Takeda, Denali Scrap Phase I Alzheimer’s Drug Showing ‘Narrow Therapeutic Window’

Pictured: Facade of Takeda's office in Massachuset

Pictured: Facade of Takeda’s office in Massachuset

hapabapa/Getty Images

The companies partnered to develop the antibody transport vehicle in late 2021, but will continue their 2018 agreement to pursue other drugs in preclinical development.

Pictured: Takeda office in Massachusetts/iStock, hapabapa

Takeda and Denali Therapeutics have jointly ended an investigation into the effectiveness of an experimental Alzheimer’s therapy after early Phase I data suggested a “narrow therapeutic window” for the treatment.

The two companies first partnered back in 2018 to investigate three different targets for neurodegenerative disorders. Later, in late 2021, they agreed to go forward with a drug collaboration using an antibody transport vehicle (ATV) called DNL919, to activate the TREM2 receptor.

However, it quickly ran into headwinds after the FDA put a clinical hold on drug development before it could enter human trials, though it got the go-ahead and entered clinics in July 2022. Denali has previously said that function loss in that receptor is associated with increased Alzheimer’s risk, and the hope was that the ATV could increase microglial function—and, early Phase I data appeared to back that up.

In its second-quarter financial results reported Tuesday, Denali said the data showed “robust target engagement and effects on microglial biomarkers” as well as the drug being “clinically well tolerated at doses with demonstrated changes” while “there were no serious adverse events or severe treatment emergent adverse events.”

Still, those data also showed “safety signals of moderate, reversible hematolic effects were observed at the highest dose tested, suggesting a narrow therapeutic window for the Alzheimer’s disease patient population,” Denali said. The companies agreed to drop drug development on that basis, citing the “rapidly evolving treatment landscape for Alzheimer’s disease whereby an understanding of drug combinations with newly approved therapies will be important.”

Denali, however, also noted that these safety findings are “believed to be specific to properties of DNL919 and TREM2 biology,” leaving the window open for other treatments. The companies “will focus research efforts on back-up molecules in preclinical development, including exploration of potential combination therapy given recent new drug approvals in Alzheimer’s disease.”

With DNL919 scrapped, the companies may switch their focus to amyloid-targeting therapies. Not only do they have these therapies in the pipeline, but they’ve already demonstrated success: Biogen and Eisai already have a monoclonal amyloid antibody treatment, Leqembi, approved, and Eli Lilly’s donanemab is undergoing Phase III clinical trials.

Denali has its own separate partnership with Biogen and noted in its financial report that “Biogen exercised their option to our ATV-amyloid-beta program for Alzheimer’s disease.” With Biogen, the company “made revisions to the BIIB122 (LRRK2 inhibitor) clinical development plan intended to increase efficiency by focusing on one study in Parkinson’s disease.”

Connor Lynch is a freelance writer based in Ottawa, Canada. Reach him at lynchjourno@gmail.com.