Rival AbbVie and Denali prospects flunk phase 2/3 ALS tests, denting hopes for shared mechanism

AbbVie, Calico and Denali Therapeutics’ hopes of treating amyotrophic lateral sclerosis (ALS) by targeting eIF2B have all taken a hit. Massachusetts General Hospital found neither AbbVie and Calico’s fosigotifator nor Denali’s DNL343 significantly slowed disease progression, causing misses on their respective primary endpoints.

Mass General tested fosigotifator and DNL343 in separate regimens of its HEALEY ALS Platform trial. Both molecules are designed to activate the protein complex eIF2B, protecting neurons by preventing further aggregation of the TDP-43 protein. Mass General evaluated the molecules—and other candidates—in parallel in a perpetual phase 2/3 study that will run until safe and effective ALS therapies are found.

The top-line results dent hopes that fosigotifator and DNL343 can meet the unmet need in ALS. Neither drug candidate significantly slowed ALS progression compared to placebo after 24 weeks or improved outcomes on key secondary endpoints that looked at muscle strength and respiratory function.

Both readouts contain some causes for optimism, though. The trial generated exploratory evidence that a high dose of fosigotifator may slow declines in muscle strength and revealed a potential effect on lung function. The hopes for DNL343 rest on upcoming assessments of prespecified subgroups, biomarker results and longer-term follow-up data.

Evercore analyst Mike DiFiore questioned whether six months is enough time to see an effect on disease progression at an event with a Denali executive last month. Alex Schuth, chief operating and financial officer at Denali, said DiFiore made “a very fair point,” adding that “frankly we would have probably wanted to treat longer than six months,” but patients and Mass General favored the shorter time frame.

“It's a balance with the desires of the patient community,” Schuth said. “In ALS, where the average survival is two to three years after diagnosis, the community felt very strongly that they would not want a trial with a one-year placebo control.”

Denali said a more comprehensive analysis of the data, including subgroup and biomarker results, will be available later this year. The data will inform the next steps. Asked last month whether a primary endpoint miss would be “the death knell” for DNL343, Schuth said Denali would make a decision once it has all the data in hand.

Shares in Denali fell 7% to $18.40 in premarket trading. The failure comes 11 months after another Denali drug candidate, the Sanofi-partnered RIPK1 inhibitor DNL788, failed a phase 2 ALS study.

AbbVie is yet to comment on the fosigotifator data. The candidate emerged from AbbVie’s 2014 deal with Calico, the biotech founded by Google’s parent company Alphabet and former Genentech CEO Art Levinson, Ph.D.

The Calico collaboration is a major undertaking, with AbbVie investing an initial $250 million, pumping a further $500 million into the partnership in 2018 and extending the alliance with another $500 million in 2021. Fosigotifator is among the key fruits of the partnership to date. The candidate is in development in major depressive disorder and vanishing white matter disease.

The failure of fosigotifator and DNL343 may have implications for Bristol Myers Squibb, which paid Evotec a $20 million option fee to license a eIF2B candidate in 2021. BMS’ phase 1 pipeline includes an eIF2B activator that is in development in Alzheimer’s disease.