A Phase III Trial of HMPL-004 in Patients With Mild to Moderate Active Ulcerative Colitis

A placebo controlled study of two doses of HMPL-004 in patients with active mild to moderate ulcerative colitis (UC), with a modified Mayo Score 4-10 and an endoscopy subscore of 2-3, taking mesalamine (or equivalent) as a concomitant medication.

The objective is to evaluate the efficacy and safety of HMPL-004 with mesalamine (mesalamine treatment failures). Efficacy will be measured by a comparison of the proportion of patients in each treatment group attaining clinical remission at Week 8 as compared to placebo.

This Phase III study of HMPL-004 was to enroll approximately 420 subjects with active mild to moderate ulcerative colitis (UC; modified Mayo Score 4-10 and endoscopy score of 2-3). The trial included male and female subjects aged 18 or older. Subjects were currently receiving ≥2.4 g/day mesalamine or equivalent, provided they had taken 5-aminosalicylate (ASA; i.e., mesalamine) at a dose ≥2.4 g/day for at least 6 weeks prior to randomization and were on a stable dosage for at least 2 weeks prior to entering the screening phase of the study.

Qualifying subjects who entered into this study received 3 daily doses of oral HMPL 004 tablets or placebo for 56 days (8 weeks). There were 3 arms in this study consisting of placebo, HMPL-004 600 mg three times a day (TID) or 800 mg TID. Approximately 420 subjects were to be randomized 1:1:1 to one of these 3 arms, stratified by country/region in up to 150 clinical centers in North America, Europe, and Asia.

Eligibility Criteria:
Inclusion Criteria:

* Patients must be currently receiving mesalamine ≥ 2.4 g/day (or the equivalent) for at least 6 weeks prior to randomization and on a stable dosage for at least 2 weeks prior to entering the screening phase of the study to ensure a stable dose is established at least 2 weeks prior to the endoscopic procedures.
* Have active mild to moderate ulcerative colitis defined by a modified Mayo Score 4-10, and with endoscopy score activity of 2-3 points confirmed by centrally read colonoscopy (within 2 weeks prior to randomization.
* Minimum modified Mayo endoscopy score of \>2 at the time of study colonoscopy.
* Age ≥ 18 years.
* Patients have no prior exposure to HMPL-004.
* Have adequate renal, hepatic and bone marrow function (see exclusion criteria).
* All fertile male and female subjects must agree to use one of the following types of contraception: abstinence, intrauterine device, implantable progesterone device, and progesterone intramuscular injection, oral contraceptive which has been started at least one month prior to visit one and continues for the duration of the trial, contraceptive patch, or condom with spermicide.
* Show evidence of a personally signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial

Exclusion Criteria:

1. Subjects with intolerance or adverse reactions to mesalamine (or equivalent medications).
2. Diagnosed with Crohn's Disease or with lesions such as fistulas or granulomas on biopsy noted either in history or at baseline endoscope, which would be suspicious for Crohn's disease, or with a diagnosis of indeterminate colitis. Subjects with Primary Sclerosing Cholangitis (PSC) are excluded..
3. Severe disease with an ulcerative colitis modified Mayo Clinic score above 10 points at baseline.
4. Positive stool test for pathogens for sample taken within the previous 2 weeks prior to study entry.
5. Active Clostridium difficile (C. diff) infection.
6. Use of Inflammatory Bowel Disease related herbal supplements including but not limited to supplements containing andrographis and probiotics two weeks prior to study entry or during the study.
7. Toxic megacolon or toxic colitis.
8. Probable requirement for intestinal surgery within 12 weeks after the start of study medication.
9. Receiving oral or rectal steroids within 1 month prior to study entry.
10. Receiving rectal mesalamine within one week prior to study entry.
11. Receiving azathioprine, 6-mercaptopurine, methotrexate, tacrolimus, cyclosporine, or other immunosuppressive therapy at the time of screening or within the preceding 6 weeks.
12. Receiving anti-tumor necrosis factor-α agents such as infliximab, adalimumab, golimumab, or certolizumab pegol at the time of screening or within the preceding 8 weeks.
13. Receiving other investigational drugs or biologics within 1 month or five half lives.
14. Receiving antibiotics within 2 weeks of study entry.
15. Hemoglobin concentration \< 9 g/dl.
16. White blood cell count (WBC) below 3,000/cmm, or platelets below 100,000/cmm.
17. Serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase \>2.5 upper limit of normal.
18. Serum creatinine \>1.5 times upper limit of normal.
19. Significant concurrent medical diseases including: active peptic ulcer disease; uncompensated congestive heart disease; myocardial infarction within the last 12 months; unstable angina pectoris; uncontrolled hypertension; pulmonary disease requiring oxygen therapy.
20. Chronic Hepatitis B or any history of Hepatitis C.
21. Previous colonic surgery except for simple polypectomy or appendectomy. .
22. History of cancer within the last 5 years other than resected cutaneous basal and squamous cell carcinomas, and in situ cervical cancer.
23. Patients with a history of or concurrent colonic dysplasia associated with UC, except those with completely excised sporadic colorectal polyps.
24. Women who are pregnant or breast feeding.
25. Patients known to be seropositive for HIV, or who have had an AIDS defining illness, or a known immunodeficiency disorder.
26. Patients with a history of tuberculosis or exposure to tuberculosis, or a history of a chest X-ray suspicious for tuberculosis, unless confirmed to be purified protein derivative (PPD) skin test negative or latent tuberculosis that has been previously treated.
27. History of alcohol or drug abuse that would interfere with the ability to be compliant with the study procedure.
28. Known allergy to plants of the Acanthaceae family.
29. Unwillingness to participate in the study.
30. Any underlying medical condition that in the Investigator's opinion will make the administration of study drug hazardous to the patient or would obscure the interpretation of adverse events.