Obefazimod in Ulcerative Colitis

Obefazimod is an oral small-molecule drug candidate in clinical development for the treatment of moderately to severely active ulcerative colitis (UC) and has demonstrated anti‐inflammatory activity in preclinical studies and in both Phase 2a and Phase 2b clinical trials. In April 2021, Abivax completed its randomized, double-blind and placebo-controlled Phase 2b trial which was conducted in 15 European countries, the United States and Canada in 252 patients. The primary endpoint (statistically significant reduction of Modified Mayo Score) was met with once-daily administration of obefazimod (25 mg, 50 mg, 100 mg) at week 8.

Further, all key secondary endpoints, including endoscopic improvement, clinical remission, clinical response and the reduction of fecal calprotectin showed significant difference in patients dosed with obefazimod as compared to placebo. Importantly, obefazimod also showed high rates of sustained and newly achieved clinical remission in the subsequent open-label maintenance extension trial of up to two years of treatment, of which approximately 45% of patients who were previously exposed to biologics and/or JAK inhibitors treatment.

In addition to the induction results, the analysis of the open-label maintenance trial after two years of treatment demonstrated clinical remission rates of 53% in 217 ulcerative colitis patients treated with once-daily oral 50 mg obefazimod.

Because of obefazimod’s ability to enhance the expression of miR-124, the mechanism of action of obefazimod is novel and has shown potential in clinical trials in its ability to bring patients into remission and achieve clinical response. Obefazimod, an investigational oral therapy, is the first and only molecule that enhances the expression of miR-124, a natural regulator of the inflammatory response.

Enhancing the expression of miR-124 results in decreases in cytokines and immune cells, helping to reduce inflammation and control the progression of diseases like UC. Obefazimod has shown potential in clinical trials in its ability to bring patients into remission and achieve clinical response.

Of the 222 patients who completed the 16-week Phase 2b induction trial, 217 patients (98%) enrolled in the subsequent open-label maintenance trial to evaluate the induction Phase 2b clinical trial long-term safety and efficacy profile of obefazimod for up to two years, irrespective of treatments or treatment outcome during the induction phase. Of those patients who received a 50 mg once-daily oral dosing with obefazimod, 178 patients (82%) had a clinical response relative to induction baseline, of which 119 patients (55%) were in clinical remission, 133 patients (61%) had an endoscopic improvement, and 72 patients (33%) had an endoscopic remission.

As of November 2022 (last safety data cut-off), 1,074 patients and volunteers were treated with obefazimod, of which 209 patients have been treated with 50mg obefazimod for one year or more. No new adverse safety signals were observed.

The Phase 2b induction trial and 48-week extension results of obefazimod in UC were published in the prestigious, peer-reviewed journal “The Lancet Gastroenterology and Hepatology” with the title “ABX464 (obefazimod) for moderate to severe active ulcerative colitis: a randomised, placebo controlled phase 2b induction trial and 48 week, open-label extension”.

In September 2023, we reported an interim analysis of step-down dosing from 50 mg to 25 mg for the third and fifth year of open-label maintenance treatment with obefazimod in UC patients. These patients were treated with 50 mg of oral, once-daily, obefazimod for approximately four years in the Phase 2a clinical trial and approximately two years in the Phase 2b clinical trial. Patients were eligible to enroll in the trial if they had a Mayo endoscopic subscore of 0 or 1. Eligible patients were switched to 25 mg and an interim analysis was performed at week 48 with a cut-off date of July 31, 2023. Of the 71 eligible patients, 63 completed their 48-week visit. Among these patients, 53 out of 63 patients (84%) demonstrated disease control (stable or improved Modified Mayo Score). No new safety signals were detected in UC patients treated up to five years with oral, once-daily, obefazimod.

1,200 moderate to severe UC patients across 36 countries will take part in the pivotal Phase 3 program which consists of two induction studies and a subsequent maintenance study (ABTECT-1 and ABTECT-2 induction trials – ABX464-105 and ABX464-106 – and ABTECT maintenance trial – ABX464-107). These three pivotal studies are all randomized, double-blind and placebo controlled, using independent and central review of the video-taped endoscopies. The primary efficacy endpoint assessed at week 8 (induction) and at week 44 (maintenance) will be clinical remission according to the modified Mayo Score, as required by FDA.

In consultation with international regulators, including FDA, EMA, PMDA and CDE, obefazimod 25mg and 50mg will be investigated in Phase 3 for the treatment of UC in advanced therapies (AT) naïve and in AT-failure patients to support the future submission of marketing authorizations.