Abstract
8 min read<h3>Objective:</h3> To describe the Phase 2 trial design (ACT16753) that evaluates the effect of SAR443820 (DNL788) on reducing neuronal damage, measured by serum neurofilament light (sNfL) levels in participants with multiple sclerosis (MS). <h3>Background:</h3> Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), a critical signaling protein involved in regulating neuroinflammation and cell death, is suggested to play an important role in MS pathology. NfL, a marker of neuronal damage, is known to increase in MS. Therapeutic administration of a central nervous system (CNS) penetrant RIPK1 inhibitor (RIPK1i) in an experimental autoimmune encephalomyelitis model improved the clinical scores and serum heavy chain neurofilament levels in a dose-dependent manner. SAR443820, an oral, first-in-class, CNS penetrant, selective RIPK1i has demonstrated good safety, tolerability, and CNS-penetration in healthy volunteers. The aim of this trial is to explore the effect of SAR443820 on sNfL levels in MS participants. <h3>Design/Methods:</h3> This trial consists of 2 parts. Part A is a 48-week, double-blind, placebo-controlled treatment period, where participants will be randomized (1:1) to receive oral SAR443820 or placebo; Part B is an open-label long-term extension period up to Week 96 after Part A, where participants will receive SAR443820. The trial will include ~168 participants (aged 18–60 years) diagnosed with relapsing-remitting, secondary progressive, or primary progressive MS; an expanded disability status scale (EDSS) score of 2–6 at screening; either untreated or stable on an allowed disease modifying therapy during the study. The trial objectives are to assess the effect of SAR443820 on sNfL levels and clinical and magnetic resonance imaging (MRI) markers of disease progression and activity, along with its safety and tolerability, in MS population. <h3>Results:</h3> Enrollment is expected to start in Q4 2022. <h3>Conclusions:</h3> This proof-of-concept study is designed to demonstrate the effect of SAR443820 on neuroaxonal damage, reflected by sNfL levels and MRI markers. <b>Disclosure:</b> The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck/ EMD Serono. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Hoffmann-La Roche. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion/ Janssen. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for BMS/ Celgene. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi/ Genzyme. Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion/ Janssen. Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS/ Celgene. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck/ EMD Serono. Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffmann-La Roche. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi-Genzyme. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic Therapeutics. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viatris/ Mylan. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. The institution of Dr. Montalban has received research support from Biogen. The institution of Dr. Montalban has received research support from Hoffmann-La Roche. The institution of Dr. Montalban has received research support from Sanofi/ Genzyme. The institution of Dr. Montalban has received research support from Merck/ EMD Serono. The institution of Dr. Montalban has received research support from Novartis. The institution of Dr. Montalban has received research support from Teva Pharmaceuticals. The institution of Dr. Montalban has received research support from Actelion/ Janssen. The institution of Dr. Montalban has received research support from BMS/ Celgene. Dr. Kuhle has nothing to disclose. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AB Science. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Janssen. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Celgene. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Immunic. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genzyme. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AB Science. The institution of Dr. Fox has received research support from National Institutes of Health. Dr. Fox has received publishing royalties from a publication relating to health care. Dr. Vartanian has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Vartanian has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Vartanian has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Vartanian has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Tisch MS Center. Dr. Vartanian has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dana Horakova has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dana Horakova has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dana Horakova has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dana Horakova has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Ernerst Roos has nothing to disclose. Dr. Wallstroem has received personal compensation for serving as an employee of Sanofi. Dr. Wallstroem has stock in Sanofi. Dr. Wallstroem has received intellectual property interests from a discovery or technology relating to health care. Dr. Atassi has received personal compensation for serving as an employee of Sanofi. Dr. Atassi has stock in Sanofi.
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