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Denali Therapeutics Inc. DNLI announced disappointing top-line results from an analysis of Regimen G of the phase II/III HEALEY ALS Platform Trial on pipeline candidate DNL343.
The HEALEY platform trial is evaluating eIF2B agonist DNL343 in the treatment of amyotrophic lateral sclerosis (ALS).
DNL343 is a novel small molecule ALS therapeutic candidate that targets eIF2B, a central regulator of the integrated stress response.
Shares of DNLI have lost 6.5% in the past six months compared with the industry’s 6.4% decline.
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DNLI’s ALS Study Fails
A total of 186 participants who were randomized to receive DNL343 treatment were compared to 139 participants randomized to receive placebo in this regimen (n=63) or shared from a concurrently enrolling regimen (n=76).
ALS causes the progressive degeneration of motor neurons, resulting in muscle weakness and atrophy. The most prevalent adult-onset progressive motor neuron disease, ALS affects approximately 30,000 people in the United States and an estimated 500,000 people worldwide.
Results showed that the study did not meet the primary endpoint of efficacy in slowing disease progression as compared with placebo. The primary endpoint was evaluated as a change in disease severity over time as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) and survival through week 24.
Key secondary endpoints, measuring muscle strength and respiratory function, were also not statistically different between the active and placebo groups at week 24.
DNL343 was found to be well tolerated. Denali will report additional data later in 2025, including neurofilament light (NfL) and other fluid biomarkers, data from pre-specified subgroups, and extended findings from the active treatment extension period.
Denali will evaluate the data before determining the next steps.
DNLI’s Other Pipeline Updates
Denali and partner Sanofi SNY were co-developing SAR443820/DNL788. However, Sanofi informed Denali that the K2 phase II study evaluating the safety and efficacy of oditrasertib (SAR443820/DNL788) on serum neurofilament light chain levels in participants with multiple sclerosis was discontinued. The decision was taken after the study did not meet the primary and key secondary endpoints.
We remind investors that Sanofi had earlier discontinued the development of SAR443820/DNL788 for the treatment of ALS, based on the results of the phase II HIMALAYA study, which did not meet the primary endpoint.
Meanwhile, Denali and partner Sanofi are also developing SAR443122/DNL758 (eclitasertib), a peripheralRIPK1 inhibitor, for the treatment of ulcerative colitis. Sanofi is currently conducting a phase II study on this candidate.