oditrasertib (DNL788) / Denali Therap, Sanofi - LARVOL DELTA

ACT16753: A Study to Evaluate the Effect of SAR443820 on Serum Neurofilament Levels in Male and Female Adult Participants With Multiple Sclerosis (clinicaltrials.gov) - P2 | N=174 | Terminated | Sponsor: Sanofi | Trial completion date: Sep 2025 ➔ Nov 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Sep 2025 ➔ Nov 2024; The study was terminated as it did not meet its primary and key secondary endpoints

Trial completion date • Trial primary completion date • Trial termination • CNS Disorders • Multiple Sclerosis

Phase 2 Trial of SAR443820 (RIPK1 Inhibitor) in Relapsing and Progressive Multiple Sclerosis: K2 Study Design and Baseline Characteristics (ECTRIMS 2024) - P2 | "This proof-of-concept trial will investigate the effect of SAR443820 on sNfL, MRI, and clinical disability, while assessing safety and tolerability in participants with relapsing and progressive MS."

P2 data • CNS Disorders • Inflammation • Multiple Sclerosis • CDK7 • GFAP • RIPK1

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

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

HIMALAYA: Phase 2 Study for SAR443820 in Participants With Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P2 | N=305 | Terminated | Sponsor: Sanofi | Trial completion date: Jan 2027 ➔ Mar 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jul 2024 ➔ Mar 2024; The study was terminated as its Part A did not meet the primary endpoint.

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

Sanofi, Denali ALS Candidate Flops in Mid-Stage Trial (BioSpace) - P2 | N=305 | HIMALAYA (NCT05237284) | Sponsor: Sanofi | "Sanofi-partnered Denali Therapeutics reported on Friday that its investigational amyotrophic lateral sclerosis therapy fell short of its primary efficacy endpoint in the Phase II HIMALAYA study. The announcement, made in an SEC filing, was scarce with details or data. The companies only said that the candidate, dubbed SAR443820/DNL788, 'did not meet the primary endpoint of change in ALS Functional Rating Scale-Revised,' which is a validated tool to assess the severity of amyotrophic lateral sclerosis (ALS) and monitor a patient’s functional performance. Sanofi plans on presenting findings from HIMALAYA at an upcoming medical congress, according to the SEC document. The partners did not reveal their plans for SAR443820/DNL788 in ALS but the candidate remains in development for multiple sclerosis, where it has first-in-class potential."

P2 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Multiple Sclerosis

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

HIMALAYA: Phase 2 Study for SAR443820 in Participants With Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P2 | N=305 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Jul 2025 ➔ Jan 2027 | Trial primary completion date: Jan 2024 ➔ Jul 2024

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

Safety, Pharmacokinetics, and Target Engagement of a Brain Penetrant RIPK1 Inhibitor, SAR443820 (DNL788), in Healthy Adult Participants. (PubMed, Clin Transl Sci) - P1, P2 | "High levels of inhibition of activated RIPK1, as measured by decrease in pS166-RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (C ) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at peripheral level. These results support further development of SAR443820 in phase 2 trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547)."

Clinical • Journal • PK/PD data • Amyotrophic Lateral Sclerosis • CNS Disorders • Multiple Sclerosis • Pain • CDK7 • RIPK1

RIPK1 inhibitor SAR443820 in adult participants with amyotrophic lateral sclerosis (ALS): Study design and participant baseline characteristics of the Himalaya trial (ALS-MND 2023) - P2 | "The enrolment of Himalaya trial is expected to complete by August 2023. The detailed baseline characteristics of the study participants enrolled in the trial will be presented at the congress. The Himalaya trial will assess the effect of SAR443820 in reducing ALS progression measured by ALSFRS-R."

Clinical • Amyotrophic Lateral Sclerosis • CNS Disorders • CDK7 • RIPK1

A Study to Evaluate the Effect of SAR443820 on Serum Neurofilament Levels in Male and Female Adult Participants With Multiple Sclerosis (clinicaltrials.gov) - P2 | N=174 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Multiple Sclerosis

HIMALAYA: Phase 2 Study for SAR443820 in Participants With Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P2 | N=304 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting

Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders • NEFL

A Study to Assess the Effect of Erythromycin on the Test Medicine (SAR443820) When Given Orally as Tablets to Healthy Adult Male and Female Participants (Part A); and the Effect of Itraconazole on the Test Medicine (SAR443820) When Given Orally as Capsules to Healthy Adult Male Participants (Part B) (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Sanofi

