Tamuzimod in patients with moderately-to-severely active ulcerative colitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 induction trial.
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BACKGROUND: Tamuzimod (VTX002) is a selective sphingosine 1-phosphate receptor 1 modulator in development for ulcerative colitis. We aimed to assess the safety and efficacy of tamuzimod in patients with moderately-to-severely active ulcerative colitis. METHODS: This double-blind, randomised, placebo-controlled, phase 2 induction trial was conducted at 122 centres across 15 countries in Asia, Europe, and North America. Patients aged 18-80 years with a modified Mayo score (MMS) of 4-9 and an inadequate response or a loss of response, or intolerance to one or more approved ulcerative colitis therapies were randomly assigned (1:1:1) to once-daily oral tamuzimod (60 mg or 30 mg) or placebo for 13 weeks. Randomisation was stratified by previous advanced therapy, baseline corticosteroid, and baseline MMS. The primary endpoint was clinical remission (defined as an MMS stool frequency subscore of ≤1, rectal bleeding subscore of 0, and endoscopic subscore ≤1, excluding friability) at week 13. Adverse events and laboratory abnormalities were assessed for safety. Efficacy and safety analyses included all randomly assigned patients who received at least one study dose, with the efficacy analysis restricted to patients with a baseline MMS of 5-9 based on regulatory feedback. The study was registered with ClinicalTrials.gov, NCT05156125, and EudraCT, 2021-003050-23. FINDINGS: Between Nov 4, 2021, and Aug 30, 2023, 367 patients were screened, and 213 (mean age 40·6 years [SD 14·2]; 116 [54%] males and 97 [46%] females) were randomly assigned to tamuzimod 60 mg (n=70), tamuzimod 30 mg (n=73), or placebo (n=70). Two in the tamuzimod 30 mg group and two in the tamuzimod 60 mg group with baseline modified Mayo score of 4 were excluded from the efficacy analysis. At week 13, clinical remission was reached by 19 (28%) of 68 patients receiving tamuzimod 60 mg, 17 (24%) of 71 patients receiving tamuzimod 30 mg, and eight (11%) of 70 patients receiving placebo (risk difference 16·5% [95% CI 3·2 to 29·4], p=0·018, for tamuzimod 60 mg vs placebo and 12·5% [-0·2 to 24·9], p=0·041, for tamuzimod 30 mg vs placebo). Treatment-emergent adverse events occurred in 33 (47%) of 70 patients receiving tamuzimod 60 mg, 34 (47%) of 73 patients receiving tamuzimod 30 mg, and 24 (34%) of 70 patients receiving placebo. Most adverse events were mild or moderate. The most frequently reported treatment-emergent adverse events (in ≥5% of in any treatment group) were upper respiratory tract infection (six [9%] of 70 patients in the tamuzimod 60 mg group, one [1%] of 73 in the tamuzimod 30 mg group, and one [1%] of 70 in the placebo group), anaemia (three [3%], four [5%], and six [9%]), and headache (four [6%], five [7%], and two [3%]). No adverse events of atrioventricular block, bradycardia, macular oedema, severe or opportunistic infections, malignancies, or deaths occurred. INTERPRETATION: Induction therapy with tamuzimod was effective and well tolerated in patients with ulcerative colitis. These results and the favourable risk-benefit profile of tamuzimod collectively support the continued clinical development of tamuzimod for the treatment of moderately-to-severely active ulcerative colitis. FUNDING: Ventyx Biosciences.