An experimental combination of medications may be effective in a certain group of people with hepatitis C (HCV) who historically have failed to respond to conventional therapy. Doctors in an ongoing Phase 2 clinical trial are testing the combination of valopicitabine (val-oh-pih-SIT-uh-been)—also known by its code name NM283—along with peginterferon alfa-2b (PEG-Intron/Schering-Plough) in a group of patients with the genotype 1 strain of the virus.
The physicians released preliminary findings of the trial at a meeting of the European Association for the Study of the Liver (EASL) in mid-April.1
Valopicitabine is an oral nucleoside analog that works by inhibiting an enzyme that HCV uses to make copies of itself.2
Thirty patients were enrolled in the study, and thus far, nine of them have completed 24 weeks of therapy. According to the researchers led by Nezam Afdhal, MD, an associate professor of Medicine at Harvard Medical School, the patients taking combination therapy have achieved an average reduction in blood levels of HCV RNA by nearly 100 percent. Tests to detect the virus' genetic material (HCV RNA) as evidence of its existence are considered the most sensitive of those available. (Reductions of HCV RNA were reported to be 4.5 log 10 in these patients, on average. Early Viral Response, or EVR, is defined as having achieved at least a 2 log 10 drop in viral levels).3
Alternative for Genotype 1 Patients?
"This is the first time that we are seeing 24-week data for an antiviral drug directly targeting a specific enzyme of the hepatitis C virus," said Afdhal, who is also chief of Hepatology at Beth Israel Deaconess Medical Center in Boston. "These preliminary data are promising, and suggest that direct antiviral drugs, such as valopicitabine, could set a new treatment standard in hepatitis C by offering hepatitis C patients—particularly patients infected with HCV genotype 1—potentially improved clinical benefit with fewer side effects."
No serious adverse events have surfaced in the trial so far, according to Nefdhal's team.
The patients in the study were assigned at random to one of two treatment groups: 18 patients are receiving the combination of valopicitabine and peginterferon alfa-2b, while an additional 12 patients are receiving valopicitabine alone. Those taking combination therapy are receiving increasingly higher doses of valopicitabine once per day up to 800 mg per day by day 8, then are continuing this dose to the end of the trial. Pegylated interferon is then added at a dose of 1.0 mcg per kg (microgram per kilogram) of body weight starting on day 8. The trial is planned to continue for a total of 48 weeks.
Combination Treatment Showing More Promise
The investigators have also found that those in the combination group had better responses to treatment than those taking valopicitabine alone. Those taking valopicitabine and peginterferon alfa-2b at 12 weeks had reductions in viral load, on average, of 99.99% (-3.01 log10 IU/mL from the start of the study) compared to an 86.5% reduction (-0.87 log 10 IU/mL from the start of the study) in the group taking valopicitabine alone.
One patient has just begun therapy, and four patients quit the trial before the 12th week.
The patients have never been treated before for hepatitis C, and are infected with the genotype 1 strain of the virus—the most common and most difficult to treat.4
Unexpected Events
"We are very encouraged by the 24-week antiviral effect reported in patients receiving the combination of valopicitabine and pegylated interferon even though this trial was designed as a drug-drug interaction trial and not to maximize the potential therapeutic response in patients," explained Nathaniel Brown, MD, executive vice-president of Clinical Development and Chief Medical Officer at Idenix, the maker of valopicitabine, which is also sponsoring the trial. "We have designed the phase 2b trials to optimize potential outcomes of the combination treatment and we will be able to evaluate the full potential of valopicitabine from these trials."
Idenix initially launched this trial with the smaller number of patients to determine whether there were any drug-to-drug interactions between valopicitabine and pegylated interferon. They didn't expect to see the positive results that followed. "Subsequently, due to the encouraging hepatitis C RNA reductions observed in most patients during the first weeks of the trial in the combination arm," the study was extended, said Jean-Pierre Sommadossi, PhD, Chairman and CEO of Idenix, in a recent conference call to investors.
Idenix is sponsoring a second phase 2 trial to test the combination of valopicitabine and peginterferon alfa-2a (Pegasys/Hoffman LaRoche) compared to standard care in a group of 171 patients with the genotype 1 strain of HCV. There will be three treatment groups in this 24-week trial: valopicitabine monotherapy, valopicitabine plus peginterferon alfa-2a, or peginterferon alfa-2a plus the antiviral medication, ribavirin. Patient enrollment is expected to conclude this summer.
As a result of the early trial results, valopicitabine "appears to be adding substantial additional antiviral efficacy" compared to pegylated interferon alone, Sommadossi said. If trial results continue to be positive, a phase 3 study could be launched in early 2006, he said.
In the meantime, Brown said the next step will be to determine if the patients achieve sustained virological responses (SVR), defined as undetectable viral levels for a minimum of 6 months after treatment ends.5
1. Afdhal N, Rodriguez-Torres M, Lawitz E et al. Enhanced antiviral efficacy for valopicitabine (NM283) plus peg-interferon in hepatitis C patients with HCV genotype-1 infection: results of a phase IIa multicenter trial. 40th Annual Meeting of The European Association for the Study of the Liver (EASL). 2005 April 13-17. Paris, France. 40th Annual Meeting of The European Association for the Study of the Liver (EASL). 2005 April 13-17. Paris, France.
2. Idenix Pharmaceuticals. Nucleosides and Nucleoside Analogs. Available at: http://www.idenix.com/science/sci_nucleosides.html. Accessed April 21, 2005.
3. Hepatitis Neighborhood. Viral Response as a Predictor of Treatment Outcome. Available at: http://www.hepatitisneighborhood.com/content
/understanding_hepatitis/treating_hepatitisc_1389.aspx. Accessed April 21, 2005.
4. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements 2002 Jun 10-12;19(3):1-46.
5. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002 Sep 26;347(13):975-82.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
