A Phase 2a Study to Evaluate the Safety, Tolerability, Pharmacodynamics and Efficacy of AG011 in Ulcerative Colitis

The purpose of this study is to verify the safety and tolerability of AG011 and to determine whether AG011 can successfully treat the symptoms of Ulcerative Colitis (UC). Three different dosages will be used in reference to a placebo.

AG011 is an experimental medication. It has been developed as potential treatment for moderately active UC.

AG011 is the clinical formulation of a genetically modified L. lactis that has been engineered to secrete human Interleukin-10 (hIL-10). By delivering hIL-10 locally at inflamed tissue in the intestine, it is believed that, compared to hIL-10 given by injection, the effectiveness may be increased, with fewer adverse effects.

Study medication will be provided in capsule and enema (topical rectal application) forms by ActoGeniX NV.

Subjects will be entered sequentially into one of three dose groups, starting from the lowest dose group. Within each of the first two dose groups, 15 subjects will be entered. Within the highest dose group, 30 subjects will be entered. Within each dose group, subjects will be randomly assigned in a 2:1 ratio to receive either AG011 or placebo for 28 days.

Timely monitoring of safety data is planned for the study, such that subject enrollment can continue without interruption for the purpose of data collection between dose groups. Safety and tolerability will be closely monitored by the Clinical Safety Specialist (CSS) assigned to the study. The CSS will review adverse events and laboratory safety data and report any safety concerns to the Sponsor and a Data Safety Monitoring Committee (DSMC).

At least 8 subjects must have safely completed study treatment for 28 days at a specific dose level, prior to escalation to the next dose group. The DSMC will convene to assess safety data when 8 subjects have completed study treatment for 28 days at the specific dose level. The role of the DSMC for the study will be complete when all subjects in the study have completed study treatment.

For those patients randomized within the active group, UC symptoms could improve. As a result of the information gathered by this study, the knowledge and understanding of UC could improve.

Inclusion criteria

• Male or non-pregnant, non-lactating females, 18 years of age or older. Females of child bearing potential must have negative serum or urine pregnancy tests at the screening visit and throughout the study, and must use a hormonal (oral, implantable or injectable) or barrier method of birth control throughout the study. Females unable to bear children must have documentation of such in the case report form (i.e. tubal ligation, hysterectomy, or post menopausal [defined as a minimum of one year since the last menstrual period]).
• Documented diagnosis of UC with a minimum disease extent of 15 cm from the anal verge.
• Presence of friability on endoscopy, with minimum of Grade 2 (modified Baron score) changes at approximately 15 cm or more from the anal verge.
• Minimum Mayo Clinic Disease Activity Score of 5, with a score of at least 1 on both the stool frequency and rectal bleeding components.
• Receiving 5-ASA treatment for at least two months and a stable dose of oral 5 ASA for at least two weeks prior to randomization. Concurrent treatment with prednisone, or equivalent glucocorticoid ≤ 20 mg/day is acceptable as follows: minimum dosing of 4 weeks prior to screening AND stable dose for 2 weeks prior to screening AND expected to remain on a constant dose during the trial. Use of 5-ASA compounds is not required for those subjects who have failed treatment with 5-ASA compounds, or are allergic or intolerant.
• Hepatic function (AST, ALT, total bilirubin, alkaline phosphatase, LDH) ≤ 2 times the upper limit of the normal range.
• Adequate renal function, as evidenced by serum creatinine ≤ 1.5 times the upper limit of the normal range.
• Hemoglobin ≥ 10 g/dL.
• ANC ≥ 1.5 x 10E9/L (1,500 mm3).
• Lymphocyte count ≥ 0.1 x 10E3/μL.
• Platelet count ≥ 100 x 10E9/L (100,000/mm3).
• Ability of subject to participate fully in all aspects of this clinical trial.
• Written informed consent must be obtained and documented.

Exclusion criteria

• Exhibiting severe ulcerative colitis as defined by the following criteria: ≥ 6 bloody stools daily with one or more of the following: oral temperature > 37.8 °C or > 100.0 °F, pulse > 90/min, hemoglobin < 10 g/dL.
• Crohn's disease.
• History of colectomy or partial colectomy.
• Clostridium (C.) difficile positive at screening visit or treated for C. difficile within the 4 weeks prior to randomization
• Treatment with antibiotics or probiotics at screening
• Treatment with cyclosporine, methotrexate, azathioprine, 6-MP, infliximab, adalimumab or other immunosuppressants/biologics within 4 weeks prior to randomization
• Use of rectal steroids or 5-ASA enemas within 2 weeks prior to randomization.
• Clinically significant active infection.
• Known chronic liver disease.
• Serious underlying disease other than UC in the opinion of the investigator.
• Alcohol or illicit drug consumption, which in the opinion of the investigator, may interfere with the subject's ability to comply with the study procedures
• Active psychiatric problems, which in the opinion of the investigator, may interfere with the subject's ability to comply with the study procedures.
• History of malignancy other than basal or squamous cell cancer of the skin that has been removed, or carcinoma in situ of the cervix that has been adequately treated.
• History of dysplasia in colonic biopsies.
• Receiving any investigational therapy or any approved therapy for investigational use within 30 days or 5 half-lives prior to randomization (whichever is longer).
• Pregnant or lactating women.
• Prior enrollment in the current study and had received study treatment.