Denali/Sanofi ALS Candidate Hits Phase II as Awareness Month Begins

ALS Concept

Denali Therapeutics, Inc. announced that dosing has begun for participants in a Phase II clinical trial that intends to evaluate the potential of SAR443820 (also known as DNL788) in patients with amyotrophic lateral sclerosis (ALS). The trial is sponsored by Sanofi, in partnership with Denali, in a joint effort to commercialize the novel central nervous system (CNS)-penetrant treatment for the treatment of the brutal degenerative disease. 

The Phase II Himalaya clinical trial (NCT05237284) will investigate the safety and efficacy of SAR443820. The study is currently recruiting for all six sites, spanning 6 countries. The study design will be double-blinded, randomized, place-controlled and comes with an open-label extension. The primary outcome measurement will evaluate a patient’s change from baseline scoring in the ALS Functional Rating Scale-Revised (ALSFRS-R), a tool used to determine how severely the disease has affected normal functionality over time. Additionally, researchers will evaluate the patient using a combination assessment of function and survival (CAFS) scoring. The study is expected to conclude in April of 2025.

CNS-penetrant treatments, including SAR443820, are unique in their ability to cross the blood-brain barrier (BBB), which allows the small molecule RIPK1 inhibitor to reach the entire CNS. After ingestion of the oral tablet, inhibition of the RIPK1 signaling protein prevents RIPK1 activity from inflicting inflammatory damage and brain cell death. The RIPK1 protein is crucial for the tumor necrosis factor (TNF) receptor pathway, meaning the protein is involved in regulating inflammation and cell death.

The partners have ambitions to expand the RIPK1 inhibitor program to include other central nervous system (CNS) and peripheral inflammatory diseases. Additional studies were mentioned in the press release, including in multiple sclerosis (MS) and Alzheimer’s disease. The encouraging potential of the drug aided the U.S. Food and Drug Administration’s (FDA) decision to grant Fast Track Designation in ALS.

Initiation of the trial represents a clinical milestone for which Denali will receive a payment of $40 million from Sanofi in exchange for an equal share of all CNS-penetrant products that are sold within the U.S. and China.

Denali’s Chief Medical Officer, Carole Ho, M.D. commented on the study’s initiation.

“The initiation of this Phase II study marks a significant milestone in the SAR443820 development program and our RIPK1 inhibitor collaboration with Sanofi. 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," she said in a statement. 

In a Phase I clinical study, the drug was shown to be well tolerated, with robust target engagement, in healthy volunteers. Preclinical studies suggest the drug has a wide therapeutic window, allowing for disease treatment without toxicity.

This announcement comes well-timied with the beginning of ALS awareness month. According to the ALS Association, a diagnosis is given every 90 minutes, primarily to people aged 40 to 70 years old. For most cases, no hereditary or genetic cause has been identified. No cure has been found.

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