The FDA has issued a complete response letter (CRL) to Merck & Co’s gefapixant candidate for refractory chronic cough, delaying the programme and giving Bayer an opportunity to close the gap with its rival eliapixant drug.
Gefapixant is still out in front in the non-narcotic, orally administered selective P2X3 receptor antagonist class – having secured a first regulatory approval in Japan as Lyfnua last week – but the FDA’s decision could threaten its chances of being first to market in the large US market.
In a statement, Merck said that the US regulator had raised questions about the “measurement of efficacy” in trials of gefapixant, adding that the reason for the rejection was “related to the safety” of the drug.
Merck filed for approval of gefapixant in March 2021 on the strength of a pair of phase 3 trials – COUGH-1 and COUGH-2 – which found that the drug reduced 24-hour cough frequency by 18% and 15% respectively compared to placebo. The frequency was measured using coughs per hour using sound recordings.
Taste-related adverse events were the top reported side effect with the drug, leading to discontinued therapy in between 15% and 20% of subjects in the phase 3 trials.
At the moment there are no approved therapies for suppressing refractory chronic cough, defined as lasting for eight weeks or more, which is estimated to affect somewhere between 5% and 10% of people worldwide, according to Merck.
Bayer is thought to be closest behind Merck with eliapixant, reporting encouraging results in the phase 2b PAGANINI trial last September, which used the same efficacy endpoint as Merck’s studies.
It is slightly ahead of Bellus Health with BLU-5937, another P2X3 inhibitor, which hit the mark in the mid-stage SOOTHE trial a few weeks later after disappointing in an earlier readout.
Both are heading for phase 3 programmes later this year, so the rivals will doubtless be looking for clues from the FDA to see how the design of those studies may be affected by the gefapixant decision.
Merck meanwhile will have to wait for further discussions with the FDA to determine whether it can tweak or supplement the data already filed for the drug, or will have to run another trial on a drug that analysts have predicted could generate fairly modest peak sales of less than $500 million.
Gefapixant was supposed to come up in front of an FDA advisory committee last year – which would have revealed more of the agency’s thinking on the drug – but that was among the meetings dropped as a result of pandemic disruption.
“We remain committed to advancing gefapixant for patients with refractory or unexplained chronic cough and will work with the FDA to address the agency’s feedback,” said Roy Baynes, Merck’s chief medical officer.
“We believe there is a significant unmet need to help patients manage their chronic cough, as there are no available treatment options indicated in the US specifically for this condition,” he added.
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