More details about MASH and MASLD can be found in the previous article, Everybody’s gotta live(r). In that article, we mentioned that at that time there were no FDA-approved drugs for these diseases. However, the approval of Resmetirom marks a significant change, establishing it as the first drug to treat MASH, thus changing the current paradigm.
The Discovery of Resmetirom
Resmetirom (also known as MGL-3196) was discovered while studying new drugs for dyslipidemia, which is an imbalance of lipids such as cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, and high-density lipoprotein (HDL). Despite the success of statins in lowering LDL cholesterol, there was a need for new drugs to treat dyslipidemia. Drugs that lower fatty acid accumulation and degeneration in the liver may also be useful in treating nonalcoholic steatohepatitis (MASH).
The beneficial metabolic effects of thyroid hormone (TH) are mediated by the thyroid hormone receptor β isoform (THR-β), the predominant liver TH receptor. The adverse effects on the heart and bones are primarily due to the interaction of TH with the thyroid hormone receptor α isoform (THR-α). Therefore, the search for therapeutic agents has focused on finding agonists selective for both THR-β and the liver.
The ligand-binding domains of the TH-α and TH-β receptors differ by only a single amino acid: Asn331 in THR-β and Ser277 in THR-α. This amino acid can form a hydrogen bond with the acidic moiety. Research on THR-β selective compounds has largely focused on close analogues of Triiodothyronine (T3), a thyroid hormone that influences nearly every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. One such analogue is KB-141, which has been extensively studied. In KB-141, the iodine atoms have been replaced with more stable chlorine or isopropyl groups, and the alpha amine carboxylic acid group has been simplified by removing the primary amine and shortening the carbon chain. This modification results in a very potent inhibitor in the low nanomolar range for both THR-α and THR-β, although it has a selectivity index lower than 10.
Key Features of the Structure-Activity Relationship (SAR) Leading to Resmetirom
Replacement of the phenol group of the KB-141 compound with a pyridazinone gave compound 20, which was 10-fold more selective for THR-β than KB-141. Replacing one or both of the chlorines from KB-141 with methyl resulted in a slight loss of both potency and selectivity. The dibrominated analogue was 5-fold more potent and equally selective as the dichlorinated analogue. However, concerns about the general safety of aromatic brominated compounds led to focusing on the dichlorinated analogues. A significant increase in potency was obtained when the acyclic acidic groups were replaced with an azauracil. Further selectivity was achieved by substituting the azauracil with a cyano group, increasing the selectivity from 12-fold to 28-fold with minimal impact on potency.
FDA Approval and Clinical Efficacy
The rates of a serious form of liver disease have been on the rise, but there have been no effective medications to treat it—until now. In March 2024, the US Food and Drug Administration (FDA) approved Resmetirom (Rezdiffra™) for people with NASH and stage 2 or 3 fibrosis (but not cirrhosis), in conjunction with a healthy diet and regular exercise. This milestone marks the first FDA-approved drug for NASH in the United States, based on its success in resolving NASH and improving fibrosis in about a quarter of patients in a large international trial (MAESTRO NASH, NCT03900429).
Resmetirom increases the metabolism of liver fat by activating the thyroid hormone pathway in the liver. Common side effects include nausea and diarrhea, with some patients also experiencing gallstones and gallbladder inflammation. It can interact with other medications like statins, gemfibrozil (Lopid), and clopidogrel (Plavix), so it's crucial for your healthcare provider to have a complete list of your medications before prescribing Rezdiffra. A liver biopsy isn't necessary to start Rezdiffra; other tests such as Fibroscan or measures of liver stiffness can provide the required information. Rezdiffra is not recommended for those without significant liver fibrosis.
Current and Future Implications
Current weight loss drugs show varying efficacy in treating metabolic dysfunction-associated fatty liver disease (MASLD) and obesity-related to metabolic dysfunction-associated steatohepatitis (MASH). Older anti-obesity drugs typically achieve modest weight loss of 3 to 8% while newer treatments, like semaglutide, have shown promise in improving metabolic parameters and reducing liver fat in patients with MASH. Additionally, future medications such as tirzepatide, which is currently evaluated in phase 3 trials and has been approved for obesity treatment, may have significant implications for metabolic liver diseases. Emerging therapies like vitamin E and pioglitazone are also being explored for their efficacy in treating MASH, with varying degrees of effectiveness. In conclusion, while current weight loss drugs offer some benefits in managing MASLD and MASH-related obesity, newer medications like semaglutide and tirzepatide show promising results in improving metabolic and liver health outcomes.
Article written by Lorenzo Cianni
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