Valopicitabine (NM283) Produces Greater Suppression of HCV When Added to Pegylated Interferon plus Ribavirin

Idenix Pharmaceuticals recently announced promising interim results from a Phase II clinical trial of its experimental hepatitis C drug valopicitabine (NM238) used in combination with pegylated interferon alfa-2a (Pegasys) plus ribavirin. Valopicitabine, a nucleoside analog polymerase inhibitor, is one of several directly targeted anti-HCV agents in the drug development pipeline.

Below are excerpts from the company's June 12 press release:

Valopicitabine Combined with Standard of Care Cleared Hepatitis C Virus in 72% of Patients Who Completed 12 Weeks of Treatment in a Phase II Trial

CAMBRIDGE, Mass., June 12 -- PRNewswire-FirstCall -- Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX) today announced results from a phase II study designed to evaluate triple combination therapy, consisting of valopicitabine (NM283), Idenix's lead drug candidate for the treatment of hepatitis C, pegylated interferon and ribavirin compared to pegylated interferon and ribavirin, the current standard of care, in patients infected with the genotype-1 strain of the hepatitis C virus (HCV).

This study demonstrated no pharmacokinetic or pharmacodynamic drug-drug interaction between valopicitabine and ribavirin. The triple combination showed consistently higher rates of HCV PCR-negativity, defined as serum HCV RNA levels below 20 copies/mL, compared to the standard of care at every point analyzed in this study. Additionally, the tolerability of the triple combination was satisfactory, with only three discontinuations from the study.

"I am very encouraged to observe this degree of viral clearance coupled with a very low rate of discontinuations in patients treated with the triple combination of valopicitabine, pegylated-interferon and ribavirin in this study," said Dr. Fred Poordad, Chief of Hepatology and Liver Transplantation, Cedars Sinai Medical Center, and an investigator in this study. "These data represent an important achievement in the development of novel HCV combination therapy."

Study Design and Results

The three-arm, partially blinded, randomized study enrolled 117 treatment-naive, HCV genotype-1 infected patients at approximately 20 centers in the United States. Patients in arm A (n=39) received 200 mg/day of valopicitabine and pegylated interferon alpha 2a; patients in arm B (n=39) received 200 mg/day of valopicitabine, weight-based dosing of ribavirin, and pegylated interferon alpha 2a; and patients in arm C (n=39) received placebo, weight-based dosing of ribavirin and pegylated interferon alpha 2a. For all patients in this study there was a seven-day lead-in period, where patients received either valopicitabine or placebo alone; the additional components of each arm's therapeutic regimen were administered beginning on day eight.

The primary endpoint of the study was to assess pharmacokinetic and pharmacodynamic drug-drug interaction between valopicitabine and ribavirin after 36 days of treatment. Drug levels for both NM107 (the active form of valopicitabine) and ribavirin when administered alone or together were within the range of 80 to 125 percent, indicating the lack of an interaction. At day 36, 23 percent of patients treated with triple combination therapy (arm B) were HCV PCR-negative per protocol, compared to 11 percent of patients treated with the standard of care (arm C) and 14 percent of patients treated with valopicitabine and pegylated interferon (arm A). These findings demonstrated no pharmacokinetic or pharmacodynamic drug-drug interaction between valopicitabine and ribavirin.

The key secondary endpoints for the study were antiviral activity, safety, and tolerability at 12 weeks. Of patients that completed 12 weeks of therapy, 72.2 percent of patients treated with triple combination therapy (arm B) achieved HCV PCR-negativity, compared to 61.5 percent of patients treated with the standard of care (arm C). There were three discontinuations from the study, all due to adverse events (AEs), one of which was attributed by the clinical investigator to valopicitabine-related gastrointestinal toxicity. The two other AEs, including a serious adverse event (SAE), were attributed by the clinical investigators to pegylated interferon or pegylated interferon/ribavirin. All of the discontinuations occurred in the triple combination arm (arm B).

At the end of 12 weeks, patients were permitted to roll over to pegylated interferon plus ribavirin for up to 48 weeks of total treatment; all eligible patients elected to do so.

"These results support our hypothesis that valopicitabine can be administered in combination with pegylated interferon and ribavirin," said Douglas Mayers, MD, executive vice president and chief medical officer of Idenix Pharmaceuticals. "We are very pleased with the viral kinetics and HCV RNA clearance rates observed in patients treated with triple combination therapy in this study and look forward to further development of this combination."

About Valopicitabine

Valopicitabine is an investigational nucleoside polymerase inhibitor being evaluated in ongoing clinical trials for the treatment of hepatitis C. The most common adverse events reported in valopicitabine clinical trials to date include nausea, vomiting, fatigue, diarrhea, headache, flu-like symptoms, and depression. Idenix is developing valopicitabine in collaboration with Novartis Pharma AG.

06/22/07

Source
Idenix Pharmaceuticals. Valopicitabine Combined with Standard of Care Cleared Hepatitis C Virus in 72% of Patients Who Completed 12 Weeks of Treatment in a Phase II Trial. Press release. June 12, 2007.