Dose-Ranging Phase 2b Study of ABX464 in Moderate to Severe Ulcerative Colitis

Abivax S.A.355 enrolled

Overview

Phase 2b study to evaluate the efficacy and the safety of 3 dose-levels of ABX464, administered daily in patients with moderate to severe Ulcerative Colitis.

This phase 2b study will evaluate the efficacy and the safety of 3 dose-levels of ABX464, administered daily in improving Modified Mayo Score (MMS) in patients with moderate to severe Ulcerative Colitis who have inadequate response, loss of response, or intolerance with at least one of the following agents: immunosuppressant treatment (i.e. azathioprine, 6-mercaptopurine, methotrexate), tumor necrosis factor alpha \[TNF-α\] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment . Eligible patients will be randomized into 4 parallel intervention/treatment groups: 100mg q.d of ABX464, 50mg q.d of ABX464, 25mg q.d of ABX464, or matching placebo and will be treated for 16 weeks.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

355

Conditions

Ulcerative Colitis

Interventions

ABX464 100 mgDRUG

ABX464 100 mg (two capsules of ABX464 50 mg) once daily for 16 weeks

ABX464 50 mgDRUG

ABX464 50 mg (one capsule of ABX464 50 mg + one capsule of placebo) once daily for 16 weeks

ABX464 25 mgDRUG

ABX464 25 mg (one capsule of ABX464 25 mg + one capsule of placebo) once daily for 16 weeks

