NEW YORK – Denali Therapeutics and Takeda have decided to cease development of DNL919, an antibody transport vehicle (ATV)-enabled TREM2 agonist, as a treatment for Alzheimer's disease.
In a statement announcing its Q2 2023 financial performance, Denali said it made the decision to stop developing the drug with Takeda after reviewing data from a Phase I trial in healthy volunteers and after considering the "rapidly evolving treatment landscape for Alzheimer's disease."
Preliminary analysis of Phase I data showed DNL919 engaged its desired target and induced changes to a "responsive microglial cell state" by impacting microglial biomarkers such as CSF1R, SPP1, IL1RA, IP10, MIP1b, and MCP-1. The drug also caused changes in cerebral spinal fluid biomarkers and appeared to be well tolerated at different doses, causing no severe adverse events.
"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," Denali said in a statement. "The Phase I safety findings are believed to be specific to properties of DNL919 and TREM2 biology."
Denali and Takeda were developing DNL919 under a collaboration they inked in 2018 around three therapeutic programs focused on Alzheimer's and other neurodegenerative diseases. In the partnership, the companies were using Denali's ATV technology to enhance blood-brain barrier penetration of the agents under development.
DNL919 is an ATV engineered to activate the TREM2 receptor expressed on microglia, immune cells in the brain. Studies have shown that some Alzheimer's patients lose TREM2 function due to mutations in the eponymous gene, and TREM2 mutations have also been shown to increase the risk of Alzheimer's.
Even though Denali and Takeda have decided to discontinue developing DNL919, they "will continue to explore backup molecules including potential combination therapies in Alzheimer's disease," according to a statement from Denali CEO Ryan Watts. The partners hope to explore the potential of preclinical molecules particularly when combined with newly approved Alzheimer's drugs.
In July, the US Food and Drug Administration converted the accelerated approval for Biogen and Eisai's Alzheimer's drug Leqembi into a full approval. The drug is indicated for treating Alzheimer's patients who have mild cognitive impairment or mild dementia and the confirmed presence of beta-amyloid biomarkers.
Also in July, data from a Phase III trial showed that Eli Lilly's anti-amyloid Alzheimer's disease drug, donanemab, significantly slowed cognitive and functional decline in patients with mild cognitive impairment and mild dementia.
Denali also had in its pipeline an investigational ATV-enabled anti-amyloid-beta drug, which it had designed to clear Alzheimer's plaque and reduce amyloid-related imaging abnormalities. In April, Biogen exercised an option to license Denali's ATV-amyloid-beta program and take up all development and commercialization responsibilities and costs.
Denali currently doesn't have any marketed therapeutic products. For the three months ended June 30, Denali reported $294.1 million in collaboration revenue, a fivefold increase compared to $52.5 million in Q2 2022, largely due to greater payouts from Biogen because of its decision to license the ATV-amyloid-beta program. South San Francisco, California-based Denali recorded net income of $183.4 million, or $1.30 per share, compared to a net loss of $58.8 million, or $.48 per share, in Q2 2022. Denali ended Q2 with $1.19 billion in cash, cash equivalents, and marketable securities.
In late afternoon trading on the Nasdaq, Denali's stock price was down around 4 percent at $24.68.