Novel P2X3 antagonist can SOOTHE chronic cough

New phase 2b data of the SOOTHE trial showed a clinical benefit for the investigational P2X3 antagonist BLU-5937 for chronic cough, with fewer side effects than in previous trials.

Prof. Jaclyn Smith (University of Manchester, UK) presented the findings of the SOOTHE study [1]. The rationale behind the study is that refractory chronic cough typically lasts >8 weeks and does not respond to treatment of possible associated disease or is simply not associated with a disease. There are no approved treatment options. Hypersensitation of cough signalling pathways, including the P2X3 receptor, is thought to play a key role in refractory chronic cough, and P2X3 antagonists have shown some promise in clinical trials [2].

SOOTHE is a randomised, double-blind, placebo-controlled, parallel-arm, dose-finding, phase 2b trial (NCT04678206) of the investigational drug BLU-5937, which is a P2X3 antagonist with high selectivity. After a 3-week run-in period, 249 enrolled participants with more than 25 awake coughs/hour were randomised to either placebo twice daily (n=63) or to BLU-5937 12.5 mg (n=62), 50 mg (n=62), or 200 mg twice daily (n=62). In addition, 61 participants whose baseline cough frequency was between 10–25 coughs/hour were randomised to receive either placebo (n=30) or BLU-5937 200 mg twice daily (n=31). Treatment was provided for 28 days, and follow-up continued until day 43, 2 weeks after the final dose. Demographics and baseline characteristics were well-balanced across all treatment arms. The primary endpoint of the trial was change in objective cough frequency, as measured over 24 hours and calculated in the log-transformed geometric means ratio.

The results showed that the higher doses of BLU-5937 of 50 mg and 200 mg met the primary endpoint. The placebo-adjusted change in 24-hour cough frequency in the 12.5 mg arm dropped by 18.3% at day 15, and by 21.1% at day 28; although those reductions were not significant. However, for the 50 mg and 200 mg arms, coughing was reduced by 32–34% at day 15, which was sustained at 34% at day 28, with all measurements being significant (2-sided P<0.005). The absolute change in cough frequency was 53% for both 50 mg and 200 mg doses from baseline compared with a 28% absolute reduction in the placebo arm. The dose-finding part of the trial concluded that there was a dose-response between 12.5 and 50 mg, with no additional clinical benefit observed beyond 50 mg.

With regard to safety, no serious adverse events were reported, and similar mild adverse events were reported for placebo as for BLU-5937. Notably, mild taste disturbances were reported in the BLU-5937 arms, although none resulted in partial or total loss of taste. Prof. Smith concluded that both the important reductions in cough frequency as well as the observed, favourable safety profile support the continued clinical development of this P2X3 antagonist.

1. Smith JA, et al. Safety and efficacy of BLU-5937 in the treatment of refractory chronic cough from the phase 2b SOOTHE trial. Session C93, ATS International Conference 2022, San Francisco, CA, USA, 13–18 May.
2. Abdulqawi R, et al. Lancet. 2015;385(9974):1198–205.

 

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Posted on 18 July, 2022