flizasertib (RG6287) / Roche - LARVOL DELTA

Discovery of Clinical Candidate GDC-8264, a Novel, Potent and Selective RIP1 Inhibitor for Amelioration of Tissue Damage and the Treatment of Inflammatory Diseases. (PubMed, J Med Chem) - "Subsequent optimization yielded clinical molecule GDC-8264 (compound 19), which has excellent target selectivity and druglike attributes for once-daily oral dosing. GDC-8264 is currently being tested in a Phase 2 trial for the prevention of cardiac surgery-associated acute kidney injury (CSA-AKI) in hopes of providing benefit for patients requiring cardio-pulmonary bypass at medium to high risk of developing CSA-AKI."

Journal • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • RIPK1

Discovery of GDC-8264, a novel and selective RIP1 inhibitor for amelioration of tissue damage and treatment of inflammatory diseases (ACS-Fall 2025) - "Structure- and property-based optimization of the HTS hit led to the discovery of GDC-8264, a novel, selective and potent RIP1 inhibitor. Due to its excellent activity in animal inflammatory models, favorable pharmacokinetics and safety profile, GDC-8264 was nominated as a clinical candidate for multiple inflammatory indications and is currently in Phase 2 clinical trial for prevention of cardiac surgery-associated acute kidney injury."

Acute Kidney Injury • Cardiovascular • CNS Disorders • Inflammation • Inflammatory Bowel Disease • Myocardial Infarction • Nephrology • Renal Disease • RIPK1

Data Science-Guided Development of Deoxyfluorination Reagents with Enhanced Reactivity, Practicality, and Safety. (PubMed, J Am Chem Soc) - "We developed predictive models to optimize sulfonyl fluoride reagents for the deoxyfluorination of a key intermediate used in the synthesis of RIPK1 inhibitor GDC-8264. The top-performing reagents demonstrated broad applicability across diverse alcohol substrate classes, including complex natural products and active pharmaceutical ingredients, highlighting the power of data science-enabled approaches in reagent development."

Journal • CXCL12 • RIPK1

A Study to Assess the Safety and Pharmacokinetics of GDC-8264 in Combination With Standard of Care in Participants With Acute Graft-Versus-Host Disease (aGVHD) (clinicaltrials.gov) - P1 | N=7 | Completed | Sponsor: Genentech, Inc. | Terminated ➔ Completed

Trial completion • Acute Graft versus Host Disease • Bone Marrow Transplantation • Graft versus Host Disease • Immunology • Transplantation

A Study to Evaluate the Efficacy and Safety of GDC-8264 in Preventing Cardiac Surgery-Associated Acute Kidney Injury (AKI) and Major Adverse Kidney Events (MAKE) (clinicaltrials.gov) - P2 | N=404 | Recruiting | Sponsor: Genentech, Inc. | Not yet recruiting ➔ Recruiting

Adverse events • Enrollment open • Acute Kidney Injury • Cardiovascular • Nephrology • Renal Disease

A Study to Evaluate the Efficacy and Safety of GDC-8264 in Preventing Cardiac Surgery-Associated Acute Kidney Injury (AKI) and Major Adverse Kidney Events (MAKE) (clinicaltrials.gov) - P2 | N=404 | Not yet recruiting | Sponsor: Genentech, Inc.

New P2 trial • Acute Kidney Injury • Cardiovascular • Nephrology • Renal Disease

A Study to Assess the Safety and Pharmacokinetics of GDC-8264 in Combination With Standard of Care in Participants With Acute Graft-Versus-Host Disease (aGVHD) (clinicaltrials.gov) - P1 | N=7 | Terminated | Sponsor: Genentech, Inc. | N=40 ➔ 7 | Trial completion date: Dec 2025 ➔ Jan 2024 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2025 ➔ Jan 2024; Study was terminated for business reasons. There were no safety or efficacy concerns regarding the study or study drug in the decision to terminate the study.

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Graft versus Host Disease • Bone Marrow Transplantation • Graft versus Host Disease • Immunology • Transplantation

A phase 1, randomized, ascending-dose study to assess safety, pharmacokinetics, and activity of GDC-8264, a RIP1 inhibitor, in healthy volunteers. (PubMed, Clin Transl Sci) - "Based on PK-PD modeling, the GDC-8264 IC for the inhibition of CCL4 release was estimated to be 0.58 ng/mL. The favorable safety, PK, and PD of GDC-8264 support its further development for treatment of RIP1-driven diseases."

IO biomarker • Journal • P1 data • PK/PD data • Oncology • RIPK1 • TNFA

A Study to Assess the Safety and Pharmacokinetics of GDC-8264 in Combination With Standard of Care in Participants With Acute Graft-Versus-Host Disease (aGVHD) (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Genentech, Inc.

Combination therapy • New P1 trial • Acute Graft versus Host Disease • Bone Marrow Transplantation • Graft versus Host Disease • Immunology • Transplantation