Telbivudine (Tyzeka) Continues to Produce Good Results for Chronic Hepatitis B Patients after 3 Years

By Liz Highleyman

Telbivudine (marketed as Tyzeka in the U.S. and Sebivo in Europe and elsewhere) is one of several nucleoside/nucleotide analog agents approved for the treatment of chronic hepatitis B virus (HBV) infection.

At the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen, researchers presented promising data from 2 recent studies of telbivudine, and a third analysis indicated that peripheral neuropathy is an uncommon side effect of telbivudine monotherapy.

GLOBE Follow-up

C.-W. Hsu and an international team of colleagues presented long-term follow-up data from the GLOBE study, a large Phase 3 trial that provided data to support approval of telbivudine.

Briefly, GLOBE compared 600 mg/day telbivudine versus 100 mg/day lamivudine (Epivir-HBV) for 2 years in 1367 chronic hepatitis B patients with compensated liver disease. As previously reported (published in the February 2009 issue of Gastroenterology), at the end of the study participants taking telbivudine were significantly more likely to respond than those taking lamivudine, with 2-year response rates of 63% for hepatitis B "e" antigen (HBeAg) positive patients and 78% for HBeAg negative patients.

Participants from GLOBE and another trial, Study 015, were offered a chance to receive open-label telbivudine for an additional 2 years in an open-label extension study (Study 2303). At EASL, the researchers presented pooled GLOBE/Study 015 efficacy and safety data for 503 patients (293 HBeAg positive and 210 HBeAg negative) who did not have genotypic resistance to telbivudine after 2 years and who continued taking the drug for 3 years. Most participants in the extension study were men and people of Asian race/ethnicity.

Results

HBV DNA suppression and ALT normalization were maintained in both HBeAg positive and HBeAg negative patients who took telbivudine for 3 years.

Among the 210 HBeAg negative participants, 85% achieved undetectable HBV DNA (< 300 copies/mL) and 84% experienced ALT normalization at year 3.

Among the 293 HBeAg positive patients, 75% achieved undetectable HBV DNA and 83% experienced ALT normalization at year 3.

55% of these patients experienced HBeAg loss and 39% achieved HBeAg seroconversion.

1.5% experienced hepatitis B surface antigen (HBsAg) loss and 0.4% (1 person) achieved HBsAg seroconversion.

HBeAg positive participants who had undetectable HBV DNA at week 24 of telbivudine therapy in the original GLOBE/Study 015 trials were more likely to achieve undetectable HBV DNA (87%), ALT normalization (86%), and HBeAg seroconversion (40%) at year 3.

Telbivudine continued to be generally well-tolerated at year 3, with a safety profile similar to that observed at year 2.

13% of patients experienced grade 3/4 creatine kinase (CK) elevation, 4% developed muscle pain, 0.6% experienced muscular weakness, and 0.3% developed myositis (muscle inflammation).

The rate of peripheral neuropathy (including paresthesia, neuralgia, polyneuropathy, and sensory loss) was low, at < 1% [See third study below]

No cases of rhabdomyolysis, lactic acidosis, or other new serious safety concerns were observed with continued telbivudine use through year 3.

5.7% of HBeAg negative patients and 8.8% of HBeAg positive patients developed genotypic resistance to telbivudine at 3 years.

In a subset of 66 patients (all but 2 HBeAg positive) who discontinued telbivudine after achieving good response in the original GLOBE/Study 015 trials but continued follow-up during the extension study, 70% maintained low or undetectable HBV DNA, 64% maintained normal ALT, and 90% maintained HBeAg loss and HBeAg seroconversion.

Based on these findings, the investigators concluded, "Over 3 years, telbivudine treatment provides effective viral suppression and ALT normalization in HBeAg positive and HBeAg negative chronic hepatitis B patients with a favorable safety profile."

They continued, "In HBeAg positive patients, telbivudine treatment achieves a high cumulative seroconversion rate, especially in patients with baseline characteristics predictive of good outcome."

Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; Middlemore Hospital, Auckland, New Zealand; Hannover Medical School, Hannover,Germany; University of Frankfurt, Frankfurt, Germany; Xi Nan Hospital, Third Military Medical University, Chongqing, China; Queen Mary Hospital, Hong Kong, China; Nanfang Hospital, Guangzhou, China; Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China; California Pacific Medical Center, San Francisco, CA; No. 1 Hospital, Changchun, China; Beijing Friendship Hospital, Beijing, China; Bundang CHA Hospital, Gyeonggi-Do, South Korea; Istanbul University, Istanbul, Turkey; Chongqing Medical University 2nd Affiliated Hospital, Chongqing, China; Hippokration Hospital, Athens, Greece; First Affiliated Hospital, Zhejiang University, Hangzhou, China; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Pharma AG, Basel, Switzerland.

HBsAg Loss

K. Wursthorn and colleagues looked at the kinetics of hepatitis B surface antigen decline among 172 HBeAg positive GLOBE participants with undetectable HBV DNA (< 300 copies/mL) after 2 years on telbivudine, who continued taking the drug during the extension study described above.

HBsAg clearance is the ultimate goal of antiviral treatment for chronic hepatitis B, the investigators noted as background. Measuring HBsAg may help predict the timing and probability of this favorable outcome. In this analysis, serum HBsAg levels were measured at baseline, at treatment week 24 in the original GLOBE study, and at years 1, 2, and 3.

