DNL343 / Denali Therap - LARVOL DELTA

Denali's ALS drug fails to redeem itself, missing key biomarker in trial extension (FierceBiotech) - P2/3 | N=249 | HEALEY ALS (NCT05842941) | Sponsor: "Denali Therapeutics’ amyotrophic lateral sclerosis (ALS) drug has racked up another clinical miss this year, leaving the company to mull the asset’s future...At the time, Denali pinned its hopes on additional analyses of the trial data assessing the drug's effect on neurofilament light (NfL)—a biomarker of neuronal damage—as well as specific subgroups of patients and longer-term treatment data...But the biotech announced in a Securities and Exchange Commission filing March 5 that these additional analyses hadn’t demonstrated a treatment effect on NfL in either the 24-week trial or in a 28-week open-label treatment extension....As a result, Denali is moving to halt the extension arm of the trial, with the data to be presented at a future medical meeting....'intends to assess potential future development opportunities for DNL343.'"

P2/3 data • Trial status • Amyotrophic Lateral Sclerosis

HEALEY ALS Platform Trial - Regimen G DNL343 (clinicaltrials.gov) - P2/3 | N=249 | Completed | Sponsor: Merit E. Cudkowicz, MD | Enrolling by invitation ➔ Completed | Trial completion date: Aug 2025 ➔ Oct 2024 | Trial primary completion date: Jul 2025 ➔ Oct 2024

Trial completion • Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

Denali Therapeutics Announces Topline Results for Regimen G Evaluating eIF2B Agonist DNL343 in the Phase 2/3 HEALEY ALS Platform Trial (GlobeNewswire) - P2/3 | N=240 | NCT05842941 | "The study did not meet the primary endpoint of efficacy in slowing disease progression as compared with placebo. The primary endpoint was evaluated as change in disease severity over time as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) and survival through week 24. Key secondary endpoints, measuring muscle strength and respiratory function, were also not statistically different between the active and placebo groups at week 24. For the primary analysis, a total of 186 participants who were randomized to receive DNL343 treatment were compared to 139 participants randomized to receive placebo in this regimen (n=63) or shared from a concurrently enrolling regimen (n=76). Overall, DNL343 was found to be safe and well tolerated. Further analyses are anticipated later in 2025..."

P2/3 data • Amyotrophic Lateral Sclerosis

A Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL343 in Participants With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1 | N=29 | Completed | Sponsor: Denali Therapeutics Inc. | Active, not recruiting ➔ Completed | Phase classification: P1b ➔ P1 | Trial completion date: Dec 2023 ➔ Jun 2024

Phase classification • Trial completion • Trial completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response. (PubMed, Elife) - "Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain-penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic."

Journal • CNS Disorders • Inflammation • EIF2B4

A Phase 1, Open-label Study of the Absorption, Metabolism, and Excretion of [14C]-DNL343 Following a Single Oral Dose in Healthy Male Participants (clinicaltrials.gov) - P1 | N=7 | Completed | Sponsor: Denali Therapeutics Inc. | Recruiting ➔ Completed

Trial completion

HEALEY ALS Platform Trial - Master Protocol (clinicaltrials.gov) - P2/3 | N=1500 | Active, not recruiting | Sponsor: Merit E. Cudkowicz, MD | Recruiting ➔ Active, not recruiting

Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders

Denali Therapeutics Announces Completion of Enrollment for Regimen G Evaluating eIF2B Agonist DNL343 in the Phase 2/3 HEALEY ALS Platform Trial (GlobeNewswire) - "Denali Therapeutics Inc...today announced that the Sean M. Healey & AMG Center in collaboration with the Northeast ALS Consortium (NEALS) completed enrollment for Regimen G of the Phase 2/3 HEALEY ALS Platform Trial, which evaluates Denali’s eIF2B agonist DNL343."

