DOP057 Obefazimod induction therapy for moderately to severely active ulcerative colitis: pooled analysis of inflammatory biomarkers from the two ABTECT Phase 3 double-blind, placebo-controlled induction trials

Abstract Background Obefazimod (Obe) is an oral, once-daily (QD), small molecule which enhances expression of microRNA-124 and has been studied in two Phase 2 induction trials and subsequent open-label maintenance studies [1-3]. In Phase 3 ABTECT-1 [NCT05507203] and ABTECT-2 [NCT05507216] 8-week induction trials, Obe achieved clinically meaningful improvements in clinical, endoscopic and histologic endpoints. Per STRIDE-II recommendations, the normalization of inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) should be an intermediate treatment target for patients (pts) with moderate to severe ulcerative colitis (UC) [4]. Here, we present a pooled analysis of inflammatory biomarkers among pts enrolled in the two Phase 3 ABTECT induction trials. Methods The multicenter, randomized, double-blind, placebo-controlled ABTECT trials enrolled pts with moderate-to-severe UC (modified Mayo score (MMS)≥ 5, rectal bleeding sub-score (RBS) ≥ 1 and centrally read endoscopic score≥2) who had inadequate response, loss of response, or intolerance to at least one prior therapy (corticosteroids, immunosuppressants, biologics, S1P receptor modulators and/or JAK inhibitors) with no limit on the number of prior advanced therapy inadequate responses. Pts were randomized 2:1:1 to Obe 50 mg QD (Obe 50), Obe 25 mg QD (Obe 25) or placebo (PBO) for 8 weeks. This post hoc analysis evaluated changes in hs-CRP and FCP levels from baseline to Week 8 (W8), as well as the proportions of pts with reduced FCP (<150 or < 250 µg/g) and normalized hs-CRP (<5 mg/L) or both. All p-values are nominal. Results Compared with PBO, FCP levels were reduced with nominal significance from W4 (first study visit) in pts treated with Obe 25 and Obe 50 (p < 0.0001), while hs-CRP levels were reduced with nominal significance at W8 in both Obe groups (p < 0.0001) (Table). At W8, 31.7% and 42.9% of pts in the Obe 25 and Obe 50 groups, respectively, achieved FCP<150 µg/g, versus 9.8% in the PBO group (Difference Obe 25-PBO: 21.9%, p < 0.0001; Difference Obe 50-PBO: 33.2%, p < 0.0001). A greater proportion of pts receiving Obe 25 or Obe 50 achieved reductions of FCP (FCP<250 µg/g, FCP<150 µg/g) and normalization of hs-CRP (<5mg/L) at W4 and W8 compared with PBO. Conclusion This pooled analysis of ABTECT induction trials provides evidence that both doses of obe led to a rapid reduction of inflammatory biomarkers in pts with moderate to severe UC. References: 1.Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697 2.Vermeire S, et al. Gastroenterology 2021; 160: 2595-2598 3.Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035 4.Turner D, et al. Gastroenterology. 2021;160:1570-1583 Conflict of interest: Siegmund, Britta: Grant: Pfizer Other: Consultant: Abbvie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Galapagos, Janssen/Johnson & Johnson, Materia Prima, MSD, Pfizer, Takeda, Wedbush Securities. Speaker: Abbvie, AlfaSigma, Bristol Myers Squibb, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, Ferring, Galapagos, Janssen/Johnson & ampJohnson, MD Education, MSD, Pfizer, Tr1xBio. Atreya, Raja: Personal Fees: AbbVie, Abivax, AstraZeneca, Bristol-Myers Squibb, Celltrion Healthcare, Falk Foundation, Galapagos, Gilead, Johnson&Johnson, Lilly, MSD Sharp & Dohme, Takeda Pharma. Cataldi, Fabio: Employee of Abivax Jacobstein, Doug: Employee of Abivax Santo, Julien: No conflict of interest Rabbat, Chris: Employee of Abivax Shan, Kevin: Employee of Abivax Miheller, Pál: No conflict of interest Gilletta de Saint Joseph, Cyrielle: Speaker/ consultant fees from Abbvie, AlfaSigma, Amgen, Celltrion, Ferring, Fresenius, Janssen, Lilly, Pfizer, Takeda and Tillots Wojnarska, Beata Gawdis: No conflict of interest Verstockt, Bram: - Research support from AbbVie, Biora Therapeutics, Celltrion, Landos, Pfizer, Sanofi, Sossei Heptares/Nxera and Takeda. - Speaker’s fees from Abbvie, Agomab, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Eli Lily, Falk, Ferring, Galapagos, Materia Prima, Johnson and Johnson, Pfizer, Sandoz, Takeda, Tillots Pharma, Truvion and Viatris. - Consultancy fees from Abbvie, Alfasigma, Alimentiv, Anaptys Bio, Applied Strategic, Astrazeneca, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Domain Therapeutics, Eli Lily, Galapagos, Guidepont, Landos, Merck, Mirador Therapeutics, Mylan, Nxera, Inotrem, Ipsos, Johnson and Johnson, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris. - Stock options Vagustim and Thethis Pharma. Magro, Fernando: Fernando Magro served as speaker and received honoraria from Abbvie, Arena, Biogen, Bristol-Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, Vifor. Dulai, Parambir: Grant: Takeda, Janssen, Pfizer, Abbvie, Polymedco, Buhlmann, Prometheus Personal Fees: Takeda, Janssen, Pfizer, Abbvie, Polymedco, Buhlmann, Prometheus