Overview

Evaluate efficacy and safety of ADI-PEG 20 in patients with NASH

Eligibility

Inclusion Criteria:

1. Males and non-lactating, pregnancy test negative females between 18 - 80 years of age with biopsy proven F1 - F3 NASH. Limit F1 fibrosis to ≤ 20% of total subject population.
2. Willingness to use appropriate contraceptive measures though out study treatment and for 90 days thereafter (see Appendix A).
3. Body mass index (BMI) > 25 kg/m2
4. Must have confirmation of ≥ 10% liver fat content on MRI-PDFF at screening.
5. Biopsy-proven NASH. Must have had a liver biopsy within 4 weeks of randomization with fibrosis stage 1 to 3 and a non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥ 4 with at least a score of 1 in each of the following NAS

   components

   1. Steatosis (scored 0 to 3),
   2. Ballooning degeneration (scored 0 to 2), and
   3. Lobular inflammation (scored 0 to 3).

6. Must have no evidence of worsening of ALT and AST (within 50%) measurements at the

   screening (-4 weeks) and pre-baseline (-2 weeks) visits.

7. Screening laboratory parameters, as determined by the central laboratory:
   1. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, as calculated by the Cockcroft- Gault equation;
   2. HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 µmol if HbA1c is unable to be resulted);
   3. Hemoglobin ≥ 11 g/dL;
   4. INR ≤ 1.3, unless due to therapeutic anticoagulation;
   5. Direct bilirubin ≤ 0.5 mg/dL;
   6. Total bilirubin ≤ 1.3 x upper limit of normal (ULN), unless due to an alternate etiology such as Gilbert's syndrome or hemolytic anemia;
   7. Creatinine kinase < 3 x ULN;
   8. Platelet count ≥ 150,000/µL;
   9. Serum triglyceride level ≤ 500 mg/dL;
   10. ALT < 5 x ULN;
   11. AST < 5 x ULN;
   12. ALP < 2 x ULN.
8. FibroScan® measurement > 7.0 kPa
9. Subjects on non-insulin dependent diabetic, weight loss, or lipid-modifying medication(s) must be on stable dose(s) for at least 3 months prior to the diagnostic liver biopsy through randomization.

Exclusion Criteria:

1. Weight gain or loss > 5% in the 3 months prior to randomization or > 10% in the 6 months prior to screening.
2. Type 1 and insulin-dependent Type 2 diabetes.
3. Presence of cirrhosis on liver biopsy (stage 4 fibrosis).
4. Poorly controlled hypertension (blood pressure [BP] > 160/100 mmHg).
5. Prior history of decompensated liver disease including ascites, hepatic encephalopathy (HE), or variceal bleeding.
6. Chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive).
7. Chronic hepatitis C virus (HCV) infection (HCV antibody [Ab] and HCV ribonucleic acid [RNA] positive). Subjects cured of HCV infection less than 2 years prior (based on date of RNA polymerase chain reaction [PCR] negative confirmation following conclusion of treatment) to the screening visit are not eligible.
8. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-en-Y gastric bypass), surgery reversal or removal of intragastric balloon > 2 years prior to enrollment would be eligible.
9. Other causes of liver disease based on medical history and/or centralized review of liver histology, including but not limited to: alcoholic liver disease, autoimmune disorders (e.g., primary biliary cholangitis [PBC], primary sclerosing cholangitis [PSC], autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment.
10. History of liver transplantation.
11. Current or prior history of hepatocellular carcinoma (HCC).
12. Alcohol intake above an average limit of 2 drinks per day for women and 3 drinks per day for men.
13. Human immunodeficiency virus (HIV) infection.
14. Unstable cardiovascular disease in the 6 months prior to screening.
15. Life expectancy less than 2 years.
16. Use of any investigational medication within 30 days or within 5 half-lives of the investigational medication, whichever is longer, prior to screening and throughout the study is prohibited.
17. Subjects with a history of (12 months prior to screening) or current use of prescription drugs associated with liver steatosis (e.g. methotrexate, amiodarone, high-dose estrogen, tamoxifen, systemic steroids, anabolic steroids, valproic acid) should be excluded.