Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptors 7 and 8

Abstract This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll‐like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In...

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Autores principales:	Andreas Port, Jamie V. Shaw, Lena Klopp‐Schulze, Afrim Bytyqi, Claudia Vetter, Elizabeth Hussey, Nadra Mammasse, Victor Ona, Angelika Bachmann, Denis Strugala, Christian Reh, Kosalaram Goteti
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	autoimmune diseases pharmacodynamics pharmacokinetics safety toll‐like receptors Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/8b6bac10490c420498e14c91c2474382
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spelling	oai:doaj.org-article:8b6bac10490c420498e14c91c24743822021-11-16T13:45:54ZPhase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptors 7 and 82052-170710.1002/prp2.842https://doaj.org/article/8b6bac10490c420498e14c91c24743822021-10-01T00:00:00Zhttps://doi.org/10.1002/prp2.842https://doaj.org/toc/2052-1707Abstract This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll‐like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In this single phase 1, randomized (3:1), double‐blind, placebo‐controlled study, 96 participants received single and multiple ascending oral doses of enpatoran. Participants in single‐dose cohorts received one dose of enpatoran (1, 3, 9, 25, 50, 100, or 200 mg) or placebo using a sentinel dosing strategy. Multiple‐dose cohorts received enpatoran (9, 25, or 200 mg once daily, or 25 or 50 mg twice daily) or placebo for 14 days. Safety, tolerability, PK, and PD (ex vivo‐stimulated cytokine secretion) were assessed in both parts. The effect of food was assessed in an open‐label, one‐way crossover study in the 25 mg single‐dose cohort. Single‐ and multiple‐oral doses of enpatoran up to 200 mg were well tolerated and no significant dose‐limiting adverse events or safety signals were observed under fasting or fed conditions. PK parameters were linear and dose‐proportional across the dose range evaluated, with a slightly delayed absorption and lower peak concentration observed at 25 mg with food. Exposure‐dependent inhibition of ex vivo‐stimulated interleukin‐6 secretion was observed, with maximum inhibition at 200 mg. Enpatoran was well tolerated at doses up to 200 mg. Further investigation of enpatoran is warranted as a potential treatment for diseases driven by TLR7/8 overactivation, such as systemic lupus erythematosus and COVID‐19 pneumonia.Andreas PortJamie V. ShawLena Klopp‐SchulzeAfrim BytyqiClaudia VetterElizabeth HusseyNadra MammasseVictor OnaAngelika BachmannDenis StrugalaChristian RehKosalaram GotetiWileyarticleautoimmune diseasespharmacodynamicspharmacokineticssafetytoll‐like receptorsTherapeutics. PharmacologyRM1-950ENPharmacology Research & Perspectives, Vol 9, Iss 5, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	autoimmune diseases pharmacodynamics pharmacokinetics safety toll‐like receptors Therapeutics. Pharmacology RM1-950
spellingShingle	autoimmune diseases pharmacodynamics pharmacokinetics safety toll‐like receptors Therapeutics. Pharmacology RM1-950 Andreas Port Jamie V. Shaw Lena Klopp‐Schulze Afrim Bytyqi Claudia Vetter Elizabeth Hussey Nadra Mammasse Victor Ona Angelika Bachmann Denis Strugala Christian Reh Kosalaram Goteti Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptors 7 and 8
description	Abstract This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll‐like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In this single phase 1, randomized (3:1), double‐blind, placebo‐controlled study, 96 participants received single and multiple ascending oral doses of enpatoran. Participants in single‐dose cohorts received one dose of enpatoran (1, 3, 9, 25, 50, 100, or 200 mg) or placebo using a sentinel dosing strategy. Multiple‐dose cohorts received enpatoran (9, 25, or 200 mg once daily, or 25 or 50 mg twice daily) or placebo for 14 days. Safety, tolerability, PK, and PD (ex vivo‐stimulated cytokine secretion) were assessed in both parts. The effect of food was assessed in an open‐label, one‐way crossover study in the 25 mg single‐dose cohort. Single‐ and multiple‐oral doses of enpatoran up to 200 mg were well tolerated and no significant dose‐limiting adverse events or safety signals were observed under fasting or fed conditions. PK parameters were linear and dose‐proportional across the dose range evaluated, with a slightly delayed absorption and lower peak concentration observed at 25 mg with food. Exposure‐dependent inhibition of ex vivo‐stimulated interleukin‐6 secretion was observed, with maximum inhibition at 200 mg. Enpatoran was well tolerated at doses up to 200 mg. Further investigation of enpatoran is warranted as a potential treatment for diseases driven by TLR7/8 overactivation, such as systemic lupus erythematosus and COVID‐19 pneumonia.
format	article
author	Andreas Port Jamie V. Shaw Lena Klopp‐Schulze Afrim Bytyqi Claudia Vetter Elizabeth Hussey Nadra Mammasse Victor Ona Angelika Bachmann Denis Strugala Christian Reh Kosalaram Goteti
author_facet	Andreas Port Jamie V. Shaw Lena Klopp‐Schulze Afrim Bytyqi Claudia Vetter Elizabeth Hussey Nadra Mammasse Victor Ona Angelika Bachmann Denis Strugala Christian Reh Kosalaram Goteti
author_sort	Andreas Port
title	Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptors 7 and 8
title_short	Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptors 7 and 8
title_full	Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptors 7 and 8
title_fullStr	Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptors 7 and 8
title_full_unstemmed	Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptors 7 and 8
title_sort	phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (m5049), a dual antagonist of toll‐like receptors 7 and 8
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/8b6bac10490c420498e14c91c2474382
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Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptors 7 and 8

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