By Michael Smith , North American Correspondent, MedPage Today
Published: November 02, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.
BOSTON -- Adding the investigational polymerase inhibitor ANA958 to standard care speeded up the clearance of hepatitis C, compared with standard care alone, a researcher reported here.
An ongoing double-blind, placebo-controlled phase II trial among more than 100 patients, found that after12 weeks of therapy with one of two doses of ANA958, 73% and 75% of patients had undetectable levels of hep C virus, depending on dose, according to Eric Lawitz, MD, of Alamo Medical Research in San Antonio, Tex.
In contrast, 63% of those getting only standard care with pegylated interferon alpha-2a and ribavirin had undetectable hep C levels, Lawitz said at the annual meeting of the American Association for the Study of Liver Diseases.
The difference at that point was not statistically significant -- but earlier in treatment significantly more of the ANA958 patients had reached undetectable levels of the virus, Lawitz added.
Specifically, at four weeks, between 42% and 56% had undetectable hepatitis C levels, depending on the dose of ANA958, while at eight weeks, the proportions were 69% and 72%, he explained.
For standard care, the proportions were 13% and 38% and all the differences were significant, Lawitz said.
ANA958 is intended to block viral replication by interfering with the hepatitis C genotype-1 polymerase NS5A. The current study was a follow-up to a phase I trial that showed a "rapid and sustained reduction" in viral RNA levels over three days, Lawitz said.
To examine the efficacy and safety of the compound, he and colleagues enrolled 105 treatment-naïve patients with genotype-1 virus and randomly assigned them to either 200 or 400 mg of ANA958 twice a day, or to placebo. Those getting active drug also had a loading dose of 800 mg on the first day of therapy.
All of the trial patients also got standard treatment with pegylated interferon alpha-2a and ribavirin.
Patients with undetectable hep C virus at weeks four and 12 weeks, Lawitz explained, were re-randomized to continue standard care for another 12 or 32 weeks.
There was little difference between the two arms in terms of the speed at which the drug cleared the virus, Lawitz said, but viral clearance was always faster than the standard care alone.
The main difference between the two arms was in the adverse events.
In general, adverse events were what would be expected with the standard therapy, but there was an elevated rate of rash among patients getting the 400-milligram dose of ANA958.
Among placebo patients, Lawitz said, 34% reported rash and all were grade one, compared with 43% among those getting 200 mg of ANA958, where all but one of the rashes were grade one.
On the other hand, he said, 62% of the patients getting 400 mg reported rash, including 17 with grade one, one with grade two, and three patients with grade three rash.
The findings "looked nice" but are still preliminary, according to Petra Munda, MD, of the University of Vienna, who was not part of the study.
"I'm always skeptical of week 12 data," she told MedPage Today, although she noted that of the 11 patients who have completed ANA958 therapy at 24 weeks, eight had undetectable hepatitis C virus, a level sustained through the following 12 weeks.
On the other hand, in the high-dose group, some 62% had rash and "that's a lot," Munda commented.
Rash is a common side effect of the drug class, she noted, and doctors are beginning to be more comfortable with it. "In the beginning we were all too much afraid of the rash," Munda said. "It's manageable, but it's not nice for the patients."
The study was sponsored by Anadys Pharmaceuticals of San Diego. Lawitz reported financial links with Abbott, Anadys, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Humman Genome Sciences, Idenix, Idera, Intarcia, Medarex, Medtronic, Merck & Co., Novartis, Pharmasset, Roche, Schering-Plough, Valeant, Vertex, ViroChem Pharma, and ZymoGenetics.
Munda said she had no disclosures.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Lawitz E, et al. "Safety and antiviral activity of ANA598 in combination with pegylated interferon 2A plus ribavirin in treatment-naïve fenotype-1 chronic HCV patients" AASLD 2010; Abstract 31.
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