Safety and pharmacokinetics of SOR102, an oral bispecific inhibitor of TNF and interleukin-23 in healthy participants and patients with ulcerative colitis: a first-in-human, double-blind, randomised, placebo-controlled, phase 1 trial.

backgroundSOR102 is an oral bispecific antibody comprised of single domain antibodies targeting TNF and interleukin (IL)-23p19. We aimed to assess the safety, pharmacokinetics, clinical, and biological activity of SOR102 in healthy participants and in patients with active ulcerative colitis.

methodsThis phase 1 first-in-human, double-blind, randomised, placebo-controlled, trial was done in the UK, Ukraine, and Georgia in clinical research centres. Central randomisation was by an interactive web response system and a randomisation scheme produced by an unmasked, independent statistician. In part 1, healthy participants were randomly assigned (6:2) to single ascending doses of SOR102 or placebo. In part 2, healthy participants were randomly assigned (8:2) to SOR102 or placebo twice daily for 7 days. In part 3, patients with mildly-to-severely active ulcerative colitis were randomly assigned (1:1:1) to once-daily or twice-daily SOR102 or placebo for 42 days. The primary objective was to evaluate the safety and tolerability of SOR102. Safety analyses were done on all participants or patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT06080048 and is complete.

findingsFrom Oct 9, 2023, to Oct 16, 2024, 157 participants were assessed for eligibility, of whom 93 were excluded and 64 were randomly assigned to either SOR102 (n=48) or placebo (n=16) across all three parts of the study. In part 1, six participants were randomly assigned to receive SOR102 135 mg, six to receive SOR102 405 mg, six to receive SOR102 1215 mg, six to receive SOR102 3645 mg, and eight to receive placebo. In part 2, eight participants were randomly assigned to receive SOR102 1215 mg twice-daily and two to receive placebo. In part 3, seven patients with ulcerative colitis were randomly assigned to receive SOR102 810 mg once-daily, nine to receive the same dose twice-daily, and six to receive placebo. In part 1, treatment-emergent adverse events (TEAEs) occurred in three (13%) of 24 participants who received SOR102 (two in the SOR102 135 mg dose group and one in the SOR102 405 mg dose group; mild diarrhoea and moderate dysmenorrhoea both in a single participant in the SOR102 135 mg group and mild flatulence in a second participant in same group; mild dysmenorrhoea in one participant in the SOR102 405 mg group) compared with two (25%) of eight participants who received placebo (mild catheter site pain; mild headache). Only the TEAE of mild diarrhoea was deemed treatment-related. No TEAEs occurred in part 2. In part 3, at least one TEAE occurred in seven (44%) of 16 patients who received SOR102 (five in the SOR102 810 mg twice-daily dose group and two in the SOR102 810 mg once-daily dose group) and three (50%) of six patients who received placebo. Two patients in the SOR102 twice-daily group had TEAEs of worsening of ulcerative colitis (one of which was severe [the only serious TEAE reported] but not deemed treatment related), leading to study discontinuation. All other TEAEs were mild to moderate in nature. No clinically significant effect of SOR102 on electrocardiogram, vital signs, physical examination, or laboratory parameters was observed at any dose, or frequency of dosing, in any part of the study, and no deaths occurred. In part 3, by day 42, three (43%) of seven participants in the SOR102 once-daily group, five (56%) of nine patients in the SOR102 twice-daily group, and one (17%) of six patients in the placebo group had achieved a Mayo score clinical response, while two (29%) patients in the once-daily group, six (67%) in the twice-daily group, and two (33%) in the placebo group achieved a modified Mayo score clinical response. Three (43%) patients in the once-daily group, five (56%) in the twice-daily group, and none in the placebo group achieved symptomatic remission by day 42.

interpretationThe favourable safety profile and preliminary evidence for efficacy support development of SOR102 for treatment of ulcerative colitis.

fundingSorriso Pharmaceuticals.