The Efficacy, Safety and Tolerability of Oral LPCN 1144 in Subjects With Nonalcoholic Steatohepatitis

This is a Phase 2, randomized, double-blind, placebo controlled, three arm study in adult men with biopsy confirmed NASH. The study is aimed at evaluating efficacy and tolerability of LPCN 1144 in adult men with NASH.

This is a Phase 2, randomized, double-blind, placebo controlled, three arm study in adult men with biopsy confirmed NASH. The study is aimed at evaluating efficacy and tolerability of LPCN 1144 in adult men with NASH. The study will be conducted across multiple centers in the United States.

Approximately 75 subjects will be randomized in 1:1:1 ratio to receive one of the following treatments:

* Treatment A: Oral LPCN 1144 Formulation A
* Treatment B: Oral LPCN 1144 Formulation B
* Treatment C: Oral matching placebo

Subjects will undergo a screening period to determine study eligibility. As a part of screening, liver biopsies will be performed for subjects who have not had a liver biopsy within 6 months of Day 1, and fat fraction will be measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) in all subjects. Adult male subjects with histologic evidence of NASH will be enrolled into the study.

Eligible subjects will be randomized to one of the three treatment arms. The treatment phase will be for a duration of 36-weeks with assessments of liver biopsies, hepatic fat fraction, liver enzymes, lipid levels and other safety parameters. Safety and tolerability will be assessed throughout the study.

Eligibility Criteria:
Inclusion Criteria:

1. Male between 18 and 80 years of age, inclusive.
2. Subject with histologic evidence of NASH upon central read of a liver biopsy.

   i. A historical biopsy no more than 4 months before Screening may be considered for use with medical monitor approval if the following criteria are met:
   * Stable weights between the time of the biopsy and Screening. Stable weight is defined as no more than a 5% change.
   * Is either not taking or is on a stable dose of Thiazolidinedione(TZDs)/glitazones for 3 months before Day 1.
3. Background therapy for other ongoing chronic conditions, and weight should be stable for at least 3 months before trial enrollment. Stable weight is defined as no more than a 5% change.
4. Judged to be in good general health as determined by the investigator at screening.

Exclusion Criteria:

1. Significant alcohol consumption more than 30 g/day on average, either currently or for a period of more than 3 consecutive months in the 5 years prior to screening.
2. Inability to reliably quantify alcohol intake.
3. Biochemical, clinical or histologic evidence of cirrhosis on liver biopsy (stage 4 fibrosis).
4. Evidence of other causes of chronic liver disease including alcoholic liver disease, viral hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, Wilson's disease, hemochromatosis, alpha-1 antitrypsin deficiency, human immunodeficiency virus, etc.
5. Suspected or proven liver cancer.
6. Clinically significant abnormal laboratory value, in the opinion of the investigator, in serum chemistry, hematology, or urinalysis including but not limited to:

   * Hematocrit \> upper limits of normal (ULN)
   * Hemoglobin \> ULN
   * Prostate-specific antigen (PSA) \> 4 ng/mL
   * Serum aspartate aminotransferase (AST) or alanine transaminase (ALT) \> 200 IU/L
   * Serum alkaline phosphatase (ALP) \> 2 x ULN
   * Serum creatinine of 2.0 mg/dL or greater
   * Total bilirubin \> ULN
   * International normalized ratio (INR) ≥ 1.3.
   * Prolactin \> ULN
7. Subjects with evidence of worsening liver function based on the two initial laboratory values used to establish the screening / baseline values.
8. Model for End-Stage Liver Disease (MELD) score greater than 12
9. Subjects with a documented history of Gilbert's syndrome
10. Evidence of portal hypertension (e.g., low platelet counts, esophageal varices, ascites, history of hepatic encephalopathy, splenomegaly).
11. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens, anabolic steroids, valproic acid, other known hepatotoxins) for more than 2 weeks in the 2 years prior to randomization.
12. Subjects who are not on a stable dose of lipid-lowering drugs, diabetic and / or hypertensive medication in the 3 months prior to biopsy or the 3 months prior to randomization
13. Any over-the-counter medication or herbal remedy that is being taken with an intent to improve hyperlipidemia must be stable for at least 3 months prior to randomization and through the end of the study.
14. Vitamin E supplementation of greater than 100 IU/day, unless completed adequate washout for at least 4 weeks prior to Day 1 or biopsy if one is required.
15. Inability to safely obtain a liver biopsy.
16. History of total parenteral nutrition in the year prior to screening.
17. History of bariatric surgery or currently undergoing evaluation for bariatric surgery.
18. History of gastric surgery, vagotomy, bowel resection or any surgical procedure that might interfere with gastrointestinal motility, pH or absorption.
19. History of biliary diversion.
20. Known positivity for antibody to Human Immunodeficiency Virus (HIV).
21. Known heart failure of New York Heart Association class 3 or 4.
22. Active, serious medical disease with likely life-expectancy less than 5 years.
23. History of current or suspected prostate or breast cancer.
24. History of diagnosed, severe, untreated, obstructive sleep apnea.
25. Active substance abuse in the year prior to screening.
26. History of significant sensitivity or allergy to any androgens, including testosterone, or product excipients
27. History of seizures or convulsions, including alcohol or drug withdrawal seizures. Childhood seizures are not exclusionary.
28. Use of known strong inhibitors (e.g., ketoconazole) or inducers (e.g., dexamethasone, phenytoin, rifampin, carbamazepine) of cytochrome P450 3A (CYP3A) within 30 days prior to study drug administration and through the end of the study.
29. Subjects who are currently receiving any androgens (testosterone or other androgens or androgen supplements). Subjects who are on testosterone may be eligible for the study following an adequate washout (12 weeks following intramuscular androgen injections; 4 weeks following topical or buccal androgens; 3 weeks following oral androgens).
30. Use of any investigational drug within 5 half-lives of the last dose or in the past 6 months prior to Study Day -2 without PI and/or Sponsor approval.
31. Receipt of any drug by injection within 30 days or 10 half-lives (whichever is longer) prior to study drug administration without PI and/or Sponsor approval. Insulin, allergy shots, and vaccines are allowed.
32. Subject who is not willing to use adequate contraception for the duration of the study.
33. Any other condition, which in the opinion of the investigator would impede compliance or hinder completion of the study.
34. Failure to give informed consent.