The European Medicines Agency (EMA)'s Committee for Medicinal Products for Human Use (CHMP) has adopted a negative opinion, recommending against approval of eteplirsen (Exondys, Sarepta Therapeutics) for the treatment of Duchenne muscular dystrophy (DMD).
The decision is at odds with the controversial accelerated approval by the US Food and Drug Administration (FDA) of eteplirsen in September 2016, against the recommendation of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee, that concluded studies of eteplirsen failed to provide persuasive evidence that the drug is effective in DMD.
The European advisory panel appears to have had the same issue.
"The CHMP was concerned that the main study, which involved just 12 patients, did not compare Exondys with placebo beyond 24 weeks, during which there was no meaningful difference between Exondys and placebo in the 6-minute walking distance," a statement from EMA notes. "The methods for comparing results of the main studies with historical data were not satisfactory for showing that the medicine was effective."
"The Committee considered 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 CHMP writes.
"Therefore, the CHMP was of the opinion that the balance of benefits and risks of Exondys in the treatment of DMD could not be established," the statement concludes. "Hence, the CHMP recommended that the marketing authorisation be refused."
The company requested a re-examination of the CHMP's opinion on June 1, the CHMP release notes.
In its own statement, Sarepta acknowledges it was expecting the decision and will appeal it.
"As previously reported on Sarepta's May 5, 2018 earnings call, a negative opinion was anticipated following the oral explanation trend vote," the company notes. "Sarepta will request a re-examination of the opinion, which will result in the assignment of a new rapporteur and co-rapporteur. The Company will also request a Scientific Advisory Group (SAG) on DMD be called so that neuromuscular specialists, experienced with working with treatments for these patients, can provide expert guidance and insight into, among other things, the validity of the external controls used and the importance of certain functional endpoints, including for instance, the relevance of meaningful slowing pulmonary decline in patients with this difficult to treat disease."
The re-examination process is expected to be completed by year-end 2018, the company said.
Eteplirsen is indicated for patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which would apply to about 13% of the roughly 9000 to 12,000 people with DMD in the United States.
Extension of Indication for Ataluren
During the same meeting May 31, the CHMP adopted a positive recommendation for extension of the marketing authorization for a similar treatment, ataluren (Translarna, PTC Therapeutics) — already approved in the European Union for DMD resulting from a nonsense mutation in the dystrophin gene in ambulatory patients aged 5 years and older — to patients aged 2 years and older.
Efficacy has not been demonstrated in nonambulatory patients, the statement notes. The presence of a nonsense mutation should be determined by genetic testing, the CHMP release said.
"Detailed recommendations for the use of this product will be described in the updated summary of product characteristics (SmPC), which will be published in the revised European public assessment report (EPAR), and will be available in all official European Union languages after a decision on this change to the marketing authorization has been granted by the European Commission," a statement from EMA notes.
As reported by Medscape Medical News, ataluren first received conditional approval in Europe in May 2014 for treatment of DMD resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 5 years and older. CHMP subsequently recommended renewal of the conditional marketing authorization for ataluren in November 2016.
In the United States, however, PTC Therapeutics received a complete response letter for its application to the FDA on October 25, 2017, after the agency concluded that evidence of effectiveness "from an additional adequate and well-controlled clinical trial(s) will be necessary at a minimum to provide substantial evidence of effectiveness," the company said in a press release at that time.
Subsequently, the company launched a formal dispute resolution request to appeal that decision, but on February 20, PTC Therapeutics released a statement noting that the FDA Office of New Drugs had "reiterated the FDA's prior position and denied PTC's appeal of the Complete Response Letter in relation to the New Drug Application (NDA) for ataluren."
In its letter, the Office of New Drugs recommended a "possible path forward" for their NDA submission based on the accelerated approval pathway, the company writes.
"This would involve a re-submission of an NDA containing the current data on effectiveness of ataluren with new data to be generated on dystrophin production in nonsense mutation Duchenne muscular dystrophy (nmDMD) patients' muscles, as quantified by procedures to be agreed upon between PTC and the FDA and using newer technologies."
The letter adds that PTC's Study 041, which is enrolling, could serve as the confirmatory postapproval trial required in connection with the accelerated approval framework, the company concluded.
"In a clarification teleconference with the FDA promptly after receiving the letter, PTC indicated its intent to follow the FDA's recommendation and preliminarily discussed methods to collect such dystrophin data and expedite this potential path forward."
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Cite this: CHMP Advises Against Approval for Eteplirsen in DMD - Medscape - Jun 01, 2018.