NASH Research Update│Resmetirom Receives Breakthrough Therapy Designation from FDA
Resmetirom (MGL-3196) recently acquired breakthrough therapy designation from the FDA for the treatment of patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis, according to an announcement made by Madrigal Pharmaceuticals.
Resmetirom is an oral THR-selective agonist that specifically targets the liver. By activating beta receptors in hepatocytes, thyroid hormones play a crucial role in liver function. This has an impact on a variety of health indicators, including serum cholesterol and triglyceride levels and the pathological buildup of fat in the liver. THR-beta regulates mitochondrial activity to control normal mitochondrial levels while promoting hepatic lipolysis. Resmetirom is a very discerning drug that can Resmetirom is very selective and can only be absorbed in the liver. Resmetirom has been proven to be safe, well tolerated, inert on THR-receptors, and not influence thyroid axis hormones, skeletal or cardiac parameters in preclinical animal and clinical investigations.
Resmetirom plays an important role in the liver
Over 950 patients participated in the 52-week, Phase 3 MAESTRO-NASH experiment, which also included a number of liver biopsies. In comparison to a placebo, the study revealed that Resmetirom met two primary objectives and had effects that may have been clinically significant at oral doses of 80 mg and 100 mg daily:
Remission of NASH symptoms, a 2-point decrease in nonalcoholic fatty liver activity score (NAS), and no worsening of liver fibrosis (p0.0001 at both doses, respectively); at least one stage of improvement in liver fibrosis with no worsening of NAS; and a significant decrease in the primary secondary endpoint LDL-C compared to the placebo group.
The choice of drug evaluation models is crucial.
A proper animal model for preclinical studies is unavoidably one of the cornerstones to drug development. In order to reduce the differences between preclinical and clinical outcomes of drugs and increase the effectiveness of drug development, selecting an appropriate NASH model can not only significantly reduce modeling time but also simulate the characteristics of metabolic disorders and liver pathological histology of human patients. To fulfill the demands of various researchers, we have a variety of NASH models available, including gene-edited mouse-based NASH models, nutrient-deficient diet induction, chemical toxin induction, and high-fat diet induction models.
List of NASH study models
NASH study model recommendations
B6-Alms1-del (T017633)+WD
Alström syndrome is linked to the ALMS1 gene, which is also linked to metabolic syndromes such childhood obesity, developmental delay, hyperlipidemia, heart disease, and type II diabetes mellitus. As people aged, the liver damage and hyperlipidemia got worse. Feeding on a Western diet (WD) speeds up the occurrence of metabolic problems and liver damage, and it may result in mild liver fibrosis. The clinical NAS scale states that a score of less than five is typically indicative of NASH, and B6-Alms1-del, which has a score of greater than five after six weeks of WD induction, can be employed as a NASH study.
Efficacy of MGL-3196 in a B6-Alms1-del NASH model
MGL-3196 administration alleviated the WD-induced steatosis and fibrosis phenotypes in the B6-Alms1-del NASH mouse model, with some reduction in NAS score and fibrosis score, and showed a dose-dependent effect.
Wild Mouse 750 (strain number: D000750) + WD
The C57BL/6JGpt mouse background, which has greater genetic variety and a closer disease susceptibility to field mice than inbred mice, was used to create the wild mouse 750, a chromosomal replacement line. Field mice from the Shanghai Yangpu area provided the chromosome 1 for this line. Wild mice 750 on a conventional diet rapidly developed spontaneous obesity at 8 weeks of age, with the amount of obesity rising with each passing week and severe anomalies in lipid metabolism. At 26 weeks of age, a considerable phenotype of fatty liver was also noticed. After roughly 18 weeks of WD feeding, feral mice 750 showed classic NASH symptoms, including steatosis and inflammation phenotypes, as well as moderate fibrosis, which was more severe than the phenotype induced in C57BL/6JGpt mice at the same time. Western diet (WD) induction further accelerated the emergence of NASH disease.
After being fed a western diet, 750 feralized rats developed lipid and liver abnormalities.
The eight-week-old feralized rats C57BL/6JGpt and 750 were fed the same common diet (CD: Chow diet) and the Western diet (WD: Western diet) at the same time. At 6, 10, 14, and 18 weeks of feeding, testing for liver pathology and cholesterol were carried out. The findings demonstrated that as WD feeding duration increased, the LDL-C index of wild rats increased significantly (750). With a more prominent phenotype than C57BL/6JGpt, feral rats 750 developed substantial fatty liver after 6 weeks of WD feeding and NASH after 18 weeks.
Testing the pharmacodynamics of MGL-3196 in 750 feral mice
In 750 mice given WD, MGL-3196 dramatically decreased the levels of cholesterol and LDL-C.
Collective Pharmachem has created many humanized mice that target NASH therapeutic targets in order to better fit the R&D requirements of NASH antibodies and nucleic acid-based therapeutics. Additionally, the company can do preclinical one-stop pharmacodynamic services to aid in the development of NASH drugs.
Reference from https://zhuanlan.zhihu.com/p/624979238
