Therapeutics

DNL593

Tools

Back to the Top

Overview

Name: DNL593
Synonyms: PTV:PGRN
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Phase 1/2)
Company: Denali Therapeutics Inc., Takeda Pharmaceutical Company

Background

DNL593 is a replacement therapy for frontotemporal dementia caused by granulin gene mutations. In this type of FTD, a deficit of brain progranulin protein interferes with proper lysosomal function, leading to build-up of toxic proteins, neuroinflammation, and neurodegeneration (e.g., Sept 2017 news). To restore brain progranulin levels, DNL593 uses a "brain shuttle" technology, aka protein transfer vehicle (PTV), to move intravenously administered protein across the blood-brain barrier into the central nervous system. Protein transfer vehicles were developed to deliver BACE-1 antibodies into the brain, but can be used to transport other payloads, as well (e.g., Kariolis et al., 2020).

DNL593 consists of progranulin protein fused to an antibody fragment that binds to the transferrin receptor. Association with transferrin receptors on BBB endothelial cells facilitates the receptor-mediated transcytosis of progranulin protein into the brain.

In preclinical studies, DNL593 enhanced brain uptake of peripherally administered progranulin by three- to 10-fold over a progranulin fusion protein that did not bind transferrin receptor. The progranulin entered neurons and glia in the brain, and improved lysosomal function. DNL593 prevented neurodegeneration and microglial dysfunction in PGRN-deficient mice (Logan et al., 2021).

Findings

In February 2022, Denali and Takeda began a Phase 1/2 study of the safety, tolerability, and pharmacokinetics of single and multiple doses of DNL593. The placebo-controlled study plans to enroll 106 participants in two parts. The first phase will evaluate single doses in healthy adults. The second phase plans to test multiple ascending doses over six months in people with FTD. An optional 18-month, open-label extension will follow the second part. Primary outcomes are adverse events and safety signals related to laboratory values, vital signs, electrocardiogram, clinical findings, and suicidality. Secondary outcomes are pharmacokinetics in serum and CSF concentrations of DNL593. The trial is running at five sites in Spain and the UK, until November 2025.

For details, see clinicaltrials.gov.

Last Updated: 11 Jan 2023

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. Lysosomes Take Center Stage in Parkinson’s and Frontotemporal Dementia

Paper Citations

  1. . Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys. Sci Transl Med. 2020 May 27;12(545) PubMed.
  2. . Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Cell. 2021 Sep 2;184(18):4651-4668.e25. Epub 2021 Aug 26 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading