AASLD: Tyzeka Bests Epivir at HBV Control at Two Years

October 30, 2006

BOSTON -- The newly approved nucleoside analog Tyzeka (telbivudine) was superior to Epivir (lamivudine) at reducing hepatitis B virus to undetectable levels at two years of follow-up, reported investigators in studies presented here.

BOSTON, Oct. 30 -- Tyzeka (telbivudine) was superior to Epivir (lamivudine) at reducing hepatitis B virus (HBV) to undetectable levels after two years, reported investigators here.

In the multicenter international GLOBE trial, significantly more HBe-antigen negative (HBeAg-) and antigen-positive (HBeAg+) patients treated with Tyzeka had undetectable levels of HBV RNA in serum than similar patients treated with Epivir, according to Ching-Lung Lai, M.D., of the University of Hong Kong, and colleagues.

The FDA last week approved Tyzeka, a nucleoside inhibitor, as a once-daily oral antiviral therapy for chronic HBV infections. Results of the GLOBE trial, which was the pivotal registration study for Tyzeka, were presented by Dr. Lai at the American Association for the Study of Liver diseases meeting here.

The GLOBE study was a randomized double-blind trial comparing oral Tyzeka at 600 mg/day with oral Epivir at 100 mg/day in 1,367 adults with chronic HBV infection at 112 centers in Asia, Oceania, Europe, and North America.

At the time of entry into the two-year study, patients had to be HB e-antigen positive, indicating a high viral load and high risk of infectivity, have HBV DNA levels at more than 6 log10 copies/mL, have alanine aminotransferase levels (ALT) at 1.3 to 10 times the upper limit of normal, and have compensated liver disease.

The primary endpoint was therapeutic response, a composite endpoint comprising viral suppression (serum HBV DNA suppression below 100,000 copies/mL) with either improved liver disease markers (ALT normalization) or loss of detectable HBeAg.

The investigators reported one-year results from the GLOBE study at the 2005 AASLD meeting. At that time, they reported that HBeAg+ patients taking Tyzeka had a mean reduction in HBV DNA of -6.5 log10, compared with -5.5 log10 among patients on Epivir (P

When they looked at the primary endpoint of therapeutic response, the investigators found that the rate was 64% among HBeAg+ patients treated with Tyzeka, compared with 48% for Epivir-treated HBeAg+ patients.

Among HBeAg- patients, the response rates were 78% for Tyzeka, vs. 66% for Epivir.

The authors also found evidence that early PCR negativity was associated with a lower chance for developing viral resistance, defined as HBV DNA return to >5 log10, or to within 1 log of baseline.

Tyzeka-treated patients who achieved PCR negativity at week 24 had a per-protocol rate of resistance at two years of 4% in HBeAg+ patients, and 2% in HBeAg- patients. In comparison, 17.8% of all patients on Tyzeka, and 30.1% of all patients on Epivir had signs of viral resistance in the per-protocol analysis.

Patients with PCR non-detectable HBV DNA at week 24 showed high positive predictive values for achieving all efficacy endpoints at year two. In contrast, negative predictive values for two-year efficacy outcomes were high for patients with HBV DNA more than 4 logs at week 24.

Disease exacerbation was defined as ALT flares, according to AASLD criteria of ALT more than 10 times the upper limit of normal, and more than two times baseline levels. ALT flares occurred in 2.8% of patients on Tyzeka, and 8.4% on Epivir.

Grade 3 or 4 creatine kinase elevations were significantly higher among patients treated with Tyzeka, at 13%, compared with only 4% of patients treated with Epivir.

The studies were funded by Idenix Pharmaceuticals, makers of Tyzeka. Dr. Lai is scientific adviser to the company.