P2X3 Receptor Antagonist Eliapixant in Phase I Clinical Trials: Safety and Inter-ethnic Comparison of Pharmacokinetics in Healthy Chinese and Japanese Participants

Background Afferent neuronal hypersensitization via P2X3 receptor signaling has been implicated as a driver of several disorders, including refractory chronic cough, endometriosis, diabetic neuropathic pain, and overactive bladder. Eliapixant, a selective P2X3 receptor antagonist, has been in clinical development for all four disorders.

This paper describes pharmacokinetic (PK) and safety data from two phase I studies of eliapixant in healthy Japanese and Chinese participants and compares those data within the two populations and with previous multiple dose data from Caucasian participants.

Two separate phase I, single-center, randomized, placebo-controlled studies were conducted with healthy male participants. The Japanese study was single-blind and the Chinese study was double-blind. Eliapixant was administered as an oral amorphous solid dispersion immediate-release tablet in strengths of 25 mg, 75 mg, and 150 mg. PK characteristics after a single dose (SD) and at steady state (multiple dose [MD], twice daily), adverse events (AEs), and tolerability were evaluated. A post hoc comparison of PK characteristics after SD of eliapixant in Japanese and Chinese participants, and after MD of eliapixant in Japanese, Chinese, and Caucasian participants, was performed.

Overall, 36/39 participants enrolled in the Japanese/Chinese studies, respectively (mean [standard deviation] age 25.4 [6.5] and 26.7 [5.0] years, respectively). After SD administration, maximum plasma concentration (Cmax) was higher among Japanese than Chinese participants in the 25 mg and 75 mg dose groups, but comparable in the 150 mg dose group. The area under the concentration–time curve (AUC) was comparable between Japanese and Chinese participants in the 25 mg and 75 mg dose groups, but lower among Japanese participants in the 150 mg group. Half-lives after SD and MD administration were also comparable in Japanese and Chinese participants. The post hoc analysis included 26 Japanese, 30 Chinese, and 50 Caucasian participants. Comparable exposure (Cmax,md and AUC[0–12]md) was observed after MD administration of eliapixant in Chinese and/or Japanese compared with Caucasian participants (geometric mean inter-ethnic ratios close to 1). The trough plasma concentration after eliapixant 150 mg MD, which was assumed to be relevant to eliapixant efficacy, was comparable across all ethnicity groups. Most AEs reported in the Japanese (eliapixant 75 mg SD, n = 2; eliapixant 150 mg MD, n = 2) and Chinese participants (eliapixant 25 mg SD, n = 7; eliapixant 75 mg SD, n = 6; eliapixant 150 mg SD, n = 7; eliapixant 150 mg MD, n = 9; placebo SD, n = 5; placebo MD, n = 1) were of mild intensity. Higher incidences of AEs in the Chinese population were likely due to differing standards of AE reporting between investigators.

Eliapixant was well tolerated by Japanese and Chinese participants. The inter-ethnic evaluation demonstrated similar PK characteristics across Japanese, Chinese, and Caucasian participants. Registration ClinicalTrials.gov identifier numbers: NCT04265781 and NCT04802343. Similar content being viewed by others

