Denali, Takeda end work on PhI Alzheimer’s drug with ‘narrow therapeutic window’

As Biogen takes a preclinical Denali compound targeting amyloid beta forward in Alzheimer’s, Denali is shelving another Alzheimer’s candidate that is partnered with Takeda and hits a different target.

Phase I data suggest that the drug, known as TAK-920 or DNL919, has a “narrow therapeutic window” given safety signals, Denali said. Together with Takeda, it now plans to go back to the drawing board, focusing on backup molecules still in the preclinical stage, including potential combinations.

“This is a strategic decision based on the totality of clinical data emerging from the single ascending dose Phase I study of DNL919 in healthy volunteers and in consideration of the rapidly evolving treatment landscape for Alzheimer’s disease, whereby an understanding of drug combinations with newly approved therapies will be important,” the biotech wrote in its second-quarter update.

Whereas Biogen and Eisai’s earlier Alzheimer’s drug, Aduhelm, struggled to gain traction, their newly-approved amyloid-targeting therapy, Leqembi, is expected to upend the landscape as the FDA’s full approval opens the door to full Medicare coverage. Analysts expect Leqembi and Eli Lilly’s donanemab, recently submitted to the FDA, to bring in $10 billion in combined sales by 2030. Even then, the documented risks of brain bleeding and swelling tied to Leqembi have raised questions and debates.

According to Denali, DNL919 showed “robust target engagement” and “no serious adverse events” in Phase I. However, investigators did flag “moderate, reversible hematologic effects” at the highest dose; Stifel analyst Paul Matteis, citing Denali executives, specified the effects as anemia.

Denali added that it believes the safety issues are specific to properties of DNL919 — a TREM2 agonist antibody designed to cross the blood-brain barrier — and TREM2 biology.

“We spoke with DNLI management, who said that this shouldn’t hold readthrough to their (transport vehicle) platform as a whole, but instead is the product of the combination of TREM2 and TfR1, whereby combining the two targets together they believe they elicit an immune response that has an impact on transferrin function,” Matteis wrote.

The FDA has previously put DNL919 on hold due to preclinical toxicology findings, but Denali won the go-ahead after adjusting its Phase I protocol, informed consent form and investigator brochure.

Takeda first teamed up with Denali in early 2018, inking an unusually rich preclinical deal, starting with $155 million upfront, for three programs being developed at the neurodegeneration-focused biotech. It was Denali’s first major pharma licensing pact after the ex-Genentech crew wrapped a big IPO on the promise of transporting large molecules to the brain and a genetically-defined approach to treating neurodegeneration.

Ryan Watts

Denali noted that another Takeda-partnered program, the protein transport vehicle-enabled progranulin replacement therapy DNL593, remains in Phase I/II. It recently reported preliminary data in healthy volunteers but is now enrolling patients with frontotemporal dementia-granulin for a second part of the trial.

Denali is also moving ahead with late-stage studies for DNL310 (Hunter syndrome) and DNL343 (ALS), while Sanofi pushes forward two RIPK1 inhibitors. The company continues to work with Biogen on a LRRK2 inhibitor following recent changes to clinical trial plans in Parkinson’s, while Biogen will be fully responsible for the preclinical Alzheimer’s drug that it recently exercised its option on.

“These strategic decisions reflect our data-driven approach to resource optimization and portfolio prioritization as we focus on late-stage programs and commercial readiness,” CEO Ryan Watts added in a statement.

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