GSK Halts Camlipixant After Mixed Phase III Results

GSK reported that its CALM-1 and CALM-2 phase III trials of camlipixant produced mixed results in refractory chronic cough (RCC), with one study meeting its primary endpoint and the other failing, prompting the company to discontinue the program. The decision closes out a five-year, USD 2 billion bet on the P2X3 receptor as a target for RCC treatment and leaves no obvious next-generation P2X3 candidate in late-stage development, with Merck's Lyfnua (gefapixant), the only approved drug in the class but one still absent from the US market.

Camlipixant, acquired by GSK when it bought Canada-based Bellus Health for USD 2 billion in 2023, is an oral small molecule that blocks the P2X3 receptor, an ATP-gated ion channel on airway sensory nerves implicated in the hypersensitized cough reflex characteristic of RCC. Selective P2X3 antagonism became a validated mechanism after Merck's gefapixant secured approval in Japan (2022) and the EU (2023), though the FDA twice rejected it — most recently in December 2023 when the overall effectiveness package was deemed insufficient. There is currently no approved RCC therapy in the US, a gap camlipixant had been positioned to fill given its improved taste-disturbance profile relative to earlier P2X3 candidates.

The CALM-1 trial, a 52-week study, met its primary endpoint: the 50mg twice-daily dose produced a statistically significant reduction in 24-hour cough frequency versus placebo at week 12. The 25mg dose did not reach significance. CALM-2, a 24-week study, failed on the same measure at week 24 for both doses. Key secondary endpoints, including a Chronic Cough Diary measure, missed target thresholds in both trials. Safety was unremarkable — the incidence and severity of treatment-related adverse events were similar between camlipixant and placebo across the program.

GSK concluded that the aggregate efficacy signal was "unlikely to transform patient care" and will not advance camlipixant further in RCC, though it plans to submit the CALM data for future publication.

The trial readouts underscore how difficult RCC has proven as a clinical target, even with genetically and pharmacologically validated mechanisms. Merck's own regulatory setbacks with gefapixant reflected similar inconsistency between efficacy signals and endpoints regulators consider clinically meaningful. The camlipixant CALM trials result suggests that modest, dose-dependent reductions in cough frequency — the standard efficacy measure across this drug class — may not reliably translate into the kind of benefit that satisfies both statistical thresholds and regulators' bar for meaningful clinical improvement.

The failure also narrows the competitive field in RCC just as the US market remains open. With gefapixant unapproved domestically and camlipixant now discontinued, no P2X3 antagonist has yet secured US approval despite multiple late-stage development programs. GSK is not abandoning the mechanism outright: the phase IIb BALANCE trial will continue testing camlipixant in irritable bowel syndrome with diarrhea and mixed subtypes, where P2X3 blockade is being explored for visceral hypersensitivity rather than cough. That shift reflects a broader trend of P2X3 antagonists finding traction in gastrointestinal indications where the mechanism is being explored in a distinct disease setting with different efficacy endpoints. For GSK, therefore, the RCC exit removes a late-stage respiratory asset from its pipeline but does not eliminate the underlying drug from development.

This article was generated with AI assistance and reviewed and edited by the AllSci editorial team. Explore more at AllSci News: https://allsci.com/news/

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