Takeda and Denali Therapeutics first partnered in early 2018 to advance drugs for neurodegenerative diseases. One asset, for Alzheimer’s disease, was previously discontinued after an FDA hold and disappointing early data.
More than eight years after linking up, Takeda and Denali Therapeutics are going their separate ways, with the Japanese pharma handing all rights to a dementia program back to Denali.
Takeda’s decision to terminate its partnership with Denali “was driven by strategic considerations,” the California biotech said in an SEC document dated April 3, and “is not related to efficacy or safety data.” The Japanese pharma informed Denali of its decision that same day, according to the securities filing.
The companies inked their partnership in January 2018, with Takeda fronting $150 million and promising unspecified milestone payments.
Takeda and Denali had also previously been working on the TREM2 agonist DNL919 for Alzheimer’s disease—but this molecule’s development path has been bumpy. In January 2022, the FDA slapped a clinical hold on the asset, though the partners at the time did not disclose why. The hold was eventually lifted, but Takeda and Denali in August 2023 nevertheless discontinued DNL919’s development, pointing to Phase 1 findings suggesting the drug had only a “narrow therapeutic window.”
In 2021, Takeda also exercised its option to co-develop and co-commercialize DNL593, a protein replacement therapy that can cross the blood-brain barrier, for frontotemporal dementia.
That asset has since been returned to Denali, the biotech said on April 3. “We are looking forward to advancing DNL593 independently,” CEO Ryan Watts said in a press statement that day, adding that the company “remain[s] confident” in the scientific rationale behind DNL593.
DNL593 works by replacing the progranulin protein, which in frontotemporal dementia is deficient, leading to lysosomal defects that, in turn, result in the accumulation of toxins across different tissues. The asset is currently in a Phase 1/2 study, enrollment for which has completed with 40 recruited participants, according to Denali’s April 3 release. There have been no reported safety signals to date, the biotech noted.
Phase 1/2 data for DNL593 are expected before the end of this year, Watts said.
Takeda’s pullback comes just days after Denali delivered a much-needed win for the rare disease space with the FDA approval of its Hunter syndrome therapy Avlayah. Like DNL593, Avlayah works by replacing a deficient player, this time targeting the IDS enzyme, which under healthy conditions clears toxic byproducts from several organs, including the brain.
Avlayah is the first Hunter syndrome therapy in nearly 20 years and is the first FDA-approved treatment to exploit the transferrin pathway to cross the blood-brain barrier.
