Efficacy and Safety of Etrasimod (APD334) in Inflammatory Bowel Disease Patients With Active Skin Extra-intestinal Manifestations

A Phase 2a, Proof of Concept, Open-label Study Evaluating the Efficacy and Safety of Etrasimod (APD334) in Inflammatory Bowel Disease Patients With Active Skin Extra-intestinal Manifestations

The purpose of this phase 2a, proof of concept, open-label clinical study is to evaluate the efficacy and safety of etrasimod (APD334) in inflammatory bowel disease patients with active skin extra-intestinal manifestations.

Inclusion Criteria:

1. Male or female (18-80 years).

2. Able to provide a signed informed consent prior to any study related procedure being conducted.

3. Considered to be in stable health in the opinion of the investigator as determined by:

   1. A pre-study physical examination with no clinically significant abnormalities unrelated to IBD.
   2. Vital signs at screening: pulse rate ≥ 55 bpm, systolic blood pressure ≥ 90, and diastolic blood pressure ≥ 55 mmHg.
   3. Liver function tests (ALT/AST, bilirubin and alkaline phosphatase) < 2x the upper limit of normal.
   4. All other pre-study clinical laboratory findings within normal range, or if outside of the normal range are not deemed clinically significant in the opinion of the investigator.
   5. 12-lead electrocardiogram showing no clinically significant abnormalities in the opinion of the investigator (for confirmation please refer to exclusion criterion # 22).
   6. A chest x- ray showing no evidence of active pulmonary disease (a chest x-ray taken within the previous 12 months from the screening visit may also be used).
   7. Ophthalmology evaluation (by an ophthalmologist) without evidence of macular edema, supported with optical coherence tomography where available (dependent on site capability) no later than 3 months prior to screening.

4. Patients receiving stable treatment for IBD and EIM.

5. Diagnosis of active psoriasis, erythema nodosum or pyoderma gangrenosum by Investigator assessments. After the enrollment of 10 patients with active EIM, patients with active psoriasis due to anti TNF-alpha therapy can also be included.

6. Diagnosis of ulcerative colitis or Crohn's disease established prior to screening by clinical and endoscopic evidence.

7. Eligible male and female patients must agree not to participate in a conception process (i.e. active attempt to let female partner to become pregnant or to impregnate, sperm donation, oocyte donation, in vitro fertilization) for at least 30 days after the last dose of study drug.

Non-sterile patients who are sexually active must take adequate contraception measures.

Exclusion Criteria:

1. Evidence of abdominal abscess or toxic megacolon at the screening visit.

2. Patients with history of extensive colitis or pancolitis (duration > 8 years) or left-sided colitis (duration > 12 years) must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial screening visit (if not, the patient should undergo a colonoscopy in lieu of a flexible proctosigmoidoscopy during screening).

3. Previous extensive colonic resection (subtotal or total colectomy).

4. Current evidence of adenomatous colonic polyps that have not been removed.

5. Current evidence of colonic mucosal dysplasia.

6. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine or stoma.

7. Clinical significant infection as judged by the investigator in the previous 6 weeks before enrollment.

8. Evidence of or treatment for C. difficile infection within 60 days, or other intestinal pathogen within 30 days, prior to randomization.

9. Exposure to natalizumab or rituximab within 5 half-lives prior to randomization.

10. Treatment of underlying disease within 30 days prior to randomization (5-ASA, corticosteroids, TNF-alpha inhibitors, probiotics, antidiarrheals, azathioprine and 6-mercaptopurine may be allowed under certain conditions).

11. Receipt of any investigational agent within 30 days or 5 half-lives (whichever is longer) prior to randomization.

12. Currently require or are anticipated to require surgical intervention for IBD during the study.

13. Abnormal (< 80% of predicted values) forced expiratory volume (FEV1) or forced vital capacity (FVC).

14. Infection with hepatitis C virus anytime in the past; confirmed active infection with hepatitis B virus at screening.

15. Active or latent tuberculosis (TB), regardless of treatment history, as evidenced by any of the following:

    1. History of TB
    2. A positive diagnostic TB test within one month of randomization
    3. Chest X-ray within 12 months of randomization in which active or latent TB cannot be excluded.

16. Any known history of congenital or acquired immunodeficiency.

17. Clinically significant extra-intestinal infection (e.g., pneumonia, pyelonephritis) within 30 days prior to randomization.

18. Recent history (within 6 months of screening visit) of cardio- or cerebrovascular disease, acute coronary syndrome, myocardial infarction, unstable angina, cerebro-vascular accident, including transient ischemic attack.

19. Any surgical procedure requiring general anesthesia within 30 days prior to randomization or plans to undergo major surgery during the study period.

20. History of retinal macular edema.

21. History of or signs and symptoms of progressive multifocal leukoencephalopathy (PML) as assessed by the PML checklist.

22. History or presence of cardiac arrhythmia, conduction system disease, or use of Class Ia or Class III anti arrhythmic agents, or baseline QTc ≥ 500 msec.

23. Infection requiring hospitalization or intravenous antimicrobial therapy, or opportunistic infection within 4 weeks of screening.

24. History of more than one episode of herpes zoster or any episode of disseminated zoster.

25. Without documented positive varicella zoster virus (VZV) IgG antibody status or who have completed VZV vaccination within 30 days prior to randomization.

26. Receipt of live vaccine within 4 weeks prior to screening.

27. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma.

28. History of malignancy except for adequately treated basal cell skin cancer.

29. History of severe allergic or anaphylactic reactions requiring medical attention.

30. Current or recent history (within one year prior to randomization) of alcohol dependence or illicit drug use.

31. History of clinically significant leukopenia or lymphopenia at screening.

32. Active psychiatric problems that, in the investigator's opinion, may interfere with compliance with the study procedures.

33. History of any clinically significant medical condition that, in the investigator's opinion, would preclude participation in the study.

34. Use of moderate to strong inhibitors of CYP2C9.

35. History of severe renal or hepatic impairment.

36. Inability to attend all the study visits or comply with study procedures.

37. Prior exposure to etrasimod (APD334).