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Men or women age 18 - 75 years; * Diagnosis of moderate to severe active UC (including ulcerative proctitis if proximal extension of disease occurs beyond 10 cm) confirmed by endoscopy and histology at least 12 Weeks prior to screening visit. Moderate to severe active UC defined by Modified Mayo Score (MMS) of 5 to 9 inclusive (on a scale of 0-9). Moderate to severe active UC should be confirmed at screening visit with a centrally read endoscopy sub-score of at least 2 (on a scale of 0-3); * Patients having 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 immunosuppressant treatment (i.e., azathioprine, 6-mercaptopurine, methotrexate), tumor necrosis factor \[TNF\] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment. Inadequate response, no response, loss of response is defined as: i. Active disease or relapse in spite of thiopurines or methotrexate given at an appropriate dose for at least 3 months (i.e. azathioprine 2-2.5 mg/kg/day or mercaptopurine 1-1.5 mg/kg/day in the absence of leukopenia), and/or ii. Active disease despite corticosteroids treatment (prednisolone up to 0.75 mg/kg/day) over a period of 4 Weeks, and/or iii. Active disease or relapse in spite of adequate treatment (as defined in the SmPC) with tumor necrosis factor \[TNF\] inhibitors or vedolizumab, and/or iv. Active disease or relapse in spite of adequate treatment with JAK inhibitors over a period of at least 6 Weeks. * Patients receiving oral corticosteroids must have been on a stable dose of prednisone or prednisone equivalent (≤20 mg/day) or on beclomethasone diproprionate (≤5mg/day) or on budesonide MMX (≤9 mg/day) for at least 2 Weeks prior to the screening visit; * Topical corticosteroids and topical 5-aminosalicylic acid preparations must have been withdrawn at least 2 Weeks prior to the screening visit; * Patients who are on oral 5-aminosalicylic acid must have been on a stable dose for at least 4 Weeks prior to the screening visit; * Patients who are receiving immunosuppressants in the form of azathioprine, 6-mercaptopurine, or methotrexate needed to be on a stable dose for at least 4 Weeks prior to screening visit. Patients taking methotrexate also are advised to take folic acid 1 mg/day (or equivalent) supplementation if there is no contraindication; * Patients on probiotics (e.g., Culturelle® \[Lactobacillus GG, i-Health, Inc.\], Saccharomyces boulardii) must be on stable doses for at least 2 Weeks prior to the screening visit; * Patients on antidiarrheals (e.g., loperamide, diphenoxylate with atropine) must be on stable doses for at least 2 Weeks prior to the screening visit; * Patients who have received tumor necrosis factor \[TNF\] inhibitors, vedolizumab or other biologics must have discontinued therapy at least 8 Weeks prior to the screening visit due to lack or insufficient efficacy or intolerance; * Patients previously treated with cyclosporine, tacrolimus or JAK inhibitors must have discontinued therapy at least 4 Weeks prior to the screening visit due to lack or insufficient efficacy or intolerance; * Patients previously treated with tube feeding, defined formula diets, or parenteral alimentation/nutrition must have discontinued treatment 3 Weeks before the screening visit and must be able to take, orally, appropriate amount of food (calories) and liquids to maintain body weight; * Patients with surveillance colonoscopy defined as per ECCO guidelines; * Patients with the following hematological and biochemical laboratory parameters obtained at screening: i. Hemoglobin \> 9.0 g dL-1; ii. Absolute neutrophil count ≥ 750 mm-3; iii. Platelets ≥ 100,000 mm-3; iv. Total serum creatinine ≤ 1.3 x ULN (upper limit of normal); v. Creatinine clearance \> 90 mL min-1 by the Cockcroft-Gault equation within 60 days prior to baseline; vi. Total serum bilirubin \< 1.5 x ULN; vii. Alkaline phosphatase, AST (SGOT) and ALT (SGPT) \< 2 x ULN; * 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 at the screening visit 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 after end of study or early termination. Contraception should be in place at least 2 Weeks prior to study participation. Women must be surgically sterile 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 an 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 participants should use condoms and not donate sperm as long as contraception is required. Exclusion Criteria: * Patients with Crohn's Disease (CD) or presence or history of fistula, indeterminate colitis (IC), infectious/ischemic colitis or microscopic colitis (lymphocytic and collagenous colitis); * History of toxic megacolon, abdominal abscess, symptomatic colonic stricture or stoma; history or imminent colectomy, colonic malignancy; * History or current evidence of colonic dysplasia or adenomatous colonic polyps. Patient with severe gastrointestinal complications; e.g., short bowel syndromes, recent or planned bowel surgery, Ileostomy and/or colostomy, recent bowel perforation; * History of more than one episode of herpes zoster or a history (single episode) of disseminated zoster; * Patients with active infections at screening such as infected abdominal abscess, Clostridium difficile (stool antigen and toxin required), CMV (positive IgM), TB and recent infectious hospitalization; * Patients previously treated with ABX464; * Acute, chronic or history of clinically relevant pulmonary, cardiovascular, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable CNS pathology such as seizure disorder, angina or cardiac arrhythmias, active malignancy 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 cured (5 years disease free survivors); * Serious illness requiring systemic treatment and/or hospitalization within 3 Weeks prior to baseline; * Pregnant or breast-feeding women; * Illicit drug or alcohol abuse or dependence; * Patients who received live vaccine 30 days or fewer before first dose of study treatment and/or who's planning to receive such a vaccine during the study duration; * Use of any investigational or non-registered product within 3 months or within 5 half-lives preceding baseline, whichever is longer and during the study; * Any condition, which in the opinion of the investigator, could compromise the patient's safety or adherence to the study protocol.

Locations (130)

Outcomes

Primary Outcomes

Reduction From Baseline in Modified Mayo Score (MMS) at Week 8

Reduction from baseline in Modified Mayo Score (MMS) MMS is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, 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.

Time frame: Week 8

Secondary Outcomes

Reduction From Baseline in MMS at Week 16

Time frame: Week 16

Number of Participants in Clinical Remission Per MMS at Week 8

Number of participants who achieved clinical remission per Modified Mayo Score at Week 8 MMS is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, 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. Clinical remission is defined as SFS ≤ 1, RBS of 0, and endoscopic subscore ≤ 1 (modified to exclude friability)

Time frame: Week 8

Data from ClinicalTrials.gov

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Two capsules of placebo once daily for 16 weeks

