Drug Improves Nonalcoholic Steatohepatitis, With Caveats

Ricki Lewis, PhD

November 12, 2014

A bile acid derivative, obeticholic acid (OCA), improves nonalcoholic steatohepatitis (NASH), according to a study published online November 7 in the Lancet.

Incidence of NASH has increased with the obesity epidemic, affecting people with diabetes, insulin resistance, and/or hypertriglyceridemia. "The condition can smoulder for decades without the patient realizing it. A liver is very resilient, so can harbor a lot of inflammation for a long time without specific symptoms," Scott L. Friedman, MD, chief, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.

Steatosis is a fatty liver; steatohepatitis is progression to inflammation. NASH diagnosis requires liver biopsy and lacks treatment other than vitamin E and thiazolidinediones for patients who do not have diabetes. NASH is a common cause of primary liver cancer and end-stage liver disease and is the third most common indication for liver transplant.

OCA is a synthetic version of chenodeoxycholic acid, and it works by activating the farnesoid X nuclear receptor. Bile acids bound to the receptor lower gluconeogenesis and circulating triglycerides and promote insulin sensitivity.

In a pilot study, and in earlier animal studies, OCA decreased liver fibrosis and fat accumulation. "It was developed primarily to stimulate bile flow in patients with primary biliary cirrhosis," said Dr Friedman. Researchers subsequently recognized the potential value in treating NASH.

The FLINT Trial

Prof Brent A. Neuschwander-Tetri, MD, from Yale University in New Haven, Connecticut, and colleagues tested OCA in adults with NASH in the multicenter, double-blinded, placebo-controlled, randomized Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) trial.

At eight clinical centers, 283 participants with histologically proven NASH received either 25 mg oral OCA daily (n = 141) or placebo (n = 142). Primary outcomes were decrease of at least two points on the nonalcoholic fatty liver disease (NAFLD) activity score, based on liver histology (steatosis, hepatocellular ballooning, and lobular inflammation), and no worsening of fibrosis.

The trial was planned to continue for 72 weeks, with follow-up 24 weeks later. The researchers also planned an interim analysis of change in alanine aminotransferase levels at 24 weeks. However, a planned interim analysis showed significant improvement with OCA in the primary endpoint, leading to early termination of treatment in the remaining patients, as well as no 72-week biopsy. (Of the 64 patients who did not have a final biopsy, 31 received OCA and 33 placebo.)

Of those patients who did undergo the 72-week biopsy, 50 (45%) of 110 patients in the OCA group had improved liver histology between baseline and 72 weeks compared with 23 (21%) of 109 such patients in the placebo group (relative risk, 1.9; 95% confidence interval, 1.3 - 2.8; P = .0002).

Patients in the OCA group also showed more improvement in individual markers of disease, including fibrosis, hepatocellular ballooning, steatosis, and lobular inflammation, compared with those in the placebo group (change from baseline, −1.7 vs −0.7; P < .0001). However, the improvements did not translate into a larger proportion of patients who had a resolution of NASH compared with the proportion with resolution in the placebo group (22 [22%] of 102 vs 13 [13%] of 98; P = .08).

The investigators also saw improvements in secondary endpoints with a drop in serum alanine aminotransferase and aspartate aminotransferase levels in the active drug group compared with the control group. However, the enzyme levels rebounded after treatment withdrawal.

Similarly, more patients in the OCA group had improvements in body weight and fasting serum insulin concentrations compared with those in the placebo group, but the improvements reverted to baseline levels after treatment.

"The drug elicited improvement in tissue features of the disease, including inflammation, death of hepatocytes, and the amount of fat in liver biopsy, and fibrosis, which is even more encouraging," said Dr Friedman.

Improvements, but at a Cost

Pruritus and elevated low-density lipoproteins/lowered high-density lipoproteins emerged as concerns. Pruritus developed in 33 (23%) of 141 patients in the OCA group compared with nine (6%) of 142 patients in the placebo group (P < 0.0001). Moreover, pruritus was severe enough to require treatment in some OCA-treated patients and to lead to withholding of study drug for some individuals.

Researchers also noted increases in total serum cholesterol and low-density lipoprotein cholesterol, as well as a decrease in high-density lipoprotein cholesterol. The lipid changes appeared to be transient, occurring in the first 12 weeks of treatment and resolving after that


In an accompanying commentary, Vlad Ratziu, MD, PhD, from the Institute for Cardiometabolism and Nutrition, Université Pierre et Marie Curie, Assistance Publique Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France, notes that the results are interesting and warrant longer, larger trials with OCA. He cautions, however, that safety will be a major issue for any NASH drug candidate.

"Any drug candidate for non-alcoholic steatohepatitis needs to have a very good tolerability and safety profile, as it targets a population of mostly asymptomatic patients with numerous metabolic and cardiovascular comorbidities," he writes. "In FLINT, obeticholic acid increased [low-density lipoprotein] and slightly decreased [high-density lipoprotein] concentrations, with both effects diminishing after the initial weeks of therapy. The clinical significance of these findings is unclear."

"The data from the trial with obeticholic acid are quite impressive. OCA represents a major step forward in the therapy of fatty liver disease," Paul J. Gaglio, MD, medical director of adult liver transplantation at Montefiore Medical Center and Albert Einstein College of Medicine in New York City, told Medscape Medical News. It will be used in combination with other therapies, including vitamin E and omega 3 fatty acids, and likely also statins and other therapies to treat dyslipidemias, he added.

Funding for this study was received from the National Institute of Diabetes and Digestive and Kidney Diseases and Intercept Pharmaceuticals Inc. Dr. Friedman consults for Angion Biomedica Corp, sanofi-aventis, BiOrion Technologies BV, GlaxoSmithKline, Galectin Therapeutics, and Conatus Pharmaceuticals, among others, and is an advisory board member for Nitto Denko Corporation. Various other authors have financial relationships with Genentech/Roche, Nimbus Discovery, Boehringer Ingelheim, Bristol-Myers Squibb. Merck, Gilead, KineMed, Promedior, Daiichi Sankyo, Janssen, Galmed, Siemens, Conatus, Ikaria, Salix, Takeda, Astellas, Novartis, Galectin, Abbott, Norgine, Roche, Nitto Denko, Genfit, Immuron, Tobira, Mochida, Islet Sciences, Taiwan JvPharmaceuticals, Intercept, Enterome, Lilly, Aegerion, AbbVie, Shire, Metabolon, AstraZeneca, Japan Tobacco, NuSI Foundation, Vertex, Evidera, Trio Health, Tekmira, Pfizer, Rottapharm, European Society of Pathology, and Synageva. Dr Ratziu consults for Abbott, AstraZeneca, Galmed, Genfit, Gilead, Intercept, Roche-Genentech, and Tobira. Dr Gaglio has disclosed no relevant financial relationships.

Lancet. Published online November 7, 2014. Article abstract, Commentary extract


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