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P2X3 cough drug: Negative Ph II = 70% loss of stock price but severe patient group may show the way.

Targeting the right patient population in clinical trials is key to avoiding a false negative and giving a medicine the best chance of success. Recent data from Bellus health shows their P2X3 compound, BLU-5937, failed in the primary endpoint measure against cough. Their stock was immediately down 70%. However, all may be not lost as they have encouraging signals from a sub-group of more severe cough patients.

P2X3 receptor channels are attractive therapeutic targets as they are expressed in sensory neurons, activated by extracellular ATP and serve important roles sensory hypersensitization including pain.

Merck is leading the field in this area after they gained gefapixant, also known as MK-7264, in the 2016 takeover of Afferent Pharmaceuticals. The therapeutic focus for P2X3 has been on chronic cough, with plenty of opportunity to expand into other areas. They recently presented positive Phase III efficacy but the top dose of the compound was associated with taste-related events, which led to some discontinuations. Bellus Health were awaiting their Phase II data with the hope of similar efficacy and superior safety. Unfortunately, the primary endpoint measure was not met within the study.

From the press release:

BELLUS Health Announces Topline Results from its Phase 2 RELIEF Trial of BLU-5937 for the Treatment of Refractory Chronic Cough

- Primary endpoint of placebo-adjusted reduction in awake cough frequency did not reach statistical significance

- Highly statistically significant and clinically meaningful reductions in placebo adjusted awake cough frequency achieved in pre-specified analysis of high cough count patients (baseline cough frequency at or above the median)

- BLU-5937 was well tolerated with low impact on taste perception; safety profile comparable to placebo

- Patient enrichment strategy with higher cough count patients to be pursued in adaptive Phase 2b trial expected to start in Q4 2020

The efficacy in the chronic cough patient group may lead a way forward for the company to progress. Despite the huge impact on the stock some analysts remain positive.

An interesting point to consider for all clinical trials is the optimum patient group for the drug target mechanism of action. In the pain area there is an over-focus on the ~10 conditions with established regulatory pathway to approval, rather than considering the ~100 conditions associated with pain which may have a better link to the drug target. At the same time, it is important to consider whether there is a sub-population to which the drug may be more effective e.g. severity of symptom and phase of disease acute/chronic.

Identifying a precise, mechanistically relevant patient population along with the most relevant endpoint measure is key for future success of any clinical trial, particularly at the Phase II PoC stage.

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