Abstract
On March 14, 2024, the US Food and Drug Administration (FDA) has granted accelerated approval to resmetirom for treating noncirrhotic nonalcoholic steatohepatitis (NASH) with liver scarring, making it the first and the only drug approved for NASH treatment. This review aims to enhance understanding of the mechanisms of this novel drug together with the pathology of NASH, potentially aiding in future NASH therapies.
Introduction
Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), characterized by not only fatty liver but also hepatitis. Due to its increasing prevalence, NAFLD has emerged as the leading cause of chronic liver disease worldwide. (Albhaisi & Sanyal, 2018; Hamid et al., 2022) In order to meet the unmet need for effective pharmacological therapy, clinical trials have been conducted on a number of candidates, including acetyl-coA carboxylase inhibitors and diacylglycerol acyltransferases. Unfortunately, none of them have received approval from the FDA or EMA. Currently, there are no medication approved for NASH, and treatment options for NASH remain limited to lifestyle modification at best. (Harrison et al., 2023)
Recently, however, a groundbreaking advance in the treatment of NASH appeared. On March 14, 2024, the US FDA has granted accelerated approval to resmetirom (Rezdiffra) for the treatment of NASH with liver fibrosis. (Krause et al., 2018) After undergoing numerous trials targeting the regulation of thyroid hormone signaling, resmetirom, a THR- β-selective agonist, arose as the first to succeed. Examining the pathophysiology of NASH and the mechanism of resmetirom would be instrumental in understanding the NASH drug development.
Discussion
NASH develops differently from alcoholic steatohepatitis (ASH). Whereas alcohol consumption and following cell damages are the major regulatory pathway of ASH, thyroid hormones play a crucial role in the progression of NASH. NASH patients show decreased levels of thyroid hormone activity in their livers, implicating the potential of thyroid hormone receptor agonists. (Harrison et al., 2023)
Thyroid hormones have a significant affect on lipid metabolism; thyroid hormones decrease serum cholesterol by affecting synthesis and elimination of cholesterol.(Sinha et al., 2019) Thyroid hormones are essential for the regulation of hepatic triacylglycerol (TAG) synthesis, fatty acid β-oxidation, phospholipid metabolism, and cholesterol metabolism. Diminished thyroid hormone signaling can lead to symptoms resembling hypothyroidism: weight gain and elevated serum TAG and LDL cholesterol levels.(Duntas, 2002) Such symptoms, and also fatty liver, appears not only with decreased thyroid hormone levels but also with decreased conversion rate from T4 to T3. T3 is the major active form of thyroid hormone and shows greater affinity with thyroid hormone receptor (THR) compared to T4.(Wejaphikul et al., 2019) If T3/T4 ratio decreases, thyroid hormone signaling via THR would diminish.
In addition to changes in the T3/T4 ratio, there are several possible theories that can explain the decrease of thyroid hormone signaling in NASH patients. One potential suggestion is that expression of THR, especially THR- β, decreases. Whereas THR-α dominates in many organs including heart and bone, THR- β is the major isoform in the liver. Therefore, decreased expression of THR- β would have critical impact on thyroid hormone signaling, including lipid metabolism. Another suggestion is conversion of T4 to the inactive metabolite rT3, also called reverse T3.(Harrison et al., 2021) rT3 weakly binds to the thyroid hormone receptors but never activates them. Rather, it diverts T4 away from T3 production by working as an inactive end-product of thyroid hormone metabolism.(Halsall & Oddy, 2021) Indeed, it is believed that all these mentioned mechanisms contribute to the decrease in thyroid hormone signaling in patients with NASH.
Resmetirom has proven its efficacy and safety through the MAESTRO-NAFLD-1 trial, regulating the mentioned pathways. Serum T4 level decreased probably due to increased conversion of T4 to T3.(Sinha et al., 2019) Serum rT3 level also decreased, strengthening the thyroid hormone signaling.(Harrison et al., 2019)
In the context of regulating the thyroid hormone signaling, thyroxine treatment might seem to be a tempting option. Unfortunately, thyroxine treatment failed show significant improvement in NASH management. Scientists are focusing on other mechanisms than direct hormone therapies. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that has proven its efficacy through phase 2b trial and is now working on its phase 3 trial.(Francque et al., 2021) Efruxifermin (AKR-001 or AMG876) is a fusion protein molecule that combined Fc of human antibody and fibroblast growth factor 21 (FGF21), which also has shown its efficacy through phase 2b trial.(Puengel & Tacke, 2023)
Conclusion
In conclusion, the emergence of resmetirom as the first FDA-approved medication for NASH with liver fibrosis marks a significant advancement in the field of hepatology. By targeting thyroid hormone signaling pathways, resmetirom offers a novel approach to addressing the complex pathophysiology of NASH. However, further research is warranted to fully understand the long-term efficacy and safety of resmetirom, as well as to explore additional therapeutic avenues beyond direct hormone therapies. The ongoing development of alternative treatments such as Lanifibranor and Efruxifermin underscores the continuous efforts to address the unmet medical needs of patients with NASH. As our understanding of NASH pathogenesis deepens and novel therapeutic agents emerge, there is hope for improved outcomes and quality of life for individuals affected by this debilitating liver disease.
Reference
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