A Phase 3 Study to Evaluate Safety and Biomarkers of Resmetirom (MGL-3196) in Non Alcoholic Fatty Liver Disease Patients

A 52-Week, Phase 3 Study to Evaluate Safety and Biomarkers of Resmetirom (MGL-3196) in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) (MAESTRO-NAFLD-1)

A double-blind placebo controlled randomized Phase 3 study to evaluate the safety and tolerability of once-daily, oral administration of 80 or 100 mg resmetirom versus matching placebo. At least 100 patients will be enrolled in a 100 mg open-label arm and will include a special safety population (eg, patients with compensated NASH cirrhosis).

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 or NAFLD (presumed NASH):

  • Fibroscan with kPa ≥5.5 and <8.5; CAP ≥280 dB.m-1 OR

  • MRE ≥2 and <4.0; MRI-PDFF ≥8% liver fat consistent with steatosis and fibrosis stage ≥1 and <4. OR

  • Recent liver biopsy (within past 2 years) documenting NASH/NAFLD with steatosis showing one of the following:

    • NAS ≥4, steatosis ≥1, fibrosis stage 0 or F1A/1C with PRO-C3 <14

    • NAS <4, steatosis ≥1, with fibrosis stage ≤3

    • NAS ≥4, steatosis ≥1, fibrosis stage ≤3 without ballooning

      • NOTE: Since the completion of enrollment of the double-blind arms, patients meeting all other criteria who have a liver biopsy result from MGL-3196-11 with the following may be enrolled in the open-label active treatment arm of MGL-3196-14 (100 mg dose):

        • NAS = 3, steatosis 1, ballooning 1, inflammation 1 with F2 or F3
        • NAS = 3, ballooning 0 with F2 or F3

      • For the compensated NASH cirrhosis arm, eligible patients must have compensated NASH cirrhosis diagnosed by liver biopsy showing NASH with F4 stage fibrosis (either historic or recent biopsy) or a historic biopsy with NASH F2-F3 fibrosis with subsequent progression to NASH cirrhosis as diagnosed by an expert hepatologist/gastroenterologist.

  • Compensated NASH cirrhosis at screening and baseline includes

    • Child Pugh-A (score 5-6) ( may have either mild hepatic encephalopathy OR mild diuretic responsive ascites OR albumin < 3.5 and ≥ 3.2 (not any two of these, unless explained by Gilbert's Syndrome or non-hepatic causes)).
    • MELD < 12 at screening/baseline unless MELD ≥ 12 based on non-cirrhotic parameters (e.g., elevated INR due to anticoagulation, bilirubin elevation due to documented Gilbert's Syndrome, elevated creatine due to renal disease (non-hepatic)).
    • Albumin ≥ 3.2.
    • Bilirubin < 2 (unless documented Gilbert's Syndrome).

• MRI-PDFF fat fraction ≥8% obtained during the Screening Period (baseline MRI-PDFF) or a historic MRI-PDFF ≤8 weeks old at the time of randomization.

• Stable dyslipidemia therapy for ≥30 days prior to randomization.

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.
• History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study.
• Weight gain or loss ≥5% total body weight within 12 weeks prior to randomization.
• HbA1c >9.0%.
• Glucagon-like peptide 1 [GLP-1] agonist therapy or high dose vitamin E (>400 IU/day) unless stable for 24 weeks prior to biopsy.
• Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis.
• Diagnosis of hepatocellular carcinoma (HCC).
• Model for End-stage Liver Disease (MELD) score ≥12, as determined at Screening, unless due to therapeutic anti coagulation or Gilbert syndrome.
• Hepatic decompensation.
• Chronic liver diseases.
• Has an active autoimmune disease.
• Serum ALT >250 U/L.
• History of biliary diversion.
• Uncontrolled hypertension (either treated or untreated).
• 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, prior to randomization.
• 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.