Therapeutics

DNL919

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Overview

Name: DNL919
Synonyms: TAK-920, ATV:TREM2
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Denali Therapeutics Inc., Takeda Pharmaceutical Company

Background

This TREM2 agonist antibody activates microglia to phagocytose amyloid. DNL919 contains a transferrin-receptor binding sequence engineered into its Fc domain. Thus, the antibody binds to the abundant transferrin receptors on endothelial cells of the blood-brain barrier, which facilitate its active transport into the brain.  

Although Denali initially provided proof of concept for its antibody transfer vehicle (ATV) technology using BACE-1 antibodies, the company focused development on the TREM2 antibody and other payloads (e.g., Kariolis et al., 2020; Ullman et al., 2020; DNL593). Takeda is partnering on the development of DNL919.

In preclinical work, the mouse version of this antibody was shown to promote TREM2 receptor signaling, increase microglia survival and Aβ phagocytosis, and enhance plaque clearance in a mouse model of amyloidosis (Schlepckow et al., 2020). DNL919 boosted brain microglial activity and glucose metabolism in the 5XFAD mouse model of Alzheimer’s. In mice, the antibody achieved sixfold higher brain entry, and was more efficient at activating TREM2, than a non-ATV version (van Lengerich et al., 2023; Zhao and Bu, 2023).

Findings

In January 2022, the FDA placed a clinical hold on Denali’s investigational new drug application for DNL919 in the U.S., pending clarification of questions regarding the preclinical toxicology, clinical trial protocol, informed consent form, and investigator brochure (press release, SEC disclosure).

In July 2022, Denali began a Phase 1 study in the Netherlands, to assess safety, tolerability, pharmacokinetics, and target engagement after single ascending doses of DNL919 in 80 healthy participants.

On August 8, 2023, Denali announced that the company and Takeda had stopped development of DNL919 (press release). According to the release, DNL919 altered multiple microglial biomarkers, such as CSF1R, SPP1, IL1RA, IP10, MIP1b, MCP-1, indicating target engagement. It caused no serious adverse events, but did trigger moderate, reversible hematological changes at the highest dose tested. A news report cited Denali executives who said the antibody caused anemia. 

For details on this trial, see clinicaltrials.gov.

Last Updated: 16 Oct 2023

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References

Therapeutics Citations

  1. DNL593

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. Ullman JC, Arguello A, Getz JA, Bhalla A, Mahon CS, Wang J, Giese T, Bedard C, Kim DJ, Blumenfeld JR, Liang N, Ravi R, Nugent AA, Davis SS, Ha C, Duque J, Tran HL, Wells RC, Lianoglou S, Daryani VM, Kwan W, Solanoy H, Nguyen H, Earr T, Dugas JC, Tuck MD, Harvey JL, Reyzer ML, Caprioli RM, Hall S, Poda S, Sanchez PE, Dennis MS, Gunasekaran K, Srivastava A, Sandmann T, Henne KR, Thorne RG, Di Paolo G, Astarita G, Diaz D, Silverman AP, Watts RJ, Sweeney ZK, Kariolis MS, Henry AG. Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice. Sci Transl Med. 2020 May 27;12(545) PubMed.
  3. Schlepckow K, Monroe KM, Kleinberger G, Cantuti-Castelvetri L, Parhizkar S, Xia D, Willem M, Werner G, Pettkus N, Brunner B, Sülzen A, Nuscher B, Hampel H, Xiang X, Feederle R, Tahirovic S, Park JI, Prorok R, Mahon C, Liang CC, Shi J, Kim DJ, Sabelström H, Huang F, Di Paolo G, Simons M, Lewcock JW, Haass C. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med. 2020 Apr 7;12(4):e11227. Epub 2020 Mar 10 PubMed.
  4. van Lengerich B, Zhan L, Xia D, Chan D, Joy D, Park JI, Tatarakis D, Calvert M, Hummel S, Lianoglou S, Pizzo ME, Prorok R, Thomsen E, Bartos LM, Beumers P, Capell A, Davis SS, de Weerd L, Dugas JC, Duque J, Earr T, Gadkar K, Giese T, Gill A, Gnörich J, Ha C, Kannuswamy M, Kim DJ, Kunte ST, Kunze LH, Lac D, Lechtenberg K, Leung AW, Liang CC, Lopez I, McQuade P, Modi A, Torres VO, Nguyen HN, Pesämaa I, Propson N, Reich M, Robles-Colmenares Y, Schlepckow K, Slemann L, Solanoy H, Suh JH, Thorne RG, Vieira C, Wind-Mark K, Xiong K, Zuchero YJ, Diaz D, Dennis MS, Huang F, Scearce-Levie K, Watts RJ, Haass C, Lewcock JW, Di Paolo G, Brendel M, Sanchez PE, Monroe KM. A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models. Nat Neurosci. 2023 Mar;26(3):416-429. Epub 2023 Jan 12 PubMed.
  5. Zhao N, Bu G. A TREM2 antibody energizes microglia. Nat Neurosci. 2023 Mar;26(3):366-368. PubMed.

External Citations

  1. press release
  2. SEC disclosure
  3. press release
  4. news report
  5. clinicaltrials.gov

Further Reading