A Phase 2B Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Namodenoson in the Treatment of Non-Alcoholic Steatohepatitis (NASH)

Prior treatment

• Concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active malignancy.
• Women of childbearing potential, unless they agree to use a "highly effective" contraceptive measure as described in Section 12.3, i.e., a method that has <1% risk of pregnancy, while on study and until 1 month after the last dose of study medication.
• Seropositivity for markers of viral hepatitis or human immunodeficiency virus (HIV) at Screening. (Notes: If anti-hepatitis C virus (HCV) antibody is positive, a negative HCV ribonucleic acid (RNA) test is required for entry. Any prior treatment for HCV must have been completed at least 2 years prior to the qualifying liver biopsy.)
• Men who partner with a woman of childbearing potential, unless they agree to use condoms for contraception from Screening until 3 months after the final dose of study medication.
• Treatment with therapeutic doses of Vitamin E (≥800-1000 IU daily), or any of the following anti-diabetic medications: GLP-1 receptor agonists (such as Januvia [sitagliptin], Byetta [incretin], etc.),pioglitazone, or SGLT2 inhibitors (“gliflozin” drugs); unless the dose and regimen has been stable for at least 3 months prior to Screening.
• Active rheumatoid arthritis treated with small-molecule (including methotrexate) or biologic disease-modifying anti-rheumatic agent concurrently or within 1 year prior to Screening
• Use of any immunosuppressive medication, anti-inflammatory monoclonal antibody treatment, or chronic systemic corticosteroids >10 mg prednisone-equivalent concurrently or within 1 year prior to Screening.
• More than 7 days of treatment with valproic acid, tamoxifen, amiodarone, or anti-cholinergic agents within 3 months prior to Screening.
• Use of any investigational agent within the longer of either 4 weeks or 5 half-lives prior to the Baseline Visit.
• Weight loss of >5% within 3 months prior to Baseline.
• Ongoing or planned use of a concomitant medication that is on the CredibleMedsTM list of drugs known to cause Torsades des Pointes (https://crediblemeds.org/healthcare-providers; Appendix 1).
• Concomitant use of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) inhibitors and/or substrates with a narrow therapeutic index unless the medication can be taken at least 3 hours before or after taking the investigational product (see Section 12.2).
• Use of any herbal supplements, homeopathic medications, or other alternative treatments in the past 3 months prior to enrollment.

Other illness

• Compensated cirrhosis, decompensated cirrhosis (i.e., history of ascites, hepatic encephalopathy, esophageal varices), or recompensated cirrhosis.
• Uncontrolled or clinically unstable thyroid disease, in the judgment of the Principal Investigator.
• History of malignancy in the past 3 years prior to Screening, even if the malignancy is in remission or cured, except subjects with non-invasive squamous cell or basal cell carcinomas of the skin.
• Daily alcohol intake >10 g (1 units=1 standard drink)/day (on average), as per Alcohol Use Disorders Identification Test (AUDIT) questionnaire at Screening or Baseline.
• Resting heart rate >100 bpm or systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg at Screening (up to 3 readings at least 5 minutes apart may be averaged for all parameters).
• Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), or other heart disease which is, in the Investigator’s judgment, clinically unstable.
• Any history of angina, myocardial infarction, cerebrovascular accident or hemorrhage, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism.
• Other active acute or chronic liver disease, such as autoimmune hepatitis, alcoholic liver disease, hepatocellular carcinoma, or viral hepatitis, including seropositivity for hepatitis B core antibody or hepatitis B surface antigen.
• History of chronic or unexplained hyponatremia
• Active gastrointestinal disease which could interfere with the absorption of oral medication.
• History of bariatric surgery within 5 years of Screening.
• Diabetes mellitus other than Type II.

Lab values

• QTcF interval on Screening Visit ECGs (average of triplicate) or Baseline Visit ECGs (average of triplicate) > 450 milliseconds. If a subject has a right or left bundle branch block at baseline, the correct QT or JT interval should be calculated to ensure this subject does not have underlying QT prolongation.
• A condition which increases proarrhythmic risk, including hypokalemia, hypomagnesemia, or congenital Long QT Syndrome.
• Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of study results and, in the investigator’s opinion, would make the patient inappropriate for entry into this study.
• Hemoglobin A1c >9.0% (subjects with diabetes).

Other

• Pregnant or lactating female.
• AUDIT questionnaire score ≥4 at Screening or Baseline4 at Screening or Baseline
• Any contraindication to percutaneous liver biopsy.

• At least 18 years of age.
• Willing to comply with scheduled visits, treatment plans, laboratory assessments, and other study-related procedures.
• AST at Screening of ≥20 IU/L.
• Diagnosis of NASH by biopsy at Screening showing NAS ≥4 by central read, with a score of at least 1 point in each of the 3 histologic categories of steatosis, inflammation, and hepatocellular ballooning (Kleiner 2005). If the subject has had a qualifying liver biopsy within 6 months prior to Baseline, this biopsy can be waived as long as the slides are available for the central read prior to randomization (Section 13.4.9).
• Concomitant biopsy-proven Stage 2-3 hepatic fibrosis by NASH CRN criteria by central read (Kleiner 2005). If the subject has had a qualifying liver biopsy within 6 months prior to Baseline, this biopsy can be waived as long as the slides are available for the central read prior to randomization (Section 13.4.9).
• At least 2 of the following criteria for the metabolic syndrome (Grundy 2005): • Obesity, defined as waist circumference >88 cm for women or >102 cm for men • Hypertriglyceridemia, defined as triglycerides >150 mg/dL (>1.7 mmol/L) or on drug treatment for hypertriglyceridemia • Reduced high-density lipoprotein (HDL) cholesterol, defined as HDL cholesterol <40 mg/dL (<1.03 mmol/L) in men or <50 mg/dL (<1.3 mmol/L) in women • History of hypertension, currently controlled in the judgment of the Investigator • Elevated fasting glucose, defined as ≥100 mg/dL (≥5.6 mmol/L).
• Acceptable hepatic metabolic and synthetic function, as indicated at Screening by: • Serum albumin ≥3.5 gm/dL • International normalized ratio (INR) ≤1.3 • ALT or AST <250 IU/L • Alkaline phosphatase <2 times the upper limit of normal• Serum total bilirubin ≤1.3 mg/dL; subjects with isolated indirect hyperbilirubinemia secondary to documented Gilbert’s syndrome may be enrolled provided that the direct bilirubin value is within normal limits.
• The following laboratory values must be confirmed at Screening: • Absolute neutrophil count 1.5 x 109/L • Platelet count 150 x 109/L • Estimated glomerular filtration rate (eGFR) ≥60 mL/min by the Cockcroft-Gault formula • Serum sodium ≥130 mEq/L
• Understand and provide written informed consent to participate.
• Willing to undergo 2 liver biopsies.