Biomarker Panels Meet Criteria for Diagnostic Enrichment Qualification in Stage 1 of NIMBLE Project

Arun Sanyal, MD

Credit: Virginia Commonwealth University

Results from stage 1 of the Non-Invasive Biomarkers for Metabolic Liver Disease (NIMBLE) project’s circulating biomarker workstream demonstrated NIS4, the ELF test, and FibroMeter VCTE met prespecified criteria for further qualification efforts for regulatory approval.

A collaboration between NIMBLE along with the adult clinical centers and the data coordinating center of the NASH Clinical Research Network (NASH CRN) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the study evaluated the performance metrics of several biomarker panels for the diagnosis of nonalcoholic steatohepatitis (NASH), at-risk NASH, and varying severity of fibrosis in individuals with nonalcoholic fatty liver disease (NAFLD).¹

“Currently, diagnosing early-stage MASH requires a liver biopsy, which is a painful, invasive and expensive process for patients. MASH is a serious disease, and once the liver starts to scar up, the risk of cirrhosis, liver cancer and death rises, often leaving transplant the only treatment option for patients,” said Arun Sanyal, MD, chair of the division of Gastroenterology, Hepatology and Nutrition at Virginia Commonwealth University.²

To assess the efficacy of noninvasive tests for liver disease, investigators evaluated the diagnostic performance of NIS4, OWLiver, PROC3, ELF, and FibroMeter VCTE in an observational cohort with full spectrum of NAFLD. Participants were selected from four NASH CRN study cohorts, which included 4,094 participants. Investigators excluded 2,479 of these participants from the present study because of age, lack of samples, or lack of evaluable liver biopsies and selected consecutive patients for each stage of disease. In total, 1,073 patients were included in the analysis.¹

The 5 blood-based panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver), or fibrosis stages >2, >3 or 4 (ELF test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over both alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Serum samples collected in a noninterventional registry (DB1 and DB2) and baseline samples from the PIVENS and FLINT clinical trials across 12 NIDDK NASH CRN clinical sites were evaluated.¹

Upon analysis, NIS4 met the prespecified criteria for further qualification efforts for diagnostic enrichment for NASH, high NAS, and at-risk NASH. The ELF test and FibroMeter VCTE also met the criteria for further qualification efforts for the diagnosis of clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) and cirrhosis (stage 4) in individuals with NAFLD.¹

NIS4 had an AUROC of 0.81 (95% confidence interval [CI], 0.78–0.84) for at-risk NASH, which was superior to both ALT (AUROC, 0.726) and FIB-4 (AUROC, 0.704) (P < .001 NIS4 versus both). For diagnosing NASH, NIS4 had an AUROC of 0.83 (95% CI, 0.8–0.86) and was superior to ALT (AUROC = 0.67) for this intended use. NIS4 had an AUROC of 0.874 for identifying clinically significant fibrosis in individuals with NAFLD and was significantly superior to FIB-4 (P < .001). The AUROC (0.815; 95% CI, 0.786–0.844) for NIS4 was significantly superior to ALT (0.726) for diagnosing high NAFLD activity (P < .001).¹

ELF and FibroMeter VCTE had AUROCs of 0.828 and 0.841, respectively, for the identification of clinically significant fibrosis in individuals with NAFLD, with investigators pointing out both outperformed the FIB-4 (P < 0.01; P < 0.001). The AUROCs of ELF and FibroMeter VCTE for the diagnosis of advanced fibrosis were 0.835 and 0.841, respectively (both P < .001 versus FIB4). The AUROCs for the diagnosis of cirrhosis were 0.855 for ELF (P < 0.001) and 0.897 for FibroMeter VCTE relative to FIB-4 (P = 0.002).¹

“This brings us a step closer to having simple blood-based tests that can be ordered virtually in any clinical setting and will provide access to care to patients,” Sanyal said. “Such a step will facilitate our ability to identify those most at risk of outcomes and target them for therapy. It will also serve as a foundation for prognostic, disease monitoring and treatment-response biomarker development,” Sanyal said.²

References

1. Sanyal A, Shankar S, Yates K, et al. Diagnostic performance of circulating biomarkers for non-alcoholic steatohepatitis. Nat Med (2023). https://doi.org/10.1038/s41591-023-02539-6
2. Virginia Commonwealth University. VCU liver institute director leads review of noninvasive tests that could be alternatives to painful biopsies. EurekAlert! Published September 7, 2023. Accessed September 7, 2023. https://www.eurekalert.org/news-releases/1000543