Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study

Abstract

ATP acting via P2X3 receptors is an important mediator of refractory chronic cough (RCC). This phase 2a double-blinded crossover study assessed the safety, tolerability and efficacy of eliapixant (BAY 1817080), a selective P2X3 receptor antagonist, in adults with RCC attending specialist centres.In period A, patients received placebo for 2 weeks then eliapixant 10 mg for 1 week. In period B, patients received eliapixant 50, 200 and 750 mg twice daily for 1 week per dose level. Patients were randomised 1:1 to period A–B (n=20) or B–A (n=20). The primary efficacy endpoint was change in cough frequency assessed over 24 h (VitaloJAK). Primary safety endpoint was frequency and severity of adverse events (AEs).Thirty-seven patients completed randomised therapy. Mean cough frequency fell by 17.4% versus baseline with placebo. Eliapixant reduced cough frequency at doses ≥50 mg (reduction versus placebo at 750 mg, 25%: 90% confidence interval, 11.5–36.5%; p=0.002). Doses ≥50 mg also significantly reduced cough severity. AEs, mostly mild or moderate, were reported in 65% of patients with placebo and 41–49% receiving eliapixant. Cumulative rates of taste-related AEs were 3% with placebo and 5–21% with eliapixant: all were mild.Selective P2X3 antagonism with eliapixant significantly reduced cough frequency and severity, confirming this as a viable therapeutic pathway for RCC. Taste-related side-effects were lower at therapeutic doses than with the less selective P2X3 antagonist gefapixant. Selective P2X3 antagonism appears to be a novel therapeutic approach for RCC.

Assessing cough symptom severity in refractory or unexplained chronic cough: findings from patient focus groups and an international expert panel

“…Other strengths of this study include strict inclusion of patients who would qualify for phase 2/3 antitussive clinical trials [ 28 , 29 ] and triangulation of focus groups with an existing framework, patient partners and clinical experts.…”

Impact of Inhaled Corticosteroids on the Modulation of Respiratory Defensive Reflexes During Artificial Limb Exercise in Ovalbumin-Sensitized Rabbits

“…Inhalation of ATP is able to induce a chemical cough by stimulating these ligand-gated ion channels, but endogenous ATP released by inflammatory cells in the airways can also trigger these receptors ( Turner and Birring, 2019 ). The efficiency of P2 × 3 receptor antagonists developed in refractory chronic cough demonstrates the major role of extracellular ATP in cough hypersensitivity syndrome (CHS) ( Morice et al, 2019 , 2021 ). Dedicated studies are needed to assess their relevance in exercise-induced cough.…”

Recommended tool compounds and drugs for blocking P2X and P2Y receptors

“…The orally administered potent and selective allosteric P2X3 antagonist gefapixant (AF-219, 11) successfully passed a phase III clinical trial for the treatment of refractory chronic cough [23] and is likely to become the first P2X3 receptor antagonist that will be approved as a drug [24]. This has revived the field, and more P2X3 receptor antagonists are now being developed and clinically evaluated for various indications (see, e.g., [21,[25][26][27]). The etymology of the international non-proprietary name (INN) "gefapixant" is explained in Fig.…”

“…In contrast, the imidazopyridine derivative BLU-5937 ( 14) was reported to be selective for the homomeric P2X3 receptor; it is currently evaluated in clinical trials for the treatment of chronic cough and pruritus [29]. Eliapixant (BAY-181780, 15), another potent and selective P2X3 receptor antagonist [21,27,30], has completed a phase 2a clinical trial for the treatment of refractory chronic cough [25] and is further clinically evaluated for the treatment of overactive bladder; another pursued indication is neuropathic pain. A further P2X3 antagonist with undisclosed structure (S-600918) is evaluated in clinical studies [10,31].…”