Antivirals
Telbivudine Demonstrates Advantages Over Lamivudine in HBeAg-positive Chronic Hepatitis B
By Idenix Pharmaceuticals, Inc.
May 17, 2005, 08:53

Idenix Pharmaceuticals, Inc. today announced the presentation of interim two-year results from an extended-treatment phase IIb clinical trial for telbivudine demonstrating continuing advantages compared to lamivudine across key efficacy endpoints through two years of treatment in HBeAg-positive chronic hepatitis B patients.

Further analyses of the two-year data indicate that the link between early and profound viral suppression and markers of improved clinical outcomes that were demonstrated at one year extends through two years of treatment. These data were presented today at the 2005 Digestive Disease Week meeting in Chicago, Illinois by Ching-Lung Lai, M.D., lead investigator and Professor of Medicine and Hepatology, Department of Medicine, University of Hong Kong.

The ongoing phase IIb clinical trial compares telbivudine monotherapy and a combination of telbivudine and lamivudine, with lamivudine monotherapy in 104 treatment-naive patients with HBeAg-positive chronic hepatitis B.

Patients receiving telbivudine monotherapy achieved a 1.5 log10, or 30-fold, greater mean viral load reduction compared to patients receiving lamivudine monotherapy at two years. At two years, the percent of patients receiving telbivudine monotherapy in whom levels of serum HBV DNA became undetectable by a sensitive PCR-based assay was 71 percent, more than double that of the 32 percent of patients receiving lamivudine monotherapy (p less than 0.05). Serum ALT normalization, a marker of reduced liver inflammation, was significantly greater in patients treated with telbivudine monotherapy (81 percent) compared to lamivudine monotherapy patients (47 percent) through two years (p less than 0.05). In addition, substantially more patients receiving telbivudine monotherapy (38 percent) achieved HBeAg seroconversion compared to patients in the lamivudine monotherapy group (22 percent).

The rate of treatment failure for patients receiving telbivudine monotherapy (4.5 percent) was significantly lower than the rate of treatment failure in the lamivudine monotherapy group (21 percent) (p less than 0.05). The study results also continue to support a favorable overall safety profile for telbivudine with no substantial safety issues being identified through two years of treatment.

"Analysis of the study data across treatment groups suggest that two-year efficacy outcomes, such as persistent control of HBV replication, serum ALT normalization, and HBeAg seroconversion, are associated with achieving rapid viral suppression early in treatment," said Professor Lai. "Forty-one percent of patients with profound viral suppression after 24 weeks of treatment achieved seroconversion at two years, compared to only 15 percent of patients who did not achieve similar rapid viral response. This correlation between early reduction of viral load levels and longer-term efficacy outcomes suggests that maximizing viral load suppression early in the course of treatment is an important therapeutic goal."

Additional scientific analyses utilized combined two-year data from all patients regardless of treatment group and evaluated two-year efficacy outcomes according to serum HBV DNA level at week 24 of treatment. The results indicated that patients who had HBV DNA levels below 1000 copies/mL by week 24 of treatment had a much higher likelihood of achieving HBeAg seroconversion (41 percent vs. 15 percent), serum ALT normalization (85 percent vs. 51 percent) and undetectable levels of HBV DNA (86 percent vs. 23 percent) after two years of treatment compared to patients whose HBV DNA level was greater than 1000 copies/mL at week 24.

These analyses also demonstrate that patients with viral load levels below 1000 copies/mL were less likely to experience treatment failure than patients with HBV DNA levels above 1000 copies/mL (2 percent vs. 17 percent). Nearly 70 percent of patients receiving telbivudine monotherapy achieved rapid and profound suppression of HBV DNA (to levels below 1000 copies/mL) within the first 24 weeks of treatment, compared to 33 percent of lamivudine monotherapy patients.

"These two-year treatment results for telbivudine demonstrate that, across key measures of virologic and clinical outcomes in hepatitis B patients, the efficacy advantages for telbivudine treatment seen after one year were maintained through two years of treatment," said Nathaniel Brown, M.D., Idenix's executive vice president clinical development and chief medical officer. "We are encouraged by these longer-term phase IIb data and look forward to the results of the comprehensive telbivudine phase III GLOBE study, evaluating more than 1370 hepatitis B patients worldwide, which we expect to be available in the fall of this year."

Study Design

The telbivudine phase IIb program is comparing the safety and antiviral effectiveness of telbivudine, and telbivudine in combination with lamivudine, with a control arm of lamivudine monotherapy in two sequential, linked trials. The first clinical trial enrolled 104 treatment naive HBeAg-positive adults with chronic hepatitis B for one year of treatment in one of five daily treatment regimens: telbivudine 400 mg, telbivudine 600 mg, telbivudine 400 mg + lamivudine 100 mg, telbivudine 600 mg + lamivudine 100 mg or standard lamivudine therapy (100 mg per day).

The telbivudine phase IIb extended treatment clinical trial is a two-year extension of the initial one-year phase IIb clinical trial, to obtain comparative data for telbivudine and lamivudine for a total of three years. The two patient groups treated with telbivudine monotherapy in the initial one-year clinical trial are receiving 600 mg/day of telbivudine in the extension trial. The patient groups that received telbivudine combined with lamivudine in the initial one-year clinical trial are receiving telbivudine 600 mg/day combined with lamivudine 100 mg/day in the extension trial. The patients who received lamivudine 100 mg/day in the initial one-year trial continue to receive such treatment in the extension trial. The two-year phase IIb analysis includes combined data from the completed one-year plus one year of the extended treatment trial.

Results from the initial one-year phase IIb clinical trial were presented by Professor Lai at the American Association for the Study of Liver Diseases (AASLD) in October 2003. After one year of treatment, telbivudine monotherapy demonstrated significantly greater viral suppression, viral clearance by PCR assay, and serum ALT normalization, and a proportionally higher HBeAg seroconversion rate, compared to lamivudine monotherapy.

About Telbivudine

Telbivudine is a specific and selective, oral, once-daily nucleoside being developed for the treatment of chronic hepatitis B. To date, preclinical and clinical data demonstrate a favorable safety profile and marked antiviral activity against HBV.

Telbivudine is currently being evaluated in a two-year international phase III clinical trial comparing telbivudine to lamivudine, referred to as the GLOBE study. The phase III clinical trial is fully enrolled with more than 1370 patients, HBeAg+ or HBeAg-, with compensated liver disease. This trial is ongoing at over 100 clinical sites located in 20 countries in Europe, North America and Asia. Idenix, working jointly with Novartis, currently expects to commence the submission of worldwide marketing applications for telbivudine, beginning with a U.S. New Drug Application filing in late 2005.

The development of telbivudine and the telbivudine/valtorcitabine combination for the treatment of chronic hepatitis B demonstrates the commitment of Idenix and Novartis Pharma AG to develop and introduce new, improved treatment options in this area of significant unmet medical need.

About Hepatitis B

Despite the presence of global immunization programs for hepatitis B virus, the World Health Organization (WHO) has estimated that approximately 350 million people, or 5% of the world's population, are chronically infected with hepatitis B virus. Chronic hepatitis B can lead to cirrhosis, liver failure and hepatocellular carcinoma (liver cancer). The WHO also estimates that annually over 50 million people become infected with hepatitis B virus and that more than one million individuals die from HBV-related chronic liver disease demonstrating the urgent need for new treatment.

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