Eliapixant

Pictured: Merck Research Laboratories building in California/iStock, hapabapa For the second time in nearly two years, Merck has failed to secure regulatory approval for its chronic cough drug gefapixant. In a Complete Response Letter issued Wednesday, the FDA said that Merck’s data package for gefapixant “did not meet substantial evidence of effectiveness” for the treatment of refractory chronic cough (RCC) or unexplained chronic cough (UCC) in adults. The regulator did not point to safety issues related to the drug candidate. Joerg Koglin, senior vice president of global clinical development at Merck Research Laboratories, said in a statement that the company is “disappointed” by the FDA’s decision, adding that there is currently a “significant unmet medical need” in the field of chronic cough and an “absence of any approved treatments for refractory or unexplained chronic cough.” The pharma giant will review the FDA’s letter and feedback to determine the next steps for gefapixant, according to Wednesday’s announcement. Gefapixant is an orally available P2X3 receptor antagonist that works by preventing the signaling cascade in the airways that culminates in a cough reflex. Merck first tried for an FDA approval in 2021 but was ultimately rejected in January 2022. Despite the regulatory speedbump, Merck said at the time that it remained “committed” to gefapixant’s development. However, Merck’s resubmission was similarly met with strong skepticism from the FDA. In a briefing document released ahead of a November 2023 advisory committee meeting, the regulator’s reviewers still found the efficacy data for gefapixant to be underwhelming. Treatment “showed a small reduction in cough frequency,” according to the reviewers, who were uncertain whether gefapixant’s effects were clinically meaningful or not. A few days later, the FDA’s Pulmonary-Allergy Drugs Advisory Committee shared the same concerns and voted 12-1 against gefapixant. Gefapixant’s regulatory stumble on Wednesday continues the industry’s losing streak in the chronic cough space. In February 2022, Bayer discontinued the Phase II development of eliapixant, which is also a P2X3 receptor antagonist, following its disappointing benefit-risk profile. Eliapixant was being developed for RFC, overactive bladder, endometriosis and diabetic neuropathic pain. Seeking to take advantage of this void in the marketplace, GSK in April 2023 signed a $2 billion contract to acquire Bellus Health, gaining access to its cough candidate camlipixant. In December 2021, the candidate aced the Phase IIb SOOTHE trial, eliciting strong reductions in cough frequency versus placebo. Like gefapixant and eliapixant, camlipixant is a P2X3 receptor agonist and has best-in-class potential, according to GSK. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

F acade of the FDA’s office in Maryland iStock, Grandbrothers In a 12-1 tally, the FDA’s Pulmonary-Allergy Drugs Advisory Committee determined that the data does not establish a clinically meaningful benefit in this indication. Pictured: Exterior of an FDA building/iStock, Grandbrothers Merck ’s gefapixant could face an uphill battle to FDA approval after an advisory committee voted overwhelmingly on Friday to reject the chronic cough treatment. The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 12-1 that the evidence supplied by Merck does not show a clinically meaningful benefit to adult patients with refractory or unexplained chronic cough. Jennifer Schwartzott, the patient advocate on the committee, provided the only yes vote. The vote does not come as a surprise after the FDA said in briefing documents prior to the meeting that gefapixant showed “a small reduction in cough frequency” and that uncertainty remained as to “whether the effect is clinically meaningful.” In a statement following the adcomm, Merck voiced its disagreement with the verdict. Joerg Koglin, senior vice president of global clinical development at Merck Research Laboratories, said there was “strong, comprehensive” data demonstrating “a meaningful clinical benefit” for adults with refractory or unexplained chronic cough. The FDA is slated to make its decision on gefapixant on or before Dec. 27. The regulator is not compelled to heed the advice of its advisory committees, though it often does. There are currently no approved treatments in the U.S. for refractory or unexplained chronic cough. Original article published Nov. 17: FDA Raises Efficacy Concerns About Merck’s Chronic Cough Drug Ahead of Adcomm Meeting Merck ’s drug to treat chronic cough, the P2X3 receptor antagonist gefapixant, is facing some concerns about its effectiveness from the FDA ahead of Friday’s advisory committee meeting. According to the FDA’s briefing document , the agency’s assessment of the data that has been submitted by Merck is that gefapixant “showed a small reduction in cough frequency” while uncertainty remains as to “whether the effect is clinically meaningful.” Merck’s briefing document makes the case for a clinically meaningful reduction in cough frequency in patients, emphasizing that the drug’s efficacy claim is based on two Phase III trials that looked at gefapixant in adults. The primary endpoint was the reduction of 24-hour cough frequency, as measured by the VitaloJAK cough counting system. Merck maintains that both studies met the primary endpoint criteria. Those with a 45-mg dose had a reduction of 18.45%, a p-value of p=0.041% at week 12, and a 14.64% reduction at week 24, earning a p-value of p=0.031. The 15-mg section did not “differentiate” from the placebo, according to the company. “Based on this result, the proposed dosing regimen is gefapixant 45 mg [twice daily] (and the results presented in this document largely focus on this regimen),” according to Merck. However, the FDA document notes that disturbance or loss of taste occurred in up to 65% of participants taking the drug, while around 14% of patients had discontinued the trial. “With a large placebo response and wide range of cough frequencies at baseline, we question if the small treatment difference in cough frequency is noticeable to patients. What constitutes a meaningful reduction in cough frequency is not established; therefore, we ask the Committee to consider whether the change in cough frequency with gefapixant will be perceptible and meaningful to patients,” the FDA said in its briefing document. Gefapixant has had a rough path in the regulatory approval process. After the drug’s NDA was accepted to be reviewed by the FDA in 2021, it encountered a speed bump a year later. In January 2022, the regulator issued a Complete Response Letter to Merck. While the company did not explain why the CRL was handed down, safety issues were not the cause and Merck said it remained “committed” to advancing the drug. Friday’s adcomm meeting for gefapixant comes as competition is bearing down on Merck in the chronic cough treatment arena. In April 2023, GSK inked a $2 billion deal to acquire Canadian biotech Bellus Health, gaining access to its chronic cough candidate camlipixant. That drug is also an antagonist of the P2X3 receptor and had met its primary endpoint in a 2021 clinical trial. Meanwhile, Bayer jumped out of the chronic cough space last year, abandoning Phase II development of eliapixant, which was being developed for chronic cough and endometriosis, diabetic neuropathic pain and overactive bladder. Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn .