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Drug for Nonalcoholic Steatohepatitis Shows Promising Results

However, effects on cholesterol levels cloud its benefits

An experimental drug aimed at treating a common liver disease showed promising results and potential problems in a clinical trial funded by the National Institutes of Health (NIH).

The FLINT study found that people with nonalcoholic steatohepatitis (NASH) had improved liver health while taking obeticholic acid (OCA), including decreased inflammation and fat in the liver and decreased body weight compared with people receiving a placebo. However, OCA was also associated with increases in itching and total cholesterol.

The findings of FLINT (the Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial) were published online in The Lancet. FLINT was sponsored by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Liver health improved in 45% of people on OCA versus 21% of the placebo group (relative risk, 1.9; 95% confidence interval, 1.3–2.8; P = 0·0002). While OCA did not eliminate liver disease, NIDDK officials termed its effects promising.

FLINT, a double-blind, placebo-controlled, parallel group, randomized clinical trial, enrolled 283 people at eight U.S. centers who were 18 years of age and older and had been diagnosed with definite or borderline NASH. One group one took 25 mg of OCA daily and one group received a placebo.

Investigators intended for the groups to receive the drug or placebo for 72 weeks, with an additional 24 weeks of follow-up. However, a planned interim analysis for safety and efficacy showed that OCA had significant beneficial effects on NASH-related liver health. The primary outcome measure was improvement in centrally scored liver histology, defined as a decrease in nonalcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. The analysis showed improved liver histology in 50 of 110 patients in the OCA group compared with 23 of 109 patients in the placebo group. The relative change in alanine aminotransferase was −24% (95% confidence interval, −45 to −3).

The analysis also found unanticipated increases in total cholesterol and low-density lipoprotein-cholesterol and decreased high-density lipoprotein-cholesterol in the OCA group — notable because NASH patients are already at higher risk for cardiovascular diseases. Further research is needed to understand the potential effect of OCA on cholesterol.

NIDDK decided to stop treatment but continue the study, move all patients into the follow-up phase, and perform no additional liver biopsies. Improvement in liver enzymes and adverse cholesterol effects were not sustained after stopping OCA.

NASH has no approved treatment and is typically managed with weight loss through diet and exercise. Its major feature is fat in the liver, along with inflammation and damage. Over time, these may lead to loss of liver function, the need for liver transplantation, and death. New cases of NASH have grown alongside the obesity epidemic. NASH is the third leading diagnosis requiring U.S. liver transplantation.

OCA is a bile acid derivative that is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease.

Sources: National Institutes of Health; November 7, 2014; Lancet, November 7, 2014.

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