Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design
Xavier Montalban1, Jens Kuhle2, Robert Fox3, Timothy Vartanian4, Dana Horakova5, Massimo Filippi6, Ernest Roos7, Erik Wallstroem7, Nazem Atassi7
1Multiple Sclerosis Centre of Catalonia, Department of Neurology–Neuroimmunology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 2Department of Neurology, University Hospital and University of Basel, 3Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, 4Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, 5Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University, 6Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 7Sanofi
Objective:
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).
Background:
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.
Design/Methods:
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.
Results:
Enrollment is expected to start in Q4 2022.
Conclusions:
This proof-of-concept study is designed to demonstrate the effect of SAR443820 on neuroaxonal damage, reflected by sNfL levels and MRI markers.