UCSD Health System

San Diego, California, United States

Atlanta Center for Gastroenterology, P.C

Decatur, Georgia, United States

Central Texas Clinical Research, LLC

Austin, Texas, United States

Southern Star Research Institute, LLC

San Antonio, Texas, United States

Medizinische Universität Innsbruck

Innsbruck, Austria

Klinikum Klagenfurt am Wörthersee

Klagenfurt, Austria

Ordensklinikum Linz GmbH - Barmherzige Schwestern

Linz, Austria

AKH - Medizinische Universität Wien

Vienna, Austria

Gomel Regional Clinical Hospital

Homyel, Belarus

Minsk city diagnostic center

Minsk, Belarus

...and 120 more locations

Number of Participants in Clinical Remission Per MMS at Week 16

Number of participants who achieved clinical remission per Modified Mayo Score at Week 16 MMS is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, 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. Clinical remission is defined as SFS ≤ 1, RBS of 0, and endoscopic subscore ≤ 1 (modified to exclude friability)

Number of Participants With Clinical Response at Week 8

Clinical response is defined as a reduction in MMS of at least 2 points and greater than or equal to 30 percent from baseline with an accompanying decrease in rectal bleeding sub-score of greater than or equal to 1 point or absolute rectal bleeding sub-score of less than or equal to 1 point.

Time frame: Week 8

Number of Participants With Clinical Response at Week 16

Time frame: Week 16

Number of Participants With Endoscopic Improvement at Week 8

Endoscopic improvement is defined as an endoscopic subscore of 0 or 1 (excluding friability) Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1. = Mild disease (erythema, decreased vascular pattern); 2. = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3. = Severe disease (spontaneous bleeding, ulceration). A higher endoscopic score indicates more severe disease.

Time frame: Week 8

Number of Participants With Endoscopic Improvement at Week 16

Time frame: Week 16

Number of Participants With Mucosal Healing at Week 8

Mucosal healing is defined as endoscopic remission (overall mucosal appearance at endoscopy subscore=0) and histological remission (Geboes score \<2.0 based on rectal biopsy). The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. A higher score is associated with higher disease activity.

Time frame: Week 8

Number of Participants With Mucosal Healing at Week 16

Time frame: Week 16

Number of Participants With Reduction of Stool Frequency Relative to Baseline (Day 1)

Participants recorded stool frequency using an electronic subject diary on a daily basis. The stool frequency subscore (SFS) 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 Decreasing score indicates improvement.

Time frame: Day 8, Day 29, Day 57, Day 85, Day 113, and Day 120 (End of Study)

Number of Participants With Reduction of Rectal Bleeding Frequency Relative to Baseline

Participants recorded rectal bleeding in an electronic subject diary on a daily basis. Rectal bleeding score (RBS) 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.

Time frame: Day 8, Day 29, Day 57, Day 85, Day 113, and Day 120 (End of Study)

Partial Modified Mayo Score Change From Baseline

Partial Modified Mayo Score (pMMS) Change from baseline The pMMS is a composite score of UC disease activity based on the following 2 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools per day) to 3 (5 or more stools per day more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). The overall pMMS score ranges from 0 to 6 with higher scores representing more severe disease.

Time frame: Day 8, Day 29, Day 57, Day 85, Day 113, and Day 120 (End of Study)

Number of Participants With Reduction Relative to Baseline in Fecal Calprotectin at Weeks 8 and 16

Fecal Calprotectin (FC) is a non-invasive surrogate marker of inflammation in the small intestine and levels below 250 ug/g is associated with mucosal healing. FC levels were measured using enzyme-linked immunosorbent assay (ELISA) and/or a validated quantitative rapid test. Outcome will be measured based on a reduction in FC relative to baseline values.

Time frame: Week 8 and Week 16

Number of Participants With Reduction Relative to Baseline in C Reactive Protein at Weeks 8 and 16

CRP is an acute-phase protein which provides an objective criterion of inflammatory activity. CRP has a short half-life (19 hours) and therefore rises early after the onset of inflammation and rapidly decreases after resolution of the inflammation. It is induced by interleukin-6, TNF-alpha and other pro-inflammatory cytokines that are produced within the intestinal lamina propria. Outcome will be measured based on a reduction in CRP relative to baseline values.

Time frame: Week 8 and Week 16

miRNA-124 Expression (Copy Number) in Whole Blood at Week 8 and Week 16

Absolute quantification (QuantaSoft Pro) of the miR-124 copy number was performed at Week 8 and Week 16 using droplet digital PCR technology (ddPCR) on whole blood samples. "0" in the placebo column means "no signal", so BLQ (Below the level of quantification).

