Denali Therapeutics Regains Full Rights to Investigational Therapy DNL593 (PTV:PGRN) for GRN-related Frontotemporal Dementia (FTD-GRN)

Denali Therapeutics Inc. (Nasdaq: DNLI) said it has received notification from Takeda of its decision to terminate the companies’ collaboration agreement to co-develop and co-commercialize DNL593 (PTV:PGRN). Denali said the decision was driven by strategic considerations and was not related to any efficacy or safety data.

Denali to regain full control of DNL593

DNL593 is an investigational progranulin replacement therapy designed to deliver progranulin across the blood-brain barrier to the brain using Denali’s Protein TransportVehicle™ (PTV) technology. Denali said it has led development activities to date and will regain full control of DNL593 and its intellectual property portfolio.

“While we have greatly valued our partnership, we are pleased to regain full ownership of DNL593. We remain confident in the scientific rationale and the data generated to date, and we look forward to advancing DNL593 independently. We plan to report results from the ongoing Phase 1/2 trial by the end of 2026,” said Ryan Watts, Ph.D., Chief Executive Officer of Denali Therapeutics.

Phase 1/2 timeline and interim findings

Denali said data from the ongoing Phase 1/2 study of DNL593, including biomarker results, are expected by the end of 2026. Enrollment is completed with 40 participants with frontotemporal dementia-granulin (FTD-GRN).

Interim results from Part A of the Phase 1/2 study in healthy volunteers showed dose-dependent increases in cerebrospinal fluid progranulin levels, which Denali said are consistent with robust brain delivery of DNL593. Denali also said DNL593 has been generally well tolerated, with no significant safety signals reported to date.

Context: frontotemporal dementia and granulin

Denali described frontotemporal dementia (FTD) as the most common form of dementia in people under 60 years of age. It said progression varies by individual and can involve decline in function along with changes in personality and social behaviors, and sometimes language and/or motor dysfunction.

Denali said mutations in the granulin (GRN) gene, which encodes the progranulin (PGRN) protein, generally result in reduced levels of PGRN and are among the most common genetic causes of FTD. The company said there are currently no approved medications to stop or slow the progression of FTD or FTD-GRN.

TransportVehicle platform and clinical development

Denali said its TransportVehicle™ (TV) platform is designed to deliver large therapeutic molecules across the blood-brain barrier after intravenous administration. The platform is based on engineered Fc domains that bind to natural transport receptors expressed at the blood-brain barrier, enabling receptor-mediated transcytosis to the brain.

Denali cited preclinical findings indicating that, in animal models, antibodies and enzymes engineered with the TV platform demonstrate more than 10- to 30-fold greater brain exposure than similar molecules without the technology. For oligonucleotides, Denali said TV-engineered candidates showed more than a 1,000-fold greater brain exposure in primates than systemically delivered oligonucleotides without the technology.

The company said the TV platform has been clinically validated and that five TV-enabled programs are currently in clinical development.

Company outlook and forward-looking statements

Denali said the collaboration termination reflects strategic considerations and that it plans to advance DNL593 independently, including reporting Phase 1/2 results by the end of 2026. The company also reiterated that the press release contains forward-looking statements subject to risks and uncertainties, including those related to clinical development timelines, regulatory processes, and the ability to complete development and commercialization activities.