Study of a Monoclonal Antibody KHK4083 in Moderate Ulcerative Colitis

A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Multiple Ascending Dose Study (Induction Therapy) & Long-term Extension Therapy of an Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects With Moderately Active UC

The purpose of this study is to determine the safety and tolerability of administration of multiple ascending doses of KHK4083 and to select the highest dose tolerated by subjects with moderately active Ulcerative Colitis (UC) followed by a Long-term Extension Therapy (LTE) phase for eligible subjects with a clinical response.

A Phase 2, double-blind clinical study of multiple ascending doses of KHK4083 (or placebo) with an Long-term Extension Therapy (LTE) phase will be conducted in approximately 60 randomized adult subjects with moderately active UC who have a documented unsuccessful previous treatment.

The Treatment Period includes double-blind Induction Therapy (12 weeks) and Open-label Therapy (OLE) phase (40 weeks) for eligible subjects at Week 12. Subjects already enrolled in the double-blind, long-term extension (LTE) under preceding versions of the protocol who worsen may be eligible to transition to the OLE up to Week 28.

The Follow Up Period after the last administration will be for up to 16 weeks.

Inclusion Criteria:

1. Subject is able and willing to comply with study procedures, and to adhere to dosing, visit schedules and follow-up procedures as described in the protocol and ICF;
2. Subject voluntarily signs/dates an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF in accordance with regulatory and Institutional Guidelines;
3. Male and female subjects ≥ 18 years of age at the time of enrollment;
4. Subject has UC that was diagnosed at least 6 months prior to the Screening visit;
5. Subject has moderately active UC with a total Mayo score of 4-9 and an endoscopic sub-score of at least 2, with disease that extends at least 15 cm from the anal verge;
6. Subject has had previous treatment (within 5 years prior to Screening) with one or more of the following: corticosteroids, immunosuppressive medications or TNF antagonist therapy that was unsuccessful because of a lack of efficacy response.
7. Female subjects (WOCBP) must have a negative pregnancy test at Screening and Baseline. WOCBP must agree to use effective contraception;
8. Male subjects (including those who have had a vasectomy) must use adequate contraception during the study and for at least 6 months after the last dose of investigational product.

Exclusion Criteria:

1. Subject, who, for any reason, is judged by the Investigator to be inappropriate for this study;

2. Subject has a medical history of other clinically significant diseases/disorders;

3. Two or more biologic treatments with different mechanisms of action (e.g., infliximab, vedolizumab and golimumab) or Three or more anti-TNF biologics e.g. infliximab, adalimumab

4. Subject requires prescription treatment for UC, except for the stable, oral treatment of UC for 4 weeks prior to screening.

5. Subject has received any of the following prior treatments or treatments within the specified time prior to the Baseline visit:

   • Natalizumab, efalizumab, rituximab or other lymphocyte-depleting treatments, including but not limited, to alkylating agents (such as cyclophosphamide or chlorambucil) and total lymphoid irradiation at any time;
   • TNF antagonists within 8 weeks, or 5 half-lives (up to 12 weeks);
   • Vedolizumab within 16 weeks;
   • Methotrexate, cyclosporine, mycophenolate, tacrolimus, thalidomide, or other immune altering drugs within 4 weeks (ophthalmologic preparations are permitted);
   • 5-ASA enema, steroid enema or suppository use within 2 weeks ; and/or Investigational agents within 8 weeks or 5 half-lives (whichever is longer).

6. Subject with recent, suspected or confirmed symptomatic stenosis of the colon, abdominal abscess, or ischemic colitis based on clinical or radiographic data; a history of toxic megacolon; or who had any previous surgery for UC;

7. Subject with known colonic dysplasia, adenomas or polyposis;

8. Subject had major surgery within 4 weeks prior to Screening or an anticipated requirement for major surgery;

9. Subject with enteric pathogens (including Clostridium difficile);

10. Subject with any of the following hematological and chemistry laboratory values:

    • Platelet count < 100,000/mm3;
    • Neutrophils < 1500/mm3;
    • Serum creatinine ≥ 1.6 mg/dL (≥ 144.4 μmol/L);
    • Alkaline phosphatase > 3 times the upper limit of normal (ULN);
    • AST or ALT > 2 times ULN;
    • Total bilirubin > 2 mg/dL, unless due to Gilbert's Syndrome;
    • Serum albumin < 3 g/dL;
    • Hemoglobin < 9 g/dL;
    • Glycated serum hemoglobin A1c ≥ 9%.

11. Subject has clinically significant cardiac disease;

12. Subject is pregnant or breastfeeding;

13. Subject has had major immunologic reaction;

14. Subject is Hepatitis B core antibody or surface antigen positive and/or Hepatitis C antibody positive with detectable RNA;

15. Subject has a history of human immunodeficiency virus (HIV) positivity, tests positive for HIV, or has congenital or acquired immunodeficiency;

16. Subject has or has had active TB, suspected extra-pulmonary TB, a history of incompletely treated TB, or latent TB or other latent infection. Subjects with latent TB (clinical findings, purified protein derivative [PPD] or interferon gamma release assay [IGRA]) may be included in the study if prophylactic therapy for latent TB is started at least 4 weeks prior to Screening. Subjects with a potentially untreated other infection (clinical findings) are to be excluded.

17. Subject has bacterial infections requiring treatment with oral or parenteral antibiotics, within 2 and 4 weeks, respectively.

18. Subject has a history of systemic opportunistic infection or recurrent infections

19. Subject has malignancy or history of malignancy, except for adequately treated basal cell skin cancer or adequately treated carcinoma in-situ of the cervix without recurrence at least 5 years.

20. Subject who received a bacille Calmette-Guérin (BCG) vaccine within 6 months of randomization or live vaccination (e.g., measles, mumps, rubella [MMR]; herpes zoster; varicella, intranasal influenza; and oral poliomyelitis) within 4 weeks of randomization.

21. Subject with a history of or active substance abuse.

22. Subject has other severe acute or chronic medical or psychiatric condition or laboratory abnormality.