Time frame: Week 8 and Week 16

IL-6 Serum Concentrations

Serum samples from participants who received ABX464 (25, 50 or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57, and Day 113). IL6 was measured using the 8-plex assay on the ELLA Platform (Biotechne). All samples were tested in duplicate at the minimum required dilution. Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n) The post baseline values are calculated as follow: post-baseline IL-6 values - Day 1 IL-6 values/Day 1 IL-6 values)\*100

Time frame: Day 1

Number of Participants With Endoscopic Remission at Week 8

Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1. = Mild disease (erythema, decreased vascular pattern); 2. = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3. = Severe disease (spontaneous bleeding, ulceration). A higher score represents more severe disease.

Time frame: Week 8

Number of Participants With Endoscopic Remission at Week 16

Time frame: Week 16

IL-10 Serum Concentrations

Serum samples from patients who received ABX464 (25, 50 or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57, and Day 113). IL10 was measured using the 8-plex assay on the ELLA Platform. All samples were tested in duplicate at the minimum required dilution. Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n) The post baseline values are calculated as follow: post-baseline IL-10 values - Day 1 IL-10 values/Day 1 IL-10 values)\*100

Time frame: Day 1

IL-1B Serum Concentrations

Serum samples from patients who received ABX464 (25, 50, or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57 and Day 113). IL1beta was measured using the 8-plex assay on the ELLA Platform. All samples were tested in duplicate at the minimum required dilution. Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n) The post baseline values are calculated as follow: post-baseline IL-1B values - Day 1 IL-1B values/Day 1 IL-1B values)\*100

Time frame: Day 1

TNFα Serum Concentrations

Serum samples from patients who received ABX464 (25, 50, or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57 and Day 113 TNF-alpha was measured using the 8-plex assay on the ELLA Platform. All samples were tested in duplicate at the minimum required dilution. Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n) The post baseline values are calculated as follow: post-baseline TNFα values - Day 1 TNFα values/Day 1 TNFα values)\*100

Time frame: Day 1

Change From Baseline in Infiltrate/Histopathology Using Robarts Histopathology Index (RHI) at Week 8 and Week 16

Infiltrate/Histopathology (Rectal/Sigmoidal Biopsies) using the Robarts Histopathology Index (RHI) Week 8 and Week 16 biopsies will be compared to biopsies at baseline to assess the disease evolution at a tissue level, based on the Robarts Histological Index. The score ranges from 0 (no disease activity) to 33 (severe disease activity) is based on evaluation of 4 parameters: chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in the epithelium and erosion and ulceration. A higher score indicates more severe disease.

Time frame: Week 8 and Week 16

Change From Baseline in Infiltrate/Histopathology - Geboes Score at Week 8 and Week 16

The Geboes score is composed of 6 major grades that assess different aspects of the biopsy findings, with each grade having its own score range: 1. Structural Changes (Grade 0): Range: 0 (No changes) to 3 (Severe changes) 2. Chronic Inflammation (Grade 1): Range: 0 (No inflammation) to 3 (Severe inflammation) 3. Lamina Propria Neutrophils (Grade 2): Range: 0 (None) to 3 (Severe infiltration of neutrophils) 4. Neutrophils in the Epithelium (Grade 3): Range: 0 (None) to 3 (Severe neutrophil infiltration) 5. Crypt Destruction (Grade 4): Range: 0 (No destruction) to 3 (Severe crypt destruction) 6. Erosion and Ulcers (Grade 5): Range: 0 (None) to 3 (Severe erosion/ulceration) Subscales are summed across all 6 grades, final total score between 0 and 18 : * 0-5: Minimal or no inflammation * 6-10: Mild inflammation * 11-15: Moderate inflammation * 16-18: Severe inflammation or damage A higher score indicates more severe disease

Time frame: Week 8 and Week 16

IL-6 Serum Concentrations

Time frame: Day 8, Day 29, Day 57, and Day 113

IL-10 Serum Concentrations

Time frame: Day 8, Day 29, Week 8 and Week 16

IL-1B Serum Concentrations

Time frame: Day 8, Day 29, Day 57 and Day 113

TNFα Serum Concentrations

Time frame: Day 8, Day 29, Day 57 and Day 113