Bernier LP, Ase AR, Séguéla P. P2X receptor channels in chronic pain pathways. Br J Pharmacol. 2018;175(12):2219–30. North RA. P2X3 receptors and peripheral pain mechanisms. J Physiol. 2004;554(Pt 2):301–8. North RA. P2X receptors. Philos Trans R Soc Lond B Biol Sci. 2016;371(1700):20150427. Cockayne DA, Dunn PM, Zhong Y, Rong W, Hamilton SG, Knight GE, et al. P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J Physiol. 2005;567(Pt 2):621–39. Burnstock G. Purinergic signalling: therapeutic developments. Front Pharmacol. 2017;8:661. Bonvini SJ, Belvisi MG. Cough and airway disease: the role of ion channels. Pulm Pharmacol Ther. 2017;47:21–8. Yuan M, Ding S, Meng T, Lu B, Shao S, Zhang X, et al. Effect of A-317491 delivered by glycolipid-like polymer micelles on endometriosis pain. Int J Nanomed. 2017;12:8171–83. Ryan NM, Vertigan AE, Birring SS. An update and systematic review on drug therapies for the treatment of refractory chronic cough. Expert Opin Pharmacother. 2018;19(7):687–711. Fabbretti E. ATP P2X3 receptors and neuronal sensitization. Front Cell Neurosci. 2013;7:236. Davenport AJ, Neagoe I, Bräuer N, Koch M, Rotgeri A, Nagel J, et al. Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers. Sci Rep. 2021;11(1):19877. Klein S, Gashaw I, Baumann S, Chang X, Hummel T, Thuß U, et al. First-in-human study of eliapixant (BAY 1817080), a highly selective P2X3 receptor antagonist: tolerability, safety and pharmacokinetics. Br J Clin Pharmacol. 2022;88(10):4552–64. Morice A, Smith JA, McGarvey L, Birring SS, Parker SM, Turner A, et al. Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study. Eur Respir J. 2021;58(5):2004240. Smith JA, Kitt MM, Butera P, Smith SA, Li Y, Xu ZJ, et al. Gefapixant in two randomised dose-escalation studies in chronic cough. Eur Respir J. 2020;55(3):1901615. Smith JA, Kitt MM, Morice AH, Birring SS, McGarvey LP, Sher MR, et al. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med. 2020;8(8):775–85. McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, et al. Efficacy and safety of gefapixant, a P2X(3) receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet. 2022;399(10328):909–23. Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ, Stone L, et al. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science. 2005;310(5753):1495–9. Friedrich C, Francke K, Gashaw I, Scheerans C, Klein S, Fels L, et al. Safety, pharmacodynamics, and pharmacokinetics of P2X3 receptor antagonist eliapixant (BAY 1817080) in healthy subjects: double-blind randomized study. Clin Pharmacokinet. 2022;61(8):1143–56. Dicpinigaitis PV, Morice AH, Smith JA, Sher MR, Vaezi M, Guilleminault L, et al. Efficacy and safety of eliapixant in refractory chronic cough: the randomized, placebo-controlled phase 2b PAGANINI study. Lung. 2023;201(3):255–66. Olafuyi O, Parekh N, Wright J, Koenig J. Inter-ethnic differences in pharmacokinetics-is there more that unites than divides? Pharmacol Res Perspect. 2021;9(6): e00890. Kadian N, Raju KS, Rashid M, Malik MY, Taneja I, Wahajuddin M. Comparative assessment of bioanalytical method validation guidelines for pharmaceutical industry. J Pharm Biomed Anal. 2016;126:83–97. Francke K, Chattopadhyay N, Klein S, Rottmann A, Krickau D, van de Wetering J, et al. Preclinical and clinical pharmacokinetics and bioavailability in healthy volunteers of a novel formulation of the selective P2X3 receptor antagonist eliapixant. Eur J Drug Metab Pharmacokinet. 2023;48(1):75–87. Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy BG, Ford AP, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015;385(9974):1198–205. Morice AH, Kitt MM, Ford AP, Tershakovec AM, Wu WC, Brindle K, et al. The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. Eur Respir J. 2019;54(1):1900439.

Medical writing services were provided by Kennedy Shaw, MSc, of Adelphi Communications Ltd, Macclesfield, UK and funded by Bayer AG, Berlin, Germany, in accordance with the Good Publication Practice guidelines, 2022. Author information Authors and Affiliations Corresponding author Ethics declarations Funding This study was funded by Bayer AG. Conflict of interest P.L., H.C., S.K., S.R., K.F., and C.F. are employees of Bayer AG; K.O. works for Bayer Yakuhin Ltd.; and X.L., M.H., and H.L. have no conflicts of interest to declare. Availability of data and material The data underpinning this publication are made available in line with Bayer’s commitment to the principles of responsible clinical trial data sharing adhered to by the European Federation of Pharmaceutical Industries and Associations and Pharmaceutical Research and the Manufacturers of America, in relation to the scope, time point, and process of data access. Bayer commits to sharing, upon request from qualified scientific and medical researchers, patient- and study-level clinical trial data and clinical trial patient protocols for medicines and indications approved in the USA and European Union as a necessary requirement for legitimate research. This commitment applies to data on new medicines and indications that have been approved by the European Union and US regulatory agencies on or after January 1 2014. Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct further research that can help to advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the study sponsor section of the portal. Data access will be granted to anonymized patient-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded. Ethics statement These studies were conducted in accordance with the Good Clinical Practice guidelines and the Declaration of Helsinki. The protocols were reviewed and approved by each study site’s institutional review board. Consent to participate All participants provided written, informed consent. Author contributions S.R., K.F., C.F., and K.O. contributed to the design of the Japanese study. M.H. was the principal investigator of the Japanese study. P.L., H.C., S.R., K.F., and C.F. contributed to the design of the Chinese study. X.L. was the principal investigator and H.L. the sub-investigator of the Chinese study. S.K. carried out the statistical analysis in the Japanese and Chinese studies, as well as the post hoc inter-ethnic analysis. All authors interpreted the data, critically reviewed and revised the manuscript, and approved the final version for publication. Code availability Not applicable. Consent for publication Not applicable. Supplementary Information Below is the link to the electronic supplementary material. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Li, X., Haranaka, M., Li, H. et al. P2X3 Receptor Antagonist Eliapixant in Phase I Clinical Trials: Safety and Inter-ethnic Comparison of Pharmacokinetics in Healthy Chinese and Japanese Participants. Clin Pharmacokinet 63, 901–915 (2024). https://doi.org/10.1007/s40262-024-01387-y Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s40262-024-01387-y