A phase 2b, multicenter, double-blind, placebo-controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of obefazimod in subjects with moderately to severely active Crohn’s disease.
General Information:
The main purpose of this study is to see if the study drug is safe and effective in treating your CD, and whether it is safe when given for an extended period of time.
This is a Phase 2 study. This means that the study drug has already been tested in small numbers of healthy volunteers. In addition, the study drug has been tested in patients with other medical conditions, including ulcerative colitis (another inflammatory bowel disease). This study is now testing the study drug in a group of patients with CD.
Eligibility:
Inclusion Criteria:
- Patients at least 18 to 75 years old
- Patients diagnosed with moderately to severely active CD
- Patients who did not respond to currently available treatments (CD therapies), responded to CD therapy at first but are no longer responding, or could not tolerate at least one of the following treatments: corticosteroids (CS), immunosuppressants (IS), biologic or biosimilar therapies, or Janus kinase (JAK)
- Male and female of childbearing potential as well as their partners must use an effective method of contraception during the study and for at least 21 days after the last study drug intake.
- Investigators will review the full medical history of their patients to check for potential contra-indication for the use of obefazimod and ensure their patients eligibility.
Main exclusion criteria:
- Women of childbearing potential (WOCBP) who is pregnant or breast-feeding at screening, or intends to become pregnant during the study; or male subject with WOCBP partner who intends to be pregnant during the study.
- Patients must not have CD without ileal and/or colonic involvement.
- Patients who have failed on 5-ASA therapy only are not eligible.
- Patients must not have untreated active external or perianal fistula or abscess, symptomatic bowel stricture and/or stenosis not passable in endoscopy.
- Patients must not have a history of colon cancer, past or current evidence of low grade or high-grade colonic dysplasia and/or adenomatous polyps that have not been completely removed.
- Patients must not have a recent or planned bowel surgery or more than 2 missing complete segments or current stoma or ileoanal pouch.
- Patients with inadequate hematological and biochemical laboratory parameters obtained during the screening period are not eligible.
- Patients with active infection or chronic or recurrent infection (grade 3 or 4) or reactivation (herpes zoster) within the last 2 months prior to screening or a history of opportunistic infection while not on immunosuppressive therapy are not eligible.
Study Details:
Study description/explanation of participation:
The ENHANCE-CD program (156 weeks including a 12-week Induction period and a 40-week Maintenance period, and a 104-week Extension period) is conducted in patients with moderately to severely active CD who have inadequate response, no response, a loss of response, or an intolerance to either conventional therapies and/or advanced therapies.
Eligible patients will be randomly allocated into one of four treatment groups (placebo, obefazimod 12,5 mg, obefazimod 25 mg, obefazimod 50 mg) and will take one capsule orally once a day. All participants who have completed the maintenance period will receive open label obefazimod 50 mg once per day until the end of Extension period.
Description of treatment or intervention (mechanism of action):
Obefazimod (ABX464) has the ability to selectively upregulate a single microRNA, called miR-124, which downregulates pro-inflammatory cytokines and chemokines, thereby “putting a brake” on inflammation. Obefazimod modulates the endogenous immune system to dampen the inflammation and control the symptoms.
Patient Participation Requirements:
Eligible patients need to go through the following examinations during the course of the study:
- Physical examinations will be done at each visit, and vital signs will be measured.
- Endoscopies with biopsies will be performed before receiving the study medication, at the end of the induction period, and at the end of the maintenance period.
- Blood samples will be collected to check patient eligibility during the screening period, and from day 1 onwards to check their safety and perform exploratory assessments.
- Collection of stools will be done at screening to check patient eligibility and during the course of the study to assess the evolution of a marker of CD activity (fecal calprotectin).
- An electrocardiogram will be done at screening, and during the course of the study to check the rhythm and activity of their heart.
- An eye examination (Visual acuity and Slit Lamp) will be done at screening and on weeks 12, 28, 52,108 and 156 visits (or End of Treatment visit for subjects early discontinuing the study).
- An electronic device (e-Diary) will be used to collect abdominal pain, number of liquid or soft stools, overall well-being as well as the number of capsules taken and the intake time.
- Questionnaires will be completed at the study center on an electronic device on weeks 1, 12, 16, 36, 52, 108 and 156. These are to record: overall quality of life, bowel movements, abdominal symptoms, physical function, level of pain, how CD affects physical ability, emotional impact, general and mental health, impairments in both paid work and unpaid work, impact on social functioning, energy levels (vitality).
- Pregnancy tests for people who can become pregnant, including a blood pregnancy test at each visit and a urine pregnancy test to be done monthly at home.
Possible risks and side effects:
As of 30 November 2024, 1300 subjects have received obefazimod, according to various administration schedules, including 97 subjects for 6 months to 1 year and 241 subjects for more than one year.
Most frequently reported adverse events were headaches, which occurred early (first 10 days of treatment) and were transient (few days), mild or moderate (grade 1 or 2) and manageable with or without over-the-counter medications.
Other adverse events (≥ 5% - related and non-related) were gastrointestinal disorders (nausea, vomiting, diarrhea and upper abdominal pain) and musculoskeletal (back pain). Cases of temporary increase in the blood levels of an enzyme called “lipase” have been observed in obefazimod clinical studies in patients receiving either placebo or the study drug obefazimod.
Progress to date (previous phase successes, links to abstracts, etc.):
In the results currently available of the Phase 2a and Phase 2b induction and maintenance trials, obefazimod has demonstrated a rapid onset of action and maintained efficacy in moderate-to-severe UC patients. The safety database of over 1,000 patients treated to date with obefazimod indicates a favorable safety and tolerability profile.
Publication highlighting the results of obefazimod (ABX464) in the Phase 2a and Phase 2b trials:
ABX464 (obefazimod) for moderate-to-severe, active ulcerative colitis: a phase 2b, double-blind, randomized, placebo-controlled induction trial and 48 week, open-label extension, Severine Vermeire et al., Lancet Gastroenterol Hepatol, Volume 7, Issue 11, Sept. 2022, P. 1024-1035
Induction and long-term follow-up with ABX464 for moderate-to-severe ulcerative colitis: Results of phase 2a trial, Severine Vermeire et al., Gastroenterology, Volume 160, Issue 7, June 2021, P. 2595-2598.E3
Publications on the mechanism of action of obefazimod (ABX464):
ABX464 (obefazimod) up-regulates miR-124 to reduce pro-inflammatory markers in inflammatory bowel diseases, Cécile Apolit et al., Clinical and Translational Gastroenterology, published online Jan. 2023
Specific and selective induction of miR-124 in immune cells by the quinoline ABX464: a transformative therapy for inflammatory diseases, Cécile Apolit et al., Clinical and Translational Gastroenterology, published online Jan. 2023
Both anti-inflammatory and antiviral properties of novel drug candidate ABX464 are mediated by modulation of RNA splicing, Audrey Vautrin et al., Nature Scientific Reports, Volume 9, Article number: 792, January 2019
Press releases issued on clinical trial results with obefazimod (ABX464) in ulcerative colitis an on publications on its mechanism of action:
Press releases issued on publications on the mechanism of action of obefazimod (ABX464):
Abivax publishes novel data with respect to obefazimod’s (ABX464) anti-inflammatory mechanism of action, (Jan. 2023)