First‐in‐human study of eliapixant (BAY 1817080), a highly selective P2X3 receptor antagonist: Tolerability, safety and pharmacokinetics

Abstract

Aims Neuronal hypersensitisation due to adenosine triphosphate‐dependent P2X3 receptor signalling plays a significant role in several disorders including chronic cough and endometriosis. This first‐in‐human study of eliapixant (BAY 1817080) investigated the tolerability, safety and pharmacokinetics (PK) of single doses of eliapixant, including the effect of food and coadministration with a CYP3A inhibitor on eliapixant relative bioavailability. Methods In this randomised, double‐blind phase I study (NCT02817100), 88 healthy male subjects received single ascending doses of immediate‐release eliapixant (10–800 mg) tablets or placebo under fasted conditions, with food (low‐fat continental or high‐fat American breakfast) or with itraconazole (fasted state). PK parameters, dose proportionality, adverse events and taste assessments (taste strips; dysgeusia questionnaire) were evaluated. Results Eliapixant had a long half‐life (23.5–58.9 h [fasted state]; 32.8–43.8 h [high‐fat breakfast]; 38.9–46.0 h [low‐fat breakfast]). Less than dose‐proportional increases in maximum plasma concentrations (Cmax) and area under the concentration–time curve from time 0 to infinity (AUC[0–inf]) were observed with ascending eliapixant doses. We observed a pronounced food effect with the high‐fat breakfast (4.1‐fold increased Cmax; 2.7‐fold increased AUC[0–inf]), a smaller food effect with the low‐fat breakfast and a mild‐to‐moderate effect of itraconazole coadministration on eliapixant (1.1–1.2‐fold increased Cmax; 1.7‐fold increased AUC from 0 to 72 h). Eliapixant was well tolerated with minimal impact on taste perception. Conclusion The PK profile, particularly the long half‐life, and favourable tolerability with no taste‐related adverse events, supports the further development of eliapixant in disorders with underlying P2X3 receptor‐mediated neuronal hypersensitisation.

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

“…the lower baseline cough counts and efficacy results in the 150 mg eliapixant group. The safety and tolerability profiles in PAGANINI are generally consistent with other studies of eliapixant in healthy subjects and the phase 2a study in patients with RCC [16][17][18]. However, a case of a moderate DILI of hepatocellular origin occurred during treatment with 150 mg eliapixant and contributed to the need for intensified liver monitoring in clinical trials with eliapixant.…”

“…Eliapixant is a potent P2X3 receptor antagonist with a good tolerability profile in healthy subjects, and high selectivity over the P2X2/3 receptor in vitro, potentially resulting in fewer off-target effects [15][16][17]. In a phase 2a study, eliapixant significantly reduced cough frequency and severity in patients with RCC, with a lower rate of taste-related side effects than those observed with therapeutic doses of gefapixant [18].…”

Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) are competitive antagonists of the human P2X3 receptor

“…Also, sivopixant was shown to reduce objective cough frequency and improved health-related quality of life, with a low incidence of taste disturbance, among patients with a refractory or unexplained chronic cough in a phase 2a trial (Niimi et al, 2022). Eliapixant showed favorable tolerability with no taste-related adverse events in its first-in-human study, and in a phase 1/2a study, eliapixant administration showed reduced cough frequency and severity and was well-tolerated with acceptable rates of taste-related events (Morice et al, 2014;Klein et al, 2022).…”

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

“…The eliapixant 150 mg BID dose was chosen based on previous studies in healthy volunteers, which used a different formulation to that used in PUCCINI, where a 750 mg dose was approximately equivalent to the 150 mg dose used in PUCCINI for bioavailability. 23,28 In healthy volunteers, the eliapixant plasma levels predicted to achieve $80% P2X3 receptor occupancy, the predicted therapeutic threshold, were reached with doses of 200 mg and 750 mg BID. 23 In a phase 2a study assessing eliapixant 50, 200, and 750 mg BID (the same formulation as used in the healthy volunteer studies) in patients with RCC, an efficacy plateau appeared to be reached at 200 mg BID for the primary endpoint of cough frequency, whereas the subjective endpoints continued to improve at the 750 mg dose.…”