Safety, Efficacy, and Tolerability Study of PF-06480605 in Subjects With Moderate to Severe Ulcerative Colitis.

A PHASE 2A, MULTICENTER, SINGLE ARM, OPEN- LABEL, TWO-STAGE, STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF-06480605 IN SUBJECTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS

The purpose of this study is to evaluate the safety, tolerability, and efficacy of PF-06480605 in subjects with moderate to severe ulcerative colitis.

This is a Phase 2a, single arm, two-stage study in subjects with moderate to severe ulcerative colitis. Subjects will receive 500 mg of PF-06480605 intravenously every 2 weeks for a total of 7 doses. Blood, stool, and tissue samples will be collected at various time points throughout the study to evaluate safety, tolerability, efficacy, pharmacokinetics, and immunogenicity. Duration of participation for subjects will be approximately 8 months.

Inclusion Criteria:

• Male or female subjects between ≥ 18 and ≤ 75 years of age at the time of informed consent
• Male subjects able to father children and female subjects of childbearing potential must agree to use two highly effective methods of contraception throughout the study and until the Week 26 visit
• Diagnosis of ulcerative colitis for ≥ 4 months
• Subjects with moderate to severe active ulcerative colitis as defined by screening colonoscopy with total Mayo score of ≥ 6, with rectal bleeding subscore of ≥ 1, and an endoscopic subscore of ≥ 2 on the Mayo
• Active disease beyond the rectum (> 15 cm of active disease at the screening colonoscopy)
• Must have inadequate response to, loss of response to, or intolerance to at least one conventional therapy for ulcerative colitis such as: Steroids; Immunosuppressants (AZA, 6-MP, or MTX); Anti -TNF inhibitors (eg, infliximab, adalimumab, or golimumab); Anti-integrin inhibitors (eg, vedolizumab).
• Subjects currently receiving the following treatment are eligible provided they have been on stable doses of Oral 5-ASA or sulfasalazine for at least 4 weeks prior to baseline; oral corticosteroids stable dose for at least 2 weeks prior to baseline; 6-MP or AZA stable dose for 8 weeks prior to baseline.

Exclusion Criteria:

• Diagnosis of indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, microscopic colitis or Crohn's Disease. Subjects with clinical findings suggestive of Crohn's disease (eg, fistulae, granulomas on biopsy) are also excluded.

• Subjects with colonic dysplasia or neoplasia, toxic megacolon, primary sclerosing cholangitis, known colonic stricture, history of colonic or small bowel stoma, history of colonic or small bowel obstruction or resection

• Presence of active enteric infections (positive stool culture and sensitivity)

• Known history of HIV based on documented history with positive serological test, or positive HIV serologic test at screening

• Presence of a transplanted organ

• Cancer or history of cancer or lymphoproliferative disease within the previous 5 years (other than resected cutaneous basal cell or squamous cell carcinoma that has been treated with no evidence of recurrence);

• Acute coronary syndrome (eg., myocardial infarction, unstable angina pectoris);

• Any history of cerebrovascular disease within 24 weeks before screening;

• Subject with current or a history of QT prolongation

• Class III or Class IV heart failure

• Prior evidence of liver injury or toxicity due to methotrexate

• Abnormality in hematology and/or chemistry profiles during screening (as detailed in the protocol)

• Subjects receiving the following therapies within the designated time period:

  • > 9 mg/day of oral budesonide or >20 mg/day prednisone or equivalent within 2 weeks prior to baseline
  • IV, IM (parenteral), or topical (rectal) treatment of 5-ASA or corticosteroid enemas/suppositories within 2 weeks prior to baseline
  • Biologics including anti-TNF inhibitors as described: Infliximab, Adalimumab, or Golimumab within 8 weeks prior to baseline
  • Anti-integrin inhibitors (eg, vedolizumab) within 12 weeks prior to baseline
  • Other investigational procedures or products, or live attenuated vaccine within 30 days prior to baseline.

• Current or history (within 2 years) of serious psychiatric disease or alcohol or drug abuse