July 19, 2017

Hits and Misses from the Cough Conferences – Part 1: A Review of the Merck P2X3 Antagonist Data

Over the course of the last couple of months, the BELLUS Health team attended two important conferences: the American Thoracic Society (ATS) Conference and the American Cough Conference (ACC). While ATS is a very large and broad respiratory conference, ACC is a highly-specialized conference focused primarily on chronic cough. It was at ATS that Merck presented for the first time the latest clinical results of their Phase 2b study for MK-7264 (formerly AF-219), our P2X3 antagonist benchmark competitor. In today’s blog, I’ll focus on the MK-7264 data, and discuss other learnings from the conferences in a subsequent post.

MK-7264 Hits the Mark on Cough…

Merck’s MK-7264, a P2X3 antagonist, performed well in two previous small Phase 2a studies. The clinical validation of the P2X3 target for the treatment of chronic cough was a major factor in our decision to invest in a P2X3 antagonist program ourselves (see April 12, 2017 blog). Presenters at the ACC repeatedly referred to Merck’s Phase 2a results as the benchmark efficacy data for treating chronic cough.

MK-7264 had not previously been studied in patients for more than 16 days however, so we (and, likely, the entire chronic cough field) were very curious to see longer term data. The Phase 2b clinical study was a 12-week study with more than 250 patients divided into four groups: one group on placebo and three groups on the drug (7.5mg, 20mg and 50mg twice daily). The effect on cough was important, particularly at the high dose of 50mg. At this dose, cough rate was reduced by more than 80% overall and by 37% compared to placebo. The two lower doses also showed trends of reduction in chronic cough rate, though not statistically different from placebo. Importantly, the reduction in cough frequency was maintained throughout the duration of the 12-week study. Overall, this kind of anti-cough effect is particularly impressive because the patient population in this study is refractory to all other treatments.

…But Misses on Taste

Many patients participating in the shorter Phase 2a studies experienced taste disturbances and even loss of taste. Patients in the 12-week Phase 2b study experienced similar gustatory adverse effects and did not get accustomed to the taste issue. To the contrary, the taste disturbances affected more patients at the 50mg dose (80% in the Phase 2b vs. 50% in the Phase 2a trial at the same dose) and persisted over the course of the study. Qualitatively, 40% of patients described the taste side effect as very or extremely bothersome in the 50mg dose group. Not surprisingly, a meaningful number – approximately 10% – of patients dropped out in this group as well. During the Q&A session, the presenter noted that patients that stopped therapy regained full taste within a couple of days.

MK-7264 Data Ideal for BELLUS’ BLU-5937

Merck’s Phase 2b data further validate the P2X3 receptor as the best target for chronic cough. MK-7264’s large and long-lasting effect on cough rate and severity strengthens our belief that the P2X3 antagonist class will deliver highly efficacious drugs for chronic cough and that BLU-5937 could be the best in its class.

The significant taste adverse effect is MK-7264’s Achilles’ heel. At the 50mg dose, MK-7264 is very effective but has a high rate of taste disturbance. At the lower doses, there is a significant reduction in taste disturbance, but only a moderate impact on cough rate. We anticipate Merck will conduct further studies with lower doses, but there does not appear to be a dose that significantly reduces cough rate without a problematic effect on taste. Merck’s presenter noted that the taste effect is likely due to MK-7264’s inhibiting P2X3 but also P2X2/3, the predominant receptor thought to be involved in taste function. Based on this conclusion, we believe that BLU-5937, which is highly selective for P2X3 (and therefore doesn’t inhibit P2X2/3), can deliver the ideal profile of having a strong effect on cough with limited or no effect on taste.

Notwithstanding the taste side effect, Merck stated that they are proceeding into Phase 3 with regulatory discussions planned over the course of this year. This bodes well for P2X3 as a drug class and for BLU-5937 as a fast-follower program.

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For those interested, we have more detailed information on Merck’s MK-7264 presentations at both ATS and ACC. Please contact me directly if you are interested in getting more information. 

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