PAGANINI phase 2b data promising for eliapixant

The 12-week dose-ranging results of the phase 2b PAGANINI trial indicated efficacy of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough, although a single liver safety signal warrants intensified monitoring going forward.

Prof. Peter Dicpinigaitis (Albert Einstein College of Medicine, NY, USA) presented the efficacy and safety data of eliapixant on chronic cough [1]. He explained that P2X3 receptors regulate afferent sensory nerve fibre ATP-mediated signalling, which in turn is thought to play an important role in sensory neural dysregulation associated with chronic cough. Eliapixant is a selective P2X3 receptor antagonist with greater potency and selectivity for the human P2X3 homotrimer than the P2X2/3 heterotrimer receptor [2].

To test the effect of eliapixant on chronic cough, the randomised, phase 2b PAGANINI (NCT04562155) enrolled 310 patients with refractory chronic cough lasting ≥12 months. Participants were randomised to 12 weeks of treatment with twice-daily placebo (n=77), or eliapixant 25 mg (n=75), 75 mg (n=78), or 150 mg (n=80). Baseline characteristics were reasonably well-balanced among the groups. The primary endpoint was the change from baseline in 24-hour cough frequency.

The results showed that a significant dose-response signal was established, with one-sided P-values of ≤0.1. From baseline to week 12, 24-hour cough count decreased with eliapixant for twice-daily doses of 25 mg, 75 mg, or 150 mg, respectively: -44%, -54%, -49%, compared with -34% for placebo. Awake cough count also decreased: -44%, -54%, and -53%, respectively, compared with -33% for placebo.

Mild adverse events were reported for both the placebo as well as eliapixant arms, and 1 serious hepatic adverse event of drug-induced liver injury did occur in a single individual in the 150 mg eliapixant arm, which spontaneously resolved upon discontinuation. Some taste- and smell-related adverse events were reported in 24% of participants in the eliapixant highest dose arm, although that decreased to background at 25 mg.

Prof. Dicpinigaitis concluded that eliapixant: (1) reduced 24-hour cough count versus placebo, with a safety and tolerability profile similar to other studies of eliapixant; (2) warrants intensified liver monitoring due to the single case of drug-induced liver injury; and (3) was associated with fewer taste-related adverse events in PAGANINI than reported in other trials with non-selective P2X3 antagonists.

1. Dicpinigaitis P et al. Eliapixant in refractory chronic cough: the 12-week randomized, double-blind, placebo-controlled phase 2 PAGANINI trial. Session C93, ATS International Conference 2022, San Francisco, CA, USA, 13–18 May.
2. Davenport AJ, et al. Sci Rep. 2021;11(1):19877.

 

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Posted on 18 July 2022