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Results from the STENOVA trial: A Phase 2a, randomized, placebo-controlled, double-blind study to assess the safety, pharmacokinetics (PK), and pharmacodynamics of ontunisertib (AGMB-129) in patients with Fibrostenotic Crohn’s Disease (FSCD)

F. Rieder, B.G. Feagan, C. Lu, A. Poulsen, W. Reinisch, J. Kierkuś, E. Ricart Gomez, P.J. Stiers, K. Thys, R. Brys, M. Brill, C. Fleurinck, R. Van Heeswijk, A. Saez, T. Van Kaem, P. Wiesel

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Slides compiled by Dr. Reena Khanna

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Introduction

Methods

    • Design: Phase 2a, randomized, placebo-controlled, double-blind study.
    • Population: Adults with symptomatic FSCD with ≥1 MRE-confirmed ileal stricture.
    • Arms (Randomized 1:1:1): Ontunisertib 200mg BID, 100mg QD, or placebo (PBO) for 12 weeks.
      • Open label treatment extension ongoing

PK, pharmacokinetics; FSCD, fibrostenotic Crohn’s Disease; TEAE, treatment-emergent adverse event; SAE, serious AE; SES-CD, Simple endoscopic score for CD; MRE, magnetic resonance enterography.

Rieder F et al. ECCO 2026; (Abstract citation ID: jjaf231.020, OP20).

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Background and objectives

    • Ontunisertib is an oral GI-restricted ALK5 inhibitor that blocks signaling of the pro-fibrotic TGFβ pathway.
    • It is designed to avoid ALK5 inhibitor systemic toxicity (including cardiac toxicity) by reducing clinically relevant systemic exposure through high first-pass liver metabolism.
    • Objective: Assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ontunisertib (AGMB-129) in patients with Fibrostenotic Crohn’s Disease (FSCD).
    • Primary outcome: Safety and tolerability
      • TEAEs/SAEs; labs, vitals, physical exam; cardiac parameters incl. ECG + echocardiography
    • Secondary outcome: Plasma PK
    • Exploratory Outcomes: PK in ileal and colonic mucosa, change in SES-CD, and change in MRE-based stricture parameters.

Assessments:

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Baseline Demographics

Rieder F et al. ECCO 2026; (Abstract citation ID: jjaf231.020, OP20).

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Parameter

Ontunisertib 200mg BID (N=34)

Ontunisertib 100mg QD (N=34)

PBO (N=35)

All subjects (N=103)

Age (years), mean (SD)

44.2 (12.6)

41.0 (13.5)

42.8 (15.3)

42.7 (13.8)

Female, n (%)

9 (26.5)

9 (26.5)

12 (34.3)

30 (29.1)

White, n (%)

32 (94.1)

31 (91.2)

30 (85.7)

93 (90.3)

Body mass index (kg/m²), mean (SD)

25.87 (5.49)

26.59 (5.33)

26.67 (5.53)

26.38 (5.41)

Disease duration (years), mean (SD)

16.98 (10.42)

15.64 (10.36)

17.79 (13.87)

16.80 (11.59)

Ileocolonic disease, n (%)

15 (45.5)

19 (55.9)

25 (71.4)

59 (57.8)

History of intestinal resection, n (%)

15 (44.1)

17 (50.0)

16 (45.7)

48 (46.6)

Crohn's Disease Activity Index, mean (SD)

144.1 (94.6)

166.0 (74.4)

152.0 (80.6)

154.1 (83.1)

SES-CD, mean (SD)

6.9 (4.0)

7.5 (5.0)

7.9 (4.1)

7.4 (4.4)

S-PRO severity score, mean (SD)

6.50 (3.78)

7.09 (3.51)

6.50 (2.82)

6.70 (3.37)

C-reactive protein (mg/L), mean (SD)

3.80 (5.28)

4.20 (4.45)

4.23 (7.21)

4.07 (5.73)

Fecal calprotectin (mg/kg), mean (SD)

