Agomab Therapeutics NV (‘Agomab’) a clinical-stage biopharmaceutical company focused on fibro-inflammation, today announced positive results of the 48-week OLE portion of the Phase 2a STENOVA trial evaluating ontunisertib in patients with FSCD, a severe manifestation of Crohn's disease characterized by progressive bowel fibrosis and intestinal strictures.

The OLE study (Part B) evaluated long-term treatment with ontunisertib 200 mg BID on top of standard of care. Of the participants eligible to roll over into the OLE study from the 12-week placebo-controlled Part A of STENOVA, 94% elected to enter the study (n=49).

The results demonstrated a generally favorable long-term safety and tolerability profile of ontunisertib 200 mg BID for up to 60 weeks of treatment, as well as maintenance of the gut-restricted pharmacokinetic (PK) profile observed in Part A of the trial. Sustained disease control, with low symptoms and disease activity scores and radiological stricture stabilization, was also observed. Importantly, a low FSCD-related annualized event rate of 3% was reported in patients treated with ontunisertib 200 mg BID up to 60 weeks.

"Fibrostenosing Crohn’s disease remains one of the most significant unmet needs in fibro-inflammatory bowel disease, with no approved therapies targeting the fibrotic component of the disease," commented Florian Rieder, MD, Vice-Chair, Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic. "Beyond the favorable safety and tolerability profile, what stands out in the OLE results is the sustained disease control as well as the low rate of interventions, with only one EBD and no surgeries reported. Importantly, patients appeared to continue to do well on long-term treatment with ontunisertib, maintaining low symptom levels and favorable outcomes on quality-of-life assessments. In a patient population often facing progressive bowel damage and recurrent procedures, these combined findings point to the potential of ontunisertib to provide a meaningful clinical benefit."

Philippe Wiesel, Chief Medical Officer of Agomab, added: "We are very pleased with the OLE results announced today. The favorable long-term safety profile, maintenance of gut-restricted exposure and signals of sustained disease control observed over up to 60 weeks of treatment provide strong support for the initiation of our global NOV-ERA Phase 2b study later this year. Importantly, these data further support our belief that targeting fibro-inflammation through a differentiated anti-fibrotic mechanism may address a key driver of disease progression that remains largely untreated today. We look forward to evaluating ontunisertib across multiple dose levels in NOV-ERA as we continue to advance what we believe is a potentially novel therapeutic approach for people living with fibro-inflammatory conditions."

Topline STENOVA OLE results

Safety and tolerability profile

Ontunisertib 200 mg BID demonstrated a generally favorable safety and tolerability profile through up to 60 weeks of treatment. Five serious adverse events were reported in four patients in Part B of the STENOVA study (48-week OLE); all of which were considered unrelated or unlikely related to study treatment.

There were no signals of cardiac injury, pro-inflammatory effects, vasculitis, liver toxicity or thrombotic events during the extended treatment period.

Pharmacokinetic (PK) profile

Systemic exposure of ontunisertib remained low throughout the OLE period and consistent with observations from the randomized-controlled 12-week portion of STENOVA. Plasma concentrations remained well below IC50 levels, supporting the efficient gut-restricted pharmacokinetic profile of ontunisertib and its differentiated approach to ALK5 inhibition.

Event rate

Only one FSCD-related event, an EBD procedure, was reported during the study, corresponding to an annualized event rate of 3%. No patients progressed to surgery during up to 60 weeks of ontunisertib 200 mg BID treatment. For reference, while not based on head-to-head studies, recent publications on a comparable FSCD patient population receiving advanced therapies reported annualized event rates ranging from 23-35%.1,2,3,4

Imaging results

Magnetic resonance enterography (MRE) assessments performed at Weeks 24 and 48 of the OLE study suggested radiological stabilization of fibrotic strictures over the course of treatment with ontunisertib 200 mg BID. While patients receiving placebo showed a trend of radiological progression during the 12-week Part A of the STENOVA study, the OLE results suggest that when switching to ontunisertib, those patients stabilized and progressively caught up with those already exposed to ontunisertib in Part A.

Given the optional nature of the Week 48 endoscopy assessment in the OLE study, the available data were too limited to allow for a reliable interpretation.

Patient-reported outcomes

Patients maintained a low symptom burden and disease activity throughout the OLE period, with sustained improvements observed across stricture-specific symptom assessments, Crohn's disease activity score (CDAI) and quality-of-life measures. At Week 48 of the OLE, 97% of evaluable patients were in clinical remission as assessed by the CDAI score.

Next steps with ontunisertib: NOV-ERA Phase 2b study

Agomab recently completed regulatory filings for NOV-ERA, a global Phase 2b trial designed to evaluate ontunisertib in approximately 320 patients with symptomatic FSCD and plans to initiate the study in the coming months. In NOV-ERA, participants will be randomized to receive either ontunisertib at one of three dose levels (400 mg BID, 200 mg BID, and 100 mg BID), or a matching placebo. Together with the favorable safety and tolerability profile previously demonstrated in Phase 1 at doses up to 400 mg BID, the positive safety and tolerability findings of the OLE study provide strong support for the inclusion of a 400 mg BID treatment arm in the NOV-ERA Phase 2b study.

Agomab intends to present detailed STENOVA OLE results at a future scientific conference.

Ontunisertib is an investigational drug and not approved by any regulatory authority. Its efficacy and safety have not been established.