Denali Therapeutics has announced that Takeda has decided to terminate its collaboration agreement for the co-development and commercialisation of DNL593 (PTV:PGRN), an investigational therapy for frontotemporal dementia linked to granulin gene mutations (FTD-GRN). The company clarified that the decision was based on strategic considerations and not due to concerns related to the drug’s safety or efficacy.

Following the termination, Denali will regain full control of DNL593 and its associated intellectual property, enabling the company to independently advance the programme. DNL593 is a progranulin replacement therapy designed using Denali’s proprietary Protein TransportVehicle (PTV) platform, which enables the delivery of therapeutic molecules across the blood-brain barrier (BBB) to target neurodegenerative conditions.

Denali’s CEO, Ryan Watts, expressed confidence in the therapy’s scientific foundation and ongoing clinical progress, stating that the company remains committed to advancing DNL593. Results from the ongoing Phase II/III clinical trial, which has completed enrolment with 40 participants, are expected by the end of 2026.

Preliminary findings from the study have shown encouraging results. Interim data from healthy volunteers demonstrated dose-dependent increases in cerebrospinal fluid progranulin levels, indicating effective delivery of the therapy to the brain. The treatment has also been generally well tolerated, with no significant safety concerns reported to date.

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder and one of the leading causes of early-onset dementia, particularly affecting individuals under the age of 60. Mutations in the granulin (GRN) gene result in reduced levels of progranulin, contributing to disease progression. Currently, there are no approved treatments that can halt or slow the progression of FTD or FTD-GRN.

Denali’s TransportVehicle platform represents a significant advancement in overcoming one of the biggest challenges in neurological drug development—the blood-brain barrier, which typically prevents therapeutic agents from reaching the brain in effective concentrations. The platform uses engineered protein domains to facilitate targeted delivery of large molecules, such as antibodies and enzymes, into the brain via receptor-mediated transport mechanisms.

Preclinical studies have demonstrated significantly higher brain exposure for therapies developed using this technology compared to conventional approaches. The platform has already been clinically validated, with multiple TransportVehicle-enabled programmes currently in development.

With full ownership of DNL593 restored, Denali aims to accelerate its efforts to develop effective therapies for neurodegenerative diseases, leveraging its innovative delivery platform to address unmet medical needs in conditions such as frontotemporal dementia.