Direct Antivirals Can Beat HCV Without Interferon
BOSTON -- The first clinical trial of direct antiviral drugs against hepatitis C virus (HCV) without interferon was a success, researchers said, although the FDA currently won't permit such a strategy in the U.S.
A combination of two investigational antivirals, one an HCV protease inhibitor and the other targeting the HCV polymerase, led to dramatic reductions in viral loads during a 13-day pilot trial, according to Edward Gane, MD, of Auckland Clinical Studies in Auckland, New Zealand, where the study took place.
The drugs' lead developer, Roche, announced that Phase II testing would begin in early 2010. But for now, the studies must be conducted outside the U.S. because of an FDA policy requiring HCV drug testing to include interferon-alfa. Along with ribavirin (Rebetol), interferon is the only agent currently proved to control HCV infection. The FDA believes it is unethical to withhold it from infected patients, though researchers close to the situation said Roche was talking with the agency about relaxing its stance.
Gane, speaking here at the American Association for the Study of Liver Diseases' annual meeting, reported data from a placebo-controlled Phase Ib trial called INFORM-1, testing various dosing regimens of two oral drugs co-developed by Roche and two other companies.
The drugs were RG7128, a nucleoside agent inhibiting the HCV polymerase enzyme, and RG7227, a small-molecule compound that inhibits the virus's protease enzyme.
Gane said the combination was attractive for several reasons. The differing targets and mechanisms discourage development of resistance, and in vitro studies confirmed that RG7128 suppressed emergence of resistance to the protease inhibitor.
There is no cross-resistance between molecules, he added, and the drugs have different routes of elimination and no signs of pharmacokinetic interaction or overlapping toxicities.
The clinical study encompassed seven treatment arms, four of which involved RG7128 given twice daily and RG7227 three times daily in treatment-naive patients. Gane reported results from those regimens earlier this year at a European liver disease meeting.
He focused his presentation here on the other three treatment arms, in which both drugs were given twice daily and the 30 patients involved included people who had previously shown incomplete (partial or relapsing) or null responses to standard treatment with interferon and ribavirin as well as previously untreated patients.
Eight patients in each group received active drugs for 13 days, and two received placebo pills. The RG7128 dose was 1,000 mg twice daily in all groups. RG7227 was given at 600 mg twice daily to the incomplete initial responders, while those with null responses or who were treatment-naive received 900 mg twice daily.
Median reductions in HCV viral loads from baseline, measured in log10 increments on day 13, were as follows:
• Incomplete initial responders: 4.0 (range 2.5 to 6.0)
• Null initial responders: 4.9 (range 3.5 to 5.3)
• Treatment-naive: 5.1 (range 3.0 to 5.9)
Gane said half of the previously-treated patients in both groups had viral loads suppressed below the lower limit of quantification. This level of virologic response was seen in seven of eight treatment-naive patients.
HCV RNA was undetectable in five treatment-naive patients, two of the null responders, and one of the partial responders.
Gane said there was no evidence of resistance to the drugs in any of the seven INFORM-1 treatment groups. Adverse effects did not appear to differ between placebo and the active drug, although the study was not powered to detect differences. No severe adverse events were noted, Gane said.
Scott Friedman, MD, president of AASLD and a hepatologist at Mount Sinai School of Medicine in New York City , said the prospect of an interferon-free, all-oral drug regimen for HCV was intriguing.
"Interferon is a nasty drug," he said, adding that patients with advanced disease often can't tolerate it.
On the other hand, Friedman said, there is some chance that treatment based solely on direct antiviral drugs could provoke resistance to those agents -- resistance that would not develop if interferon were also given.
That outcome could leave patients worse off, even taking the toxicities of interferon into account, he suggested.
Primary source: Hepatology
Gane E, et al "Combination therapy with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor in HCV: Safety, pharmacokinetics, and virologic results from INFORM-1" Hepatology 2009; 50: 394A-395A.