tilpisertib (GS-4875) / Gilead - LARVOL DELTA

Validation of pERK as a robust pharmacodynamic biomarker for first-in-class TPL2 inhibitors, GS-4875 and TIP, in non-clinical and clinical studies (ECCO-IBD 2026) - P2 | "GS-4875 is a highly selective, first-in-class small molecule inhibitor of TPL2, and tilpisertib fosmecarbil (TIP; GS-5290) is an intestinally cleaved prodrug of GS-4875 in development for moderately to severely active UC (NCT06029972). Given the durable and robust effect of TIP on inhibition of TPL2 pathway demonstrated in blood, and the elevated TPL2 pathway activity observed in UC and CD tissue, TPL2 inhibition represents a promising therapeutic strategy for IBD. TIP is currently in evaluation in a Phase 2 clinical trial in UC."

Biomarker • Clinical • First-in-human • PK/PD data • Crohn's disease • Inflammatory Bowel Disease • Ulcerative Colitis • MAP3K8 • TNFA

Falcon: Study to Evaluate the Efficacy and Safety of Tilpisertib in Adults With Moderately to Severely Active Ulcerative Colitis (clinicaltrials.gov) - P2 | N=19 | Terminated | Sponsor: Gilead Sciences | Completed ➔ Terminated; Sponsor terminated the study since a new molecular entity was able to achieve greater target coverage

Trial termination • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Falcon: Study to Evaluate the Efficacy and Safety of Tilpisertib in Adults With Moderately to Severely Active Ulcerative Colitis (clinicaltrials.gov) - P2; N=19; Completed; Sponsor: Gilead Sciences; Active, not recruiting ➔ Completed

Clinical • Trial completion • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Falcon: Study to Evaluate the Efficacy and Safety of GS-4875 in Adults With Moderately to Severely Active Ulcerative Colitis (clinicaltrials.gov) - P2; N=19; Active, not recruiting; Sponsor: Gilead Sciences; Recruiting ➔ Active, not recruiting; N=180 ➔ 19; Trial completion date: Oct 2021 ➔ Feb 2022

Clinical • Enrollment change • Enrollment closed • Trial completion date • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

APPLICATION OF A WHOLE BLOOD PHARMACODYNAMIC BIOMARKER ASSAY TO QUANTIFY TPL2 ANTAGONIST, GS-4875 IN PRE-CLINICAL RAT STUDIES (DDW 2020) - "This work describes a novel PD biomarker to monitor TPL2 inhibition in whole blood. With this assay, GS-4875 demonstrated dose-dependent and reversible inhibition of the TPL2 pathway following oral administration in healthy rats"

Biomarker Assay • PK/PD data • Gastroenterology • Gene Therapies • Genetic Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Primary Immunodeficiency • CXCL8 • IL1B • IL6

Falcon: Study to Evaluate the Efficacy and Safety of GS-4875 in Adults With Moderately to Severely Active Ulcerative Colitis (clinicaltrials.gov) - P2; N=180; Recruiting; Sponsor: Gilead Sciences; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

GS-4875, a First-in-Class TPL2 Inhibitor Suppresses MEK-ERK Inflammatory Signaling and Proinflammatory Cytokine Production in Primary Human Monocytes (ACR-ARHP 2019) - "Background/Purpose: Tumor progression locus 2 (TPL2, also known as MAP3K8) is a mitogen-activated protein kinase kinase kinase and the primary regulator of ERK-mediated gene transcription downstream of multiple proinflammatory stimuli including bacterial products (eg, LPS and bacterial peptidoglycans), damage-associated molecular patterns (DAMPs), TNFα, and IL-1β.1 TPL2 regulates the expression of several proinflammatory cytokines, including TNFα, IL-1β, IL-6 and IL-8. This work demonstrates the selective effects of TPL2 inhibition on ERK-mediated signaling and proinflammatory cytokine production and highlights the potential for TPL2 inhibition to treat diseases associated with dysregulated inflammatory signaling and chronic inflammation."

GS-4875, A FIRST-IN-CLASS TPL2 INHIBITOR SUPPRESSES MEK-ERK INFLAMMATORY SIGNALING AND PROINFLAMMATORY CYTOKINE PRODUCTION IN PRIMARY HUMAN MONOCYTES (UEGW 2019) - "Introduction: Tumor progression locus 2 (TPL2, also known as MAP3K8) is a mitogen-activated protein kinase kinase kinase and the primary regulator of ERK-mediated gene transcription downstream of multiple proinflammatory stimuli including bacterial products (eg, LPS and bacterial peptidoglycans), damage-associated molecular patterns (DAMPs), TNFα, and IL-1β.1 TPL2 regulates the expression of several proinflammatory cytokines, including TNFα, IL-1β, IL-6 and IL-8. This work demonstrates the selective effects of TPL2 inhibition on ERK-mediated signaling and proinflammatory cytokine production and highlights the potential for TPL2 inhibition to treat IBD and other chronic inflammatory and autoimmune diseases."

Falcon: Study to Evaluate the Efficacy and Safety of GS-4875 in Adults With Moderately to Severely Active Ulcerative Colitis (clinicaltrials.gov) - P2; N=180; Not yet recruiting; Sponsor: Gilead Sciences

Clinical • New P2 trial