P2X3 receptor

Nocion Therapeutics on Monday said it raised $62 million in a Series B round to advance development of an inhaled treatment it hopes will help silence unrelenting bouts of coughing."There is a real need for novel treatments beyond P2X3 antagonists and we believe that… taplucanium has the potential to become a novel modality for refractory chronic cough patients," said Pini Orbach, head of pharma at Arkin Bio Capital, which co-led the fundraise along with Monograph Capital.P2X3 disappointmentsHopes for the P2X3 class fizzled last December after Merck & Co. failed for a second time in its bid to secure an FDA approval for gefapixant after the agency concluded the candidate did not meet the efficacy bar when it comes to treating refractory or unexplained chronic cough. The drug is authorised in the EU and Japan, however, under the name Lyfnua.Similarly, Bayer scrapped an Evotec-partnered P2X3 antagonist programme in 2022. The pair had been working on filapixant (BAY 1902607) and eliapixant (BAY 1817080), both of which were associated with a concerning level of taste-related side effects.Broader mechanismNocion says its dry-powder inhalation treatment, currently in Phase IIb testing, could overcome the limitations of previous cough therapies. Taplucanium, formerly NTX-1175, belongs to a new class of compounds called permanently charged sodium channel blockers (CSCBs), which the company refers to as "nocions." These molecules are designed to preferentially target activated nociceptors, the sensory neurons responsible for triggering cough, itch, and pain responses.Unlike other investigational cough therapies, such as P2X3 receptor antagonists, which target a specific large pore channel (LPC), taplucanium gains access to the nociceptor through any open LPC. Once inside, nocions block sodium channels responsible for initiating the pathological cough response. Moreover, because they are charged, nocions are essentially trapped inside target cells, allowing them to provide a targeted and sustained effect.Taplucanium’s broad mechanism of action has shown significant antitussive effects in preclinical models of cough, according to the company.Phase III readinessCEO Richard Batycky said proceeds from the Series B will enable the company to conduct additional toxicology and product development, "with an eye towards being ready for Phase III clinical trials."The fundraise included contributions from new and existing investors such as Canaan Partners, F-Prime Capital, Mass General Brigham Ventures, Mission BioCapital and Osage University Partners. Nocion has raised $122 million since its founding in 2018.

Investors have poured $62 million into a biotechnology startup developing a drug to treat chronic cough.Nocion Therapeutics, headquartered in Watertown, Massachusetts, announced Monday it completed a Series B fundraise that was co-led by Arkin Bio Capital and Monograph Capital and included participation from Canaan Partners, F-Prime Capital and others. The company has now raised $122 million since its launch in 2018.Nocion is developing small molecule drugs that, as its name suggests, target nociceptors, sensory neurons that respond to the environment. Activation of those neurons can result in pain, itching or coughs. Nocions medicines are designed to silence them, a strategy it believes could help treat a range of conditions.The companys lead drug is an experimental, inhalable therapy called taplucanium. Its being tested in people with chronic cough, a type of cough that lasts for more than eight weeks. A Phase 1 study completed in 2022. Nocion will use its latest funds to start a Phase 2b study in refractory chronic cough, a persistent cough that doesnt have a clear cause and cant be relieved by treating whatevers thought to be the underlying condition. The company also said in a statement it will begin preparations for a late-stage study.In targeting refractory chronic cough, Nocion is chasing after medicines owned by larger drugmakers. Merck & Co. developed a drug known as gefapixant that succeeded in testing but was twice rejected by the Food and Drug Administration due to questions about its effectiveness. GSK acquired a similar type of medicine when it bought Bellus Health for $2 billion last year. Results from a Phase 3 study of GSKs drug are expected in 2025.Both of those therapies work differently than taplucanium, instead targeting a receptor called P2X3.There is a real need for novel treatments beyond P2X3 antagonists and we believe that Nocions inhaled taplucanium has the potential to become a novel treatment modality for refractory chronic cough patients, said Pini Orbach, the head of pharma at Arkin Bio.Nocion is led by Richard Batycky, the former founder of Civitas Therapeutics, a startup Acorda Therapeutics acquired in 2014 and that developed the Parkinsons disease therapy Inbrija. Its technology was licensed from Harvard University and Boston Childrens Hospital. '

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.