Considerations for Resmetirom Use, Monitoring in Patients with MASH, Fibrosis

Mazen Noureddin, MD, MHSc

Credit: Houston Methodist

An expert panel recommendation is providing clinicians with an overview of considerations for identifying the intended population for treatment with resmetirom and proposing criteria for treatment discontinuation.¹

Historically, there have been no therapeutic options for patients with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH). However, the landmark US Food and Drug Administration approval of resmetirom (Rezdiffra) for noncirrhotic MASH with moderate to advanced fibrosis on March 14, 2024, presented patients and clinicians with a long-awaited first pharmacologic therapy for MASH. The accelerated approval hinges on verification and description of clinical benefit in ongoing confirmatory trials, expected to be accomplished with completion of the ongoing 54-month, randomized, double-blind placebo-controlled MAESTRO-NASH trial as well as a second ongoing outcomes trial evaluating progression to liver decompensation events in patients with well-compensated MASH cirrhosis.²

Using data from the first portion of the MAESTRO-NASH trial in addition to benchmarks set forth in the published literature, Mazen Noureddin, MD, MHSc, medical director of the Houston Research Institute and professor of medicine at Houston Methodist Academic Institute, and colleagues provide guidance on the identification of at-risk MASH patients who may benefit from initiating treatment with resmetirom and recommendations for the assessment of treatment response.¹

Selecting the Target Treatment Population

In order to select the appropriate patient for resmetirom, a MASLD diagnosis must first be made. Investigators acknowledged MAESTRO-NASH was designed and enrolled prior to the nomenclature change from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD) but pointed out the overlap between the old and new nomenclature is 99%.¹

Prior to the initiation of treatment, investigators note the importance of excluding other causes of liver disease. Although liver biopsy remains an important diagnostic option, particularly in instances of discordance between noninvasive tests (NITs), studies have demonstrated employing multiple NITs can increase precision for staging hepatic fibrosis and predict clinical outcomes.¹

If a historical liver biopsy within 12 months indicates MASH with stage 2 or stage 3 fibrosis, resmetirom may be considered irrespective of NIT values, other than if there is clinical or imaging evidence of portal hypertension. In the absence of a biopsy confirming MASH with stage 2 or stage 3 fibrosis, investigators propose using several non-invasive criteria.¹

Patients in MAESTRO-NASH were required to have ≥ 3 cardiometabolic risk factors and undergo prescreening vibration-controlled transient elastography (VCTE) within the past 3 months revealing a controlled attenuation parameter (CAP) of 280 dB/m or more and a liver stiffness measurement (LSM) of 8.5 kPa or more. Additional key inclusion criteria were histologic evidence of MASH with NAFLD Activity Score (NAS) ≥4 and F2 or F3 fibrosis.¹

Investigators acknowledged poor correlation between FIB-4 and identification of F2 or F3 disease in the MAESTRO-NASH population compared with the general population, asserting that FIB-4 may not be an ideal decision-making tool for initiating resmetirom or assessing treatment response since it was not developed for this context of use.¹

Although the target treatment population for resmetirom was anchored to a histological diagnosis in clinical trials leading to its FDA approval, investigators point out the impracticality of liver biopsy in clinical practice, instead highlighting the utility of NITs to identify eligible patients with moderate to advanced fibrosis (F2 to F3) and the need for verification with more than 1 NIT.¹

After assessing baseline liver disease and confirming the appropriateness of resmetirom treatment, patients should be dosed according to their weight and then monitored for safety and disease progression through regular liver chemistry tests and yearly liver stiffness measurements.¹

Patients Who Should Not Be Treated with Resmetirom

Investigators noted the benefit of resmetirom in patients with cirrhosis is still being assessed in a phase 3 cirrhosis trial and while it is likely safe in such patients, resmetirom should not be used in patients diagnosed with or suspected to have cirrhosis until full efficacy and safety data from the MAESTRO OUTCOMES trial are published.¹

Currently, investigators suggest excluding those with advanced cirrhosis based on the following criteria:

• History of fibrosis stage 4 on liver biopsy
• Imaging with signs of portal hypertension, ascites, portosystemic venous collaterals or varices, irrespective of liver biopsy.
• History of clinical manifestations of hepatic decompensation, irrespective of liver biopsy.
• Clinical or laboratory data suggesting portal hypertension or synthetic dysfunction

Additionally, investigators assert patients with early-stage MASLD with stage 0 or 1 fibrosis should not be considered for treatment with resmetirom since they are at low risk for adverse liver-related outcomes. Instead, such patients should be managed with lifestyle intervention and optimization of cardiometabolic disease, as outlined in the AASLD practice guidance.¹

Assessing Resmetirom Treatment Response

Citing evidence demonstrating an association between improvement in NITs, most notably liver enzymes and MRI-PDFF, and improvement in liver histology and liver clinical outcomes, investigators suggest the use of parameters that have been associated with histological response in the resmetirom program as well as other clinical trials. However, they also caution the predictivity of NITs in isolation should be interpreted with caution until further analysis from the MAESTRO-NASH trial is available.¹

The recommendations assert those with worsening values on VCTE (>30%) suggest the possibility of disease progression and have been linked to worse outcomes, while other data suggest an increase of 5 Kpa accompanied by a 20% increase in LSM measured by transient elastography is associated with a poorer prognosis. Based on MAESTRO-NASH, histological improvements may occur without corresponding changes in VCTE or liver enzymes, emphasizing the importance of considering MRI-PDFF or liver biopsy before labeling patients as unresponsive to treatment.¹

Until more robust data regarding NITs as reliable surrogates for histological improvement are available, investigators recommend full efficacy assessment at 12 months of therapy and breaking the overall assessment of response to resmetirom into 3 periods:

• Initial assessment for safety and tolerability at week 12
• Disease monitoring assessment at 6 months
• Efficacy monitoring at 12 months and annually

Safety, Other Considerations

Resmetirom has demonstrated a favorable safety and tolerability profile in clinical trials, with the most common adverse reactions induced by resmetirom being mild to moderate gastrointestinal disorders, mainly nausea and diarrhea, followed by constipation, abdominal pain, and vomiting. Investigators recommend checking liver enzymes 12 weeks after treatment initiation to assess for hepatotoxicity.¹

GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists are frequently used for the management of comorbidities in patients with MASH, and for patients currently managed with these therapies, investigators recommend initiating resmetirom in case of residual active MASH with stage 2 or 3 fibrosis. Existing GLP-1 receptor agonist therapy, which was present at baseline in ~14% of patients in the MAESTRO-NASH, did not appear to affect tolerability or efficacy of resmetirom, but due to the lack of evidence supporting the efficacy and safety of initiation of GLP-1-based therapy and resmetirom concomitantly, this is not recommended.¹

References

1. ^{Noureddin M, Charlton MR, Harrison SA, et al. Expert Panel Recommendations: Practical Clinical Applications for Initiating and Monitoring Resmetirom in Patients with MASH/NASH and Moderate to noncirrhotic Advanced Fibrosis. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2024.07.003}
2. ^{Brooks, A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed August 2, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash}