Efficacy and Safety of Eliapixant in Refractory Chronic Cough: The Randomized, Placebo-Controlled Phase 2b PAGANINI Study

Abstract

Introduction The PAGANINI study evaluated the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough (RCC). Methods PAGANINI was a randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose-finding, phase 2b study. Adults with RCC lasting ≥ 12 months and cough severity ≥ 40 mm on a visual analog scale at screening were enrolled. Participants were randomized 1:1:1:1 to twice-daily 25 mg, 75 mg, or 150 mg oral eliapixant or placebo for 12 weeks. The primary endpoint was change from baseline in 24-h cough count after 12 weeks of intervention. Results Overall, 310 participants were randomized to twice-daily eliapixant 25 mg ( n = 75), 75 mg ( n = 78), 150 mg ( n = 80), or placebo ( n = 77). A statistically significant dose–response signal with eliapixant was detected for the primary endpoint (all dose–response models, adjusted p < 0.1; one-sided). Adverse events (AEs) were reported in 39 (51%) participants with placebo and 43–51 (57–65%) participants receiving eliapixant. The most common AE was dysgeusia, occurring in 1% ( n = 1) of the placebo group and 1–16% ( n = 1–13) of the eliapixant groups in a dose-related manner. One case of a moderate drug-induced liver injury occurred in a participant receiving 150 mg twice-daily eliapixant. Conclusion Eliapixant demonstrated efficacy and a favorable taste tolerability profile in RCC. However, a drug-induced liver injury contributed to intensified liver monitoring in clinical trials with eliapixant and discontinuation of the entire development program in all indications by Bayer AG. Trial Registration ClinicalTrials.gov identifier NCT04562155; registered September 18, 2020. Supplementary Information The online version contains supplementary material available at 10.1007/s00408-023-00621-x.

Efficacy and safety of eliapixant in diabetic neuropathic pain and prediction of placebo responders with an exploratory novel algorithm: results from the randomized controlled phase 2a PUCCINI study

“…31 In the phase 2b PAGANINI study in patients with RCC, which used the same formulation as PUCCINI (25 mg, 75 mg, and 150 mg BID), an efficacy plateau effect was observed with the 75 mg BID dose group. 16 These previous results suggest that the use of the eliapixant 150 mg BID dose in this study was likely not to have been a limiting factor in observing a treatment effect.…”

“…Eliapixant was generally well tolerated in patients with DNP, with a similar safety and tolerability profile to that seen in phase 2 studies in patients with RCC. 16,31 Adverse events related to taste and smell were reported in 14% of participants receiving eliapixant 150 mg BID, similar to a rate of 15% reported in participants receiving 200 mg BID eliapixant in a phase 2a trial in RCC. 31…”

“…Eliapixant has demonstrated efficacy in clinical trials of refractory chronic cough (RCC), which, like DNP, is associated with P2X3-mediated neuronal hypersensitization. 16,31 The phase 2a/b PUCCINI study was a two-part proof-of-concept and dose-finding study initiated to evaluate the efficacy and safety of eliapixant in patients with DNP. Here, we present results from the phase 2a proof-of-concept part of the PUCCINI study, the primary objective of which was to evaluate the effect of eliapixant for the treatment of pain associated with DNP compared with placebo.…”

Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough

“…This article differs from the protocol in that it focuses on gefapixant rather than all P2X3 antagonists. Several reasons informed this protocol deviation: (1) of all P2X3 antagonists, gefapixant was most likely to become imminently available for use in clinical practice; (2) while we conducted the current study, drug development programs for eliapixant and sivopixant discontinued after their phase 2b trials; and (3) we believed that evidence syntheses on camlipixant were premature with phase 3 trials still ongoing.…”

ERS International Congress 2023: highlights from the Airway Diseases Assembly

“…CC remains a prevalent issue with limited treatment options, and discussions surrounding its management have been extensive. There are currently no approved therapies for refractory CC, except in Japan and Switzerland, where gefapixant is approved [ 113 ]. Table 1 summarises current and future therapeutic opportunities.…”