Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534

Abstract The nuclear receptor retinoid-related orphan receptor gamma t (RORγt) plays a critical role in driving Th17 cell differentiation and expansion, as well as IL-17 production in innate and adaptive immune cells. The IL-23/IL-17 axis is implicated in several autoimmune and inflammatory diseases...

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Autores principales:	Xiaohua Xue, Aimee De Leon-Tabaldo, Rosa Luna-Roman, Glenda Castro, Michael Albers, Freddy Schoetens, Samuel DePrimo, Damayanthi Devineni, Thomas Wilde, Steve Goldberg, Thomas Hoffmann, Anne M. Fourie, Robin L. Thurmond
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b41726b0e6ed4617b45bd45046be2ee9
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spelling	oai:doaj.org-article:b41726b0e6ed4617b45bd45046be2ee92021-12-02T15:00:14ZPreclinical and clinical characterization of the RORγt inhibitor JNJ-6180353410.1038/s41598-021-90497-92045-2322https://doaj.org/article/b41726b0e6ed4617b45bd45046be2ee92021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90497-9https://doaj.org/toc/2045-2322Abstract The nuclear receptor retinoid-related orphan receptor gamma t (RORγt) plays a critical role in driving Th17 cell differentiation and expansion, as well as IL-17 production in innate and adaptive immune cells. The IL-23/IL-17 axis is implicated in several autoimmune and inflammatory diseases, and biologics targeting IL-23 and IL-17 have shown significant clinical efficacy in treating psoriasis and psoriatic arthritis. JNJ-61803534 is a potent RORγt inverse agonist, selectively inhibiting RORγt-driven transcription versus closely-related family members, RORα and RORβ. JNJ-61803534 inhibited IL-17A production in human CD4+ T cells under Th17 differentiation conditions, but did not inhibit IFNγ production under Th1 differentiation conditions, and had no impact on in vitro differentiation of regulatory T cells (Treg), nor on the suppressive activity of natural Tregs. In the mouse collagen-induced arthritis model, JNJ-61803534 dose-dependently attenuated inflammation, achieving ~ 90% maximum inhibition of clinical score. JNJ-61803534 significantly inhibited disease score in the imiquimod-induced mouse skin inflammation model, and dose-dependently inhibited the expression of RORγt-regulated genes, including IL-17A, IL-17F, IL-22 and IL-23R. Preclinical 1-month toxicity studies in rats and dogs identified doses that were well tolerated supporting progression into first-in-human studies. An oral formulation of JNJ-61803534 was studied in a phase 1 randomized double-blind study in healthy human volunteers to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated in single ascending doses (SAD) up to 200 mg, and exhibited dose-dependent increases in exposure upon oral dosing, with a plasma half-life of 164 to 170 h. In addition, dose-dependent inhibition of ex vivo stimulated IL-17A production in whole blood was observed, demonstrating in vivo target engagement. In conclusion, JNJ-61803534 is a potent and selective RORγt inhibitor that exhibited acceptable preclinical safety and efficacy, as well as an acceptable safety profile in a healthy volunteer SAD study, with clear evidence of a pharmacodynamic effect in humans.Xiaohua XueAimee De Leon-TabaldoRosa Luna-RomanGlenda CastroMichael AlbersFreddy SchoetensSamuel DePrimoDamayanthi DevineniThomas WildeSteve GoldbergThomas HoffmannAnne M. FourieRobin L. ThurmondNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiaohua Xue Aimee De Leon-Tabaldo Rosa Luna-Roman Glenda Castro Michael Albers Freddy Schoetens Samuel DePrimo Damayanthi Devineni Thomas Wilde Steve Goldberg Thomas Hoffmann Anne M. Fourie Robin L. Thurmond Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534
description	Abstract The nuclear receptor retinoid-related orphan receptor gamma t (RORγt) plays a critical role in driving Th17 cell differentiation and expansion, as well as IL-17 production in innate and adaptive immune cells. The IL-23/IL-17 axis is implicated in several autoimmune and inflammatory diseases, and biologics targeting IL-23 and IL-17 have shown significant clinical efficacy in treating psoriasis and psoriatic arthritis. JNJ-61803534 is a potent RORγt inverse agonist, selectively inhibiting RORγt-driven transcription versus closely-related family members, RORα and RORβ. JNJ-61803534 inhibited IL-17A production in human CD4+ T cells under Th17 differentiation conditions, but did not inhibit IFNγ production under Th1 differentiation conditions, and had no impact on in vitro differentiation of regulatory T cells (Treg), nor on the suppressive activity of natural Tregs. In the mouse collagen-induced arthritis model, JNJ-61803534 dose-dependently attenuated inflammation, achieving ~ 90% maximum inhibition of clinical score. JNJ-61803534 significantly inhibited disease score in the imiquimod-induced mouse skin inflammation model, and dose-dependently inhibited the expression of RORγt-regulated genes, including IL-17A, IL-17F, IL-22 and IL-23R. Preclinical 1-month toxicity studies in rats and dogs identified doses that were well tolerated supporting progression into first-in-human studies. An oral formulation of JNJ-61803534 was studied in a phase 1 randomized double-blind study in healthy human volunteers to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated in single ascending doses (SAD) up to 200 mg, and exhibited dose-dependent increases in exposure upon oral dosing, with a plasma half-life of 164 to 170 h. In addition, dose-dependent inhibition of ex vivo stimulated IL-17A production in whole blood was observed, demonstrating in vivo target engagement. In conclusion, JNJ-61803534 is a potent and selective RORγt inhibitor that exhibited acceptable preclinical safety and efficacy, as well as an acceptable safety profile in a healthy volunteer SAD study, with clear evidence of a pharmacodynamic effect in humans.
format	article
author	Xiaohua Xue Aimee De Leon-Tabaldo Rosa Luna-Roman Glenda Castro Michael Albers Freddy Schoetens Samuel DePrimo Damayanthi Devineni Thomas Wilde Steve Goldberg Thomas Hoffmann Anne M. Fourie Robin L. Thurmond
author_facet	Xiaohua Xue Aimee De Leon-Tabaldo Rosa Luna-Roman Glenda Castro Michael Albers Freddy Schoetens Samuel DePrimo Damayanthi Devineni Thomas Wilde Steve Goldberg Thomas Hoffmann Anne M. Fourie Robin L. Thurmond
author_sort	Xiaohua Xue
title	Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534
title_short	Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534
title_full	Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534
title_fullStr	Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534
title_full_unstemmed	Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534
title_sort	preclinical and clinical characterization of the rorγt inhibitor jnj-61803534
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b41726b0e6ed4617b45bd45046be2ee9
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Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534

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