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

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).


Eligibility Criteria:
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.