DNL593 / Takeda, Denali Therap - LARVOL DELTA

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN) (clinicaltrials.gov) - P1/2 | N=106 | Recruiting | Sponsor: Denali Therapeutics Inc. | Active, not recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • GRN

Denali Therapeutics Reports Second Quarter 2024 Financial Results and Business Highlights (GlobeNewswire) - "Sanofi is evaluating SAR443820/DNL788 in a Phase 2 study in participants with MS, which is fully enrolled...TAK-594/DNL593:...Denali has finalized the protocol amendment for the Phase 1/2 study and prescreening of participants for Cohort B2 is ongoing."

Clinical protocol • Enrollment closed • CNS Disorders • Dementia • Immunology • Multiple Sclerosis

Rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral AAV-mediated expression of brain-penetrant progranulin (AAIC 2024) - "As in mice, aberrant TDP-43, lysosomal dysfunction and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies can ameliorate FTLD- GRN relevant phenotypes including TDP-43 pathology, neurodegeneration and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD- GRN and potentially other CNS disorders."

Alzheimer's Disease • CNS Disorders • Frontotemporal Lobar Degeneration • Gene Therapies • Metabolic Disorders • Targeted Protein Degradation • TARDBP

Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration. (PubMed, Sci Transl Med) - "As in mice, aberrant TDP-43, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies ameliorate FTLD-GRN relevant phenotypes including TDP-43 pathology, neurodegeneration, and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-GRN and potentially other CNS disorders."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Frontotemporal Lobar Degeneration • Gene Therapies • Metabolic Disorders • Targeted Protein Degradation • TARDBP

Denali Therapeutics Reports First Quarter 2024 Financial Results and Business Highlights (GlobeNewswire) - "In February, Sanofi discontinued development of SAR443820/DNL788 in ALS based on the results of the Phase 2 HIMALAYA study, which did not meet the primary endpoint. BIIB122/DNL151:...Denali plans to initiate the Phase 2a study in 2024....In January, Denali announced a voluntary pause in the DNL593 Phase 1/2 study in participants with FTD-GRN to implement protocol modifications and expects the study to resume this year."

Discontinued • New P2a trial • Trial status • Amyotrophic Lateral Sclerosis • CNS Disorders

RESCUE OF FTLD-ASSOCIATED TDP-43 PATHOLOGY AND NEURODEGENERATION BY PERIPHERAL AAV-MEDIATED EXPRESSION OF BRAIN-PENETRANT PROGRANULIN (ADPD 2024) - "As in mice, TDP-43 phosphorylation and hyper-processing, lysosomal dysfunction, and neuronal loss were reduced after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our results show that peripherally administered brain-penetrant PGRN replacement strategies can ameliorate FTLD-GRN-related phenotypes in preclinical models. Our data provide proof of concept for the use of this AAV platform in the treatment of FTLD-GRN and potentially other CNS disorders."

Alzheimer's Disease • CNS Disorders • Frontotemporal Lobar Degeneration • Gene Therapies • Metabolic Disorders • Targeted Protein Degradation • TARDBP

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN) (clinicaltrials.gov) - P1/2 | N=106 | Active, not recruiting | Sponsor: Denali Therapeutics Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • GRN

Safety and pharmacokinetics of single ascending doses of TAK-594/DNL593, a brain-penetrant progranulin replacement therapy, in healthy volunteers: Interim results from Part A of a Phase 1/2 clinical trial (AAIC 2023) - P1/2 | "Single dose safety and PK of TAK-594/DNL593 in healthy participants support initiation of the multiple dose study in participants with FTD-GRN. The dose-dependent increase in CSF PGRN is consistent with delivery of TAK-594/DNL593 across the BBB and supports the potential of TAK-594/DNL593 to treat FTD-GRN. References Logan, Todd, Matthew J. Simon, Anil Rana, Gerald M. Cherf, Ankita Srivastava, Sonnet S. Davis, Ray Lieh Yoon Low, et al."

Clinical • P1/2 data • PK/PD data • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Inflammation • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • GRN

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

Denali Therapeutics Announces Phase 1/2 Study Single Dose Healthy Volunteer Data with TAK-594/DNL593 (PTV:PGRN) and Progression to Enrolling Participants with FTD-GRN (GlobeNewswire) - P1/2 | N=106 | NCT05262023 | Sponsor: Denali Therapeutics Inc | “Denali Therapeutics Inc…announced interim results from Part A of a Phase 1/2 study evaluating TAK-594/DNL593 (PTV:PGRN) in healthy subjects. Progranulin (PGRN) levels measured in cerebrospinal fluid (CSF) increased in a dose-dependent manner compared to baseline and placebo, consistent with brain delivery of DNL593 and exceeding levels believed to be necessary to rescue deficits associated with progranulin deficiency…Single doses of DNL593 were generally well tolerated, based on blinded safety analysis. These data support dosing in participants with frontotemporal dementia and a mutation in the granulin gene (FTD-GRN) in Part B of the study. DNL593 is an investigational, brain-penetrant progranulin replacement therapy being co-developed by Denali and Takeda. These data were presented at the FTD Prevention Initiative meeting in Paris, France.”

