Obeticholic Acid for NASH: Revolution or Just a Ripple?

Updated July 29, 2020 // Editor's note: This commentary has been updated to include that Intercept Pharmaceuticals received a Complete Response Letter on June 29, 2020, regarding its New Drug Application for obeticholic acid for the treatment of fibrosis due to nonalcoholic steatohepatitis.

In the middle of the last decade, nonalcoholic steatohepatitis (NASH) overtook chronic hepatitis C virus infection as the leading indication for liver transplantation wait-listing in US adults born between 1945 and 1965. If predictive modeling proves accurate, NASH is unlikely to surrender this dubious distinction anytime soon. Owing to an increased rate of diabetes and obesity in an aging population, the prevalence of NASH is forecasted to surge 63% between 2015 and 2030.

As the clinical burden wrought by NASH has become increasingly clear, so too has the failure to develop effective treatments against it. There are currently no US Food and Drug Administration (FDA)-approved pharmaceutical therapies for this pervasive and deadly disease, despite there being over 200 active clinical trials of nonalcoholic fatty liver disease treatments. There was cautious optimism, however, that 2020 would mark the year that this begins to change.

Obeticholic acid (OCA), which is already approved for the management of primary biliary cholangitis, is currently the only investigational therapy to receive a breakthrough therapy designation from the FDA for use in NASH. Although its ultimate approval has been delayed by the COVID-19 pandemic and a request for additional data, it is still possible that it may be approved by the end of the year.

The Long Road to an Approved Treatment in NASH

Because nonalcoholic fatty liver disease is a slowly progressive injury, it would take several years and thousands of patients for drug development trials to show an improvement in mortality and morbidity in this area. Instead, they must rely on surrogate endpoints for liver-related outcomes. Multiple longitudinal studies have found that the degree of fibrosis is the only histologic feature that predicts mortality in NASH. Thus, stabilization and reversal of fibrosis are paramount for a drug to be considered successful.

This has proven to be a difficult task, with multiple agents failing to attain this elusive goal. The most recent example of this occurred this past May, when elafibranor, a dual agonist of the peroxisome proliferator–activated receptors alpha and delta, failed to demonstrate a significant effect after interim analysis of the RESOLVE-IT phase 3 trial. This left one drug candidate ahead of the pack: the first-in-class farnesoid X receptor (FXR) agonist OCA.

The FXR-fibroblast growth factor 19 axis found in the liver plays a role in the regulation of metabolism when stimulated. Activation of this receptor can reduce hepatic fibrosis and inflammation. FXR regulates lipid and glucose metabolism through a complex pathway involving multiple target genes, cytochromes, and enzymes, but ultimately when activated it converts cholesterol into bile acids, puts glucose into storage, and reduces storage of fat.

OCA is a potent and selective agonist of FXR. A 2013 analysis showed that short-term administration of OCA reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Two years later, the multicenter, randomized, placebo-controlled FLINT trial demonstrated that OCA led to histologic improvement in NASH.

Promising Results, Nagging Questions

An interim analysis of a phase 3 trial published late last year suggests that OCA might improve fibrosis in a portion of patients affected by NASH. In this multicenter, double-blind study conducted across 332 centers in 20 countries, patients were randomly assigned to receive placebo, OCA 10 mg/d, or OCA 25 mg/d. Liver biopsies were obtained at baseline and at month 18 or at the end of treatment.

Liver fibrosis improvement was reached more frequently and with statistical significance in the groups taking OCA. Improvement in fibrosis was seen in 23% of patients taking 25 mg OCA, 18% taking 10 mg OCA, and 12% in the placebo group. Liver function tests (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, and alkaline phosphatase) performed every 3 months while on treatment also showed improvement.

Although this is the first phase 3 trial to show a benefit in fibrosis in patients with NASH, there are still areas of concern.

Despite OCA being well tolerated across all groups, pruritus (most of which occurred during the first 3 months) led to treatment discontinuation in 9% of the 25-mg OCA group, compared with <1% in the placebo and 10-mg OCA groups. In addition, OCA can elevate low-density lipoprotein (LDL) cholesterol levels. Patients receiving OCA in the phase 3 trial were more likely to require a statin compared with placebo, which tempered the LDL increases. However, increasing LDL in a group of individuals at risk for cardiovascular disease–related mortality may not be ideal. Statins have also been shown to affect hepatic fibrosis, making the effects of OCA harder to interpret. Finally, the FDA issued a boxed warning after incorrect dosing of OCA in patients with primary biliary cholangitis resulted in liver injury. Because the current trial recruited patients with fibrosis stage F2-F3, ensuring safety and efficacy in those with cirrhosis is essential.

In addition, on June 29, 2020, the FDA issued a Complete Response Letter to Intercept Pharmaceuticals that requested additional post-interim analysis to support the accelerated approval of OCA. Despite the improvement in liver fibrosis, the FDA did not feel the existing data demonstrated adequate benefit to outweigh potential risk and emphasized the importance of long-term outcome. This decision not only is a setback to Intercept Pharmaceuticals but also sends a message to other pharmaceutical companies with therapeutic agents in development that there will be a high bar for a surrogate endpoint to gain FDA approval.

Patients with significant fibrosis have limited options, and OCA (if approved) could become a breakthrough in our fight toward improving outcomes in NASH. It remains to be seen whether it will be a remedy for the millions affected by NASH, or an additive therapy that doesn't take the place of lifestyle interventions but nonetheless gets us one step closer to our ultimate treatment goals.

Jason B. Kramer, MD, MS, is a fellow in gastroenterology/hepatology at Rush University Medical Center in Chicago.

Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair for the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.

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