The First FDA-Approved NASH Treatment Arrives After Almost Half a Century in the Making
The FDA has approved Madrigal Pharmaceuticals’ Rezdiffra™ (resmetirom) for nonalcoholic steatohepatitis (NASH). The approval is a watershed event, marking a historic turning point in the long-standing quest to find an effective treatment for the millions of Americans afflicted by this devastating condition.
A targeted treatment for NASH has eluded pharmaceutical scientists for nearly a half century…
The specific indication is a crucial one in the NASH disease spectrum: NASH with liver fibrosis—a severe stage of non-alcoholic fatty liver disease (NAFLD) that precedes progression to the point of causing significant scarring—referred to as cirrhosis.
Since NASH was first described by Ludwig et al1 in 1980, the development of drugs for NAFLD/ NASH has been marked by numerous challenges and failures. The key factors contributing to these failures include the complexity of the disease pathophysiology, the diversity of the patient population, the lack of reliable biomarkers, and various safety concerns.
…key factors contributing to these failures include the complexity of the disease pathophysiology, the diversity of the patient population, the lack of reliable biomarkers, and various safety concerns.
The most recent failure was Intercept Pharmaceuticals’ obeticholic acid (sold under the brand name Ocaliva)—a highly selective agonist for the farnesoid X receptor (FXR), which impacts glucose and lipid metabolism, as well as liver inflammation. Despite showing promise in early trials, obeticholic acid underwent a series of regulatory challenges, culminating in the FDA convening an advisory committee meeting of outside experts in May of 2023. Concerns regarding the drug’s safety profile, especially the risk it posed to liver health, was a significant factor that ultimately contributed to the FDA’s decision to deny approval.
Resmetirom Gets Under the Hood of NASH
The holy grail in drug development is to discover disease-modifying drugs that address the underlying pathophysiology and alter the clinical course of the disease. Resmetirom gets under the hood, acting as a key—a selective agonist—that fits into a specific lock found predominantly in the liver: the thyroid hormone receptor-beta (THR-β). THR-β is believed to be a key driver of altered lipid metabolism in fatty liver disease that ultimately drives inflammation and fibrosis. By restoring normal THR-β signaling in the liver, resmetirom can stimulate increased hepatic fatty acid β-oxidation, thereby lowering lipotoxic lipids. The result is a reduction in accumulated liver fat—hepatic steatosis—and inflammation, which are key factors in the progression of NASH. This targeted approach for managing NASH fulfils a long-standing unmet need.
Resmetirom gets under the hood, acting as a key—a selective agonist—that fits into a specific lock found predominantly in the liver: the thyroid hormone receptor-beta (THR-β ).
Madrigal’s Positive Phase 3 Results Spur Filing for Approval
In December 2022, Madrigal Pharmaceuticals announced positive results from their pivotal Phase 3 MAESTRO-NASH trial. The study met both co-primary endpoints at 52 weeks, which were:
- NASH resolution with no worsening of fibrosis: This was defined as having no liver cell ballooning, inflammation scores of 0 or 1, and a ≥2 point reduction in the NAFLD Activity Score, with no worsening of fibrosis.
- Fibrosis improvement: A ≥1-stage reduction in fibrosis with no worsening of NAFLD Activity Score.
The trial, published Feb 8th in the New England Journal of Medicine, demonstrated that resmetirom was effective at both doses tested (80 mg and 100 mg), with significant improvements compared to placebo, and was safe and well tolerated. In addition, resmetirom improved liver enzymes and markers of lipid metabolism.
In the MAESTRO-NASH clinical trial, resmetirom significantly reduced atherogenic lipid levels, including low-density lipoprotein cholesterol (LDL-C)—an effect that has the potential to impact the constellation of metabolic syndromes associated with NAFLD/NASH, strengthening the case that resmetirom is a disease-modifying drug.
