Resmetirom (Rezdiffra): The First Approved MASH Drug and MAESTRO-NASH Trial
Resmetirom becomes the first approved treatment for MASH. A deep dive into its THR-β selectivity mechanism and the full Phase 3 MAESTRO-NASH results, including secondary endpoints like LDL-C and liver enzymes.
The Long-Awaited First Approval: Resmetirom
In March 2024, the U.S. FDA approved Madrigal Pharmaceuticals' Resmetirom (brand name Rezdiffra) for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3). This approval was granted under the Accelerated Approval pathway based on surrogate endpoints (histological improvement), and continued approval for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials.
With this approval, the first-ever approved treatment has finally emerged in a field that has long been devoid of specific medications. This marks a historic milestone in liver disease research, achieved approximately more than 40 years after the disease concept was first proposed in 1980.
(Reference: MAESTRO-NASH ClinicalTrials.gov Identifier: NCT03900429)
Please note that Rezdiffra is approved for use in conjunction with diet and exercise.
Mechanism of Action: Why THR-β?
Resmetirom is not just a metabolism modifier. Its most defining characteristic is its high selectivity for the thyroid hormone receptor-beta (THR-β).
The Division of Roles Between THR-β and THR-α
Thyroid hormone receptors (THR) primarily exist as two subtypes, with significantly different distributions and roles in the body.
- THR-β: Primarily distributed in the liver. It functions as a "master regulator" of lipid metabolism (lipolysis, mitochondrial biogenesis, autophagy). However, in the livers of MASH patients, this THR-β function is known to be impaired (a state similar to thyroid hormone resistance).
- THR-α: Primarily distributed in the heart (increasing heart rate and contractility) and bone (bone turnover). Excessive stimulation leads to arrhythmias and osteoporosis.
"Safety" and "Efficacy" Brought by Selectivity
Thyroid hormone mimetics developed in the past were discontinued due to cardiotoxicity caused by their action on THR-α. Resmetirom possesses high selectivity for THR-β (with extremely low binding affinity for THR-α), specifically turning "on" metabolic signals only in the liver. This allows it to successfully avoid side effects in the heart and bones while powerfully resolving lipotoxicity within the liver, thereby breaking the chain of inflammation and fibrosis.
MAESTRO-NASH Trial: The Deciding Factor for Approval
The Phase 3 clinical trial (MAESTRO-NASH) enrolled 1,050 participants, with 966 patients with fibrosis stages F1B, F2, and F3 randomized in a 1:1:1 ratio. In this trial, Resmetirom achieved both of its Primary Endpoints.
1. MASH Resolution
The proportion of patients achieving "MASH resolution without worsening of fibrosis" (improvement in NAS score):
- 100mg Group: 29.9% (vs Placebo 9.7%, p<0.001)
- 80mg Group: 25.9% (p<0.001)
2. Fibrosis Improvement
The proportion of patients achieving "Fibrosis improvement of at least one stage without worsening of MASH":
- 100mg Group: 25.9% (vs Placebo 14.2%, p<0.001)
- 80mg Group: 24.2% (p<0.001)
These results demonstrate that Resmetirom is a rare drug capable of simultaneously intervening in both the "steatohepatitis" and "fibrosis" pathological processes.
Important Secondary Endpoints
Also notable in the MAESTRO-NASH trial are the significant improvements in cardiovascular risk factors and liver injury markers. Since the leading cause of death in MASH patients is cardiovascular disease (CVD), these effects are extremely important for prognosis improvement.
Reduction in LDL Cholesterol (LDL-C)
Resmetirom showed potent lipid-lowering effects (at Week 24).
- LDL-C: Reduced by -16.3% in the 100mg group (vs almost no change in Placebo).
- Apolipoprotein B (ApoB): Important indicators of atherosclerosis in MASH, such as ApoB and triglycerides, were also significantly reduced. This was confirmed regardless of concurrent statin use.
Improvement in Liver Enzymes
Major enzymes reflecting hepatocellular injury also improved dramatically and early after initiation of administration (at Week 52).
- ALT: In the 100mg group without concurrent statin use, a maximum reduction of -43% from baseline has been reported (Harrison SA et al. NEJM 2024).
- AST, GGT: Significant reductions were similarly observed, corroborating the subsiding of liver inflammation.
Safety Profile and Management of Side Effects
Gastrointestinal Symptoms
The main adverse events were diarrhea (approx. 30%) and nausea (approx. 20%).
- These were predominantly mild to moderate, and the majority were transient, occurring primarily during the initial weeks of treatment.
- Discontinuation of the trial due to severe gastrointestinal symptoms was rare.
Impact on Bone and Cardiovascular System
Demonstrating its high THR-β selectivity, no increase in heart rate or increase in fracture risk was observed. Additionally, the impact on thyroid function (TSH, free T4) was minimal, and it did not induce hypothyroidism.
Future Outlook
Resmetirom is a groundbreaking new drug approved for use in combination with diet and exercise, but it does not show efficacy in all patients (fibrosis improvement rate is approx. 25%). Moving forward, the urgent development of technologies to identify "Resmetirom Responders" prior to treatment using non-invasive tests (NITs: FIB-4, ELF, FibroScan, etc.) and biomarkers (PRO-C3, etc.) is essential. Long-term outcome trials are also underway, and if its efficacy in preventing progression to cirrhosis and suppressing liver failure events is demonstrated, its position will become solidified.