SAN ANTONIO – The therapeutic Dark Ages of nonalcoholic steatohepatitis (NASH) are finally drawing to a close.
“NASH-specific therapies are coming soon – sooner than you think,” Naim Alkhouri, MD, predicted at the annual meeting of the American College of Gastroenterology.
And that, he added, has important implications for clinical practice. Physicians are going to need to step up their game with regard to screening and staging patients with nonalcoholic fatty liver disease to identify the right candidates for the coming effective treatments.
The new treatment era in NASH could dawn as soon as the spring of 2020, by which time the Food and Drug Administration is expected to issue a decision on obeticholic acid, an oral FXR agonist for which the agency has granted breakthrough therapy status. Intercept Pharmaceuticals has filed for marketing approval of obeticholic acid for NASH on the strength of the positive 18-month histologic results of the pivotal phase 3 REGENERATE trial, the first-ever successful phase 3 study of a medication for NASH, noted Dr. Alkhouri, a gastroenterologist at the University of Texas, San Antonio, and director of the Metabolic Health Center at the Texas Liver Institute.
At present there are no FDA-approved pharmacotherapies for NASH. The unmet medical need is huge, since NASH is now recognized to be a full-blown, burgeoning epidemic. NASH will soon become the No. 1 indication for liver transplantation in the United States. A full-throttle race is on to find effective therapies targeting the various dimensions of NASH, with more than 70 drugs now in phase 2 studies. These drugs collectively address all four mechanisms of the disease’s development and progression: the metabolic targets, perturbations in the gut-liver axis, liver inflammation, and fibrosis.
Moreover, even as the FDA considers the application for approval of obeticholic acid in NASH, at least four other investigational drugs are in pivotal phase 3 clinical trials. These include elafibranor, aramchol, resmetirom, and cenicriviroc.
Cenicriviroc is a dual CCR 2/5 receptor antagonist that targets the hepatic inflammation and fibrosis dimensions of NASH. It is now being evaluated in the phase 3 AURORA trial on the strength of the earlier positive phase 2b Centaur study, in which patients randomized to cenicriviroc were twice as likely to experience significant improvement in fibrosis as were placebo-treated controls.
Elafibranor, aramchol, and resmetirom employ different mechanisms of action to address the metabolic derangements of NASH. What they share in common is their aim to reduce the influx of free fatty acids from adipose tissue to the liver, and/or to inhibit lipogenesis from carbohydrate building blocks. In so doing, these medications should result in reduced hepatocyte injury and liver inflammation.
Elafibranor is a peroxisome proliferator-activated receptor alpha/delta agonist that achieved significant biopsy-proven reversal of NASH in moderate- or severely affected patients in the phase 2 GOLDEN study. The phase 3 RESOLVE IT trial is underway.
Aramchol is a first-in-class synthetic fatty acid/bile acid conjugate that inhibits stearoyl-CoA desaturate activity. It’s designed to improve insulin resistance and curb accumulation of triglycerides in hepatocytes. In the 52-week, phase 2 ARREST trial, oral aramchol at 600 mg/day was 4.7-fold more likely than was placebo to achieve NASH resolution without worsening of fibrosis. The drug is now in phase 3 in the ARMOR study.
Resmetirom is a selective thyroid hormone receptor–beta agonist. Activation of the beta receptor lowers LDL cholesterol, triglycerides, and liver fat, whereas activation of the alpha receptor has the unwanted effects of promoting bone loss, thyrotoxicosis, and arrhythmias. In phase 2, 75% of patients on high-dose resmetirom achieved at least a 30% reduction in hepatic fat by MRI at week 12, compared with 18% of placebo-treated controls. And 39% of the high-dose resmetirom group showed histologic resolution of NASH on a week-36 liver biopsy, as did a mere 6% of controls. The phase 3 MAESTRO randomized trial is underway.
Obeticholic acid addresses the gut-liver axis abnormalities present in NASH, especially the exuberant bile acid circulation.