OP20 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)

Abstract Background Ontunisertib is an oral GI-restricted ALK5 inhibitor, developed for the treatment of FSCD, which potently blocks signalling of the key pro-fibrotic TGFβ pathway. To date, development of systemic ALK5 inhibitors has been hampered by systemic, particularly cardiac, toxicities. Ontunisertib was designed to have high local GI exposure while avoiding clinically relevant systemic exposure through high first-pass liver metabolism. STENOVA is the first randomized, placebo-controlled clinical trial conducted in FSCD. We report results from the primary analysis in patients having completed the 12-week placebo-controlled treatment period. An open-label treatment extension study is ongoing. Methods Adults with symptomatic FSCD with at least 1 MRE-confirmed ileal stricture were randomized 1:1:1 to receive ontunisertib 200mg BID, 100mg QD, or placebo (PBO) for 12 weeks. The primary objective was to evaluate safety and tolerability. The evaluation of plasma PK was included as a secondary objective. Exploratory outcomes encompassed PK in ileal and colonic mucosa, change in SES-CD, and change in MRE-based stricture parameters. Results The primary analysis included 103 participants (34/34/35 in the 200mg/100mg/PBO groups), of which 92 completed the treatment period. Baseline characteristics were comparable across groups (table). Ontunisertib was generally well tolerated at both doses. The proportion of patients with at least 1 treatment-emergent AE in the 200mg BID, 100mg QD, and PBO groups was 61.8%, 64.7%, and 71.4%, respectively. The number of SAEs in the 200mg BID, 100mg QD, and PBO groups were 4, 0, and 4, respectively. There were no treatment-related safety signals in labs, vital signs, physical exams, and cardiac parameters including ECGs and echocardiography. Low systemic exposure to ontunisertib, but high exposure to its inactive main metabolite MET-158 was observed. High ileal and colonic ontunisertib exposure was confirmed. At the 200mg BID dose and compared to PBO, SES-CD showed higher endoscopic response and remission rates, driven by improvement of both inflammatory and narrowing components, and a higher proportion of non-passable strictures became passable. For both doses, MRE showed positive trends, mainly on stricture length, compared to PBO. No significant difference in obstructive symptoms was noted. Conclusion Treatment with ontunisertib for 12 weeks was generally well tolerated at both doses. The GI-restricted profile of ontunisertib was confirmed. A trend of improvements in endoscopic and MRE outcomes was observed. The data suggest that ontunisertib has potential to be the first ALK5 inhibitor suitable for chronic dosing in humans and may provide a therapeutic option for FSCD patients. Conflict of interest: Rieder, Florian: Personal Fees: Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, Astra Zeneca, Boehringer-Ingelheim, Celgene/BMS, Celltrion, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Jannsen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Palisade, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, 89Bio Feagan, Brian Gordon: Employee of Agomab Therapeutics Lu, Cathy: Advisory board - Abbvie, JnJ, Takeda, Ferring, Merck, Celltrion, Pfizer Research Funding - Abbvie, JnJ Poulsen, Anja: No conflict of interest Reinisch, Walter: Personal Fees: WR has served as a speaker for AbbVie, Alfasigma, Celltrion, Ferring, JNJ, Galapagos Medice, Lilly, MSD, Roche, Pfizer, Sobi, Takeda, as a consultant for AbbVie, Agomab, Alfasigma, Alvotech, Amgen, Anaptys Bio, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead, Index Pharma, Janssen, Medahead, Merck, Microbiotica, Pfizer, Sanofi, Teva, Takeda as an advisory board member for AbbVie, Alfasigma, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, JNJ, Pfizer, Teva and has received research funding from AbbVie, JNJ, Sandoz, Sanofi, Takeda. Kierkuś, Jarosław: Grant: Nestle Other: Nutricia, Abbvie, Nestle Ricart Gomez, Elena: E. Ricart has received support for congress and conference attendance, speaker fees, research support or consulting fees from MSD, Abbvie, Ferring, Janssen, Otsuka, Pfizer, Takeda, Faes Farma, Galapagos/Alphasigma, Kern Pharma, Lilly, J & J, Dr Falk Pharma, and Fresenius-Kabi. Stiers, Pieter-Jan: Employee of Agomab Therapeutics NV Thys, Kim: I have no conflicts of interest Brys, Reginald: employee of Agomab Therapeutics Brill, Margreke: Employee of Agomab Therapeutics No conflicts of interests Fleurinck, Carmen: employee of Agomab therapeutics Van Heeswijk, Rolf: Employee of Agomab Therapeutics Saez, Andrea: Agomab employee Van Kaem, Tim: employee of Agomab Therapeutics Wiesel, Philippe: employee of Agomab Therapeutics