Efficacy and Safety Study of ABX464 as Maintenance Therapy in Patients With Moderate to Severe Ulcerative Colitis

This study is an open-label study aiming at evaluating the long-term safety and the efficacy profile of ABX464 given once a day (o.d) at 50 mg in subjects who have been previously enrolled in the ABX464-103 clinical study (induction study) and who are willing to continue their treatment. All subjects will receive ABX464 given at 50mg o.d regardless of their previous treatment and dose received in the ABX464-103 study (i.e. ABX464 100mg, ABX464 50mg, ABX464 25mg or Placebo). The enrolment in this follow-up study will be based on the willingness of the subject to carry on his/her participation. Subjects will be treated with ABX464 for an overall period of 48 weeks. Subjects will be followed up on a monthly basis.

• ABX464 (Drug), also known as Obefazimod: ABX464 All subjects will receive ABX464 administered at 50 mg o.d for an overall period of 96 weeks.

Primary outcomes

• Proportion of Patients With Clinical Remission at Week 48 Compared to Baseline of Induction Study (ABX464-103) [week 48]: Clinical remission (based on the Mayo scoring system) is defined as: a rectal bleeding sub-score = 0, and an endoscopy sub-score ≤1 (excluding friability), and at least 1-point decrease in stool frequency sub-score from baseline to achieve a stool frequency sub-score ≤1

Secondary outcomes

• Proportion of Patients With Clinical Response at Weeks 48 and 96 Compared to Baseline of Induction Study [Weeks 48 and 96]: Proportion of patients with clinical response at week 48 Clinical response is defined as: a reduction in Mayo Score ≥ 3 points and ≥ 30 % from baseline with an accompanying decrease in rectal bleeding sub-score ≥ 1 point or absolute rectal bleeding sub-score ≤ 1 point.
• Endoscopic Improvement at Weeks 48 and 96 [week 48 and week 96]: Proportion of patients with endoscopic improvement at week 48 among all patients. Proportion of patients with endoscopic improvement at week 96 among all patients. Endoscopic improvement is defined as a Mayo endoscopic sub score of ≤1 (excluding friability).
• Endoscopic Remission at Weeks 48 and 96 [week 48 and week 96]: Proportion of patients with endoscopic remission at week 48 among all patients. Proportion of patients with endoscopic remission at week 96 among all patients. Endoscopic remission is defined as a Mayo endoscopic sub score of 0.
• Sustained Endoscopic Changes at Week 48 and Week 96 [weeks 48 and 96]: Proportion of patients with sustained endoscopic changes at week 48 and 96. Sustained endoscopic changes is defined as the number of patients with endoscopic changes at week 48 among patients who had endoscopic changes during the Induction study (at week 8 or week 16 of study ABX464-103).
• Change in Modified Mayo Score and in Partial Modified Mayo Score [From baseline to week 96]: Change in Modified Mayo Score (MMS) at weeks 48 and 96 and in partial Modified Mayo Score (pMMS) MMS is a composite score of UC disease activity calculated as the sum of the following 3 subscores: 1. Stool frequency, scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding, scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic evaluation, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall MMS ranges from 0 to 9 where higher scores represent more severe disease. pMMS is a composite score of UC disease activity calculed as the sum of the following 2 subscores: 1. Stool frequency, scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding, scored from 0 (no blood seen) to 3 (blood alone passed). The overall pMMS ranges from 0 to 6 where higher scores represent more severe disease.
• Stool Frequency Subscore [From baseline to week 96]: Participants recorded stool frequency using a paper subject diary on a daily basis. The stool frequency subscore ranges from 0 to 3 according to the following scale: Score 0: Normal number of stools Score 1: 1 to 2 stools per day more than normal Score 2: 3 to 4 stools per day more than normal Score 3: 5 or more stools per day more than normal
• Rectal Bleeding Score [From baseline to week 96]: Participants recorded rectal bleeding in a paper subject diary on a daily basis. Rectal bleeding score is taken as the worst subscore of the three most recent scores within 7 days prior to the visit. The rectal bleeding subscore ranges from 0 to 3 according to the following scale: Score 0: No blood seen Score 1: Streaks of blood with stool less than half the time Score 2: Obvious blood with stool most of the time Score 3: Blood alone passed A lower score represents an improvement in rectal bleeding.
• C-Reactive Protein [baseline, week 24, week 48]: Change to baseline in C-Reactive Protein levels
• miRNA-124 Expression [baseline, week 24 and week 48]: Change relative to baseline in miRNA-124 expression in rectal/sigmoidal biopsies at week 48 and in total blood at week 24 and week 48.
• Incidence and Description of Adverse Events [From baseline to week 96]: Number and rate of all adverse events, causally-related adverse events, all serious adverse events and causally-related serious adverse events classified by severity. Incidence of treatment-emergent serious adverse events, hospitalizations, total inpatient days. Incidence of adverse events leading to investigational product discontinuation. Number of clinically significant laboratory abnormalities.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Patients must have completed the 16-week induction treatment period (ABX464-103);
* Patients are able and willing to comply with study visits and procedures as per protocol;
* Patients should understand, sign and date the written voluntary informed consent form prior to any protocol-specific procedures are performed;
* Patients should be affiliated to a social security regimen (for French sites only);
* Females and males receiving the study treatment (potentially in combination with immunosuppressant) and their partners must agree to use a highly effective contraceptive method during the study and for 6 months (180 days) after end of study or early termination. Contraception should be in place at least 2 weeks prior to screening. Women must be surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) or in the postmenopausal state (no menses for 12 months without an alternative medical cause) or if of childbearing potential must use a highly effective contraceptive method. Women of childbearing potential (WOCBP) will enter the study after confirmed menstrual period and a negative pregnancy test. Highly effective methods of contraception include true abstinence, intrauterine device (IUD) or hormonal contraception aiming at inhibition of ovulation, intrauterine hormone releasing system, bilateral tubal ligation, vasectomized partner. True abstinence is defined when this is in line with the preferred and usual lifestyle of the patient. In each case of delayed menstrual period (over one month between menstruations) confirmation of absence of pregnancy is required. This recommendation also applies to WOCBP with infrequent or irregular menstrual cycle. Female and male patients must not be planning pregnancy during the trial and for 6 months post completion of their participation in the trial. In addition, male patients should use condom during the trial and for 6 months (180 days) post completion of their participation in the study. Male patients must not donate sperm as long as contraception is required.

