MGL_3196



NAME OF DRUG : MGL_3196

ALSO KNOWN AS : MGL_3196

LABORATORY : MADRIGAL

STATUS AND ADVANCEMENT

Type of drug : THR-β Agonist

Clinical trials advancement : Analysing Results Phase 2b

and is eligible for Subpart H on intermediate results of Phase 3

Estimated time to market : 52 months.

LABORATORY ABSTRACT ON THE DRUG

GL-3196 is an orally administered, small-molecule liver-directed β-selective THR agonist designed to specifically target receptors in the liver involved in metabolism and cholesterol regulation, and avoid side effects associated with thyroid hormone receptor activation outside the liver, including those mediated by THR-? receptors. MGL-3196 has currently completed Phase I single and multiple dose trials in healthy volunteers. MGL-3196 is being developed for dyslipidemia/hypercholesterolemia to lower LDL cholesterol, triglyceride levels and Lp(a), and was inlicensed from Roche Pharmaceuticals. MGL-3196 has excellent safety in comparative studies with other THR agonists tested previously because of MGL-3196 high liver uptake and high ß-selectivity and nearly complete lack of THR-? activity. MGL-3196 has completed a single ascending dose study in healthy volunteers in which the compound appeared safe at all doses tested. The multiple ascending dose study in healthy volunteers with mildly elevated LDL cholesterol was completed in October 2012 and provided additional safety and pharmacodynamic information. The Phase I multiple dose, proof of concept study enrolled 48 healthy volunteers with mildly elevated LDL cholesterol to evaluate the safety, pharmacokinetics and pharmacodynamics of MGL-3196 after two weeks of daily dosing. Results showed that MGL-3196 was well tolerated and appeared safe at all doses tested. Daily doses of 50-200 mg showed highly statistically significant reductions relative to placebo of up to 30% LDL-cholesterol (p=.05-<.0001; 28%, non-HDL cholesterol (p=.027-.0001); 24% Apolipoprotein B (p=.008-.0004); and strong trends and up to 60% reduction of triglycerides (range, p=.13-.016). The results suggest that MGL-3196 has a unique lipid lowering profile as compared with other agents with the potential to significantly reduce cholesterol, triglycerides and liver triglycerides. Unlike other thyroid hormone ß-agonists, MGL-3196 is well tolerated. Elevated cholesterol, triglycerides and fatty liver are an underlying cause of many metabolic and cardiovascular diseases, which, themselves, are associated with increased mortality. The next step is to move into disease directed studies where control of these lipid levels in the blood and liver, particularly triglycerides, is clinically important and measurable – areas such as diabetes with associated fatty liver disease or patients with very high triglycerides at risk for associated side-effects – diseases in which large cardiovascular outcome studies may not be required for drug approval. Based on preclinical studies, MGL-3196 is a potent regulator of hepatic triglyceride metabolism and cholesterol lowering. Preclinical studies demonstrated a rapid reduction of non-HDL cholesterol and the drug was shown to be synergistic with statins in animal studies. THR-ß agonists are believed to promote reverse cholesterol metabolism by causing increased uptake of cholesterol into the liver and increased cholesterol elimination from the body through excretion into the bile. The compound also reduces triglycerides in the plasma and liver by increasing fat metabolism and shows an anti-diabetic action. MGL-3196 is designed to specifically activate receptors in the liver involved in metabolism and cholesterol regulation, and avoid side effects associated with THR activation outside the liver. Its mechanisms of action are distinct from and complementary to statins.

HISTORY AND ANALYSIS

Result provided are based on PP and not ITT , they are good and close to the result of Elafibranor on a similar subgroup of patients 

 

KNOWN RESULTS

Madrigal Pharmaceuticals Completes Enrollment In Phase 2 Proof-Of-Concept Study With MGL-3196 For Treatment Of NASH

 
  • Primary endpoint is the reduction of liver fat, assessed by MRI-PDFF, at 12 weeks
  • Company expects to report top-line results by year-end

Conshohocken, PA (GLOBE NEWSWIRE) -- Madrigal Pharmaceuticals, Inc. (Nasdaq: MDGL) today announced that it has completed patient enrollment of 125 patients, exceeding its targeted enrollment of 117 patients, in its Phase 2 proof-of-concept study evaluating MGL-3196 for the treatment of non-alcoholic steatohepatitis (NASH). MGL-3196 is a first-in-class, oral, once-daily, liver-directed, thyroid hormone receptor (THR) β-selective agonist medication.