New P1 trial • Amyotrophic Lateral Sclerosis • CNS Disorders

A Study in Healthy Adult Male & Female Participants to Assess the Amount of the Study Medicine (SAR443820) Absorbed by the Body, When Given Orally in Fasted Condition as a Tablet Versus as a Capsule (Part 1) and When Given Orally as a Tablet in Fasted Condition Versus as a Tablet After Food (Part 2) (clinicaltrials.gov) - P1 | N=18 | Completed | Sponsor: Sanofi

New P1 trial • Amyotrophic Lateral Sclerosis • CNS Disorders

First-in-Human Study of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SAR443820, a Central Nervous System Penetrant RIPK1 Inhibitor in Healthy Participants (AAN 2023) - P2 | "Maximum median inhibition of phosphorylated-Ser166-RIPK1 levels across all SAR443820 groups reflected a marked target engagement. Conclusions The first-in-human study demonstrated that single and repeated SAR443820 doses were generally safe and well-tolerated, with favorable pharmacokinetics, high CNS-penetrance, and robust RIPK1-target engagement, supporting further development in actively recruiting Phase 2 trials in ALS (Himalaya; NCT05237284) and MS (K2; ACT16753)."

Clinical • P1 data • PK/PD data • Amyotrophic Lateral Sclerosis • CNS Disorders • Hematological Disorders • Multiple Sclerosis • Pain • CDK7 • RIPK1

Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design (AAN 2023) - "Results Enrollment is expected to start in Q4 2022. Conclusions This proof-of-concept study is designed to demonstrate the effect of SAR443820 on neuroaxonal damage, reflected by sNfL levels and MRI markers."

Clinical • P2 data • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • CDK7 • RIPK1

Single & Multiple Ascending Dose Study of SAR443820 in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=84 | Completed | Sponsor: Sanofi

New P1 trial • Amyotrophic Lateral Sclerosis • CNS Disorders

Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Chain Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design (ACTRIMS Forum 2023) - "This proof-of-concept study is designed to demonstrate the effect of SAR443820 on neuroaxonal damage, reflected by sNfL levels and MRI markers."

Clinical • P2 data • CNS Disorders • Inflammation • Multiple Sclerosis • CDK7 • NEFL • RIPK1

Denali Therapeutics Announces Achievement of RIPK1 Milestone for Phase 2 Clinical Trial Initiation in Multiple Sclerosis by Sanofi (GlobeNewswire) - “Denali Therapeutics Inc…announced that its partner Sanofi has commenced dosing in a Phase 2 study of SAR443820 (DNL788) in individuals with multiple sclerosis. SAR443820 is a central nervous system (CNS)-penetrant investigational small molecule inhibitor of RIPK1….‘We look forward to collaborating with Sanofi as we aim to make a meaningful difference for individuals living with neurodegenerative diseases by delivering novel treatment options’….Under the collaboration agreement, Denali will receive a milestone payment of $25 million from Sanofi for initiation of the Phase 2 study with SAR443820 in multiple sclerosis. Denali is entitled to receive additional development and regulatory milestone payments.”

Commercial • Trial status • CNS Disorders • Immunology • Multiple Sclerosis

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

HIMALAYA: Phase 2 Study for SAR443820 in Participants With Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P2 | N=261 | Recruiting | Sponsor: Sanofi | Trial primary completion date: Sep 2023 ➔ Feb 2024

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

A Study to Evaluate the Effect of SAR443820 on Serum Neurofilament Levels in Male and Female Adult Participants With Multiple Sclerosis (clinicaltrials.gov) - P2 | N=168 | Recruiting | Sponsor: Sanofi | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Multiple Sclerosis

A Study to Evaluate the Effect of SAR443820 on Serum Neurofilament Levels in Male and Female Adult Participants With Multiple Sclerosis (clinicaltrials.gov) - P2 | N=168 | Not yet recruiting | Sponsor: Sanofi

New P2 trial • CNS Disorders • Multiple Sclerosis

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

Phase 2 study of SAR443820 in participants with multiple sclerosis (MS) (clinicaltrialsregister.eu) - P2 | N=280 | Ongoing | Sponsor: Sanofi-aventis recherche & développement

New P2 trial • CNS Disorders • Multiple Sclerosis