Phase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID‐19

Abstract Nezulcitinib (TD‐0903), a lung‐selective pan–Janus‐associated kinase (JAK) inhibitor designed for inhaled delivery, is under development for treatment of acute lung injury associated with coronavirus disease 2019 (COVID‐19). This two‐part, double‐blind, randomized, placebo‐controlled, singl...

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Autores principales:	Nathan D. Pfeifer, Arthur Lo, David L. Bourdet, Kenneth Colley, Dave Singh
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/15037cc6b9a34adf8465d0c461bdbabf
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spelling	oai:doaj.org-article:15037cc6b9a34adf8465d0c461bdbabf2021-11-19T17:51:35ZPhase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID‐191752-80621752-805410.1111/cts.13123https://doaj.org/article/15037cc6b9a34adf8465d0c461bdbabf2021-11-01T00:00:00Zhttps://doi.org/10.1111/cts.13123https://doaj.org/toc/1752-8054https://doaj.org/toc/1752-8062Abstract Nezulcitinib (TD‐0903), a lung‐selective pan–Janus‐associated kinase (JAK) inhibitor designed for inhaled delivery, is under development for treatment of acute lung injury associated with coronavirus disease 2019 (COVID‐19). This two‐part, double‐blind, randomized, placebo‐controlled, single ascending dose (part A) and multiple ascending dose (part B) phase I study evaluated the safety, tolerability, and pharmacokinetics (PK) of nezulcitinib in healthy participants. Part A included three cohorts randomized 6:2 to receive a single inhaled dose of nezulcitinib (1, 3, or 10 mg) or matching placebo. Part B included three cohorts randomized 8:2 to receive inhaled nezulcitinib (1, 3, or 10 mg) or matching placebo for 7 days. The primary outcome was nezulcitinib safety and tolerability assessed from treatment‐emergent adverse events (TEAEs). The secondary outcome was nezulcitinib PK. All participants completed the study. All TEAEs were mild or moderate in severity, and none led to treatment discontinuation. Overall (area under the plasma concentration‐time curve) and peak (maximal plasma concentration) plasma exposures of nezulcitinib were low and increased in a dose‐proportional manner from 1 to 10 mg in both parts, with no suggestion of clinically meaningful drug accumulation. Maximal plasma exposures were below levels expected to result in systemic target engagement, consistent with a lung‐selective profile. No reductions in natural killer cell counts were observed, consistent with the lack of a systemic pharmacological effect and the observed PK. In summary, single and multiple doses of inhaled nezulcitinib at 1, 3, and 10 mg were well‐tolerated in healthy participants, with dose‐proportional PK supporting once‐daily administration.Nathan D. PfeiferArthur LoDavid L. BourdetKenneth ColleyDave SinghWileyarticleTherapeutics. PharmacologyRM1-950Public aspects of medicineRA1-1270ENClinical and Translational Science, Vol 14, Iss 6, Pp 2556-2565 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
spellingShingle	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 Nathan D. Pfeifer Arthur Lo David L. Bourdet Kenneth Colley Dave Singh Phase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID‐19
description	Abstract Nezulcitinib (TD‐0903), a lung‐selective pan–Janus‐associated kinase (JAK) inhibitor designed for inhaled delivery, is under development for treatment of acute lung injury associated with coronavirus disease 2019 (COVID‐19). This two‐part, double‐blind, randomized, placebo‐controlled, single ascending dose (part A) and multiple ascending dose (part B) phase I study evaluated the safety, tolerability, and pharmacokinetics (PK) of nezulcitinib in healthy participants. Part A included three cohorts randomized 6:2 to receive a single inhaled dose of nezulcitinib (1, 3, or 10 mg) or matching placebo. Part B included three cohorts randomized 8:2 to receive inhaled nezulcitinib (1, 3, or 10 mg) or matching placebo for 7 days. The primary outcome was nezulcitinib safety and tolerability assessed from treatment‐emergent adverse events (TEAEs). The secondary outcome was nezulcitinib PK. All participants completed the study. All TEAEs were mild or moderate in severity, and none led to treatment discontinuation. Overall (area under the plasma concentration‐time curve) and peak (maximal plasma concentration) plasma exposures of nezulcitinib were low and increased in a dose‐proportional manner from 1 to 10 mg in both parts, with no suggestion of clinically meaningful drug accumulation. Maximal plasma exposures were below levels expected to result in systemic target engagement, consistent with a lung‐selective profile. No reductions in natural killer cell counts were observed, consistent with the lack of a systemic pharmacological effect and the observed PK. In summary, single and multiple doses of inhaled nezulcitinib at 1, 3, and 10 mg were well‐tolerated in healthy participants, with dose‐proportional PK supporting once‐daily administration.
format	article
author	Nathan D. Pfeifer Arthur Lo David L. Bourdet Kenneth Colley Dave Singh
author_facet	Nathan D. Pfeifer Arthur Lo David L. Bourdet Kenneth Colley Dave Singh
author_sort	Nathan D. Pfeifer
title	Phase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID‐19
title_short	Phase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID‐19
title_full	Phase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID‐19
title_fullStr	Phase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID‐19
title_full_unstemmed	Phase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID‐19
title_sort	phase i study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for covid‐19
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/15037cc6b9a34adf8465d0c461bdbabf
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Phase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID‐19

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