A Phase 3 Study to Evaluate the Efficacy and Safety of MGL-3196 (Resmetirom) in Patients With NASH and Fibrosis

Primary and secondary endpoint population at Week 52 will be at least 900 patients, more than half fibrosis score 3 (F3), the remainder fibrosis score 2 (F2) and <10% fibrosis score F1B (F1B) based on final liver biopsy baseline fibrosis score.

Inclusion criteria

• Must be willing to participate in the study and provide written informed consent.
• Male and female adults ≥ 18 years of age.
• Suspected or confirmed diagnosis of NASH fibrosis suggested by the historical data. Meet one of the following criteria that is consistent with NASH liver fibrosis:

• Historical biochemical test for fibrosis: PRO-C3 >14 ng/mL or ELF ≥9
• FibroScan with transient elastography ≥8.5 kPa and controlled attenuation parameter ≥280 dB.m-1
• Historical liver biopsy obtained <2 years before expected randomization showing Stage 1B, 2 or 3 fibrosis with NASH based on existing pathology review, with no significant change in body weight >5% or medication that might affect NAS or fibrosis stage.
• MRI-PDFF fat fraction ≥8% obtained during the screening period
• Biopsy-proven NASH (baseline liver biopsy) based on a liver biopsy obtained ≤6 months before anticipated date of randomization (if the biopsy is deemed acceptable for interpretation by the central reader) with fibrosis stage 1A/1C, 1B, 2, or 3 on liver biopsy and NAS of ≥4 with a score of at least 1 in each of the following NAS components:

• Steatosis (scored 0 to 3)
• Ballooning degeneration (scored 0 to 2)
• Lobular inflammation (scored 0 to 3)

Exclusion criteria

• History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening.
• Regular use of drugs historically associated with NAFLD
• Thyroid diseases:

• Active hyperthyroidism.
• Untreated clinical hypothyroidism defined by thyroid stimulating hormone (TSH) >7 IU/L with symptoms of hypothyroidism or >10 IU/L without symptoms.
• Patients who have had a thyroidectomy and are on replacement thyroxine doses >75 µg per day are allowed.
• History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study.
• Recent significant weight gain or loss
• HbA1c ≥ 9.0%.
• Glucagon-like peptide 1 [GLP-1] agonist, high dose Vitamin E (> 400 IU/day), or pioglitazone therapy unless stable dose for 24 weeks prior to biopsy.
• Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis.
• Diagnosis of hepatocellular carcinoma (HCC).
• MELD score ≥12, as determined at Screening, unless due to therapeutic anti coagulation.
• Hepatic decompensation
• Chronic liver diseases other than NASH
• Active autoimmune disease
• Serum ALT > 250 U/L.
• Active, serious medical disease with a likely life expectancy < 2 years.
• Participation in an investigational new drug trial in the 60 days or 5 half-lives, whichever is longer.
• Any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, compromise the well-being of the patient, or interfere with the study outcomes.