Results

Serum HBsAg levels declined progressively during 3 years on telbivudine.

Telbivudine significantly reduced HBsAg levels from baseline (mean 3.8 log10 IU/mL) to year 1 (3.3 log10 IU/mL) and year 3 (3.0 log10 IU/mL).

By year 3, 6% of patients experienced HBsAg loss, and 2 of these individuals also experience HBsAg seroconversion.

Patients who lost HBsAg had significantly higher baseline HBsAg levels than patients without HBsAg loss (mean 4.2 vs 3.8 log10IU/mL, respectively).

Participants who lost HBsAg also experienced a greater decline in HBsAg during the first year of treatment (2.1 vs 0.3 log10IU/mL, respectively).

3 distinct patterns of HBsAg kinetics were observed at year 1:

Rapid decline of > 1 log10 IU/mL: 31 patients, 26% of whom had HBsAg loss at year 3;

Slow progressive decline of < 1 log10 IU/mL: 73 patients, 1.4% of whom had HBsAg loss at year 3;

Fluctuating HBsAg levels: 55 patients.

Patients who experienced rapid HBsAg decline during the first year on telbivudine were more likely to later experience HBsAg loss.

At year 3, 68% of patients achieved HBeAg loss and 54% experienced HBeAg seroconversion.

In this comparison, baseline HBsAg levels were similar in both groups (3.8 log10 IU/mL).

However, patients with HBeAg loss at 3 years had a significantly greater average decline in HBsAg levels at year 1 than patients without HBeAg loss.

In this first study of HBsAg kinetics during long-term nucleoside analog therapy, the researchers concluded, "Telbivudine treatment significantly reduces serum HBsAg levels in patients with HBeAg positive chronic hepatitis B."

"Rapid on-treatment HBsAg decline of >1 log10 IU/mL during the first year is highly predictive of future HBsAg clearance," they added.

Hannover Medical School, Hannover, Germany; Novartis Pharma AG, Basel, Switzerlan.

Peripheral Neuropathy

Finally, J. Goncalves and colleagues from telbivudine manufacturer Novartis looked at rates of peripheral neuropathy as a side effect of therapy in people treated with telbivudine alone or in combination with pegylated interferon. Peripheral neuropathy was defined as muscle weakness with decreased muscle tone, flaccid paralysis (muscle wasting and weakened reflexes), and/or sensory impairment (pain or impaired autonomic function).

The investigators previously reported that Study CLDT600A2406 was prematurely halted after they observed an increased risk of developing peripheral neuropathy among patients who received combination therapy with 600 mg daily telbivudine plus 180 mcg/week pegylated interferon alfa-2a (Pegasys).

At EASL, the researchers presented an analysis comparing rates of peripheral neuropathy in Study CLDT600A2406 versus a retrospective analysis of all Phase 2-4 trials of telbivudine monotherapy included in the telbivudine Global Clinical Trial Programme, encompassing approximately 3500 patients. They searched for serious adverse events (SAEs) and non-serious adverse events (AEs) observed in clinical trials in the Novartis safety database (ARGUS) through the end of August 2008.

Results

Overall, 19 peripheral neuropathy-related SAEs were observed.

11 in Study CLDT600A2406; 9 of 48 in patients who took telbivudine plus pegylated interferon (a rate of 18.8%) and 2 of 53 who received telbivudine alone (3.8%).

2 in the telbivudine monotherapy arm of Study NV-02C-004, which compared telbivudine alone versus telbivudine plus valtorcitabine.

6 among the more than 1800 participants taking telbivudine monotherapy in the open-label Study CLDT600A2303.

On the whole, serious peripheral neuropathy was more common among patients receiving telbivudine plus pegylated interferon compared with telbivudine monotherapy.

Looking at all participants across all studies, the rate of peripheral neuropathy-related SAEs was 0.28%).

In Study CLDT600A2406, the time to onset of peripheral neuropathy was shorter in the telbivudine/pegylated interferon group (2-6 months) than in the telbivudine monotherapy group (4-10 months).

In that study, 8 of the 11 affected patients (6 in the combination group, 2 in the telbivudine monotherapy group) reported improvement in peripheral neuropathy during follow-up.

In addition, there were a total of 17 reported non-serious peripheral neuropathy AEs:

8 among patients who took telbivudine/pegylated interferon and 3 who received pegylated interferon alone in CLDT600A2406 (but none of the patients who received telbivudine alone).

1 patient with liver cirrhosis taking telbivudine monotherapy in Study CLDT600A2301.

2 patients receiving telbivudine monotherapy in the GLOBE Study.

3 patients taking telbivudine alone in Study NV-02B-015.

"This report from the telbivudine Global Clinical Trial Programme confirms that peripheral neuropathy remains uncommon with telbivudine monotherapy," the investigators concluded.

"If peripheral neuropathy is suspected, treatment should be reviewed, telbivudine use should be interrupted and discontinued if peripheral neuropathy is confirmed," they recommended.

Novartis Pharmaceuticals Corporation, East Hanover, NJ; Novartis Pharma AG, Basel, Switzerland.

5/08/09

References

C-W Hsu, Y-C Chen, Y-F Liaw, and others. