Denali Therapeutics and Sanofi have announced that their investigational drug, SAR443820/DNL788, failed to meet the primary endpoint in the Phase 2 HIMALAYA trial for amyotrophic lateral sclerosis (ALS). The study aimed to assess the efficacy of the oral brain-penetrant inhibitor in slowing disease progression in adults with ALS.
The HIMALAYA trial (NCT05237284) enrolled 305 adults with ALS, evaluating the change in ALS Functional Rating Scale-Revised (ALSFRS-R) score after 24 weeks as the primary outcome measure. ALSFRS-R is a validated tool used to assess the severity of ALS and monitor a patient’s functional performance. While the primary goal was not met, Sanofi intends to present detailed efficacy and safety results from the study at a future scientific forum.
Mechanism of Action and Previous Development
SAR443820/DNL788 is an oral inhibitor of RIPK1, an enzyme involved in inflammation and cell death within the central nervous system (CNS). Increased RIPK1 levels have been observed in the spinal cord of ALS patients. The drug is designed to penetrate the blood-brain barrier, potentially easing neuroinflammation and cell death, thereby slowing neurodegeneration.
Continued Development in Multiple Sclerosis
Despite the setback in ALS, Sanofi will continue to evaluate SAR443820/DNL788 in a Phase 2 trial for multiple sclerosis (MS). The K2 Phase 2 study (NCT05630547) is ongoing, assessing the drug's potential in treating MS, a disease of the central nervous system.
Background on ALS and Current Treatment Landscape
ALS is a rare and fatal neurodegenerative disease affecting 16,000 to 32,000 people in the United States. It leads to the progressive loss of motor neurons, causing muscle weakness, paralysis, and eventually death. Current FDA-approved treatments for ALS include Radicava (edaravone), Riluzole, Relyvrio (sodium phenylbutyrate and taurursodiol), and Qalsody, offering limited benefits in slowing disease progression or managing symptoms.
Sanofi and Denali Collaboration
Sanofi and Denali entered into a partnership in 2018, with Sanofi licensing multiple drug candidates from Denali in a deal valued at $1 billion. This collaboration aimed to develop therapies targeting neurological and inflammatory diseases. However, the partnership has faced previous setbacks, including the discontinuation of a Phase II trial for another RIPK1 inhibitor, eclitasertib, in patients with cutaneous lupus erythematosus in October 2023.
