Biomarkers and diagnostics are playing an ever-increasing role in drug development. Personalized medicines, defined as drug therapies used alongside specific diagnostic tests, topped 40% of all FDA approvals in 2018. Across biopharma, drug developers increased their utilization of selection biomarkers, significantly improving the probability of success for their clinical programs.1, 2 While the first, and perhaps best known examples are in oncology, biomarkers as candidate diagnostics are becoming increasingly important in complex, multifactorial chronic diseases including non-alcoholic fatty liver disease (fat accumulation in the liver not due to alcohol overconsumption, or NAFLD) and non-alcoholic steatohepatitis (NASH).
Advancing Precision Medicine for NAFLD/NASH
The statistics are staggering. Nearly one-third of U.S. adults, and nearly one-quarter of adults worldwide, are thought to have NAFLD.3 Depending upon a complex combination of genetic and environmental risk factors, between 11% and 40% of individuals with NAFLD will progress to NASH, in which inflammation, hepatocyte ballooning and fibrosis markedly affect liver function.3 The rise in pediatric NAFLD is particularly alarming, as it is estimated that nearly a quarter of children diagnosed with NAFLD (10% of the pediatric population) have already progressed to NASH.4 With NASH patients significantly predisposed to hepatocellular carcinoma,5 and NASH already the leading cause of liver transplantation among females and the second leading cause overall,6 the gravity of this burgeoning epidemic is clear.
None of this has been lost on drug developers; dozens of biopharma companies, from small to large, have recognized that new treatments for NASH are a significant opportunity to improve outcomes of large, global populations.
Despite the large numbers of individuals thought to be affected, patient identification remains one of the key challenges in NASH drug development. Most clinical trials use a variety of liver biopsy-based criteria to identify and stratify eligible patients for enrollment.7 However, biopsies are invasive, uncomfortable, and risky for patients, and expensive for investigators (an estimated $3,000-$5,000 per patient).8,9 Recent publications have highlighted variability in biopsy-based disease diagnosis and staging introduced by both the fine needle sampling, as well as intra- and inter-reader differences between interpreting pathologists.10-11 This variability
has contributed to challenges inherent in measuring the impact of new candidate therapies, and is being recognized as untenable for future clinical care once new NASH drugs are available.12-14
The challenge with liver biopsies highlights the need for noninvasive tools for refining clinical trial enrollment, as well as predicting and monitoring therapeutic response. Non-invasive tests can also serve as important, accessible tools for clinicians in patient education, relevant for both clinical trial and clinical care setting. If patient screening could begin with a noninvasive test, results from which were used to then characterize an individual as either at higher vs. no or minimal risk of disease progression, a prospective pool of trial enrollees could be enriched prior to undergoing biopsy.
By avoiding unnecessary biopsy screening in a larger population, this approach would be significantly less expensive and far safer for patients. It is notable that, in the future, noninvasive testing, including circulating biomarkers and imaging methodologies are widely anticipated to replace liver biopsy for NASH diagnosis in clinical care, simply due to the scale of this global health problem.12-16
Katherine Landschulz, PhD
Cardiovascular and Metabolic Disease Therapeutic
Area Lead, Biomarker Solution Center, Covance
Margery Connelly, PhD, MBA
Strategic Director, LabCorp Diagnostics R&D
1. Personalized Medicine Coalition. Personalized Medicine at FDA: A Progress & Outlook Report, 2018. http://www.personalizedmedicinecoalition.org/Resources/Personalized_Medicine_at_FDA_An_Annual_Research_Report
2. BIO, Biomedtracker, Amplion. Clinical Development Success Rates 2006-2015, 2016. https://www.bio.org/sites/default/fi les/legacy/bioorg/docs/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf
3. Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018; 15: 11-20
4. The National Institute of Diabetes and Digestive and Kidney Diseases. Definition & Facts of NAFLD & NASH in Children. https://www.niddk.nih.gov/healthinformation/liver-disease/nafl d-nash-children/defi nition-facts
5. Anstee QM, Reeves HL, Kotsiliti E, et al. From NASH to HCC: current concepts and future challenges. Nature Reviews Gastroenterology & Hepatology 2019; 16: 411–428
6. Noureddin M, Vipani A, Bresee C, et al. NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications for Liver Transplant and Ethnic and Gender Variances. Am J Gastroenterol 2018;1131649-1659
7. Rockey DC, Caldwell SH, Goodman ZD, et. al. Liver Biopsy. Hepatology 2009; 49:1017-44.
8. CostHelper Health Rx; How Much Does a Biopsy Cost? https://health.costhelper.com/biopsy.html
9. JCP Editors. Increasing Use of Percutaneous Liver Biopsy Accompanied by Growing Costs. Journal of Clinical Pathways 2016:2:10-13.
10. Ratziu V, Charlotte F, Heurtier A, et al. Sampling Variability of Liver Biopsy in Nonalcoholic Fatty Liver Disease. Gastroenterology 2005; 128: 1898-1906.
11. Juluri R, Vuppalanchi R, Olson J, et al. Generalizability of the nonalcoholic steatohepatitis Clinical Research Network histologic scoring system for nonalcoholic fatty liver disease. Journal of Clinical Gastroenterology, 2010; 45:55-58
12. Zhang E, Wartelle-Bladou C, Lepanto L, et al. Cost-Utility Analysis of Nonalcoholic Steatohepatitis Screening. Eur Radiol. 2015; 25: 3282–3294.
13. Shetty A and Syn WK, Health and Economic Burden of Nonalcoholic Fatty Liver Disease in the United States and Its Impact on Veterans. Fed Pract. 2019; 36: 14-19.
14. Armstrong MJ and Marchesini G, Referral pathways for NAFLD fibrosis in primary care – No longer a “needle in a haystack.” Editorial, Journal of Hepatology 2019; 71: 246–248
15. Castera L, Friedrich-Rust M, Loomba R. Noninvasive Assessment of Liver Disease in Patients with Nonalcoholic Fatty Liver Disease. Gastroenterology 2019;156:1264–1281
16. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA Brunt EM, Sanyal, AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67:328-357