Obeticholic acid promising against NASH liver damage

Last Updated: 2014-11-24

By David Douglas

NEW YORK (Reuters Health) - Obeticholic acid, a farnesoid X nuclear receptor ligand (FXR), shows clear benefit in some patients with non-cirrhotic, non-alcoholic steatohepatitis (NASH).

"FXR agonists are part of a whole set of new compounds, which are 'smart' anti-NASH drugs since their mechanisms of action target critical predisposing conditions and pathways of liver injury in NASH," said Dr. Brent A. Neuschwander-Tetri of Saint Louis University School of Medicine in St. Louis, Missouri.

"Obeticholic acid, the most advanced agent in this class, has shown clear histological efficacy, across the spectrum of histological lesions," he told Reuters Health by email. "The improvement in fibrosis is unprecedented for a relatively small trial and is therefore promising."

The findings were published online November 7 in The Lancet to coincide with a presentation at The American Association for the Study of Liver Diseases' meeting in Boston.

Dr. Neuschwander-Tetri and colleagues note in their report that obeticholic acid is a potent activator of the FXR receptor that reduces liver fat and fibrosis in animal models of fatty liver disease.

To investigate further, the researchers randomized 283 patients to obeticholic acid given orally (25 mg daily) or placebo.

Intention-to-treat analysis based on 219 patients eligible for a 72-week biopsy showed that 50 of 110 (45%) patients on active treatment had improved liver histology compared to 21% of 109 patients in the placebo group (p=0.0002).

However, 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared to nine (6%) of 142 in the placebo group. This led to the use of antipruritic medications or short periods of withholding treatment in some patients, and treatment discontinuation in one patient.

Also, serum cholesterol concentrations increased more in the obeticholic acid patients than in the placebo group.

Overall, said Dr. Neuschwander-Tetri, the findings "validate this method-of-action specific therapy for NASH. The lipid changes need to be studied in detail to understand if they are linked to cardiovascular risk and if they can be mitigated by simple, additional interventions."

Dr. Vlad Ratziu, author of an accompanying editorial, told Reuters Health by email that "Lifestyle modification defined as healthy eating habits and regular exercise remains the primary recommendation for patients with NASH. It is unlikely that any one medication will work for everybody with NASH."

However, added Dr. Ratziu of the Université Pierre et Marie Curie in Paris, "Obeticholic acid was clearly beneficial in some patients with NASH in (this) trial."

"Further studies," he concluded, "are needed to determine who might benefit the most. Further studies are also needed to determine the significance of the increased cholesterol levels and if these can be managed with statins."

The trial was partly supported by Intercept Pharmaceuticals.

SOURCE: http://bit.ly/1tpS06x and http://bit.ly/1yMhHTq

Lancet 2014.