“I am pleased to be participating in this important study as the results will confirm if MGL-3196 is safe and well-tolerated and shows efficacy in NASH patients,” stated Stephen A. Harrison, M.D., Medical Director of Pinnacle Clinical Research, San Antonio, Texas and Principal Investigator of the study. “Additionally, since the study incorporates both magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), a non-invasive measure of liver fat, along with liver biopsy, there is the potential to provide additional evidence for a correlation between improvement in non-invasive imaging and the histopathologic components associated with NASH on biopsy.”

“As we completed patient recruitment within the timeframe we had anticipated, we are on track to release top-line results for the primary endpoint, the reduction of liver fat assessed by MRI-PDFF at 12 weeks, by the end of this year,” stated Rebecca Taub, M.D., Chief Medical Officer, Executive Vice President and Founding Scientist of Madrigal. “This also means that we will be on track to provide top-line 36 week results, which include a final MRI-PDFF and an end-of-study liver biopsy in the second quarter of 2018.”

“Data from this study will help us better design our phase 3 trial, planning for which is already underway,” stated Paul Friedman, M.D., Chief Executive Officer of Madrigal. “I also point out that top-line data from our phase 2 study with MGL-3196 in heterozygous familial hypercholesterolemia will also become available by year end or very early in 2018.”

About the Phase 2 NASH Study
The randomized, double-blind, placebo-controlled, multi-center Phase 2 study enrolled 125 patients 18 years of age and older with liver biopsy-confirmed NASH and included approximately 25 clinical sites in the United States. Patients were randomized to receive either placebo or MGL-3196 with twice as many patients receiving MGL-3196 as placebo.

The primary endpoint of the study is the reduction of liver fat at 12 weeks, assessed by MRI-PDFF, with efficacy confirmed at the end of the trial (36 weeks) by repeat MRI-PDFF and conventional liver biopsy to examine histological evidence for the resolution of NASH. Recent published data show a high correlation of reduction of liver fat measured by MRI-PDFF to NASH scoring on liver biopsy.

Other secondary endpoints include changes in clinically relevant biomarkers at 12 and 36 weeks, improvement in fibrosis by at least one stage with no worsening of steatohepatitis, and safety and tolerability. Additional information about the study [NCT02912260] can be obtained at www.ClinicalTrials.gov.

 

RECENT NEWS ON MGL_3196

2018-05-31 : Madrigal’s MGL-3196 Achieves Liver Biopsy Endpoints in Patients with Non-alcoholic Steatohepatitis (NASH) at 36 Weeks in Phase 2 Clinical Trial

2017-12-06 : Madrigal’s MGL-3196 Achieves Primary Endpoint in Patients with Biopsy-proven Non-alcoholic Steatohepatitis (NASH) in Phase 2 Clinical Trial

2017-08-01 : Madrigal Pharmaceuticals Completes Enrollment in Phase 2 Proof-of-Concept Study with MGL-3196 for Treatment of NASH

2017-06-01 : On May26, 2017, the Data and Safety Monitoring Committee (the DSMC) for clinical studies of Madrigal Pharmaceuticals,Inc.'s (the Company) MGL-3196, for the treatment of non-alcoholic steatohepatitis, held a pre-scheduled meeting to review data from the Company's Phase 2 clinical NASH trial.

SOME PUBLICATIONS RELATED WITH MGL_3196

June 2018 : A critical review of endpoints for non-cirrhotic NASH therapeutic trials

SOME NASHBIOTECHS POINTS OF VIEW RELATED WITH MGL_3196

June 2018 : MGL-3196 RESULTS QUICK ANALYSIS


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