Phase 1 SOR102 trial: authors report data supporting further study in ulcerative colitis

Evidence before the study

Therapeutic options for ulcerative colitis have expanded considerably in the last decade to include agents targeting key biological components of the inflammatory process(es) that contribute to and perpetuate the disease. Among these, the proinflammatory cytokines TNF and interleukin (IL)-23 are fundamental to the pathophysiology of ulcerative colitis and are established targets for systemically dosed antibody therapeutics. Despite these advances, a therapeutic ceiling has been reached that requires new treatment approaches. Remission rates in induction trials for individual therapies have generally not exceeded 30%. Combination therapies that concurrently target more than one biological pathway involved in the pathogenesis of ulcerative colitis might be additive or synergistic in terms of efficacy and might potentially address the unmet therapeutic need in ulcerative colitis. We searched PubMed for articles published in English between Jan 1, 2009, and Dec 31, 2024, using the terms “ulcerative colitis”, “advanced combination therapy”, “TNF”, and “IL-23”. Our search yielded four narrative and one systematic review describing the therapeutic potential of advanced combination therapy. Importantly, the systematic review and meta-analysis of ten randomised controlled trials involving 1154 patients with immune-mediated inflammatory disease found higher rates of clinical remission and no difference in the likelihood of adverse events in patients with inflammatory bowel disease who received advanced combination therapy. However, these data were based on a small number of trials (including the randomised, controlled, phase 2 VEGA trial, which showed that treatment of patients with ulcerative colitis for 12 weeks with the combination of golimumab [anti-TNF monoclonal antibody] and guselkumab [anti-IL-23p19 monoclonal antibody] was superior to treatment with either monotherapy). The need for additional controlled trials with embedded translational research was also identified in the systematic review.

Added value of this study

This phase 1, randomised, first-in-human trial provides preliminary evidence in support of the safety and tolerability of simultaneously targeting TNF and IL-23 within intestinal tissue upon oral dosing of SOR102. SOR102 comprises two single domain antibodies (anti-TNF and anti-IL-23p19) connected by a trypsin-cleavable linker. SOR102 can bind and neutralise TNF and IL-23 while intact or after trypsin cleavage into monomers. Low concentrations of SOR102 and high concentrations of biologically active monomers in faeces in both healthy participants and patients with ulcerative colitis confirm that the intact SOR102 molecule is efficiently cleaved after oral dosing, providing the first empirical evidence for proof of mechanism. Pharmacokinetic data in this study suggests minimal systemic exposure of SOR102 given mostly unquantifiable serum concentrations of SOR102 and the monomers SOR102-TNF and SOR102-IL-23 in healthy participants and patients with ulcerative colitis at any dose administered. Minimal systemic exposure is also supported by unquantifiable concentrations of SOR102, SOR102-TNF, and SOR102-IL-23 in the urine of healthy participants, and variable detection of SOR102-TNF in the urine of patients with ulcerative colitis treated with SOR102. This study was not powered to detect statistical differences between treatment groups for efficacy outcomes; however, data from this trial provide preliminary clinical evidence for the therapeutic potential of SOR102. These data are supported by tissue penetration of SOR102 monomers and possible trends for reductions in pathologically relevant tissue cytokines.

Implications of all the evidence

The safety profile and evidence for the therapeutic potential of SOR102 in this phase 1 trial support further clinical development of this molecule for treatment of ulcerative colitis.

Source: The Lancet Gastroenterology & Hepatology