Efficacy and Safety of Obefazimod for Induction in Adults with Moderately to Severely Active Ulcerative Colitis: Randomized, Double‑Blind, Placebo‑Controlled III Trial

The primary objective of this study is to compare the **efficacy** of obefazimod versus placebo on endoscopic improvement and symptomatic remission in subjects with moderately to severely active **ulcerative colitis**. This is clinically relevant as achieving endoscopic improvement and symptomatic remission are critical goals in the management of ulcerative colitis, potentially leading to better patient outcomes and quality of life.

Secondary objectives include:

• Comparing the efficacy of obefazimod versus placebo on clinical remission.
• Comparing the efficacy of obefazimod versus placebo on clinical response.
• Comparing the efficacy of obefazimod versus placebo on histologic-endoscopic mucosal improvement (HEMI).
• Evaluating the safety profile of obefazimod versus placebo during induction.

The clinical trial involves a total of **394 participants** diagnosed with **moderately to severely active ulcerative colitis**. The study population includes both male and female subjects, with an age range starting from 16 years, except in the EU/EEA and Ukraine, where participants must be at least 18 years old. The trial includes individuals who have a documented diagnosis of ulcerative colitis confirmed by endoscopy and histology. Participants are required to have an active disease as defined by a modified Mayo score of 5 or higher, with specific subscores for rectal bleeding and endoscopy. The trial population was selected based on their documented inadequate response to certain treatments, including corticosteroids, immunosuppressants, biologic or biosimilar therapies, S1P receptor modulators, JAK inhibitors, and other new drugs approved during the study. Both male and female subjects of childbearing potential must adhere to specific contraception requirements. Participants are expected to comply with study visits and procedures and should be affiliated with a health insurance policy if required by their country or state. The trial also includes a vulnerable population, ensuring a comprehensive assessment of the treatment's efficacy across diverse groups.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of the investigational product, ABX464, in subjects with moderately to severely active **ulcerative colitis**. The trial is a Phase III study, conducted over an estimated duration from June 2023 to April 2025. Participants will be randomly assigned to receive either ABX464 or a placebo, administered orally in the form of hard capsules. The primary objective is to compare the efficacy of **obefazimod** versus placebo on endoscopic improvement and symptomatic remission.

The trial will include several key study visits. The initial visit, known as the inclusion or screening visit, will determine participant eligibility based on specific criteria, including age, documented diagnosis of ulcerative colitis, and previous treatment responses. Following successful screening, participants will undergo a series of follow-up visits, with the primary endpoints assessed at week 8. These endpoints include the proportion of subjects achieving endoscopic improvement and symptomatic remission. Secondary endpoints will also be evaluated, such as clinical remission, clinical response, and the incidence of treatment-emergent adverse events (TEAEs).

The expected length of participant involvement in the study is up to 8 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the occurrence of serious TEAEs, non-compliance with study procedures, or withdrawal of consent. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the overall safety and efficacy of the treatment. The study is structured to ensure rigorous monitoring and data collection throughout the trial duration, adhering to the highest standards of clinical research methodology.

The clinical trial involves the administration of **ABX464**, a pharmaceutical product in the form of a hard capsule. The active substance in ABX464 is **obefazimod**, a chemical compound. The medication is manufactured by ABIVAX and is administered orally. Participants in the trial receive ABX464 at a dosage of either 25 mg or 50 mg per day. The maximum daily dose for the 25 mg capsule is 25 mg, with a total maximum dose of 1400 mg over the treatment period. For the 50 mg capsule, the maximum daily dose is 50 mg, with a total maximum dose of 2800 mg. The treatment period for both dosages is up to 8 weeks. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The study also includes a placebo group, which receives a placebo designed to match the 25 mg and 50 mg ABX464 hard capsules. The placebo is administered in the same manner as the active treatment, ensuring that the study remains double-blind. The placebo does not contain any active substance and serves as a control to evaluate the efficacy and safety of ABX464 in subjects with moderately to severely active **ulcerative colitis**. The use of a placebo allows for a comparison of endoscopic improvement and symptomatic remission between the treatment and control groups.

The efficacy of the investigational product, **obefazimod**, will be assessed in a randomized, double-blind, placebo-controlled, multicenter phase III clinical trial. The primary endpoints for evaluating efficacy include the proportion of subjects who achieve endoscopic improvement and the proportion of subjects with symptomatic remission at week 8. These endpoints are designed to measure the effectiveness of obefazimod in treating moderately to severely active ulcerative colitis.

Secondary endpoints will further assess efficacy and safety, including the proportion of subjects achieving clinical remission and clinical response at week 8, as well as the proportion of subjects with histological evidence of mucosal improvement (HEMI) per Geboes scoring. Additionally, the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and adverse events of special interest (AESIs) will be monitored. Clinically significant laboratory abnormalities, vital signs, and electrocardiogram (ECG) changes will also be evaluated to ensure comprehensive safety and efficacy assessment.