344.8 (445.5)

460.0 (696.2)

522.9 (588.5)

442.6 (583.9)

Prior biologics, n (%)

30 (88.2)

29 (85.3)

29 (82.9)

88 (85.4)

Concomitant biologics, n (%)

26 (76.5)

25 (73.5)

27 (77.1)

78 (75.7)

Concomitant thiopurine, n (%)

3 (8.8)

3 (8.8)

4 (11.4)

10 (9.7)

Concomitant corticosteroids, n (%)

5 (14.7)

4 (11.8)

6 (17.1)

15 (14.6)

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Results:

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Subjects with any, n (%)

Ontunisertib 200 mg BID (N=34)

Ontunisertib 100 mg QD (N=34)

Placebo (N=35)

TEAE

21 (61.8)

22 (64.7)

25 (71.4)

Serious TEAE

4 (11.8)

0

4 (11.4)

Worst-case:

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Moderate TEAE

5 (14.7)

9 (26.5)

5 (14.3)

Severe TEAE

4 (11.8)

1 (2.9)

4 (11.4)

Life-threatening TEAE

0

0

1 (2.9)*

Fatal TEAE

1 (2.9)**

0

0

Related TEAE

8 (23.5)

2 (5.9)

4 (11.4)

Temporary treatment interruption due to TEAE

1 (2.9)

3 (8.8)

3 (8.6)

Permanent treatment interruption due to TEAE

5 (14.7)

0

2 (5.7)

Study discontinuation due to TEAE

0

0

1 (2.9)

Serious = requires hospitalization. Worst-case = Severity grading based. *Small intestinal obstruction not related. ** Atrial fibrillation and lacunar infarct not related.

TEAE, treatment-emergent adverse event; SAE, serious adverse event.

Rieder F et al. ECCO 2026; (Abstract citation ID: jjaf231.020, OP20).

    • High study completion rate (89%)
    • AE incidence and severity balanced across treatment arms, with no dose-related increase
    • No evidence of cardiac valve toxicity, pro-inflammatory effects, or vasculitis
    • No safety signals observed in laboratory parameters, vital signs, or physical examinations
    • No safety concerns identified by the Data Safety Monitoring Board

Primary Endpoint: Safety and Tolerability

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Results:

PK, pharmacokinetics; SES-CD, simple endoscopic score for CD

Rieder F et al. ECCO 2026; (Abstract citation ID: jjaf231.020, OP20).

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GI-restricted PK profile

    • Low systemic exposure to ontunisertib; high exposure to inactive metabolite MET-158.
    • High ileal and colonic ontunisertib exposure confirmed.

Endoscopy (SES-CD)

    • 200 mg BID vs placebo: higher endoscopic response and remission rates, driven by improvement in inflammatory & narrowing components.
    • Non-passable strictures: higher proportion became passable with 200 mg BID vs placebo.

MRE

    • Both doses vs placebo: positive trends, mainly stricture length.

No significant difference in obstructive symptoms was noted.

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Results:

Mean values at baseline: structure length = 104 mm; associated dilatation diameter = 28.3 mm; bowel wall thickness = 8.16 mm.�BSL, baseline; W12, Week 12; SE, standard error of the mean.

Rieder F et al. ECCO 2026; (Abstract citation ID: jjaf231.020, OP20).

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Centrally-read MRE stricture features

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Conclusions

    • In this phase 2a study, Ontunisertib demonstrated the ability to improve Crohn’s related strictures
    • It has a favourable PK profile and was well tolerated in this study

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Significance to clinical practice

    • Although additional studies are required to confirm safety and efficacy, this is a promising therapy for the treatment of fibrostenotic strictures in addition to baseline therapy.
    • Given the limited treatment options for fibrostenotic strictures and the associated morbidity, this would have a substantial impact for patients if the results are proven in larger phase 3 studies

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Rieder F et al. ECCO 2026; (Abstract citation ID: jjaf231.020, OP20).

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