Patient Dosing Starts in MS Phase 2 Clinical Trial of Oral SAR443820
Study will assess medicine's effects on biomarker of nerve cell damage
Patient dosing has begun in a Phase 2 trial testing Denali Therapeutics‘ investigational oral RIPK1 inhibitor SAR443820 in people with multiple sclerosis (MS).
The clinical trial (NCT05630547) seeks to enroll about 168 patients, age 18–60, with either relapsing-remitting MS (RRMS), active and nonactive secondary progressive MS (SPMS), or primary progressive MS (PPMS). Recruitment is ongoing at sites in China and Europe.
The study, conducted by Denali’s partner Sanofi, is divided into two parts. In part A, participants will go through a four-week screening period and then be randomly assigned to receive oral SAR443820 or a placebo for 48 weeks (about 11 months). All who complete this part will be eligible to receive the therapy for another 11 months in the study’s open-label extension phase (part B).
Its main goal is to assess the effects of SAR443820 in serum neurofilament light chain (sNfL) levels, a biomarker of nerve cell damage that can help monitor disease activity and treatment response.
Secondary goals include changes in the number of lesions and in the rate of brain shrinkage, time to confirmed disability progression, relapse rates, and changes in walking function and hand and finger dexterity. Top-line data from the trial is expected in August 2025.
“Multiple sclerosis is a chronic and disabling, inflammation-mediated neurodegenerative disease with limited treatment options that target disease progression,” said Nazem Atassi, MD, global head of early neurology development at Sanofi, in a Denali press release. “RIPK1 inhibition with SAR443820 is a novel therapeutic approach that may reduce inflammation and cell death associated with disease progression in multiple sclerosis.”
Inhibiting enzyme that drives inflammation
SAR443820 (also known as DNL788) is a small molecule that inhibits RIPK1, an enzyme that drives inflammation and nerve cell death in the central nervous system (CNS, the brain and spinal cord).
It’s able to cross the blood-brain barrier, a highly selective membrane that “shields” the CNS from substances circulating in the bloodstream, with minimal activity outside that region. This is often a challenge for CNS-targeting therapies.
By targeting this enzyme, SAR443820 is expected to slow disease progression in conditions such as MS, amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease.
“SAR443820 has demonstrated robust target engagement and CNS penetration at doses that were generally well tolerated in Phase 1 studies in healthy volunteers, and we are eager to learn more from this Phase 2 study of SAR443820 in multiple sclerosis as we strive to bring innovative therapies to people with unmet medical needs,” Atassi said.
Denali joined with Sanofi in 2018 to advance the experimental therapy into those conditions. Under the collaboration, Sanofi is leading Phase 1 and Phase 2 studies of SAR443820 in MS and ALS. Denali will co-lead Phase 3 trials in ALS, MS, and Alzheimer’s.
The start of the Phase 2 trial will be accompanied by a milestone payment of $25 million to Denali and the company is entitled to receive additional development and regulatory milestone payments.
Sanofi is also conducting another Phase 2 trial, called HIMALAYA (NCT05237284), to test SAR443820 in people with ALS. The start of that trial also prompted a $40 million milestone payment from Sanofi.
“Following the initiation of the Phase 2 HIMALAYA study in ALS with SAR443820 last year by Sanofi, this Phase 2 study in multiple sclerosis marks another important milestone for our RIPK1 program,” said Carole Ho, MD, chief medical officer at Denali. “We look forward to collaborating with Sanofi as we aim to make a meaningful difference for individuals living with neurodegenerative diseases by delivering novel treatment options.”
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