High HCV response rates with daclatasvir/asunaprevir: phase III data

Last Updated: 2014-08-06

By Anne Harding

NEW YORK (Reuters Health) - A combination of daclatasvir plus asunaprevir yielded high rates of sustained virological response (SVR) in treatment-naive patients with hepatitis C 1B infection, including those with cirrhosis, in a multinational phase III trial.

Response rates were nearly as high in patients who either hadn't responded to peginterferon alfa (IFN) plus ribavirin, could not tolerate the drug combination, or who were ineligible to take it, according to Dr. Michael Manns of Hannover Medical School in Hannover, Germany and colleagues.

They reported the findings online July 28 in The Lancet.

"In this study it really showed that there is almost no significant side effects beyond the placebo," Dr. Manns told Reuters Health in a telephone interview. "The drawback is that it's a 24-week treatment."

Both drugs are being developed by Bristol-Myers Squibb and are expected to be approved in the U.S. and Europe in September, Dr. Manns said.

If the drug combination is approved, he noted, it will be the first oral regimen including two direct-acting antiviral agents (DAA) made by the same company. Daclatasvir would also be the first non-structural protein 5A (NS5A) inhibitor to be approved, Dr. Manns said. "Now with this drug we are able to intervene with three different steps in the hepatitis C life cycle."

In the HALLMARK-DUAL study, Dr. Mann and colleagues at 116 sites in 18 countries enrolled 307 treatment-naive patients, 205 patients who had not responded to IFN and ribavirin, and 235 patients who were either medically ineligible for IFN and ribavirin, could not tolerate the drug combination, or both. A third of patients had cirrhosis.

Treatment-naive patients were initially randomized to daclatasvir 60 mg once a day and asunaprevir 100 mg twice daily, or placebo, for 12 weeks. Afterward, the patients in the active-treatment group continued on the drug combination for 12 more weeks, while the placebo group patients were switched to a different daclatasvir plus asunaprevir study.

Everyone else - i.e., the non-responders and ineligible, intolerant, or ineligible/intolerant patients - received open-label daclatasvir plus asunaprevir for 24 weeks.

Ninety percent of patients in the treatment-naive group had a sustained virological response, as did 82% of the non-responders and 82% of the ineligible/intolerant group, the researchers found.

During the initial 12 weeks of the study, adverse event rates and grade 3 or 4 laboratory abnormalities were similar for the placebo and active-treatment groups. Rates of serious adverse events were 6% in the treatment-naive group, 5% among non-responders, and 7% in the ineligible/intolerant group. Adverse events leading to discontinuation occurred in 3%, 1%, and 1% of patients in each group, respectively.

Response rates were similar for patients with cirrhosis or without cirrhosis, except in patients with significant portal hypertension and thrombocytopenia, Dr. Manns noted.

Signature-resistance-associated variants (RAV)s in NS5A or NS3 sequences were the only baseline predictors for treatment failure in the HALLMARK-DUAL trial, Dr. Ed Gane of Auckland City Hospital in New Zealand noted in an editorial accompanying the study.

"This association suggests that testing for these RAVs should be done before asunaprevir plus daclatasvir are started and that this regimen should be avoided in affected patients," Dr. Gane writes.

Several other DAAs have recently been approved or awaiting approval, Dr. Gane noted. "When combined with targeted testing and treatment of populations who transmit infection...these DAA regimens might eventually eliminate HCV infection," he adds. "The only barrier to achieving this goal will be the ability to access these new therapies."

In developing countries with high rates of HCV, IFN-based treatments may still be the treatment of choice, given the costliness of DAAs, according to Dr. Gane. He concludes: "As almost 75% of all patients with HCV infection reside in economically deprived regions of eastern Europe, Asia, and the Middle East, consideration should be given to discounting prices in those regions. Eradication of HCV infection worldwide will only be achievable through universal access to HCV testing and new DAA regimens."

SOURCE: http://bit.ly/UYh8ri

Lancet 2014.