Drugs

2 ALS Drugs Miss Endpoints

Two eukaryotic initiation factor 2B (eIF2B) activator drugs from Denali Therapeutics and Calico Life Sciences each failed to meet primary and secondary endpoints in an innovative platform trial studying their safety and effectiveness in treating amyotrophic lateral sclerosis (ALS; also known as Lou Gerig’s Disease), according to company statements.

The studies were conducted under the HEALEY ALS Platform Trial at Massachusetts General Hospital. The platform is described as a patient-centric clinical trial designed in collaboration with the Northeast ALS Consortium to accelerate breakthrough ALS treatments. It is designed to evaluate multiple drugs (regimens) at the same time with “efficient use of patient, scientific, and operational resources,” the institution says. To date, seven regimens have been included in the trial and more regimens are becoming active soon, with the goal to add three each year.

Denali Therapeutics says its study of DNL343 failed to meet the primary efficacy endpoint in slowing disease progression as compared to a placebo. “The primary endpoint was evaluated as change in disease severity over time as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) and survival through week 24,” it says. “Key secondary endpoints, measuring muscle strength and respiratory function, were also not statistically different between the active and placebo groups at week 24.”

Calico Life Sciences says its fosigotifator regimen also did not meet the study’s primary endpoint of disease progression (a combined analysis of function and mortality) for either the primary or the exploratory high dose. “Key secondary endpoints based on the Revised ALS Functional Rating Scale (ALSFRS-R), respiratory function, and health-related quality-of-life, were also not statistically different from placebo groups for the primary dose,” it says. “Of note, endpoints of muscle strength, as measured by hand-held dynamometry (HHD) appeared to be different between the exploratory high dose and placebo groups, with slower deterioration in both upper and lower extremities in the exploratory high dose treatment group compared to placebo.”

Both drugs target eIF2B, a key component of the integrated stress response (ISR) pathway. They are designed to activativate eIF2B to reduce the effect of the ISR pathway and restore normal protein production in stressed nerve cells, potentially slowing the ALS progression.

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