Takeda, Denali drop Alzheimer's asset after phase 1 peak reveals 'narrow therapeutic window'

Takeda and Denali Therapeutics have made the joint decision to end work on their Alzheimer’s disease therapy after a glimpse at early phase 1 data suggested they couldn't pursue the highest dose tested.

The Japanese Big Pharma took up the offer at the tail end of 2021 to co-develop the asset, an antibody transport vehicle (ATV) called DNL919 or TAK-920, but the program was soon hit by a clinical hold from the FDA due to a preclinical toxicology assessment. While the drug eventually entered the clinic in July 2022, it seems that the early data have raised some alarm bells.

“In the phase 1 study, DNL919 was clinically well tolerated at doses with demonstrated changes in CSF biomarkers and there were no serious adverse events or severe treatment emergent adverse events,” Denali explained in its second-quarter earnings report.

“However, safety signals of moderate, reversible hematologic effects were observed at the highest dose tested, suggesting a narrow therapeutic window for the Alzheimer’s disease patient population,” the biotech added.

It’s not the end of Takeda and Denali’s partnership, which was established back in 2018 to look at three targets for “neurodegenerative disorders, including Alzheimer’s disease and other indications.” With DNL919 cast aside, the two 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.”

Judging by the biotech’s comments elsewhere in the release, this consideration of potential combo therapies also played a part in the decision to scrap DNL919, with Denali saying that along with the “totality of clinical data emerging” from the phase 1 trial, it had also considered “the rapidly evolving treatment landscape for Alzheimer's disease whereby an understanding of drug combinations with newly approved therapies will be important.”

It could be that the two companies hope to have more luck hooking their wagons onto Biogen and Eisai's already approved Leqembi or Eli Lilly’s close contender donanemab.

Unlike those amyloid-targeting antibody therapies, the aim of DNL919 is to activate TREM2 in the hopes of improving microglial function, which the biotech has previously described as the "resident immune cells of the brain." Function loss in the TREM2 receptor is associated with increased risk for Alzheimer's, according to the biotech.

That appears to have been backed up in the same batch of early phase 1 data, which Denali said had indicated “robust target engagement and effects on microglial biomarkers, which were consistent with preclinical studies that demonstrate that ATV:TREM2 induces robust changes to a responsive microglial cell state.”

Biogen has its own Alzheimer’s collaboration with Denali, having exercised its option in April to license the biotech’s ATV-amyloid-beta program. The two companies are also investigating a LRRK2 inhibitor called BIIB122 in Parkinson’s disease.