Merck has presented detailed phase 3 data on P2X3 receptor antagonist gefapixant. Across the two late-phase trials, the higher dose of the drug triggered improvements in several measures of chronic cough symptoms but also caused adverse events that drove a significant minority of patients to drop out of the study.
The phase 3 COUGH-1 and COUGH-2 trials are the biggest test of the class of P2X3 antagonists in development at companies including Merck, Bayer, Bellus Health and Shionogi to date, and largely confirm the strengths and weaknesses that emerged earlier in development.
In COUGH-1, Merck linked the 45-mg dose of gefapixant to an 18.5% estimated relative risk reduction in 24-hour coughs per hour at week 12, causing the trial to meet its primary endpoint. In COUGH-2, the same dose drove a 14.6% relative risk reduction at week 24. The 15-mg dose failed in both trials.
Secondary endpoints included assessments of awake coughs per hour and questionnaire scores. Neither dose of gefapixant statistically improved awake coughs per hour in COUGH-1, but the higher dose did move the needle in COUGH-2. Merck linked the higher dose to a 15.8% estimated relative risk reduction in COUGH-2.
The assessment of Leicester Cough Questionnaire scores in COUGH-2 also hit statistical significance. Merck reported the higher dose had an estimated difference versus placebo of 6.6%. Most people in all three cohorts, including the placebo arm, of the trial were classed as responders by their scores.
While the data show there is scope to improve on the efficacy of gefapixant, they also suggest the higher dose of the drug helps some patients. However, the drug also caused adverse events in most people.
In COUGH-1 and COUGH-2, 58.0% and 68.6% of 45-mg subjects, respectively, experienced an adverse event related to taste. Few patients suffered serious adverse events in either trial, but there are signs that the taste effects are intolerable for some patients. The dropout rates due to adverse events in the 45-mg arms of the two trials were 15% and 20%, compared to 3% and 5% in the placebo cohorts.
Those tolerability issues could become a big factor if competition for the market hots up. P2X3 and P2X2/3 are found on taste buds, suggesting a class-wide issue, but there is evidence the selectivity of molecules may affect the extent of the problem.
The competitive landscape has changed since Merck released top-line findings in March. Over the summer, Bellus reported that a phase 2 trial of BLU-5937 missed its primary endpoint. Bellus sees the midphase data as supportive of the efficacy of the P2X3 antagonist in higher cough patients, though, encouraging it to work to move the asset into a phase 2b trial later this year.
Bellus’ data, while raising doubts about efficacy, validated the tolerability benefits that the biotech sees as one of the advantages of its molecule. Less than 10% of patients experienced disturbances to their taste in the phase 2 and nobody dropped out due to that effect of BLU-5937.
Taste disturbances have been far more prevalent in other trials of P2X3 antagonists. Most patients in Merck’s phase 3 studies suffered taste disturbance. A small trial of Bayer’s BAY 1902607 found 61% of people experienced a taste-related adverse event after taking the drug. Even so, with phase 3 data in the bag, Merck is poised to take the first crack at the refractory and unexplained cough market.