Noninvasive biomarkers are an essential piece in the NASH drug development pipeline
Kay Pepin, Ph.D. is Manager, Research Translation for Resoundant
For the moment, needle biopsy remains the standard for liver fibrosis diagnosis. However, many stakeholders including patients, clinicians, and regulators recognize its limitations for NAFLD/NASH. The global prevalence of NAFLD is currently estimated at 24% , which means a staggering 1.9 billion people are living with NAFLD. Of those with NAFLD, 468 million (25%) are at risk for NASH/advanced fibrosis and will require periodic fibrosis assessment. Given this staggering prevalence, it is impossible for hospitals to perform liver biopsies on this scale due to practical, ethical, and cost considerations. Noninvasive alternatives are urgently needed to assess fibrosis longitudinally on a population level.
There are no pharmacological agents approved to treat NASH - yet. Despite the poor clinical outcomes associated with NASH, there are very few options to treat this disease. The currently available treatment options include lifestyle modifications, bariatric surgery, off-label pharmacological treatments (ex: vitamin E), and liver transplantation. However, a number of pharmaceutical candidates are showing promise, including Intercept’s obeticholic acid, or OCA, and may soon be available.
What is a reliable noninvasive test? A number of quantitative imaging biomarkers (QIB) are demonstrating promise as highly accurate and reliable noninvasive tests for NAFLD/NASH. Ideally, the QIB must also be both sensitive and specific for those parameters relevant to NASH, particularly fibrosis staging. In the case of NASH clinical trials, a test should have high sensitivity to rule in the presence of advanced fibrosis. If sensitivity is low, there can be an unacceptable number of False Negatives – resulting in the study being underpowered by losing patients who would otherwise qualify for the trial. Conversely, a QIB should also have high specificity for reliably excluding patients that do not have the target condition. If specificity is too low, the trial could end up conducting too many downstream, confirmatory biopsies (both costly and invasive). Or if the QIB is the primary biomarker used to enroll patients, the trial could have too many False Positives, thus including patients that do not actually have advanced fibrosis. This is harmful to the trial results by potentially causing unintended and artificial response effects (patients in the placebo arm may appear to have improved upon follow up). For trial sponsors, the FDA’s BEST (Biomarkers, Endpoints, and Other Tools) Resource is an excellent reference and should be used throughout the entire biomarker development process.
FDA efficacy endpoints for Phase III trials focus on histologic improvement in steatohepatitis and/or fibrosis. These include NASH resolution and no worsening of liver fibrosis OR a ≥1 stage improvement in fibrosis and no worsening of NASH. Of these disease pathways (NASH and fibrosis), only significant fibrosis has been shown to increase the risk of liver-related morbidity and mortality . Therefore, therapies that can halt or reverse fibrosis remain a priority for regulators and translational scientists. Consequently, there is a parallel need for a noninvasive biomarker of fibrosis that can be used to diagnose, stage, and monitor fibrosis in these Phase III trials.
There is a critical need for noninvasive diagnostic biomarkers in adolescents. Pediatric NAFLD is a growing problem and is the most frequent cause of chronic liver disease in children with a global prevalence of 7.6% . The drug development landscape for pediatric NAFLD is expanding, along with the need for noninvasive biomarkers. Elastography is an excellent option in this patient population because it is accurate, noninvasive, and widely available. However, more work is needed to determine appropriate thresholds in pediatric and adolescent populations .
A path forward. Effective strategies to noninvasively diagnose fibrosis and monitor pharmacodynamic response in NASH trials are needed, as liver fibrosis is the main determinant of prognosis in NAFLD/NASH. Stakeholders in this field – from patient groups to clinicians – recognize the pitfalls of relying on biopsy for clinical trial work and for eventually meeting patient needs on a population level. While a number of NITs appear promising, MRE for fibrosis and inflammation assessment and MRI-PDFF for steatosis meet many of the requirements of QIBs, and are particularly well-poised to meet the needs of trial sponsors. Aside from their well-validated role as a Diagnostic biomarker, additional evidence is being rapidly gathered for their use as surrogate endpoints and for tracking pharmacodynamic response in NASH trials. Altogether, both trial sponsors and patients may soon benefit from highly accurate and noninvasive MRI biomarkers in the search for treatments for NAFLD/NASH.
1. Younossi, Z., et al., Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nature Reviews Gastroenterology & Hepatology, 2018. 15(1): p. 11-20.
2. Hagström, H., et al., Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol, 2017. 67(6): p. 1265-1273.
3. Nobili, V., et al., NAFLD in children: new genes, new diagnostic modalities and new drugs. Nat Rev Gastroenterol Hepatol, 2019. 16(9): p. 517-530.
4. Ferraioli, G., R.G. Barr, and J.R. Dillman, Elastography for Pediatric Chronic Liver Disease: A Review and Expert Opinion. J Ultrasound Med, 2020.