Study of Safety and Efficacy of Tropifexor (LJN452) in Patients With Non-alcoholic Steatohepatitis (NASH)

The purpose of the study was to assess the effects of different doses of tropifexor (LJN452) with respect to safety, tolerability, and on markers of liver inflammation in patients with NASH

Part A In Part A, 77 subjects were randomized at baseline to receive tropifexor (10 μg, 30 μg, 60 μg or 90 μg) or placebo (Arms A, B, C, D and E) for 12 weeks. After ≥ 90% of the subjects from Part A completed 8 weeks of treatment, the first interim analysis of all Part A data was performed and the Data Monitoring Committee (DMC) recommended evaluation of 90 μg tropifexor (safe andefficacious) in Part B. The treatment arms of Part A were completed through Week 16 without adaptation.

Part B Randomization for Part B was started after the DMC recommendations on the dose to be used in Part B were implemented by the sponsor. As planned in the study protocol, since the first interim analysis selected one active dose (90 μg) to be tested in Part B, one of the other originally planned active treatment arms (60 μg) was included with a smaller sample size to confirm the earlier findings of this dose observed in Part A. Therefore, in Part B, 121 subjects, were randomized at baseline to receive tropifexor (90 μg and 60 μg) or placebo (Arms F, G and H) for 12 weeks.

Part C was introduced as a result of the DMC recommendation to pursue doses \> 90 μg. Randomization in Part C started once the Part B randomization was completed. In Part C, 152 subjects were randomized at baseline to receive 140 μg or 200 μg tropifexor or placebo (Arms I, J and K) for 48 weeks.

One patient was treated at 2 sites but is still only one patient. 350 total enrollment, and not 351.

Eligibility Criteria:
Inclusion Criteria:

* male/female patients, 18 years or older
* written informed consent
* Part A and B patients : presence of NASH by histological evidence (liver biopsy obtained 2 years or less prior to randomization) with fibrosis level of F1, F2 or F3 (fibrosis in the absence of cirrhosis) and no diagnosis of chronic liver disease and elevated alanine aminotransferase (ALT) OR phenotypic diagnosis based on elevated ALT, BMI and diagnosis of Type 2 diabetes mellitus (DM)
* Part C patients: presence of NASH by histological evidence (liver biopsy obtained during the Screening period or 6 months or less prior to randomization) with fibrosis level of F2 or F3 and no diagnosis of chronic liver disease

And ( All Parts):

* ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females)
* Liver fat equal to or higher than 10% by MRI

Exclusion Criteria:

* previous exposure to OCA
* patients taking prohibited medications
* patients taking the following medicines UNLESS on a stable dose (within 25% of baseline dose) for at least 1 month before randomization: (for Part C patients, dose must be stable for at least 1 month prior to biopsy through Screening : anti- diabetic medications, insulin, beta-blockers, thiazide diuretics, fibrates, statins, niacin, ezetimibe, vitamin E (if doses \> 200 IU/day; doses \> 800 IU/day are prohibited), thyroid hormone, psychotropic medications, estrogen or estrogen containing birth control
* pregnant or nursing (lactating) women
* current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening
* uncontrolled diabetes mellitus
* new use of GLP-1 agonists such as liraglutide, exenatide, lixisenatide, albiglutide or dulaglutide within 3 months of screening
* presence of cirrhosis
* hepatic decompensation or severe liver impairment
* previous diagnosis of other forms of chronic liver disease
* patients with contraindications to MRI imaging