The phase 2 study will feature a 24-week treatment period followed by an 80-week open-label treatment period with the small-molecule RIPK1 inhibitor. It seeks to enroll 260 patients with ALS.
Sanofi has initiated dosing of SAR443820, its central nervous system penetrant small-molecule RIPK1 inhibitor, in the phase 2 HIMALAYA study (NCT05237284) in individuals with amyotrophic lateral sclerosis (ALS).1
The phase 2 study is still recruiting and has an estimated enrollment of 260 patients. It has a 2-part design: 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.
The randomization is stratified by study site geographic region, bulbar vs other areas of disease onset, as well as exposure to riluzole (Rilutek; Sanofi) and edaravone (Radicava; Mitsubishi Tanabe Pharma America). Those included will attend in-clinic study assessments at baseline, weeks 2, 4, 8, 16, and 24, and will receive phone calls at weeks 12 and 20.
“ALS is a devastating neurodegenerative disease for which effective treatment options are a critical unmet medical need,” Nazem Atassi, MD, global head, Early Neuro Development, Sanofi, said in a statement.1 “We are very encouraged by the results from the phase 1 trial of SAR443820 in healthy volunteers in which robust target engagement was demonstrated at doses that were generally well tolerated. Based on these results, we are excited to start the HIMALAYA phase 2 ALS study and look forward to working with Denali and the ALS community to advance the development of this novel investigational therapy.”
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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).
SAR443820 is a central nervous system (CNS)-penetrant small molecule inhibitor of RIPK1. In preclinical models of both ALS and multiple sclerosis (MS), inhibition of the tumor necrosis factor pathway protein has been shown to slow disease progression. The FDA has previously granted fast track designation to SAR443820 in the treatment of ALS.
The phase 1 trial (NCT04982991) results were announced at the 2021 Annual Northeast ALS (NEALS) Meeting, held virtually October 6-7.2 SAR443820, previously known as DNL788, was developed by scientists at Denali Therapeutics, which entered into a partnership with Sanofi to develop and commercialize the class of therapies in late 2018. Denali will receive a milestone payment of $40 million from Sanofi for this trial initiation.
“The initiation of this phase 2 study marks a significant milestone in the SAR443820 development program and our RIPK1 inhibitor collaboration with Sanofi,” Carole Ho, MD, chief medical officer, Denali, said in a statement.1 “We are excited about the progression of Denali’s portfolio in ALS with this milestone. Denali is committed to collaborating with the ALS community as we work toward a unified goal of developing potentially life-saving therapeutics for people living with ALS.”
In January 2022, The FDA had a clinical hold placed on Denali’s investigational new drug application for DNL919, an antibody transport vehicle (ATV) designed to activate the TREM2 protein and normalize microglial function in patients with Alzheimer disease (AD).3 The official clinical hold letter notification from the FDA came on January 12, 2022, via email. Denali noted that it planned to provide an update once it identified "clear path forward," though failed to provide specific details.
That news followed a Denali announcement from 2 days earlier, which stated that Takeda Pharmaceutical Company would be exercising its option to codevelop and cocommercialize the treatment for patients with AD.4 Takeda has also partnered with Denali on DNL593, a treatment for frontotemporal dementia granulin. In the same statement, Denali also announced plans to release the first clinical data on DNL919 to further validate its transport vehicle platform.