A randomized, double-blind, placebo-controlled, multicenter phase III study to evaluate the efficacy and safety of ABX464 once daily for induction treatment in subjects with moderately to severely active ulcerative colitis

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 can significantly enhance the quality of life for patients and reduce the long-term complications associated with ulcerative colitis.

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 **380 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 old, except in certain regions where the minimum age is 18. Participants are required to have a documented diagnosis of ulcerative colitis confirmed by endoscopy and histology. The trial includes individuals who have shown an inadequate response to treatments such as corticosteroids, immunosuppressants, biologic or biosimilar therapies, S1P receptor modulators, JAK inhibitors, or new drugs approved during the study. The selection process ensures that participants are able and willing to comply with study visits and procedures, and they must be affiliated with a health insurance policy if required by their country or state. Both genders are represented, and the trial includes a vulnerable population. Participants must adhere to specific contraception requirements if applicable. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

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 visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. During the **screening visit**, eligibility will be assessed based on criteria such as age, documented diagnosis of ulcerative colitis, and previous treatment responses. Participants must have a modified Mayo score of at least 5, with specific subscores for rectal bleeding and endoscopy. The **follow-up visits** will occur at regular intervals to monitor the participants' response to treatment, assess any adverse events, and ensure compliance with the study protocol. The **end-of-study visit** will evaluate the primary and secondary endpoints, including endoscopic improvement and symptomatic remission at week 8, as well as the incidence of treatment-emergent adverse events.

Participant involvement is expected to last for a maximum of 8 weeks, corresponding to the treatment period. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide comprehensive data on the safety and efficacy of ABX464, contributing to the understanding of its potential as a treatment for ulcerative colitis.

The clinical trial involves the administration of **ABX464**, an experimental medication containing the active substance **obefazimod**. This medication is provided in the form of a hard capsule and is intended for **oral use**. Two dosage strengths are utilized in the study: 50 mg and 25 mg. The maximum daily dose for the 50 mg capsule is 50 mg, with a total maximum dose of 2800 mg over the treatment period. For the 25 mg capsule, the maximum daily dose is 25 mg, with a total maximum dose of 1400 mg. The treatment period for both dosages is up to 8 weeks. The medication is manufactured by ABIVAX and is of chemical origin. Participant compliance with the dosing schedule is monitored throughout the study.

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 used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo does not contain any active substance and is administered in the same manner as the experimental medication, ensuring consistency in the administration process.

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 symptomatic remission at week 8. Secondary endpoints will further assess efficacy through the proportion of subjects achieving clinical remission, clinical response, and histological endpoints such as HEMI per Geboes scoring, all measured at week 8.

Data collection will occur at specified timepoints, with the primary focus on week 8 for both primary and secondary endpoints. The trial will utilize validated scales and methodologies to ensure accurate and reliable measurement of these endpoints. The analysis will include the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and adverse events of special interest (AESIs), as well as clinically significant laboratory abnormalities, vital signs, and electrocardiograms (ECGs). These assessments will provide a comprehensive evaluation of the efficacy and safety of **obefazimod** in subjects with moderately to severely active ulcerative colitis.