esmetirom, a novel therapy for metabolic dysfunction-associated steatohepatitis (MASH), the progressive subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), was recently approved by the US Food and Drug Administration (FDA). Blue Cross Blue Shield of America (BCBSA) and other payers subsequently issued approval criteria for resmetirom that include specified thresholds for quantitative results from clinical imaging studies: i.e., magnetic resonance elastography (MRE) and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF). This is one of the first examples where quantitative results from a clinical imaging study (i.e., an imaging assay) are being required to be used as a companion diagnostic.

Imaging as an Assay

Although clinical imaging has become an essential component of personalized medicine, the traditional subjective, qualitative interpretations of clinical imaging exams, based on visual inspection of the images, result in marked inter- and intra-reader variability. However, because all clinical imaging studies today are digital, it is very feasible to extract objective, reproducible, quantitative results from clinical imaging exams. These constitute quantitative imaging biomarkers (QIB), defined as “objectively measured characteristics derived from in vivo images as indicators of normal biological processes, pathogenic processes, or response to a therapeutic intervention.” QIBs are conceptually the same as laboratory assays of tissue or fluid specimens. Therefore, the same principles, standards, and procedures that have evolved for laboratory assays can and should be applied to imaging assays.

Although quantitative results from imaging studies have been used as endpoints in clinical trials for over two decades, their use in routine clinical decision-making has been more limited.

MASH

Prior to 2023, MASH was known as non-alcoholic steatohepatitis (NASH). It is the liver disease which occurs when fat builds up in hepatocytes (steatosis) and results in inflammation and damage. Unlike alcohol-related liver disease, MASH is primarily driven by metabolic factors, such as obesity, insulin resistance, high blood pressure, and high cholesterol levels. If left untreated, MASH can progress to more severe liver conditions, including cirrhosis and liver failure.

Diagnosis typically involves blood tests, imaging studies, and often a liver biopsy to assess the extent of liver damage. Although biopsy remains the best means of assessing the individual components of MASLD, there are limitations to the use of biopsy including patient risks and the meticulous technical processing necessary for optimal specimen interpretation. Therefore, quantitative blood and noninvasive imaging tests have been developed to replace biopsy.

Liver fibrosis is staged using several scoring systems, most commonly from zero to four. Stage 2 or greater is considered significant fibrosis and stage 3 or greater is considered advanced fibrosis.

Treatment of MASH

The management of MASH focuses on addressing the underlying metabolic dysfunction including lifestyle modifications such as adopting a healthy diet, increasing physical activity, and managing weight. In addition, on March 14, 2024, the FDA approved resmetirom for the treatment of MASH with moderate to advanced liver fibrosis (stages F2 to F3). The approval was based on the drug’s ability to improve liver fibrosis and resolve MASH when used alongside diet and exercise. Resmetirom works by acting as a partial agonist of thyroid hormone receptor beta (THR-β) in the liver, which helps reduce liver fat accumulation and improve liver function. THR-β action is key to proper liver function, including regulation of mitochondrial activity such as breakdown of liver fat and control of the level of normal, healthy mitochondria. People with MASH have reduced levels of THR-β receptor activity in the liver.

The accelerated approval of resmetirom was based on results from the phase 3 MAESTRO-NASH trial that enrolled 1,759 patients with biopsy-confirmed NASH (i.e., MASH). Following 52 weeks of treatment, resmetirom demonstrated statistically significant improvement compared to placebo on two primary endpoints: NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points) with no worsening of fibrosis, and an improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score.

Although the primary endpoint in the MAESTRO-NASH study was liver biopsy, the study included quantitative imaging technologies, MRE and MRI-PDFF, as secondary endpoints. These are well-validated technologies already in use in clinical practice, widely available in the US, and recognized in practice guidelines. They are also already covered by insurance providers such as CMS for clinical assessment of liver fibrosis and/or liver fat. The combined cost for MRE and PDFF scans in the US is in the range of $200.

The FDA approval for resmetirom requires clinicians to rule in a relatively specific patient profile: moderate to severe fibrosis (F2-F3) with moderate to severe steatosis (S2-S3). To accomplish this, the BCBSA guidelines recommend a two-step approach:

Step 1: Rule in MASH with fibrosis, for which clinicians can use MRE values between 2.0 and 4.0 kPa; and

Step 2: Rule in liver fat, using MRI-PDFF values of ≥8.

Note that the resmetirom eligibility requirements for prescription and reimbursement do not include a liver biopsy for diagnosis. Instead, the noninvasive blood and quantitative imaging tests serve as companion diagnostics. These evaluation criteria for prescription and reimbursement provide an evidence-based approach for clinical eligibility largely mirroring the entry criteria for MAESTRO-NASH. It is also worth noting that the FDA labeling for resmetirom indications specifically excludes F4 patients (evidence of cirrhosis was an excluding factor for the MAESTRO-NASH trial).

The published report of the MAESTRO-NASH trial states: “One of the key findings of the study is the clinical validation in the setting of a clinical trial that MRE provides the highest accuracy and positive predictive value for detecting patients with NASH and stage 2 or 3 fibrosis who need pharmacologic therapy.” The study report also noted that only MRI-PDFF demonstrated suitable accuracy in the MAESTRO-NASH trial for diagnosing both MASLD and MASH. Thus, to reliably target therapy to the appropriate patients, and monitor efficacy of therapy, it is essential that the quantitative results from MRE and PDFF be accurate and reproducible. Guidelines for image acquisition and processing, to achieve specified levels of precision, have been published (e.g. MRI Quiba Profile and MRE Quiba Profile). Radiology departments must adhere to these protocols, just as it is necessary for pathology laboratories to follow standardized practices.

Conclusion

The resmetirom/MASH example shows how quantitative imaging (QI) has the potential to remove the need for an invasive biopsy and provide objective information for monitoring efficacy. But one of the impediments to widespread clinical adoption of quantitative imaging biomarkers is the absence of an external accreditation or certification program for quantitative imaging quality assurance. In clinical practice today, imaging measurements differ based on numerous factors such as system manufacturer, software version, or imaging protocol. This variability reduces the generalizability of, and confidence in, quantitative imaging test results. Although numerous medical, radiological, and standards organizations recognize and support the power of QI and the need for rigorous QA/QC and metrology standards, no single US organization currently has the oversight capabilities, breadth, mandate, or funding to effectively implement and regulate QI. Our healthcare system needs an oversight program for QI, similar to the Clinical Laboratory Improvement Amendments (CLIA) which ensure quality laboratory testing.

The combination of PDFF and MRE is an essential companion diagnostic for appropriate use of resmetirom. PDFF and MRE are the only MRI tests capable of providing the necessary diagnosis for resmetirom reimbursement approval. PDFF is the gold standard for liver fat assessment. MRE is the gold standard for fibrosis assessment, and the only MRI biomarker capable of distinguishing between stages of fibrosis, notably the resmetirom targeted population of F2-F3. Use of this companion diagnostic will increase access to this novel treatment, minimize false positives, and ensure accurate and effective therapy.