Colon to Rectum
Lancet Gastroenterol Hepatol. 2022;7(11):1024–35
ABX464 (obefazimod) for moderate-to-severe, active ulcerative colitis: a phase 2b, double-blind, randomized, placebo-controlled induction trial and 48 week, open-label extension
Background: ABX464 (obefazimod) is a small molecule that selectively upregulates miR-124 in immune cells. The aim of this study was to assess ABX464 as a treatment for patients with moderate-to-severe, active ulcerative colitis (UC).
Methods: In this phase 2b, double-blind, randomized, placebo-controlled induction trial, patients were recruited from 95 centers (hospitals and health-care centers) in 16 countries. Eligible patients were aged 18–75 years, with a diagnosis of moderate-to-severe, active UC and a modified Mayo score (MMS) of 5 points or higher, and a documented non-response or intolerance to previous treatment. Enrolled patients were randomly assigned (1:1:1:1) via an interactive voice and web response system to receive once daily oral ABX464 100 mg, ABX464 50 mg, ABX464 25 mg, or matched placebo. Randomization was stratified according to study site (US vs. non-US) and to whether the patient had previous exposure to second-line treatment with biologics or Janus kinase inhibitors. The primary end point was the change from baseline in MMS at week 8. The primary efficacy analysis was done in the full analysis set (FAS), defined as all randomly assigned patients who received at least 1 dose of study treatment and had baseline data for at least 1 efficacy variable, and was analyzed according to the principles of intention-to-treat. Safety analyses included patients who had been randomly assigned and who received at least 1 dose of study treatment. The 96-week open-label extension is ongoing.
Findings: Between August 13, 2019, and April 16, 2021, 254 patients were randomly allocated to ABX464 100 mg (n = 64), ABX464 50 mg (n = 63), ABX464 25 mg (n = 63), or placebo (n = 64). Two patients, both in the ABX464 25-mg group, were excluded from the FAS. In the FAS at week 8, the least squares mean (LSM) change from baseline in MMS was -2.9 (95% confidence interval [CI]: -3.4 to -2.5) for the ABX464 100-mg group, -3.2 (95% CI: -3.7 to -2.7) for the ABX464 50-mg group, -3.1 (95% CI: -3.6 to -2.6) for the ABX464 25-mg group, and -1.9 (95% CI: -2.4 to -1.5) for placebo group; the magnitude of the difference in MMS from baseline was significantly greater in all 3 ABX464 groups compared with placebo (p = 0.0039 for ABX464 100 mg vs. placebo, p = 0.0003 for ABX464 50 mg vs. placebo, and p = 0.0010 for ABX464 25 mg vs. placebo). The most frequently reported adverse event was headache, which was reported for 27 of 64 patients (42%) in the ABX464 100-mg group, 19 of 63 (30%) in the 50-mg group, 13 of 62 (21%) in the 25-mg group, and 5 of 64 (8%) in the placebo group. Severe (grade 3) headache was reported for 3 patients (5%) in the ABX464 100-mg group, 2 (3%) in the ABX464 50-mg group, 1 (2%) in the ABX464 25-mg group, and none in the placebo group. The only serious adverse event reported for 2 or more patients in any group was UC (1 in each of the ABX464 100-mg and 50-mg groups, and 3 [5%] in the placebo group).
Interpretation: All doses of ABX464 significantly improved moderate-to-severe, active ulcerative colitis compared with placebo, as measured by changes in modified Mayo score from baseline to week 8. A phase 3 clinical program is ongoing.