Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study

Abstract

Background and Objective There is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers. Methods We conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant. Results Peak plasma concentrations of eliapixant were reached 3–4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak–trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events. Conclusions Eliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough. Clinical Trial Registration Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017). Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01126-1.

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

“…The first postdose taste tests were administered 3 hours postdosing, which was within 1 SD of t max under fasted conditions, or very close to t max under fed conditions, yet there was no clear difference in response compared with the baseline tests. Findings from the proof‐of‐concept studies with eliapixant, which commenced following the research described here, are consistent with these early observations that eliapixant appears to have fewer taste‐related AEs than observed with nonselective P2X3 and P2X2/3 receptor antagonism 13–17,25,26 . A multiple‐dose PK study of eliapixant 10–750 mg in healthy volunteers showed no clinically relevant effects on taste perception, in addition to a less than dose‐proportional increase in exposure with increasing dose 25 .…”

“…Findings from the proof-of-concept studies with eliapixant, which commenced following the research described here, are consistent with these early observations that eliapixant appears to have fewer tasterelated AEs than observed with nonselective P2X3 and P2X2/3 receptor antagonism. [13][14][15][16][17]25,26 A multiple-dose PK study of eliapixant 10-750 mg in healthy volunteers showed no clinically relevant effects on taste perception, in addition to a less than dose-proportional increase in exposure with increasing dose. 25 Furthermore, in a phase II study, eliapixant was well tolerated in patients with RCC, with a lower incidence of taste-related AEs (8-21% of patients) 26 than has previously been reported for gefapixant (up to 80% of patients with 50 mg twice daily) in RCC.…”

“…[13][14][15][16][17]25,26 A multiple-dose PK study of eliapixant 10-750 mg in healthy volunteers showed no clinically relevant effects on taste perception, in addition to a less than dose-proportional increase in exposure with increasing dose. 25 Furthermore, in a phase II study, eliapixant was well tolerated in patients with RCC, with a lower incidence of taste-related AEs (8-21% of patients) 26 than has previously been reported for gefapixant (up to 80% of patients with 50 mg twice daily) in RCC. 15,16 It is possible that a lower incidence of taste disturbances in healthy volunteers compared with patients may be due to a higher sensitivity in patients, although a study evaluating gefapixant in healthy volunteers and patients with chronic cough showed a numerically higher incidence of dysgeusia and ageusia in the healthy volunteers.…”

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

“…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. 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.…”

“…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.…”