Evaluation of NTP42 , a novel thromboxane receptor antagonist, in a first-in-human phase I clinical trial.

Autor: Reid HM; ATXA Therapeutics Limited, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland., Maginn M; ATXA Therapeutics Limited, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland., Perkins CM; ATXA Therapeutics Limited, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland., Mulvaney EP; ATXA Therapeutics Limited, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland., Boyce M; Hammersmith Medicines Research, London, United Kingdom., Yamamoto T; Hammersmith Medicines Research, London, United Kingdom., Kinsella BT; ATXA Therapeutics Limited, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland.
Jazyk: angličtina
Zdroj: Frontiers in pharmacology [Front Pharmacol] 2023 Dec 21; Vol. 14, pp. 1296188. Date of Electronic Publication: 2023 Dec 21 (Print Publication: 2023).
DOI: 10.3389/fphar.2023.1296188
Abstrakt: Background: The thromboxane receptor (TP) antagonist NTP42 is in clinical development for treatment of cardiopulmonary diseases, such as pulmonary arterial hypertension. In this randomized, placebo-controlled Phase I clinical trial, NTP42 , administered as the oral formulation NTP42:KVA4 , was evaluated for safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy males. Methods: The first-in-human trial had three Parts: A, single ascending dose (SAD) study with seven groups given 0.25-243 mg NTP42:KVA4 or placebo; B, food effect study where one SAD group (9 mg) was also given NTP42:KVA4 or placebo after a high-fat breakfast; C, multiple ascending dose study with three groups given 15-135 mg NTP42:KVA4 or placebo once-daily for 7 days. Results: Seventy-nine volunteers participated. No serious adverse events occurred, where any drug- or placebo-related adverse events were mild to moderate, with no correlation to NTP42:KVA4 dose. NTP42 was rapidly absorbed, yielding dose proportional increases in exposure after single and repeat dosing. PK confirmed that, with a clearance (T 1/2 ) of 18.7 h, NTP42:KVA4 is suited to once-daily dosing, can be taken with or without food, and does not accumulate on repeat dosing. At doses ≥1 mg, NTP42 led to complete and sustained inhibition of thromboxane-, but not ADP-, induced platelet aggregation ex vivo , with direct correlation between NTP42 exposure and duration of PD effects. Conclusion: Orally administered NTP42:KVA4 was well tolerated, with favorable PK/PD profiles and evidence of specific TP target engagement. These findings support continued clinical development of NTP42:KVA4 for cardiopulmonary or other relevant diseases with unmet needs. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04919863.
Competing Interests: HR, EM, and BK were employees of ATXA Therapeutics Limited at the time of conducting the work reported in this manuscript. BK is also the founder and a member of the board of directors of ATXA Therapeutics Limited. The clinical trial, performed at Hammersmith Medicines Research, was sponsored by ATXA Therapeutics Ltd. ATXA received grant funding from the European Commission Horizon 2020 SME Instrument Program (Project Number: 822258) and, since 2023, is a recipient of European Commission funding through European Innovation Council Accelerator (Project Number: 190143893) program. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Reid, Maginn, Perkins, Mulvaney, Boyce, Yamamoto and Kinsella.)
Databáze: MEDLINE
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