ALS Agent SAR443820 Shows High CNS Penetration, Promising Safety Profile in Phase 1 Study

Author(s):

In single-ascending dose and multiple-ascending dose studies, no clinically meaningful changes were noted in hematology, chemistry, vital signs, or electrocardiogram parameters.

Nazem Atassi, MD

Findings from the first-in-human phase 1 study assessing SAR443820 (Sanofi), an oral RIPK1 inhibitor in development for amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), showed potential central nervous system (CNS) penetrance in health participants, with a safety profile that is safe and well-tolerated.¹

In a multi-cohort trial, SAR44380, previously known as DNL788, was well-tolerated with no treatment-related serious adverse events (AEs) or permanent treatment discontinuation. The most common AEs identified were dizziness and headache. Presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, patients showed no meaningful changes in hematology, chemistry, vital signs, or electrocardiogram parameters.

The study included several groups of patients, and was split in Part 1 and 2. In Part 1a, 4 cohorts (n = 8 each; SAR443820: n = 6; placebo = 2) who received single-ascending doses of the active therapy or placebo, while Part 1b included 2 single-dose cohorts (n = 6 each) who received the lowest and 4-fold the lowest doses of SAR443820. In Part 2, 4 cohorts (n = 10 each; SAR443820: n = 8; placebo: n = 2) received 14-day SAR443820 or placebo in multiple-ascending doses.

Led by Nazem Atassi, MD, Head, Early Neuro Development at Sanofi, results showed no major deviations from dose proportionality for maximum concentration (Cmax) and area under the curve over the range of SAR443820 doses. For the single-ascending dose and multiple ascending dose cohorts, mean plasma half-lives ranged between 6-8 hours and 7-9 hours, respectively. Investigators noted that the mean cerebrospinal fluid-to-unbound plasma concentration ratio suggests high CNS-penetrance. Across all SAR443820 groups, target engagement was reached, reflected by maximum median inhibition of phosphorylated-Ser166-RIPK1 levels.

In May 2022, Sanofi initiated dosing of SAR443820 in a phase 2 study–HIMALAYA (NCT05237284)–in individuals with ALS. With ongoing recruitment expected to reach 260 individuals, the study includes 2 parts. First, a double-blind, 24-week period with the administration of twice-daily oral SAR443820 or placebo, followed second by an open-label placebo-switch period that will continue until week 106 for those who successfully complete the first portion. Prior to the 24-week treatment period will be a 4-week screening period, and the open-label portion will be followed by a 2-week posttreatment follow-up period, with a maximum total study duration of 110 weeks.²

The coprimary outcome measures of HIMALAYA are the change from baseline in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at week 24, as well as the combined assessment of the function and survival (CAFS) score at week 52. The trial includes more than 15 secondary measures, several measured at week 24, including the CAFS score, slow vital capacity, muscle strength measured by handheld dynamometry, change in ALS Assessment Questionnaire, serum neurofilament light chain, and the number of patients with treatment-emergent adverse events (TEAE) and serious adverse events (SAE).

Earlier this year, in January, dosing commenced for a phase 2 study of SAR443820 (NCT05630547) in individuals with MS. Expected to include 168 individuals with relapsing-remitting MS, secondary progressive MS, or primary progressive MS, the study included a 4-week screening period, followed by a 48-week double-blind treatment period and a 48-week open-label extension. Designed to be double-blind, placebo-controlled in nature, investigators will assess the effect of SAR443820 on neurofilament light levels as the primary end point, with secondary outcomes that include number of gadolinium-enhancing T1 and T2 hypertense lesions.³

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REFERENCES
1. Hincelin-Mary A, Lewanczk P, Cantalloube C, et al. First-in-human study of safety, tolerability, pharmacokinectics, and pharmacodynamics of SAR443820, a central nervous system penetrant RIPK1 inhibitor in healthy participants. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. Abstract 001927
2. Denali Therapeutics Announces Achievement of RIPK1 Milestone for Phase 2 Clinical Trial Initiation in ALS by Sanofi. News release. Denali Therapeutics. May 2, 2022. Accessed April 24, 2023 https://www.globenewswire.com/news-release/2022/05/02/2433539/0/en/Denali-Therapeutics-Announces-Achievement-of-RIPK1-Milestone-for-Phase-2-Clinical-Trial-Initiation-in-ALS-by-Sanofi.html

3. Denali Therapeutics announces achievement of RIPK1 milestone for phase 2 clinical trial initiation in multiple sclerosis by Sanofi. News release. Denali Therapeutics. January 25, 2023. Accessed April 24, 2023. https://www.globenewswire.com/news-release/2023/01/25/2595146/0/en/Denali-Therapeutics-Announces-Achievement-of-RIPK1-Milestone-for-Phase-2-Clinical-Trial-Initiation-in-Multiple-Sclerosis-by-Sanofi.html