A Randomized, Double-Blind and Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIR2446M after Oral Administrations in Healthy Volunteers

Start Date17 Dec 2021

Sponsor / Collaborator

SIRONAX AUS PTY LTD

100 Clinical Results associated with SIR-2446M

100 Translational Medicine associated with SIR-2446M

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01 Jul 2024·Clinical and Translational Science

A phase I randomized study to evaluate safety, pharmacokinetics, and pharmacodynamics of SIR2446M, a selective RIPK1 inhibitor, in healthy participants

Article

Author: Song, Linan ; Gillies, John David ; Deng, Huajun ; Sun, Ana Liza Andresan ; Ma, Yongfen ; Xue, Fenchao ; Shen, Yang

AbstractActivation of receptor‐interacting protein kinase 1 (RIPK1), a broadly expressed serine/threonine protein kinase, by pro‐inflammatory cytokines and pathogens can result in apoptosis, necroptosis, or inflammation. RIPK1 inhibition has been shown to reduce inflammation and cell damage in preclinical studies and may have therapeutic potential for degenerative and inflammatory diseases. SIR2446 is a potent and selective novel small molecule RIPK1 kinase inhibitor. This phase I, randomized, double‐blind, placebo‐controlled study in Australia (ACTRN12621001621808) evaluated the safety (primary objective), pharmacokinetics, and pharmacodynamics of single (3–600 mg) and multiple (5–400 mg for 10 days) ascending oral doses of SIR2446M (SIR2446 magnesium salt form) in healthy adults from Nov 24, 2021, until May 01, 2023. All treatment‐emergent adverse events (TEAEs) were mild/moderate. The most reported TEAEs were vascular access site pain, headache, and rash morbilliform. SIR2446M plasma half‐lives ranged from 11 to 19 h and there were no major deviations from dose proportionality for maximum concentration and area under the curve across doses. Renal excretion of unchanged SIR2446 was minimal. No marked accumulation was observed (mean accumulation ratio, 1.2–1.6) after multiple daily doses. A high‐fat meal mildly reduced the exposure but was not considered clinically significant. SIR2446M had a rapid and sustained inhibitory effect on the activity of RIPK1, with an overall 90% target engagement at repeated doses ranging from 30 to 400 mg in peripheral blood mononuclear cells ex vivo stimulated to undergo necroptosis. The favorable safety, pharmacokinetic, and pharmacodynamic profile of SIR2446M in healthy participants supports its further clinical development in patients with degenerative and inflammatory diseases.

100 Deals associated with SIR-2446M

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	AU	SIRONAX AUS PTY LTD	17 Dec 2021
Multiple Sclerosis	Phase 2	AU	SIRONAX AUS PTY LTD	17 Dec 2021

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