Oral OKT3 for the Treatment of Active Ulcerative Colitis

Ulcerative colitis (UC) is a chronic disease of unknown etiology characterized by infiltration of inflammatory cells into the intestinal tract. OKT3 is an approved drug for intravenous use in the treatment of solid-organ transplantation. However, intravenous dosing has been limited by significant toxicities. Data from animal models suggest that antibody recognizing the T3 antigen complex Cluster of Differentiation 3 (anti-CD3) administered via the oral route is effective at treating a variety of autoimmune diseases. No side effects were observed in a recent phase I study of healthy participants receiving oral anti-CD3 monoclonal antibody (mAb).

The objectives of the current study are to assess the safety, immunologic effects and efficacy of short-term oral administration of OKT3 in participants with active ulcerative colitis. OKT3 will be delivered orally as a 1 milligram (mg) or 2 mg dose with Omeprazole 20 mg daily for 30 consecutive days in an open-label pilot trial. Thirty two participants will be screened for a targeted completion of 16 enrolled participants. The participants will be evaluated at baseline, day 1, day 2, week 1, week 3, as well as after completion of therapy at week 5 and 10 after the initiation of treatment. Lab tests will be performed at screening, baseline, day 2, week 1, week 3, week 5 and week 10. Clinical data will be collected at all study visits and via diary entries throughout the study period. A flexible sigmoidoscopy will be done at baseline and at week 5. Stool studies will be performed at screening to rule out infection.

To be eligible for this study, participants must be between the ages of 18 and 65 years and have a history of moderately to severely active UC as defined by a Mayo score of 6 to 12. They may not be taking concurrent biologic or immunomodulator therapy for UC.

1.1 Inclusion Criteria

• Ability to provide informed consent
• Age between 18 and 65 years
• Confirmed diagnosis of UC for at least 3 months with the extent defined within the previous year
• Moderate to severe UC as defined by a Mayo score of 6-12
• Concomitant medications: Can be on 5-amino salicylate (5-ASA) medications and stable doses (same dose > 4 weeks) of oral steroids
• Concomitant medications cannot include Infliximab, Adalimumab, Certolizumab or Natalizumab for 4 weeks; rectal steroids, 6-mercaptopurine (6-MP), Azathioprine, Tacrolimus, Methotrexate, Thalidomide, Cellcept for 4 weeks; Theophylline, sulfonylureas, non-steroidal anti-inflammatory drug (NSAIDs) or aspirin for 10 days
• Negative serum pregnancy test within 2 weeks prior to receiving the first dose of study drug in female participants of child-bearing potential
• Female participants of child-bearing potential must be willing to use birth control during the study and for 4 weeks following the last dose of study drug.

1.2 Exclusion Criteria

• Crohn's disease or indeterminate colitis
• Mayo score of <6 (mild UC)
• Hospitalized or exhibiting signs of toxicity (abdominal distension, severe abdominal tenderness, fever, nausea, vomiting, or tachycardia)
• A history of colorectal cancer or colorectal dysplasia
• Pregnant or breastfeeding females or females wishing to become pregnant within the next 6 months or unwilling to use birth control
• Serum creatinine ≥ 2.0 milligrams per deciliter (mg/dL)
• Alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), or direct bilirubin >1.5x normal: elevated indirect bilirubin related to likely Gilbert's disease permissible
• Use of any of the following medications: Azathioprine, 6-MP, Methotrexate, Mycophenolate Mofetil, Tacrolimus, Cyclosporine, Thalidomide, Adalimumab, Infliximab, Certolizumab, Natalizumab, rectal steroids. Theophylline, sulfonylureas, NSAIDs or aspirin within 10 days of study enrollment
• Psychiatric illness or substance abuse that would interfere with ability to comply with protocol requirements or give informed consent
• Surgery within the last 3 months
• Prior gastrointestinal surgery
• Clinically significant infectious, immune mediated or malignant disease
• Receiving an elemental diet or parenteral nutrition
• History of coagulopathy
• Human immunodeficiency virus (HIV) positive
• Hepatitis B surface antigen (HBsAg) positive
• Active cytomegalovirus (CMV)
• Anemia: hemoglobin (Hb) < 8 grams/deciliter (g/dL). If the subject has known significant cardiac disease, subjects with Hb < 10.5 g/dL will be excluded.
• Thrombocytopenia (platelets < 100,000 per microliter [100K/mcL])
• Lymphopenia (absolute lymphocyte count <0.7)
• Immunoglobulin G (IgG) anti-cardiolipin antibody positive >16 International Units (IU)
• Prior exposure to OKT3
• Positive quantiferon gold, tuberculosis (TB) spot test, or purified protein derivative (PPD) test
• Known sensitivity to any ingredients in the study drug
• Anti-mouse antibody titer >1:1000
• Any known autoimmune disease except for ulcerative colitis
• Allergy or hypersensitivity to Omeprazole
• Participated in another clinical trial within 30 days of screening for this trial