Neil Canavan

November 11, 2011

November 21, 2011 (San Francisco, California) — Patients with hepatitis C virus infection who failed interferon treatment showed no symptom improvement or slowing of disease progression with the popular herbal extract silymarin (milk thistle), compared with placebo, in a randomized trial. The results were presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.

"Silymarin is widely used as a botanical treatment for liver disorders," said Michael W. Fried, MD, professor of medicine and director of hepatology at the University of North Carolina at Chapel Hill. The extract is a mixture of flavonolignans, and is approximately 50% silybin A and B. Silymarin has demonstrated anti-inflammatory and immunomodulatory properties in vitro, as well as effects on the HCV core and CS5A expression in the replicon system.

Evidence for the clinical effects of silymarin are not well validated, Dr. Fried noted. Clinical studies of the compound have been conducted in patients with cirrhosis, alcoholic liver disease, and viral hepatitis, but results have been inconsistent. Previous studies were confounded by a lack of well-defined efficacy end points, the inclusion of heterogeneous populations of patients with liver disease, and the use of nonstandardized silymarin preparations.

In the SYNCH study, a prospective, randomized, double-blind, placebo-controlled trial, Dr. Fried, and colleagues randomized 154 patients with HCV infection, who had previously failed interferon-based regimens, to treatment with a standardized silymarin preparation (Legalon, Rottapharm Madaus) or placebo. "The customary oral dose is 140 mg [3 times daily]," said Dr. Fried, "but in accordance with findings from our phase 1 trial, doses 3- to 5-fold higher were chosen for SYNCH to provide the highest likelihood of finding a therapeutic benefit."

Patients received a total dose of 700 mg 3 times daily in 5 capsules, 420 mg 3 times daily in 5 capsules (2 capsules being placebo), or placebo in 5 capsules 3 times daily for 24 weeks. Twelve weeks of off-treatment observation followed.

Study end points at 24 weeks were an alanine transaminase (ALT) level of at least 45 IU (defined as the upper limit of normal) or a serum ALT decline of at least 50%, to 65 IU (1.5 times the upper limit of normal). Secondary outcomes included changes in ALT, HCV RNA measures, adverse events, adherence to treatment, pharmacokinetics, and quality-of-life measures.

In the cohort, average age was 54 years, median body mass index was 29 kg/m², 75% of patients were white, 27% had evidence of cirrhosis, and 45% had previously used silymarin to alleviate HCV-related symptoms.

"Adherence in the trial was excellent," reported Dr. Fried. "Up to 98% of participants maintained more than an 80% dosing adherence throughout the 24 weeks of treatment," which is no small accomplishment, considering the pill burden.

Adherence did not translate into efficacy. Only 1 patient in the placebo group and 2 in each of the silymarin groups achieved ALT levels of at least 45 IU. Only 3 patients in the silymarin groups and 2 in the placebo group achieved an ALT decrease of at least 50%.

"The results for secondary end points also showed no significant differences between treatments," said Dr. Fried. Change in serum ALT was negligible during the course of the 24-week treatment, and there were no changes in HCV RNA levels. There were also no changes in measures of quality of life.

Silymarin was well tolerated. The most common adverse events were mild and were gastrointestinal-related.

Still Hope for IV Administration?

The negative results for silymarin came as a disappointment to some; others suggested there is room for further consideration. Researchers in a previous study used an intravenous (IV) formulation of silymarin, administering 10 to 20 mg/kg daily to HCV-infected interferon nonresponders for 14 days. Results of this small investigation demonstrated a significant reduction in HCV RNA levels, with levels becoming undetectable in 7 of 16 patients.

With the pharmacokinetic data from SYNCH showing a lower serum concentration than that achieved with IV administration, why weren't higher oral doses used?

'We had to balance the levels of drug known to affect HCV with the pill burden," said Dr. Fried. To match the IV levels would have just been too many pills. "There is discussion about creating a more potent oral formulation, and at least one group is looking at boosting silymarin levels with another botanical formulation," but for now, when shopping for this particular herbal remedy, it's buyer beware.

Dr. Fried reports serving as a consultant for Genentech, Tibotec, Vertex, Merck, Abbott, and Pharmasset; receiving grants and other research support from Genentech, Tibotec, Vertex, Merck, Anadys, BMS, and Abbott; serving as an advisor for GlaxoSmithKline; and being a shareholder in Pharmasset.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 228. Presented November 8, 2011.

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