Non-invasive tests for fibrotic MASH for reducing screen failure in therapeutic trials

Abstract

Background & aims: Therapeutic trials in metabolic dysfunction-associated steatohepatitis (MASH) are hampered by a high 70-80% screen failure rate mostly because of the absence of fibrotic MASH on baseline liver biopsies, underscoring the need for better selection of candidates. We compared the performance of eight non-invasive tests, designed or not for the diagnosis of fibrotic MASH.

Methods: A total of 1,005 patients with histologically proven MASLD were included in five tertiary care centers. Three non-invasive tests developed for fibrotic MASH were evaluated: the simple blood test Fibrotic NASH Index (FNI), the specialized blood test MACK-3, and the elastography-based test FAST. Five non-invasive tests recommended for advanced fibrosis were evaluated as well: the simple blood test FIB-4, the specialized blood tests FibroTest and Enhanced Liver Fibrosis test (ELF™), and the elastography-based tests FibroScan and Agile3+. Fibrotic MASH was defined as MASH with MASLD activity score ≥4 and fibrosis score F ≥2.

Results: Among simple blood tests (n = 1,005), FNI had a significantly higher area under the receiver operating characteristic (AUROC) for fibrotic MASH than FIB-4 (0.709 [0.677-0.741] vs. 0.662 [0.628-0.695], p = 0.019). Among elastography-based tests (n = 817), FAST had a significantly higher AUROC (0.774 [0.743-0.806]) than FibroScan (0.728 [0.694-0.763], p = 0.013) and Agile3+ (0.708 [0.672-0.744], p = 0.004). Among specialized blood tests (n = 545), MACK-3 had a significantly higher AUROC (0.772 [0.734-0.811]) than FibroTest (0.615 [0.568-0.663], p <0.001) and ELF (0.700 [0.656-0.744], p = 0.028). Sequential combination (FAST then Agile3+; MACK-3 then ELF) identified a subset including one-third of patients in whom the false-positive rate was only 30%.

Conclusions: Sequential combinations using first-line tests designed for fibrotic MASH improves the identification of candidates for MASH therapeutic trials.

Impact and implications: Drug development in metabolic dysfunction-associated steatohepatitis (MASH) is hampered by a high screen failure rate, one of the main reasons being the absence of MASH and significant fibrosis (fibrotic MASH) on the baseline liver biopsy, a key inclusion criterion in MASH therapeutic trials. Non-invasive tests represent an attractive opportunity to better select candidates for these trials, but most of them have been developed for advanced fibrosis and the new tests designed for the diagnosis of fibrotic MASH remain poorly validated. In this work, we demonstrate that the tests specifically designed for fibrotic MASH are more accurate for this diagnostic target than the tests currently recommended and initially developed for advanced fibrosis. We propose sequential combinations that will facilitate the identification of patients with fibrotic MASH in need of treatment, and their inclusion in MASH therapeutic trials.

Keywords: Fibrotic MASH; MASH; MASLD; Non-invasive tests.

Graphical abstract

Fig. 1

Rate of patients included in the diagnostic intervals of the non-invasive tests using the diagnostic thresholds for fibrotic MASH. The diagnostic thresholds for FAST and MACK-3 (in yellow) were those previously published as they were confirmed to provide the targeted sensitivity and specificity (see Table 3). The diagnostic thresholds for the other tests were recalculated and optimized in the study population to reach 90% sensitivity (rule-out threshold) and 90% specificity (rule-in threshold). ELF test, Enhanced liver fibrosis test; FIB-4, Fibrosis-4; FNI, Fibrotic NASH Index; VCTE, vibration-controlled transient elastography.

Fig. 2

FAST/Agile3+ and MACK-3/ELF algorithms for the diagnosis of fibrotic MASH. ELF, Enhanced Liver Fibrosis test; MASH, metabolic dysfunction-associated steatohepatitis; NPV, negative predictive value; PPV, positive predictive value.

Fig. 3

Prevalence of MASLD lesions as a function of the three diagnostic intervals of FAST/Agile3+ and MACK-3/ELF algorithms. ELF, Enhanced liver fibrosis test; MAS, MASLD activity score; MASLD, metabolic dysfunction-associated steatotic liver disease.