SAR443060 / Sanofi, Denali Therap - LARVOL DELTA

Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients. (PubMed, Clin Transl Sci) - P1b | "However, SAR443060 development was discontinued due to long-term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early-stage clinical trials. The dose-limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1-inhibitors, suggesting that these toxicities are compound-specific (related to SAR443060) rather than RIPK1 pathway-specific."

Journal • P1 data • PK/PD data • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Developmental Disorders • RIPK1

Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1b; N=15; Terminated; Sponsor: Sanofi; Trial primary completion date: Mar 2020 ➔ Jun 2020

Clinical • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders

Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1b; N=15; Terminated; Sponsor: Sanofi; Trial completion date: Jun 2021 ➔ Jun 2020; Active, not recruiting ➔ Terminated; Due to change in Sanofi's development strategy for DNL747/SAR443060 - not due to any safety concerns

Clinical • Trial completion date • Trial termination • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Pain

Denali Therapeutics provides broad update on its RIPK1 program partnered with Sanofi (GlobeNewswire) - "Denali Therapeutics...announced the results from its Phase 1b studies with small molecule RIPK1 inhibitor DNL747 in Alzheimer’s disease and ALS, and provided a broad RIPK1 program update including DNL788 and DNL758. 'Together with our partner Sanofi, we have decided to pause clinical studies with DNL747 and focus our efforts on...DNL788...toward proof-of-concept clinical studies in patients in multiple neurological indications'...Data...showed that DNL747 was safe and well tolerated at the dose tested with no significant treatment related adverse events; Denali and Sanofi intend to accelerate DNL788 for development in neurological indications, with plans to initiate clinical testing by early 2021."

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

As one hopeful Alzheimer's, ALS drug fizzles, Peninsula biotech brings up a second (Biz Journal) - “Denali Therapeutics Inc. and partner Sanofi paused clinical studies of an experimental drug…the drug DNL-747 was safe, well tolerated and had reached its target, an enzyme called RIPK1. But a parallel study of the drug in monkeys showed side effects could occur if the drug was dosed at higher levels in humans over time.”

Trial suspension • Amyotrophic Lateral Sclerosis • CNS Disorders

Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1b; N=15; Active, not recruiting; Sponsor: Sanofi; Trial completion date: Dec 2020 ➔ May 2021

Clinical • Trial completion date

Denali Therapeutics announces broad pipeline progress including positive results from its LRRK2 program for Parkinson’s disease (GlobeNewswire, Denali Therapeutics Inc.) - P1, N=34; NCT04056689; Sponsor: Denali Therapeutics; "Denali Therapeutics Inc....today announced the results of its Phase 1b clinical trial of LRRK2 inhibitor DNL201 in patients with Parkinson’s disease and its Phase 1 clinical trial of LRRK2 inhibitor DNL151 in healthy volunteers....Given these positive data, the DNL151 Phase 1 and Phase 1b clinical trials have been expanded to study higher doses. Denali intends to select either DNL201 or DNL151 in mid-2020 to advance into Phase 2/3 clinical trials in patients with Parkinson’s disease; RIPK1 inhibitor DNL747 Phase 1b trials in Alzheimer’s and ALS fully enrolled and open label extension in ALS ongoing with data readouts on track for mid-2020."

Enrollment closed • New P2/3 trial • P1 data

Why Denali Therapeutics stock is soaring today (Nasdaq) - “Shares of Denali Therapeutics…rose 24% as of 2:36 p.m. EST on Tuesday in response to announcing that its pipeline is progressing….DNL747 phase 1b trial in Alzheimer's disease and amyotrophic lateral sclerosis…is fully enrolled. Data is expected by the middle of 2020.”

Enrollment status • P1 data • Stock price

Study to Evaluate DNL747 in Subjects With Alzheimer's Disease (clinicaltrials.gov) - P1b; N=16; Completed; Sponsor: Denali Therapeutics Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion

Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1b; N=15; Active, not recruiting; Sponsor: Denali Therapeutics Inc.; Recruiting ➔ Active, not recruiting; Trial completion date: Dec 2019 ➔ Dec 2020; Trial primary completion date: Dec 2019 ➔ Mar 2020

Clinical • Enrollment closed • Trial completion date • Trial primary completion date

Study to Evaluate DNL747 in Subjects With Alzheimer's Disease (clinicaltrials.gov) - P1b; N=16; Active, not recruiting; Sponsor: Denali Therapeutics Inc.; Recruiting ➔ Active, not recruiting; Trial completion date: Aug 2019 ➔ Dec 2019; Trial primary completion date: Aug 2019 ➔ Dec 2019

Clinical • Enrollment closed • Trial completion date • Trial primary completion date

Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P1b; N=16; Recruiting; Sponsor: Denali Therapeutics Inc.; Trial completion date: Aug 2019 ➔ Dec 2019; Trial primary completion date: Aug 2019 ➔ Dec 2019

Clinical • Trial completion date • Trial primary completion date

Denali Therapeutics Reports Full Year 2018 Financial Results and Business Highlights (GlobeNewswire, Denali Therapeutics Inc.) - "... in collaboration with our partner Sanofi, we announced the first patient dosed in two Phase 1b studies of DNL747 in ALS and Alzheimer’s patients, respectively."

Clinical • Enrollment status

Denali Therapeutics Announces First Patient Dosed in Phase 1b Study of DNL747 for Alzheimer’s Disease (GlobeNewswire, Denali Therapeutics Inc.) - "Denali Therapeutics...today announced initiation of dosing in a Phase 1b clinical study of DNL747 in patients with Alzheimer’s disease, in collaboration with its partner Sanofi."

Trial status

Newly added product (Sanofi Press Release) - P1, Alzheimer's Disease, Multiple Sclerosis

Pipeline update