Two Studies Yield Mixed Results for HCV Polymerase Inhibitor Valopicitabine

By Liz Highleyman

Valopicitabine (NM283) is a first-in-class nucleoside polymerase inhibitor being evaluated in ongoing clinical trials for the treatment of hepatitis C. Currently, valopicitabine is in phase II clinical testing.

At the 42nd Annual Meeting of the European Association for the Study of the Liver this month in Barcelona, Spain, researchers presented the latest data from 2 studies of valopicitabine (NM 283), an oral HCV NS5B polymerase inhibitor being developed by Idenix.

Treatment-Naive Patients

In a multicenter Phase IIb trial, E. Lawitz and colleagues studied 173 treatment-naive patients with chronic genotype 1 HCV, HCV RNA levels of at least 5 log₁₀, and compensated liver disease.

Participants were randomly assigned to 5 arms:

·  Pegylated interferon alfa-2a (Pegasys) monotherapy for 4 weeks, with 800 mg/day oral valopicitabine added in Week 5;

·  Pegasys + 200 mg/day valopicitabine;

·  Pegasys + 800 mg/day valopicitabine using 3 different induction regimens.

Partway through the study, due to gastrointestinal side effects, the maximum valopicitabine dose was reduced to 400 mg. No subjects received ribavirin.

Results

·  The initial rate of HCV RNA decline was dependent on valopicitabine dose.

·  At Week 24, 63%-81% of participants achieved HCV RNA levels below 600 IU/mL.

·  49%-67% achieved HCV viral loads below 20 IU/mL.

·  Most of these subjects had continued virological suppression at Week 36.

·  53% in the 200 mg valopicitabine group had an end-of-treatment response (< 20 IU/mL) at Week 48.

·  At lower doses, valopicitabine was generally well tolerated.

The authors concluded that, “At a dose of 200 mg/day, valopicitabine plus [pegylated interferon] markedly suppresses viremia in treatment-naive patients with HCV-1 infection, with satisfactory tolerability.”

These data suggest that for some patients being treated for the first time, valopicitabine may be used with pegylated interferon instead of ribavirin, although the study is ongoing and sustained virological response (SVR) data are still pending. Idenix is also studying valopicitabine in combination with both pegylated interferon and ribavirin.

Alamo Medical Research, San Antonio, TX; Gastroenterology Center of the Mid-South, Germantown, TN; AGA Clinical Research Association, Egg Harbor, NJ; Atlanta Gastroenterology Associates, Emory University, Atlanta, GA; Northwest Medical Specialties, Tacoma, WA; Maryland Digestive Disease Research, Laurel, MD; Rocky Mountain Gastroenterology, Lakewood, CO; Mount Sinai School of Medicine, New York, NY; Idenix Pharmaceuticals, Cambridge, MA.

In a second Phase IIb study, N. Afdhal and colleagues studied 178 genotype 1 non-responders with HCV RNA levels of at least 5 log₁₀ and compensated liver disease; 16% were prior partial responders (at least a 2 log reduction in HCV RNA, but not full suppression) and the remainder were “true” non-responders (null responders).

Here too, participants were randomly assigned to 5 arms:

·  800 mg/day valopicitabine monotherapy;

·  Pegasys + 400 mg/day valopicitabine;

·  Pegasys + valopicitabine at doses escalating from 400 to 800 mg/day;

·  Pegasys + 800 mg/day valopicitabine;

·  Pegasys + 1000-1200 mg/day ribavirin (standard therapy).

Again, the maximum valopicitabine dose was reduced to 400 mg partway through the study (about 40 weeks). Treatment continued for 9 months after patients achieved undetectable HCV RNA, up to a maximum of 72 weeks. The valopicitabine monotherapy arm was discontinued early due to lack of efficacy.

Results

·  At Week 48, similar proportions of patients receiving Pegasys plus valopicitabine and those receiving Pegasys plus ribavirin achieved undetectable HCV RNA.

·  Here too, virological suppression increased with higher valopicitabine doses in the combination therapy arms.

·  42% of prior partial responders and 16% of true non-responders treated with Pegasys plus valopicitabine achieved an end-of-treatment response.

·  There were 7 serious adverse events -- mostly gastrointestinal -- attributable to either valopicitabine or valopicitabine/Pegasys, but none occurred after the maximum dose was reduced to 400 mg/day.

The researchers concluded that, “Week 48 results continue to support valopicitabine as a component of future combination regimens for patients who have failed [pegylated interferon + ribavirin] therapy.

The results of this trial were less favorable than those in the treatment-naive study described above, demonstrating the difficulty of suppressing HCV in prior non-responders. Since overall sustained response rates were low, the investigators suggested that effective treatment of non-responders “will likely require the contribution of 2 or more novel and complementary agents for optimal clinical outcomes.”

Beth Israel Deaconess Medical Center, Boston, MA; University of Miami, Miami, FL; Bach And Godofsky, Bradenton, FL; Fundacion de Investigacion de Diego, Santurce, Puerto Rico; St. Lukes Episcopal Hospital, Houston, TX; Alamo Medical Research, San Antonio, TX; Scripps Clinic, La Jolla, CA; Johns Hopkins University School of Medicine, Baltimore, MD; Weill Medical College of Cornell University, New York, NY; Idenix Pharmaceuticals, Cambridge, MA.

04/27/07

Sources

E Lawitz, T Nguyen, Z Younes, and others. Clearance of HCV RNA with valopicitabine (NM283) plus peg-interferon in treatment-naïve patients with HCV-1 infection: results at 24 and 48 weeks. 42nd Annual Meeting of the European Association for the Study of the Liver (42nd EASL). Barcelona, Spain. April 11-15, 2007.

N Afdhal, C OBrien, E Godofsky, and others. Valopictibaine (NM283), alone or with peg-interferon, compared to peg interferon/ribavirin (PEGIFN/RBV) retreatment in patients with HCV-1 infection and prior non-response to PEGIFN/RBV: one-year results. 42nd EASL.

Idenix. Additional Preclinical Data Presented on Valopicitabine Combined with an Investigational Protease Inhibitor. Press release. April 12, 2007.

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