Phase 2b/3 Study of ABX464 in Moderate to Severe Active Crohn's Disease Patients

Phase 2b/3, Randomized, Double Blind, Placebo Controlled Induction Phase Followed by a Maintenance Phase to Evaluate the Efficacy & Safety of ABX464 in Patients With Moderate to Severe Active Crohn's Disease & to Determine the Optimal Dose

This is a multicenter, randomized, placebo controlled study to evaluate the efficacy and safety of ABX464, administered once daily (QD), in inducing clinical remission and endoscopic response in patients with moderate to severe active Crohn's disease (CD) who have inadequate response, loss of response, or intolerance to prior corticosteroid and/or immunosuppressant treatment and/or biologics. This study consists of a 28 day Screening Period, a 52 week Treatment Period; including a 12 week double blinded (Cohort 1) or open label (Cohort 2) Induction Phase and a 40 week double blinded (responders) or open label (nonresponders) Maintenance Phase; and a 4 week Follow up Period, which will consist of an End of Study (EOS) visit

This is a multicenter, randomized, placebo controlled study to evaluate the efficacy and safety of ABX464, administered once daily (QD), in inducing clinical remission and endoscopic response in patients with moderate to severe active Crohn's disease (CD) who have inadequate response, loss of response, or intolerance to prior corticosteroid and/or immunosuppressant treatment and/or biologics. This study consists of a 28 day Screening Period, a 52 week Treatment Period; including a 12 week double blinded (Cohort 1) or open label (Cohort 2) Induction Phase and a 40 week double blinded (responders) or open label (nonresponders) Maintenance Phase; and a 4 week Follow up Period, which will consist of an End of Study (EOS) visit

Patient eligibility will be determined during a 4 week (28 days) Screening Period. Entry criteria will be based on confirmation of active moderate to severe ileal, ileocolic, or colonic CD. Approximately 930 patients will participate in this study (ABX464 Dose A N = 380, ABX464 Dose B N = 380, placebo N = 170).

On Day 0, eligible patients will be randomized into 2 cohorts:

• Cohort 1: Double blinded Induction Phase according to a 1:1:1 ratio into 3 treatment groups as follows:

  • ABX464 - Dose A QD: 170 patients
  • ABX464 - Dose B QD: 170 patients
  • Matching Placebo: 170 patients

• Cohort 2: Open-label Induction Phase according to a 1:1 ratio into 2 treatment groups as follows:

  • ABX464 - Dose A QD: 210 patients

At the end of the 12-week Induction Phase, all patients will be evaluated for the co-primary endpoints, namely induction of clinical remission and endoscopic improvement in addition to the secondary and exploratory endpoints. All patients will also be evaluated for treatment response. The determination of whether patients will be considered treatment responders versus nonresponders, responders being defined as patients with a reduction from baseline in Crohn's Disease Activity Index (CDAI) of ≥ 70 points.

Patients will be allocated to the different maintenance treatment regimens according to the following rules:

• Patients who received ABX464 in the Induction Phase (coming from Cohort 1 and 2) and who were responders at Week 12 will be randomized 1:1:1 to receive either ABX464 Dose A QD, ABX464 Dose B QD, or placebo in a double-blinded manner, for an additional 40 weeks. Stratification factors used for re-randomization in the Maintenance Phase are previous failure to biologics and current corticosteroid treatment use.
• Patients who received ABX464 or placebo in the Induction Phase (coming from Cohort 1 and 2) but who were not responders at Week 12 will be allocated to open label ABX464 Dose A QD. They will be evaluated 12 weeks later, and they will continue only if they have achieved clinical response at that timepoint.
• Patients who received placebo (coming from Cohort 1) in the Induction Phase and who were responders at Week 12 will be allocated to receive placebo as part of their double blinded maintenance treatment.

At Week 24, nonresponders who received open label ABX464 Dose A QD in the Maintenance Phase will be assessed for treatment response. If patients have not achieved treatment response at Week 24, patients should discontinue study drug. All patients, including those who have had treatment response in Week 12, can be discontinued due to disease worsening.

Patients will also be evaluated for safety and efficacy throughout the Induction and Maintenance Phases. From Day 0 onwards, all eligible patients will be followed at the investigational site on Week 1, Week 2, Week 4, Week 8, Week 12, and every 4 weeks until Week 52. Ileocolonoscopy will be performed in accordance with the Schedule of Activities.

Inclusion Criteria:

• Men or women age 18-75 years;
• Patients must have a documented diagnosis (endoscopic with histology) of CD for ≥ 3 months before screening;
• Patients must have active moderate to severe ileal, ileocolic, or colonic CD at baseline as defined by 220 ≤ CDAI > 450,
• Patients must have a SES-CD score > 6 (≥4 if isolated ileal disease) at screening, assessed by ileocolonoscopy and confirmed by a central reading.
• Patients must be willing and able to undergo endoscopy during screening after all other inclusion criteria have been met and at the end of Week 16.
• Patients must have had either a documented inadequate response, no response, a loss of response, or an intolerance (defined as the occurrence of at least one Adverse Reaction leading to treatment discontinuation) to either amino-salicylates, immunosuppressant treatment (i.e., azathioprine, 6-mercaptopurine, methotrexate, biologics (i.e. tumor necrosis factor inhibitors, vedolizumab, ustekinumab), and/or corticosteroid treatment.
• Patients should be 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 at the screening visit prior to any protocol-specific procedures being performed;
• Patients should be affiliated to a social security regimen (for French sites only);
• Females and males receiving the study treatment and their partners must agree to use a highly effective contraceptive method during the study and for 3 months after end of study or early termination.

Exclusion Criteria:

• Patients with indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis or clinical/histologic findings suggestive of ulcerative colitis;
• Patients with colonic dysplasia or neoplasia or adenomatous colonic polyp;
• Patients with presence of fistulae;
• Patients with current symptomatic diverticulitis or diverticulosis;
• Patients with obstructive colonic stricture/stenosis, past medical history of colonic resection, a history of bowel surgery within 6 months before screening, or who are likely to require surgery for CD during the treatment period;
• Patients with past medical history of clinically significant short bowel syndrome;
• Patients requiring parenteral nutrition;
• Patients with past medical history of bowel surgery resulting in an existing or current stoma;
• Patients with active infections at screening such as infected abdominal abscess, Clostridium difficile (stool antigen and toxin required), cytomegalovirus, tuberculous colitis and recent infectious hospitalization;
• Acute, chronic or history of clinically relevant pulmonary, cardiovascular, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable central nervous system pathology such as seizure disorder, angina or cardiac arrhythmias, or any other clinically significant medical problems as determined by physical examination and/or laboratory screening tests and/or medical history;
• Acute, chronic or history of immunodeficiency or autoimmune disease;
• History of malignancy excluding patients considered cure (5 years disease free survivors);
• Active malignancy that may require chemotherapy or radiation therapy;
• Serious illness requiring systemic treatment and/or hospitalization within 3 Weeks prior to baseline;
• Pregnant or breast-feeding woman;
• Illicit drug or alcohol abuse or dependence;
• Use of any investigational or non-registered product within 3 months or within 5 half-lives preceding baseline, whichever is longer;
• Any condition, which in the opinion of the investigator, could compromise the patient's safety or adherence to the study protocol.