Investigating Camlipixant P2X3 Selectivity And Taste Disturbance: A Model-Based Dose–Response Meta-Analysis

Rationale: The rate of P2X3 antagonist-associated dysgeusia varies in patients (pts) with refractory chronic cough (RCC). Camlipixant, a P2X3 antagonist in development for RCC in adults, has high selectivity (>1500´) for P2X3 over P2X2/3 and is expected to mitigate P2X2/3-modulated dysgeusia. P2X3 antagonists with varying selectivity have been investigated for RCC: sivopixant (262´), eliapixant (13´), gefapixant (1.5´), filapixant (unknown). We hypothesized that rates of dysgeusia are explained by selectivity, and all P2X3 antagonists would fall on a common potency-adjusted dose–response curve. Methods: Dysgeusia data from five P2X3 antagonists across nine clinical trials were collated by treatment arm. P2X3 antagonist dose was scaled by known selectivity (filapixant – inferred by eventual visual concordance) and transformed using a log 2 scale. The number of pts with dysgeusia was calculated from intention-to-treat population. Proportions were reported with exact Clopper–Pearson 95% confidence intervals and plotted against potency-scaled dose on a log 2 scale. Concordance between dysgeusia rates and potency was assessed using Loess regression. A linear mixed-effects logistic regression model was used to estimate the proportion of pts with dysgeusia with relative potency. Results: Among 3,596 pts receiving P2X3 antagonists (potency-adjusted dose of