a phase 3 study to evaluate safety and biomarkers of resmetirom (mgl-3196) in non alcoholic fatty liver disease patients

Conditions: Non-Alcoholic Fatty Liver Disease

Summary: 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.

Keywords: nafld nash hyperlipidemia resmetirom thyroid hormone receptor beta hepatic fibrosis nash resolution thyroid hormone receptor agonist cardiovascular dyslipidemia fatty liver disease nonalcoholic steatohepatitis cirrhosis