked was 65 metres (range of -335 to 83; SD 100.08 m).  The authors concluded that whether or not this increase in percentage dystrophin-positive fibers and distance walked was clinically significant was unclear, and there is therefore a need for more clinical trials.

Appendix

Exondys 51 injection is supplied in single-dose vials containing 100 mg/2 ml (50 mg/ml) eteplirsen or single-dose vials containing 500 mg/10 ml (50 mg/ml) eteplirsen.

The approved dosage of eteplirsen is 30 mg/kg body weight once-weekly.

U.S Food and Drug Administration(FDA).

The above policy is based on the following references: