First-in-Human Study of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SAR443820, a Central Nervous System Penetrant RIPK1 Inhibitor in Healthy Participants (S46.005)

Abstract

<h3>Objective:</h3> To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of SAR443820 in first-in-human, Phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (SAD; Part-1a) and multiple-ascending dose (MAD; Part-2) studies in healthy participants. Part-1b was a separate open-label single-dose study for assessing SAR443820 levels in cerebrospinal fluid (CSF). <h3>Background:</h3> Receptor-interacting serine/threonine protein kinase-1 (RIPK1), which regulates inflammatory signaling and necroptotic cell death, is implicated in several neurodegenerative diseases. SAR443820, a central nervous system (CNS) penetrant oral RIPK1 inhibitor, is being developed in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). <h3>Design/Methods:</h3> In Part-1a, 4 cohorts (n=8 each; 6 SAR443820, 2 placebo) received single-ascending doses of SAR443820 (up to 4-fold the lowest dose) or placebo. Part-1b included 2 single-dose cohorts (n=6 each) receiving the lowest and 4-fold the lowest doses of SAR443820. In Part-2, 4 cohorts (n=10 each; 8 SAR443820, 2 placebo) received 14-day SAR443820 or placebo in multiple-ascending doses. <h3>Results:</h3> Overall, SAR443820 was well-tolerated with no treatment-related serious adverse events (AEs) or permanent treatment discontinuation. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in hematology, chemistry, vital signs, or electrocardiogram parameters. There were no major deviations from dose proportionality for maximum concentration (C_max) and area under the curve (AUC) over the range of SAR443820 doses. Mean plasma half-lives ranged between 6–8h and 7–9h in SAD and MAD cohorts, respectively. Mean CSF-to-unbound plasma concentration ratio suggested high CNS-penetrance. Concentration-QTcF analyses did not indicate any potential for SAR443820 to cause relevant change in QTcF. Maximum median inhibition of phosphorylated-Ser166-RIPK1 levels across all SAR443820 groups reflected a marked target engagement. <h3>Conclusions:</h3> The first-in-human study demonstrated that single and repeated SAR443820 doses were generally safe and well-tolerated, with favorable pharmacokinetics, high CNS-penetrance, and robust RIPK1-target engagement, supporting further development in actively recruiting Phase 2 trials in ALS (Himalaya; NCT05237284) and MS (K2; ACT16753). <b>Disclosure:</b> Mrs. HINCELIN-MERY has nothing to disclose. Pascale Lewanczyk has nothing to disclose. Mrs. Cantalloube has received personal compensation for serving as an employee of Sanofi. Mr. Nicolas has nothing to disclose. Myriam Benamor has nothing to disclose. Dr. Pomponio has received personal compensation for serving as an employee of Sanofi. Dr. Pomponio has stock in sanofi. Dr. KRUPKA has nothing to disclose. Dimitry Ofengeim has received personal compensation for serving as an employee of Sanofi. Dimitry Ofengeim has received stock or an ownership interest from Sanofi. Dimitry Ofengeim has received personal compensation in the range of $500-$4,999 for serving as a Study Section Reveiwer with NIH. Dr. Eastenson has nothing to disclose. Dr. Xiong has received personal compensation for serving as an employee of Sanofi. Dr. Atassi has received personal compensation for serving as an employee of Sanofi. Dr. Atassi has stock in Sanofi.