DNL919 / Denali Therap, Takeda - LARVOL DELTA

Unraveling the Immune Puzzle: Role of Immunomodulation in Alzheimer's Disease. (PubMed, J Neuroimmune Pharmacol) - "Preclinical studies of immunomodulatory agents, including salidroside, festidinol, astragalin, sulforaphane, BM-MSC, simvastatin, Ab-T1, hTREM2, and XENP345, demonstrate promising effects. Additionally, clinical investigations of drugs such as simufilam, AL002, TB006, VGL101, DNL919, XPro1595, astragalus, and IBC-Ab002 underscore the therapeutic potential of targeting immune pathways in AD. This review emphasizes how neuroinflammation, microglial activation, and peripheral immune responses contribute to disease progression. By exploring immunomodulatory mechanisms, the article sheds light on potential therapeutic targets that could help mitigate AD pathology which may pave the way for novel interventions preventing neurodegeneration in AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Immunology • Oncology • CTNNB1 • TNFA

PET imaging using a Copper-64 labeled TREM2 antibody with blood-brain barrier transport vehicle facilitates selective assessment of tumor associated immune cells in glioblastoma mice (EANM 2024) - "PET imaging with radiolabeled ATV:TREM2 antibodies indicated high specificity for immune cells and facilitated sufficient targeting of TAMs within the TME. Successful performance of a human ATV:TREM2 antibody holds promise for translation towards imaging of patients with glioblastoma."

Immune cell • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • TREM2

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL919 in Healthy Participants (clinicaltrials.gov) - P1 | N=47 | Completed | Sponsor: Denali Therapeutics Inc. | Recruiting ➔ Completed | N=80 ➔ 47

Enrollment change • Trial completion

Denali Therapeutics Reports Second Quarter 2023 Financial Results and Business Highlights (GlobeNewswire) - "Denali announced that, in agreement with Takeda, the companies will discontinue clinical development of DNL919 in Alzheimer’s disease. This is a strategic decision based on the totality of clinical data emerging from the single ascending dose Phase 1 study of DNL919 in healthy volunteers and in consideration of the rapidly evolving treatment landscape for Alzheimer's disease whereby an understanding of drug combinations with newly approved therapies will be important....Denali and Takeda will focus research efforts on back-up molecules in preclinical development, including exploration of potential combination therapy given recent new drug approvals in Alzheimer's disease."

Discontinued • Alzheimer's Disease • CNS Disorders

A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglia function (AAIC 2023) - "Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD."

Alzheimer's Disease • CNS Disorders

A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models. (PubMed, Nat Neurosci) - "In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD."

Journal • Alzheimer's Disease • CNS Disorders

Denali Therapeutics Announces Key Anticipated 2023 Milestones for Its Therapeutic Portfolio for Neurodegeneration and Lysosomal Storage Diseases (GlobeNewswire) - “TAK-594/DNL593 (PTV:PGRN): Frontotemporal dementia-granulin (FTD-GRN): Final data from Phase 1/2 Part A healthy volunteer study in mid 2023….TAK-920/DNL919 (ATV:TREM2): Alzheimer’s disease (AD): Data from the Phase 1 single ascending dose study in healthy volunteers by year-end 2023….SAR443820/DNL788 (CNS-penetrant RIPK1 inhibitor): ALS, MS, AD: Initiation of Phase 2 study in MS in early 2023. Completion of recruitment of participants with ALS in the Phase 2 HIMALAYA study….DNL343 (eIF2B activator): ALS: Final data from the 28-day double-blind, placebo-controlled portion of the Phase 1b study in mid 2023. Initiation of Phase 2/3 study in the HEALEY ALS Platform Trial in mid 2023.”

New P2 trial • New P2/3 trial • P1 data • P1/2 data • Trial status • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Immunology • Multiple Sclerosis

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL919 in Healthy Participants (clinicaltrials.gov) - P1 | N=80 | Recruiting | Sponsor: Denali Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL919 in Healthy Participants (clinicaltrials.gov) - P1 | N=80 | Not yet recruiting | Sponsor: Denali Therapeutics Inc.

New P1 trial

Denali Therapeutics Reports First Quarter 2021 Financial Results and Business Highlights (GlobeNewswire) - "Sanofi plans to commence dosing in a Phase 2 study of DNL758 (SAR443122) in CLE patients in the first half of 2021....EIF2B activator (DNL343): Initiate Phase 1b study in ALS patients: 2H 2021; PTV:PGRN (DNL593): File IND application or CTA: Late 2021; ATV:TREM2 (DNL919): File IND application or CTA: Late 2021/Early 2022;"

IND • New P1 trial • New P2 trial • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Lupus

Denali Therapeutics Reports Full Year 2020 Financial Results and Business Highlights (GlobeNewswire) - "Denali plans to initiate a Phase 1b study of DNL343 in patients with ALS in 2H 2021....Milestones with Takeda met for progress in PTV:PGRN and ATV:TREM2 programs... expects to receive another $8 million milestone payment for DNL919 later in Q1 2021....ATV:TREM2 (DNL919): File IND application or CTA - Alzheimer’s disease - Late 2021/Early 2022...PTV:PRGN (DNL593): File IND application or CTA - FTD - Late 2021...RIPK1 inhibitor (DNL788): Phase 1 data in healthy volunteers - ALS, Alzheimer’s disease - 2H 2021..."

Commercial • IND • New P1 trial • P1 data • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration