OP31 Phase 1b study of SOR102, a novel, orally delivered bispecific anti-TNF/anti-IL-23 domain antibody in patients with mild to severe ulcerative colitis

Abstract Background SOR102 is a novel, orally delivered, bispecific antibody construct containing two humanized single domain antibodies (SDA) targeting TNFα and IL-23p19 connected by a trypsin-labile linker, enabling monomer separation within the small intestine and inhibition of TNFα and IL-23 activity within GI tissue. SOR102 SDAs were engineered for stability to intestinal and inflammatory proteases. The Phase 1, first-in-human study (SOR102-101; NCT06080048) had 3 parts. Parts 1 and 2 enrolled healthy subjects. Here, we present results for Part 3, a Phase 1b randomized, double-blind, placebo-controlled study in patients (pts) with mild to severe UC. Methods Pts with Mayo endoscopy score (ES) ≥2, rectal bleeding score (RBS) ≥1 and stool frequency score (SFS) ≥1 were randomized 1:1:1 to receive SOR102 810mg BID, SOR102 810mg QD, or placebo for 6 weeks. The primary objective was safety and tolerability of SOR102. Secondary objectives were the concentration of SOR102 and monomers in serum, urine and feces, and antidrug antibodies. Exploratory efficacy endpoints were Mayo Score (MS) and modified MS (mMS) clinical response, symptomatic remission (SR), and mean change from baseline in MS, mMS, UC-100 score, SFS, RBS, fecal calprotectin (FC), C-reactive protein (CRP), and Robarts Histopathology Index (RHI). Safety and efficacy were evaluated in pts who received ≥1 dose of SOR102 or placebo. Efficacy was also evaluated in pts who completed the study. Results Twenty-two pts were randomized (SOR102 810mg BID=9; SOR102 810mg QD=7; placebo=6); 17 pts completed the study. Reasons for discontinuation were worsening of UC (N=2), study schedule non-compliance (N=2) and consent withdrawal (N=1). Mean age was 50 yrs; 45% were male; median MS was 8 (range 6-11). Most pts were advanced therapy-naïve. TEAEs were reported in 57%, 29%, and 50% of pts receiving SOR102 810mg BID, SOR102 810mg QD, or placebo, respectively (Table 1); most were mild-to-moderate in severity. One AE (SOR102 810mg BID arm) was considered possibly related to SOR102 (abdominal pain of mild severity). One serious AE of worsening of UC that led to hospitalization occurred in the SOR102 810mg BID arm. Figure 1 shows exploratory efficacy results. Higher rates of MS and mMS clinical response and SR, and greater decreases from baseline in MS, mMS, UC-100, combined SFS+RBS, and RHI were observed in the SOR102 BID arm compared with QD and placebo. There were no significant differences in FC and CRP between the treatment groups. Conclusion SOR102 was safe and well tolerated. Efficacy across multiple endpoints was observed in the SOR102 BID arm compared to QD and placebo, despite the short treatment duration. Further clinical development of SOR102 is warranted. References 1.Roberts KJ et al. Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease. Sci Rep 2021;11:19422. 2.Feagan BG et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol 2023;8:307-320.