Enrollment closed

Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases. (PubMed, J Med Chem) - "These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • EIF2B4

Denali Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Business Highlights (GlobeNewswire) - "DNL343: eIF2B activator in development for the treatment of amyotrophic lateral sclerosis (ALS); Enrollment continues in Regimen G (DNL343) of the Phase 2/3 HEALEY ALS Platform Trial and is expected to be completed in 2024....Today Denali also announced the execution of a Collaboration and Development Funding Agreement in January 2024 with a third party related to a global Phase 2a study of BIIB122/DNL151, which Denali plans to solely operationalize to evaluate safety and biomarkers associated with BIIB122 in participants with Parkinson’s disease and confirmed pathogenic variants of LRRK2. This agreement includes committed funding of $75.0 million, of which $12.5 million was received in January 2024, and the remainder will be triggered based on time and operational milestones in the study."

Enrollment status • Licensing / partnership • Amyotrophic Lateral Sclerosis • CNS Disorders • Parkinson's Disease

A Phase 1, Open-label Study of the Absorption, Metabolism, and Excretion of [14C]-DNL343 Following a Single Oral Dose in Healthy Male Participants (clinicaltrials.gov) - P1 | N=7 | Recruiting | Sponsor: Denali Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open

A Phase 1, Open-label Study of the Absorption, Metabolism, and Excretion of [14C]-DNL343 Following a Single Oral Dose in Healthy Male Participants (clinicaltrials.gov) - P1 | N=7 | Not yet recruiting | Sponsor: Denali Therapeutics Inc.

New P1 trial

Denali Therapeutics Announces Key Anticipated 2024 Milestones and Priorities to Further Advance Its Therapeutics Portfolio for Neurodegeneration and Lysosomal Storage Diseases (GlobeNewswire) - "Complete enrollment of participants in Regimen G (DNL343) in Phase 2/3 HEALEY ALS Platform Trial....Sanofi to announce topline results from the Phase 2 HIMALAYA study in ALS in the first half of 2024."

Enrollment status • P2 data • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders

The integrated stress response is modulated by eIF2B agonist DNL343: results from phase 1 healthy subject and phase 1b ALS patient studies (ALS-MND 2023) - P1, P1b | "In the Phase 1 study, DNL343 was generally safe and well-tolerated, showed extensive CSF distribution and a long half-life (38–46 hours) supporting once-daily dosing, and showed potent ISR biomarker responses in all MAD cohorts. Similarly, in the Phase 1b DB study, DNL343 was generally safe and well-tolerated with no serious adverse events. DNL343 plasma concentrations were dose-dependent and had similar concentrations in CSF as in plasma with a ratio of 1.2."

Clinical • P1 data • ATF4 • CHAC1 • EIF2B4 • TARDBP

HEALEY ALS Platform Trial - Regimen G DNL343 (clinicaltrials.gov) - P2/3 | N=240 | Enrolling by invitation | Sponsor: Merit E. Cudkowicz, MD | Not yet recruiting ➔ Enrolling by invitation

Enrollment open • Amyotrophic Lateral Sclerosis • CNS Disorders

HEALEY ALS Platform Trial - Master Protocol (clinicaltrials.gov) - P2/3 | N=1500 | Recruiting | Sponsor: Merit E. Cudkowicz, MD | Trial completion date: Dec 2025 ➔ Apr 2026 | Trial primary completion date: Apr 2025 ➔ Jul 2025

Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

HEALEY ALS Platform Trial - Regimen G DNL343 (clinicaltrials.gov) - P2/3 | N=240 | Not yet recruiting | Sponsor: Merit E. Cudkowicz, MD

New P2/3 trial • Amyotrophic Lateral Sclerosis • CNS Disorders

Denali Therapeutics Announces New DNL343 (eIF2B Agonist) Phase 1b Data in ALS To Be Presented at the Upcoming AAN Annual Meeting (GlobeNewswire) - P1 | N=30 | NCT05006352 | Sponsor: Denali Therapeutics Inc. | "Data show that DNL343 is generally well-tolerated at doses that demonstrate robust inhibition of biomarkers associated with the integrated stress response (ISR). Clinical pharmacokinetic and ISR pharmacodynamic data, along with preclinical data, are consistent with extensive CNS distribution and support once-daily dosing....As previously announced, DNL343 has been selected to enter the Phase 2/3 HEALEY ALS Platform Trial; Denali expects that recruiting will begin in mid 2023."

