Recently, Madrigal Pharmaceuticals announced the positive results of phase 2 clinical trial in patients with heterozygous familial hypercholesterolemia (HeFH), a serious genetic disorder that causes premature cardiovascular disease. Mgl-3196 is a first-in-class oral, daily, hepatic targeted thyroid hormone receptor (THR- beta) selective agonist drug. It is also being developed to treat patients with non-alcoholic steatohepatitis (NASH).
Heterozygous familial hypercholesterolemia (HeFH) and much rarer homozygous familial hypercholesterolemia (HoFH) is a serious genetic dyslipidemia, usually caused by the loss of activity of LDL receptors mutation. Both forms of FH lead to premature cardiovascular disease. HeFH is one of the most common dominant genetic diseases, and up to one in 200 people have the disease. The incidence of the disease is higher in people with higher homologous levels of genes. HeFH and HoFH have the corresponding treatment, but many patients (up to 40% of patients with HeFH) after the treatment still can't let the level of cholesterol (LDL - C), the accumulation of cholesterol in the body they become the life-long burden.
But thankfully, thyroid hormone plays a core role in the control of lipid metabolism, the influences from the serum cholesterol, triglycerides, to the pathologic accumulation of fat in the liver and a series of health parameters. But attempts to treat this pathway were hampered by the lack of selective, chemical-related toxicity and undesired distribution of THR- beta. Madrigal believes that the high selectivity of THR- and the targeted liver can overcome these challenges and provide the full therapeutic potential of THR- beta agonist. Madrigal believes that mgl-3196 is the first truly selective thr-beta-agonist for oral, small-molecule, and hepatic targeting. It has been shown to have the potential to provide a wide range of therapeutic benefits, to improve metabolic syndrome (such as insulin resistance and dyslipidemia) and fatty liver disease (including lipotoxicity and inflammation). Its versatility and excellent safety suggest that mgl-3196 may be the preferred treatment for NASH.
The results showed that the ldl-c level of patients treated with mgl-3196 (placebo) was significantly reduced by 18.8% (p <0.0001), and the ldl-c in the optimal dose of mgl-3196 was significantly reduced by 21%. Among predetermined patients who were not able to stand high levels of statins, the mgl-3196 group had a 28.5% reduction in ldl-c levels compared with the placebo group. ApoB level also observed highly significant and similar results (p <0.0001). Not consider statins, TG, apolipoprotein CIII (Apo CIII) and Lp (a) in all patients treated by the built - 3196 and preset subgroups are observed in the highly significant (p < 0.0001) in lowering effect, TG is 25-31%, Lp (a) of 25 to 40%. In addition, mgl-3196 has good tolerability, mainly with mild and moderately adverse events (AE).
Reference materials: new drug selection of statin drugs for drugs, and significant effect of new drugs on cholesterol-lowering drugs, February 9, 2018.