Ontunisertib (AGMB-129) is an oral, small molecule GI-restricted inhibitor of ALK5 (or TGFβR1) currently in clinical development for the treatment of Fibrostenosing Crohn’s Disease (FSCD). TGFβ is a major driver of fibrosis. Ontunisertib is specifically designed to inhibit ALK5/ TGFβR1in the GI-tract. Rapid first-pass metabolism in the liver prevents clinically relevant systemic exposure, potentially delivering an improved safety profile over systemically available inhibitors in this class.

Ontunisertib successfully completed a Phase 1 study, which included single ascending dose (SAD), multiple ascending dose (MAD) and food-effect (FE) stages, as well as an additional multiple-dose stage for the assessment of local drug exposure in terminal ileal mucosa, where the fibrostenosing strictures in FSCD patients are most often located. A total of 82 healthy subjects were randomized to receive either single or multiple daily oral doses of ontunisertib, or matching placebo.

Ontunisertib was well-tolerated at all doses tested. The incidence and intensity of adverse events were similar across all dose cohorts including the placebo cohort. No drug-related safety signal or dose-limiting toxicities were identified. In addition, the trial showed high local exposure to ontunisertib in the ileum but no clinically relevant systemic exposure, demonstrating that the GI restricted mechanism operated efficiently in humans.

Ontunisertib is currently being investigated in the STENOVA global Phase 2a study in patients with Fibrostenotic Crohn’s Disease (NCT05843578), with investigational sites in the USA, Canada and Europe. STENOVA is a randomized, double-blind, placebo-controlled study in 103 patients with symptomatic FSCD. Patients are randomized to receive one of two doses of ontunisertib (AGMB-129 200mg twice-daily or 100mg once-daily) or placebo for 12 weeks on top of standard of care, including anti-inflammatory biologics.

An interim analysis conducted on the first 44 patients after 12 weeks of treatment indicated that the primary endpoint of favorable safety and tolerability of ontunisertib was met at both doses. The severity and incidence of adverse events were similar among treatment arms, including placebo, and there were no signs of cardiac toxicity, no pro-inflammatory effects, and no signals in safety labs, vital signs, physical exams or ECGs.

The study also met its two predefined secondary endpoints of pharmacokinetics (PK) and target engagement in the first 44 patients. The PK data indicated very low systemic exposure to ontunisertib and high exposure to its inactive main metabolite MET-158. These results are consistent with prior data in healthy subjects and support the gut-restricted profile of ontunisertib in FSCD patients.

Target engagement, measured through transcriptomics in mucosal biopsies collected at the site of the ileal strictures at screening and Week 12, showed significant downregulation of both fibrotic (p=0.0036) and inflammatory pathways (p<0.0001) for the high dose cohort versus placebo.

A consistent positive trend was also observed for the high dose versus placebo across several exploratory endpoints, including Stricturing Patient-Reported Outcome (S-PRO) and disease severity in centrally read Simple Endoscopic Score (SES-CD).

The interim results were shared as a late-breaking presentation at Digestive Disease Week® (DDW) 2025, taking place in San Diego on May 3-6, 2025.

The STENOVA study is fully recruited, and on track to report results on 103 patients in the fourth quarter of 2025.

The open-label treatment extension of the STENOVA study with ontunisertib is currently ongoing. Study participants who have completed the double-blind 12-week treatment period are eligible to participate and can receive treatment for up to an additional 48 weeks.

Ontunisertib (AGMB-129) has received U.S. FDA Fast Track Designation