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Sarepta Therapeutics Seeks FDA Review of Eteplirsen for Treatment of Duchenne Muscular Dystrophy

CEO resigns after tardy submission

Sarepta Therapeutics, Inc. has held a pre–new drug application (NDA) meeting with the FDA regarding eteplirsen for the treatment of patients with Duchenne muscular dystrophy (DMD).

The company agreed with the agency to initiate a rolling NDA submission and expects to submit the final component of the NDA by mid-year 2015.

According to Sarepta, the underlying cause of DMD is a mutation or error in the gene for dystrophin, an essential protein involved in muscle-fiber function. The company’s investigational therapies for the disease are designed to skip an exon of the dystrophin gene to correct specific genetic mutations and to restore the gene’s ability to make a functional, although shorter, form of the dystrophin protein.

Eteplirsen is designed to skip exon 51 in the dystrophin gene. About 13% of DMD patients may be treated with an exon 51-skipping therapy. Other drug candidates in early-stage development skip exons 8, 44, 45, 50, 52, 53, and 55.

In January, Sarepta announced mixed data from a small, phase IIb, open-label extension study of eteplirsen in patients with DMD. After more than 3 years of treatment, the results of the 6-minute walk test (6MWT) at 168 weeks showed continued ambulation in all patients evaluable on the test; however, all patients also showed a decline in the distance walked on this measure after week 144. The study met its primary endpoint of increased novel dystrophin, as assessed by muscle biopsy at week 48.

At week 168, the six patients in the modified intent-to-treat (ITT) cohorts receiving eteplirsen (30 or 50 mg/kg) who were able to perform the 6MWT experienced a decline of 76.7 meters, or about 19.5%, from baseline in walking ability. A statistically significant treatment benefit of 65.4 meters (P ≤ 0.017) was observed compared with the placebo/delayed-treatment cohort (n = 4), which initiated active treatment at week 25 after receiving placebo for 24 weeks. This cohort, after experiencing a substantial decline of 68.4 meters from baseline to week 36, demonstrated a decline of 73.0 meters in walking ability from week 36 through week 168, the period from which meaningful levels of dystrophin were likely produced. These analyses were based on the maximum 6MWT score when the test was performed on two consecutive days.

Respiratory muscle function from baseline through week 168 in the ITT population (n = 12), as measured by maximum inspiratory and expiratory pressure (MIP and MEP), continued to show a 11.1% mean increase in MIP and a 14.7% mean increase in MEP. Analyses of MIP percent predicted (MIP adjusted for weight) and MEP percent predicted (MEP adjusted for age) demonstrated a mean change from 91.7% at baseline to 89.5% at week 168 in MIP percent predicted, and a mean change from 79.3% at baseline to 74.3% at week 168 in MEP percent predicted. In addition, a mean increase in forced vital capacity (FVC), a measure of lung volume, of 11.6% was noted. The FVC percent predicted (FVC adjusted for age and weight) was maintained above a mean of 90% at week 168, with 101.3% at baseline and 91.9% at week 168.

According to a report on the BioSpace website, Sarepta had been criticized during the past year for failing to receive timely approval of eteplirsen from the FDA, which ultimately led to the resignation of the company’s chief executive officer.

Sources: Sarepta Therapeutics; May 19, 2015; Exon Skipping; 2014; Sarepta Therapeutics; January 12, 2015; and BioSpace; May 20, 2015.

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