Criteria that should be met by patients at week 48 to be eligible for 48 additional weeks of study treatment.

* Patients should be in clinical response. Clinical response is defined as: a reduction in Modified Mayo Score ≥ 2 points and ≥ 30 % from baseline (induction) with an accompanying decrease in rectal bleeding sub-score ≥ 1 point or absolute rectal bleeding sub-score ≤ 1 point.
* Patients able and willing to continue the study treatment and who are compliant with study visits and procedures and who signed the update of the written voluntary informed consent.

Exclusion Criteria:

* Patients who had major protocol deviation(s) in the induction study;
* Patients who permanently discontinued study the treatment in induction study (ABX464-103) because of an adverse event (AE) regardless of relatedness to investigational product;
* Patients who have developed any major illness/condition or evidence of an unstable clinical condition (except UC) that, in the investigator's judgment, will substantially increase the risk to the participant if he or she participates in the study;
* Patients with any other severe acute or chronic medical or psychiatric condition or laboratory or electrocardiogram (ECG) abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study;
* Patients who are participating or plan to participate in other investigational studies (other than induction study) during the study.

Participant flow

Outcome results

• Proportion of Patients With Clinical Remission at Week 48 Compared to Baseline of Induction Study (ABX464-103) (Primary), Count of participants, Participants: ABX464 50mg 119
• Proportion of Patients With Clinical Response at Weeks 48 and 96 Compared to Baseline of Induction Study (Secondary), Count of participants, Participants: ABX464 50mg 177
• Endoscopic Improvement at Weeks 48 and 96 (Secondary), Count of participants, Participants: ABX464 50mg 133
• Endoscopic Remission at Weeks 48 and 96 (Secondary), Count of participants, Participants: ABX464 50mg 72
• Sustained Endoscopic Changes at Week 48 and Week 96 (Secondary), Count of participants, Participants: ABX464 50mg 53
• Change in Modified Mayo Score and in Partial Modified Mayo Score (Secondary), Mean, units on a scale: ABX464 50mg 7.0 +/- 1.07
• Stool Frequency Subscore (Secondary), Mean, score on a scale: ABX464 50mg 2.6 +/- 0.66
• Rectal Bleeding Score (Secondary), Mean, score on a scale: ABX464 50mg 1.6 +/- 0.72
• C-Reactive Protein (Secondary), Mean, mg/L: ABX464 50mg 6.66 +/- 12.17
• miRNA-124 Expression (Secondary), Mean, copy number/cell: ABX464 50mg 0.00065 +/- 0.00211
• Incidence and Description of Adverse Events (Secondary), Count of participants, Participants: ABX464 50mg 149

Adverse events

Time frame: 96 weeks

Serious adverse events by term

Other adverse events by term

20 more sites not listed.

• Results publication: Vermeire S, Nitcheu J, Gineste P, Flatres A, Santo J, Scherrer D, Peyrin-Biroulet L, Dulai PS, Danese S, Dubinsky M, Tilg H, Siegmund B, Hisamatsu T, Shan K, Rabbat CJ, Sands BE. Obefazimod in patients with moderate-to-severely active ulcerative colitis: efficacy and safety analysis from the 96-week open-label maintenance phase 2b study. J Crohns Colitis. 2025 May 8;19(5):jjaf074. doi: 10.1093/ecco-jcc/jjaf074. PMID 40417999
• Results publication: Vermeire S, Sands BE, Tilg H, Tulassay Z, Kempinski R, Danese S, Bunganic I, Nitcheu J, Santo J, Scherrer D, Biguenet S, Ehrlich HJ, Steens JM, Gineste P, Sandborn WJ. ABX464 (obefazimod) for moderate-to-severe, active ulcerative colitis: a phase 2b, double-blind, randomised, placebo-controlled induction trial and 48 week, open-label extension. Lancet Gastroenterol Hepatol. 2022 Nov;7(11):1024-1035. doi: 10.1016/S2468-1253(22)00233-3. Epub 2022 Sep 6. PMID 36075249

• Study Protocol (PDF, 2022-07-11)
• Statistical Analysis Plan (PDF, 2023-03-28)

• Severine VERMEIRE, MD, Principal investigator, Universitaire Ziekenhuizen KU Leuven