A Dose Escalation Study of IG3018 in Subjects With Hyperuricemia With or Without Chronic Kidney Disease

The study has two parts:

Part 1 is a randomized, double-blind, placebo-controlled, dose escalation study in hyperuricemia subjects without CKD. Initiation Dose shall be at 0.25 g tablets (Cohort A) and doses are escalated to 0.5 g (Cohort B) and then to 1.0 g (Cohort C) in a planned manner.

Part 2 is an open-label, proof of concept study involving hyperuricemia subjects with advanced predialysis CKD (Stage 3a, Stage 3b and Stage 4), and treated with two doses [0.5 g BID IG3018 (Cohort D) and 1.0 g BID IG3018 (Cohort E)].

Inclusion criteria

For Part 1 and Part 2:

Subjects must meet all the following criteria to be included in the study:

• Male or female, aged 18 to 75 years (both inclusive).
• According to the investigator's judgment, eGFR must be met as:

Part 1 only: subjects without CKD and have eGFR ≥ 60 mL/minute/1.73 m2 at screening phase; Part 2 only: subjects with advanced predialysis CKD (Stage 3a, 3b and Stage 4) have eGFR≥15 and <60 mL/minute/1.73 m2 at screening phase.

• The serum uric acid level for subjects need to meet any of the following:

For subjects already on ULT within 2 weeks prior to the screening visit, the serum uric acid would be measured during the screening visit/phase, and then at the end of the run-in phase, prior to confirming their eligibility. Subjects with ULT within 2 weeks before screening has fasting serum uric acid ≥ 0.48 mmol/L at the end of run-in phase.

For subjects without ULT in 2 weeks prior to screening visit，the serum uric acid should be measured twice on 2 different days (at least 24 hours apart) prior to confirming their eligibility. Subjects without ULT within 2 weeks before screening has fasting serum uric acid ≥ 0.48 mmol/L at screening phase.

• Body Mass Index (BMI) ≥ 18 and ≤ 35 kg/m2 (both inclusive) at screening.
• Female subjects of child-bearing potential [defined as women who have experienced menarche but have not reached postmenopausal status (defined as at least 12 consecutive months of amenorrhea without any other identifiable cause other than menopause), and who have not undergone surgery (i.e., bilateral oophorectomy and/or bilateral salpingectomy and/or hysterectomy) or have no other cause of permanent infertility as determined by the investigator (e.g., Müllerian agenesis).] must agree to use highly effective contraceptive methods and must abstain from egg collection or donation from the screening phase to 90 days after the last dose of the IMP. And the male partner of a female subject also needs to agree to use highly effective method of birth control during this phase.
• Male subjects considered fertile must agree to not donate sperm, and take effective contraceptive methods from the screening phase to 90 days after the last dose of the IMP. And the female partner of male subjects also needs to agree to use a highly effective method of female contraception during this phase.
• Able to understand and give signed written informed consent form (ICF) and willing to comply with all study procedures.

Only for Part 2

• For subjects with anemia who require iron supplementation, steady iron or iron-containing drugs should be used for at least 3 months, and the original treatment regimen should be maintained during the study period.

Exclusion criteria

For Part 1 and Part 2:

Subjects who meet any of the following criteria will be excluded from the study:

• Prior uricase/recombinant uricase (such as Rasburicase or Pegloticase) therapy within 2 weeks prior to screening or last dose of therapy< 5 times the half-life (whichever is longer).
• Subjects who have acute gout flares requiring treatment within 4 weeks prior to or during screening.
• Major surgery within 3 months prior to the first administration.
• History of malignant tumors within 6 months prior to screening.
• Subjects within the last 3 months have: myocardial infarction, angina, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, or transient ischemia attack.
• Subjects who are on other urate-lowering medication (allopurinol, febuxostat, probenecid and benzbromarone) and cannot stop during the study periods included in the run-in phase.
• Subject with underlying medical conditions requiring changes or introduction of drugs that have the potential impact on the serum uric acid levels (e.g., salicylic acids, diuretics, angiotensin receptor blockers, etc.) within at least 1 month prior the screening phase.
• History of gastrointestinal (GI) surgery, including gastric sleeve, colostomy/enterostomy, Roux-en-Y or gastric banding (unless gastric band removed for a minimum of 12 months prior to screening.
• History of GI diseases, including gastrointestinal bleeding moderate to severe gastrointestinal dysfunction, moderate to severe chronic constipation for a minimum of 3 months prior to screening, or newly diagnosed peptic or duodenal ulcer diseases within 4 weeks prior to screening.
• Chronic use of parenteral nutrition including manganese within 3 months prior to screening.
• Subjects who have the history of manganese toxicity or excessive exposure to manganese (i.e., having worked in a mine, foundry, smelter, dry cell battery manufacturing facility) within 2 months prior to screening.
• Inability to swallow oral medications.
• Received treatment with or exposure to an investigational drug or device within 30 days of signing informed consent.
• Subjects with one of positive results of HIV virus or syphilis, or positive hepatitis B virus surface antigen (HBsAg) and the number of copies of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) ≥ 500 IU/mL (or 2500 copies, or the lower limit of the positive detection value of the study site) at screening, or HBsAg (-), hepatitis B core antibody (HBcAb) (+) and the number of copies of HBV DNA ≥ 500 IU/mL (or 2500 copies, or the lower limit of the positive detection value of the study site) after treatment of HBV infection, or positive hepatitis C antibody (HCV-Ab), and hepatitis C virus (HCV) ribonucleic acid (RNA) ≥upper limit of normal (ULN) of the study site during screening phase.
• History of alcohol abuse, or subjects who consumed alcohol within 48 h before the first administration or did not agree to stop using alcohol products during the study.
• Subjects who have previously been diagnosed with the following diseases and have not been able to control them after medication therapy or other treatment. Uncontrolled is defined as hypertension: sSBP ≥ 180 mmHg and/or sDBP ≥ 110 mmHg; or Diabetes mellitus: HbA1c ≥ 9% at screening.
• Subjects with secondary hyperuricemia caused by tumor, hematological system diseases, drugs, etc. except for chronic kidney disease; or hereditary hyperuricemia at screening.
• Subjects undergone kidney transplantation or planning to undergo kidney transplantation at screening.
• Subjects with abnormal biliary function, biliary obstruction, or biliary gallstone at screening; Subjects with alanine aminotransferase (ALT) ≥3 ULN, aspartate aminotransferase (AST)≥3 ULN, or total bilirubin (TBIL) ≥1.5 ULN at screening.
• Prior or current cholestatic liver disease defined as a clinical condition associated with decrease in bile flow due to impaired secretion by hepatocytes or to obstruction of bile flow through intra-or extrahepatic bile ducts.
• History of serious hypersensitivity reaction to a known ingredient of IG3018 tablet judged by the investigator.
• Subjects who are considered unsuitable for participating in the study in the opinion of the investigator judgment.