P1/2 data • Trial status • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

Denali Therapeutics Announces Initiation of Phase 1/2 Clinical Trial of DNL593 (PTV:PGRN) for Frontotemporal Dementia-Granulin (FTD-GRN) (GlobeNewswire) - “Denali Therapeutics Inc…announced that dosing has begun in a Phase 1/2 clinical trial of DNL593 (PTV:PGRN) for the potential treatment of frontotemporal dementia (FTD) caused by mutations in the granulin gene (GRN). Pending initial clinical data from the Phase 1 healthy volunteer portion of the clinical trial, Denali expects to begin dosing individuals with FTD-GRN in the second half of 2022. Denali and Takeda have a strategic collaboration to co-develop and co-commercialize DNL593.”

Trial status • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

RESCUE OF A LYSOSOMAL STORAGE DISORDER CAUSED BY GRN LOSS-OF-FUNCTION WITH A BRAIN PENETRANT PROGRANULIN BIOLOGIC (ADPD 2022) - "Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn–/– CNS, including microgliosis, lipofuscinosis, and neuronal damage. Conclusions PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD."

Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • Targeted Protein Degradation

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN) (clinicaltrials.gov) - P1/2 | N=106 | Recruiting | Sponsor: Denali Therapeutics Inc.

New P1/2 trial • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology

Rescue of lysosomal storage disorder phenotypes caused by Grn loss of function with a brain penetrant progranulin biologic (Neuroscience 2021) - "Moreover, the data suggest that lysosomal phenotypes may underlie glial activation and neuronal degeneration observed in Grn KO mice, which are also rescued with PTV:PGRN treatment. Taken together our data provide preclinical proof of concept for PTV:PGRN, supporting its use as a potential therapeutic in the treatment of PGRN loss-of function and GRN-FTD."

Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

Denali Therapeutics Announces Strategic Partner Takeda Exercises Option to Co-Develop and Co-Commercialize DNL593 (PTV:PGRN) (Yahoo Finance) - “Companies to advance clinical development of DNL593 as a brain-penetrant progranulin replacement therapy for frontotemporal dementia-granulin (FTD-GRN). Denali Therapeutics Inc…today announced that its strategic partner Takeda Pharmaceutical Company Limited (‘Takeda’) has exercised an option, pursuant to an existing collaboration agreement between the two companies, to co-develop and co-commercialize DNL593 (PTV:PGRN), an investigational, brain-penetrant progranulin replacement therapy for the potential treatment of frontotemporal dementia-granulin (FTD-GRN).”

Licensing / partnership • CNS Disorders • Frontotemporal Lobar Degeneration

Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. (PubMed, Cell) - "Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • Targeted Protein Degradation

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

[VIRTUAL] A BRAIN PENETRANT PROGRANULIN BIOLOGIC RESCUES LYSOSOMAL AND INFLAMMATORY BIOMARKERS IN Grn KNOCKOUT MOUSE BRAIN (ADPD 2021) - "Intravenous administration of PTV:PGRN in knock-in (KI) mice expressing huTfR led to significant increase in brain PGRN levels relative to Fc:PGRN fusion control, highlighting the ability of huTfR binding to increase brain uptake of PGRN. Systemic administration of PTV:PGRN corrected disease-associated lysosomal phenotypes, including BMP deficiency and lipofuscinosis, as well as inflammatory markers in the brain of Grn KO x huTfR KI mice.  Conclusions Our data suggest that PTV:PGRN may represent a viable therapeutic strategy for the treatment of GRN-FTD and potentially other neurological disorders associated with PGRN deficiency."

Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology • Inflammation • Targeted Protein Degradation

Denali Therapeutics Announces Significant Program Progress and Expected Key Milestones in 2021 for Its Broad Therapeutic Portfolio in Neurodegeneration (GlobeNewswire) - “Denali’s most advanced EIF2B activator, DNL343, is a brain-penetrant small molecule designed to rescue EIF2B function and restore normal RNA metabolism. Results from a Phase 1 study of DNL343 in healthy volunteers are expected to be available in 1H 2021. Denali plans to initiate a Phase 1b study of DNL343 in patients with ALS in 2H 2021....In Q4 2020, Sanofi initiated a Phase 1 healthy volunteer study of DNL788 (SAR443820), a potent, selective, and brain-penetrant small molecule RIPK1 inhibitor intended to treat patients with ALS, Alzheimer’s disease, and multiple sclerosis; data is expected to be available in 2H 2021....DNL593 (PTV:PGRN), an intravenously administered recombinant progranulin...for the potential treatment of FTD. In December 2020, Denali initiated IND-enabling studies for DNL593 for which Denali will receive a related milestone payment of $8 million from Takeda. Denali plans to file an IND application or a clinical trial application (CTA) in late 2021."

IND • New P1 trial • P1 data • Preclinical • Trial status • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Multiple Sclerosis

[VIRTUAL] A brain penetrant progranulin biotherapeutic rescues lysosomal and inflammatory phenotypes in the brain of Grn knockout mice (AAIC 2020) - "Our data suggest that PTV:PGRN may represent a viable therapeutic strategy for the treatment of GRN-FTD and potentially other disorders associated with PGRN deficiency."

Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology • Lysosomal Storage Diseases • Rare Diseases • Targeted Protein Degradation

[VIRTUAL] A brain penetrant progranulin biotherapeutic rescues lysosomal and inflammatory phenotypes in the brain of Grn knockout mice (AAIC 2020) - "Our data suggest that PTV:PGRN may represent a viable therapeutic strategy for the treatment of GRN-FTD and potentially other disorders associated with PGRN deficiency."

Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology • Lysosomal Storage Diseases • Rare Diseases • Targeted Protein Degradation