The Committee for Medicinal Products for Human Use (CHMP) — part of the European Medicines Agency (EMA) — is recommending against Exondys 51 (eteplirsen) as a therapy for Duchenne muscular dystrophy (DMD) patients amenable to skipping exon 51 of the dystrophin gene, the treatment’s developer, Sarepta Therapeutics, has announced.
The company supported its marketing request for Exondys with results from two studies involving 12 boys with DMD, ages 7 to 13.
The first, a Phase 2 trial (NCT01396239), randomized 12 patients to receive weekly infusions of Exondys 51 or a placebo over 24 weeks. Its primary goal was dystrophin production, and researchers also assessed patients’ performance on the six-minute walk test. Results showed no significant difference in change walking distance in six minutes between treated and placebo patients.
All study participants continued on weekly Exondys 51 treatment the second study, an open-label trial (NCT01540409) that ran for four years and moved the walk test to a co-primary study objective.
Clinical data collected from these Duchenne patients and covering both trials were compared with established DMD natural history data.
Analysis showed that patients who received weekly intravenous administrations of Exondys 51, at either 30 mg per kilogram of body weight, or 50 mg/kg, experienced a statistically significant and clinically meaningful reduction in pulmonary function decline. It also showed an increase in the amount of dystrophin protein up to 0.44% of normal levels after 48 weeks of treatment.
CHMP, in its negative opinion, questioned the evidence provided, particularly in the study’s small size, use of historical data, and failure to compare treated to placebo patients for beyond 24 weeks.
In their letter, committee members wrote that “the methods for comparing results of the main studies with historical data were not satisfactory for showing that the medicine was effective. … further data were needed to show that the very low amounts of shortened dystrophin produced as a result of Exondys treatment bring lasting benefits relevant to the patient.”
The letter concluded that “the CHMP was of the opinion that the balance of benefits and risks of Exondys in the treatment of DMD could not be established. Hence, the CHMP recommended that the marketing authorisation be refused.”
Sarepta said it would request a re-evaluation of the CHMP’s opinion and also request that a Scientific Advisory Group, composed of neuromuscular specialists, be assembled to provide “expert guidance and insight” into the data it offered regarding “the relevance of meaningful slowing pulmonary decline in patients with this difficult to treat disease.”
A re-examination is expected to be completed by year’s end, the company said in its release.
Exondys 51 was given conditional approval by the U.S. Food and Drug Administration (FDA) to treat DMD patients amenable to exon 51 skipping in September 2016.
A confirmatory and open-label Phase 3 study (NCT02255552) into Exondys 51’s efficacy, required by the FDA as part of its approval decision, is ongoing and due to conclude in May 2019. The trial’s primary endpoint, or goal, is improvements in the six-minute walk test after 96 weeks of treatment.
An estimated 80 patients, ages 7 to 16, with a mutation amenable to exon 51 skipping will receive Exondys. Another group of about 30 patients without such a mutation will remain untreated and serve as controls. The trial is underway at 39 sites across the United States.
Results of this Phase 3 trial results are expected to determine if the FDA continues to approve use of Exondys 51 as a DMD treatment.