New P2/3 trial • P1 data • Amyotrophic Lateral Sclerosis • CNS Disorders

The Integrated Stress Response Is Modulated by eIF2B Agonist DNL343: Results From Phase 1 Healthy Subject and Phase 1b ALS Patient Studies. (AAN 2023) - P1, P1b | "The pharmacokinetic profile supports once daily oral dosing and there is extensive CSF distribution. Data from these early-stage studies in HV and ALS patients support further development of DNL343 as a potential therapeutic for the treatment of ALS."

Clinical • P1 data • Amyotrophic Lateral Sclerosis • CNS Disorders • ATF4 • CHAC1 • EIF2B4 • TARDBP

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 Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL343 in Participants With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1b | N=30 | Active, not recruiting | Sponsor: Denali Therapeutics Inc. | Recruiting ➔ Active, not recruiting | Trial primary completion date: Jun 2022 ➔ Dec 2022

Enrollment closed • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

Denali Therapeutics Announces DNL343 Interim Phase 1b Data in ALS and Entry into the HEALEY ALS Platform Trial (GlobeNewswire) - P1b | N=30 | NCT05006352 | Sponsor: Denali Therapeutics Inc. | “Denali Therapeutics Inc…announced interim results from a Phase 1b study of its eIF2B agonist, DNL343, in participants with amyotrophic lateral sclerosis (ALS). Once-daily oral dosing with DNL343 for 28 days was generally well tolerated and demonstrated extensive BBB penetration as well as robust inhibition of biomarkers associated with the integrated stress response (ISR) in blood samples from study participants. By inhibiting the ISR pathway, DNL343 is intended to prevent or slow disease progression associated with stress granule formation and TDP-43 aggregation…The Phase 1b results will be presented at the 33rd International Symposium on ALS/MND, which is being held virtually December 6-9, 2022….Denali also announced initiation of the design phase of a Phase 2/3 study for entry into the HEALEY ALS Platform Trial...”

New P2/3 trial • P1 data • Amyotrophic Lateral Sclerosis • CNS Disorders

Denali Therapeutics Reports Third Quarter 2022 Financial Results and Business Highlights (GlobeNewswire) - P1 | N=N/A | “In November 2022, Sanofi presented Phase 1 healthy volunteer data on SAR443820 at the Annual Northeast Amyotrophic Lateral Sclerosis (NEALS) Meeting demonstrating a safety profile that was well-tolerated after single ascending doses and 14 days of multiple ascending doses taken orally once or twice daily, with favorable pharmacokinetic properties and excellent CNS penetrance. Maximum median inhibition of pS66-RIPK1 levels in blood cells from the study participants ranged between 93% to 99% after multiple doses, reflecting marked RIPK1-target engagement….DNL343 (eIF2B activator): ALS: Denali plans to present data from the ongoing Phase 1b study of DNL343 in participants with ALS at the International Symposium on ALS/MND being held virtually, December 6 – 9, 2022. Based on Phase 1 data and ongoing blinded Phase 1b data, Denali has initiated planning for a late-stage study in ALS in 2023.”

New trial • P1 data • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders

Denali Therapeutics Reports Second Quarter 2022 Financial Results and Business Highlights (GlobeNewswire) - “DNL343 (eIF2B activator): Amyotrophic Lateral Sclerosis (ALS): Denali plans to present data from the ongoing Phase 1b study in ALS in the second half of 2022. Based on Phase 1 data and ongoing blinded Phase 1b data, Denali has initiated planning for late-stage development of DNL343 in ALS.”

P1 data • Amyotrophic Lateral Sclerosis • CNS Disorders

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL343 in Healthy Volunteers (clinicaltrials.gov) - P1; N=96; Completed; Sponsor: Denali Therapeutics Inc.; Recruiting ➔ Completed

Clinical • Trial completion • PCR