Ontunisertib (AGMB-129) is an investigational, oral, gastrointestinal (GI)-restricted small molecule inhibitor of ALK5 (TGFβR1) in clinical development for Fibrostenosing Crohn’s Disease (FSCD).

Core description

FSCD is a severe complication of Crohn’s disease characterized by fibrotic strictures in the intestinal tract, which can cause obstructive symptoms, dietary changes, malnutrition, and ultimately surgery. Approximately 46% of Crohn’s disease patients under treatment in the seven major markets are estimated to have FSCD, yet there are currently no approved pharmacologic therapies for this condition. Chronic intestinal inflammation can drive fibroblast activation and excessive extracellular matrix deposition, leading to progressive intestinal wall thickening, luminal narrowing, and fibrotic stricture formation.

Ontunisertib is an investigational, oral, GI-restricted small molecule inhibitor of ALK5, or TGFβR1, designed to act locally in the gastrointestinal tract. By targeting TGFβ/ALK5 signaling, a pathway implicated in fibrotic remodeling, ontunisertib is intended to address the fibrostenosing biology underlying FSCD while limiting systemic exposure through rapid metabolization after absorption. Clinical data to date have shown high local exposure in GI tissue with low systemic exposure, consistent with its GI-restricted design, and positive results from the Phase 2a STENOVA study support further development.

Development program

Phase 1 program
A Phase 1 clinical study of ontunisertib has been completed in 125 healthy volunteers, including SAD, MAD, and food-effect stages, as well as an additional multiple-dose stage assessing local drug exposure in terminal ileal mucosa. NCT04933565

STENOVA Phase 2a study
STENOVA is Agomab’s Phase 2a clinical study of ontunisertib in patients with symptomatic Fibrostenosing Crohn’s Disease (FSCD). We reported positive results  from the 12-week placebo-controlled part of the study, including achievement of the primary endpoint  on safety, a GI-restricted pharmacokinetic profile with low systemic exposure, and encouraging exploratory efficacy signals across clinical, endoscopic, and imaging-based measures. NCT05843578

Patients continue to be followed in the STENOVA 48-week open-label extension, with additional data expected in the second half of 2026.

NOV-ERA Phase 2b study
NOV-ERA is Agomab’s planned Phase 2b clinical study of ontunisertib in patients with symptomatic Fibrostenosing Crohn’s Disease (FSCD). The study is designed as a randomized, double-blind, placebo-controlled, dose-ranging study to further evaluate ontunisertib, with endoscopic passability at Week 24 as the primary endpoint. NCT07683325

We expect to initiate NOV-ERA in the second half of 2026 as the next step in the clinical development of ontunisertib for FSCD.

 

Ontunisertib has received U.S. FDA Fast Track Designation.
Ontunisertib (AGMB-129) is an investigational product candidate and is not approved by any regulatory authority. Its safety and efficacy have not been established.