…resmetirom significantly reduced atherogenic lipid levels, including low-density lipoprotein cholesterol (LDL-C)—an effect that has the potential to impact the constellation of metabolic syndromes associated with NAFLD/NASH…
Those data prompted Madrigal to file a New Drug Application (NDA) on July 17, 2023, seeking accelerated approval for resmetirom for the treatment of NASH with liver fibrosis. Although resmetirom has now been granted accelerated approval, Madrigal will need to confirm clinical benefit. To do so, the participants in MAESTRO-NASH will be followed for 54 months to determine whether resmetirom reduces disease progression to cirrhosis and improves overall survival.
Uncertainty Remains Around Clinical Trial Endpoints
Despite the NASH field forging ahead with many clinical trials—including Madrigal’s MAESTRO-NASH—there remains a degree of uncertainty regarding regulatory endpoints. This is largely due to an incomplete understanding of the histological alterations that occur as fibrosis progresses, leading to a lack of agreement among pathologists.
Our recent blog detailed a workshop that the US FDA recently convened to engage experts in the field to discuss biomarkers and noninvasive testing for NASH clinical trials (and beyond). There was a consensus around the need for further development and validation of imaging and circulating (blood) biomarkers to measure parameters like liver stiffness, fat content, and fibrosis.
Non-invasive Tests Will Be Integral in the New NASH Clinic
The limitations of liver biopsy, including its invasive nature, potential for complications, and variability in results, underscore the necessity for alternative methods to diagnose and select appropriate patients for treatment.
Noninvasive testing is being developed to fill this gap and will be a significant part of the new NASH clinic, enabling: (1) accurate screening and diagnosis, (2) appropriate prescribing decisions, and (3) monitoring of treatment responses in the real-world setting. The combination of targeted, disease-specific therapies together with non-invasive testing will be critical to address the growing global epidemic of NAFLD/NASH.
Noninvasive testing is being developed to fill this gap and will be a significant part of the new NASH clinic, enabling: (1) accurate screening and diagnosis, (2) appropriate prescribing decisions, and (3) monitoring of treatment responses in the real-world setting.
Potential for a GLP-1 Combination Approach for NASH Management
Due to the multiple mechanisms at play in NAFLD/NASH, additional treatments that address this complex pathology will be needed. To that end, researchers are investigating GLP-1 (glucagon-like peptide-1) receptor agonists, which have shown promise in reducing liver fat content and serum liver enzyme levels3.
The combination of GLP-1 receptor agonists with resmetirom could offer a synergistic approach to NASH treatment. GLP-1 agonists aid in glucose control and weight loss, while resmetirom targets liver fat and inflammation. This dual action could enhance the overall therapeutic effect, as seen in Madrigal’s Phase 3 trial where fibrosis improvement was noted alongside GLP-1 therapy.
The combination of GLP-1 receptor agonists with resmetirom could offer a synergistic approach to NASH treatment.
Future research may focus on the potential for combining these therapies to provide a more a holistic NASH management strategy, which would be particularly beneficial for patients with coexisting metabolic disorders.
A landmark drug approval, non-invasive testing, and combination therapies in the pipeline all catalyze the advancement of NASH disease management.
Muzamil Saleem, PhD
Associate Scientific Director
Muz is passionate about helping biotech and pharma companies communicate the journey of their groundbreaking medicine from lab bench to patient. He combines diverse experience from a neuroscience research career, scientific consulting, and a tenure in healthcare equity research on Wall Street into his current scientific services role at ProEd Regulatory. A philosophy of positioning effective scientific communication to all types of audiences is central to Muz’s work. Connect with Muz on LinkedIn.
References
- Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55(7):434-8. (https://www.ncbi.nlm.nih.gov/pubmed/7382552).
- Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD and type 2 diabetes mellitus – mechanisms and treatments. Nat Rev Gastroenterol Hepatol 2021;18(9):599-612. DOI: 10.1038/s41575-021-00448-y.
- Mantovani A, Petracca G, Beatrice G, Csermely A, Lonardo A, Targher G. Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials. Metabolites 2021;11(2). DOI: 10.3390/metabo11020073.