Study of Various Treatments in Non-alcoholic Fatty Liver Disease (NAFLD) Patients Who Have Aspects of Non-alcoholic Steatohepatitis (NASH)

NASH EXploratory Single and COmbination Treatment (NEXSCOT): An Open Label, Multicenter, Platform Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of Various Single and Combination Treatments in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) Who Manifest a Non-alcoholic Steatohepatitis (NASH)-Like Biomarker Phenotype

This clinical study was designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of various single and combination treatments in adult patients with non-alcoholic fatty liver disease (NAFLD) who manifest a non-alcoholic steatohepatitis (NASH)-like biomarker phenotype.

This was a Phase II, non-confirmatory, multicenter, open label, platform study in NAFLD participants with a NASH-like biomarker phenotype to examine the effects of single and combination therapies over 12 weeks of treatment. The study consisted of four distinct study periods:

• Screening Period (Day -60 to -28): Lasted up to a maximum of 33 days where participants were assessed for inclusion and exclusion criteria prior the baseline assessments.
• Baseline Period (Day -27 to -1): Lasted up to a maximum of 27 days and comprised baseline assessments and randomization.
• Treatment Period (Day 1 to 85): Participants were randomized in a 1:1 ratio to LYS006 20 mg (twice a day) arm or to LYS006 20 mg (twice a day) and tropifexor 200ug (once a day). Participants were treated daily during 12 weeks.
• Follow-up Period (Day 85 to 113): After completion of the treatment period, participants were observed until the End Of Study (EOS) visit at Day 113.

Inclusion Criteria:

Phenotypic diagnosis of NASH based on the presence of all of the following:

• ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females)
• BMI ≥ 27 kg/m2 (race other than Asian) or ≥ 23 kg/m2 (Asian race)
• History of type 2 diabetes mellitus with HbA1c ≤ 9%
• ELF test score ≥ 8.5 and ≤ 10.5
• Liver fat ≥ 8%
• Patients must weigh between 40 kg (88 lbs.) and 150 kg (330 lbs.)

Exclusion Criteria:

• Use of other investigational drugs within 5 half-lives of randomization or within 3 months, whichever is longer
• Use of obeticholic acid (OCA) or pharmacologically-active weight loss drugs within 1 month of randomization
• Use of strong CYP3A4/5 inhibitors or strong CYP3A4 inducers within 5 half-lives or 7 days of randomization, whichever is longer
• History or presence of other concomitant liver diseases
• History or current diagnosis of ECG abnormalities
• Patients with contraindications to MRI imaging
• Current or history of significant alcohol consumption
• Clinical evidence of hepatic decompensation or severe liver impairment
• Women of child bearing potential (unless on highly effective methods of contraception)
• Presence of liver cirrhosis
• Use of OAT3 inhibitors within 5 half-lives or 7 days of randomization, whichever is longer