Therapeutics

DNL593

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Overview

Name: DNL593
Synonyms: PTV:PGRN, TAK-594
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 14 sites in Europe, Turkey, and Brazil, until November 2025.

The company presented results of the single-dose study at the July 2023 AAIC in Amsterdam. DNL593 was well tolerated over a 30-fold dose range, with no serious adverse events. Mild to moderate side effects were similar to placebo. The drug showed predictable pharmacokinetics with low person-to-person variability. CSF PRGN concentrations increased with dose.

For details, see clinicaltrials.gov.

Last Updated: 23 Oct 2023

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References

News Citations

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

Paper Citations

  1. Kariolis MS, Wells RC, Getz JA, Kwan W, Mahon CS, Tong R, Kim DJ, Srivastava A, Bedard C, Henne KR, Giese T, Assimon VA, Chen X, Zhang Y, Solanoy H, Jenkins K, Sanchez PE, Kane L, Miyamoto T, Chew KS, Pizzo ME, Liang N, Calvert ME, DeVos SL, Baskaran S, Hall S, Sweeney ZK, Thorne RG, Watts RJ, Dennis MS, Silverman AP, Zuchero YJ. 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. Logan T, Simon MJ, Rana A, Cherf GM, Srivastava A, Davis SS, Low RL, Chiu CL, Fang M, Huang F, Bhalla A, Llapashtica C, Prorok R, Pizzo ME, Calvert ME, Sun EW, Hsiao-Nakamoto J, Rajendra Y, Lexa KW, Srivastava DB, van Lengerich B, Wang J, Robles-Colmenares Y, Kim DJ, Duque J, Lenser M, Earr TK, Nguyen H, Chau R, Tsogtbaatar B, Ravi R, Skuja LL, Solanoy H, Rosen HJ, Boeve BF, Boxer AL, Heuer HW, Dennis MS, Kariolis MS, Monroe KM, Przybyla L, Sanchez PE, Meisner R, Diaz D, Henne KR, Watts RJ, Henry AG, Gunasekaran K, Astarita G, Suh JH, Lewcock JW, DeVos SL, Di Paolo G. 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

Papers

  1. Simon MJ, Logan T, DeVos SL, Di Paolo G. Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia. Trends Cell Biol. 2022 Oct 13; PubMed.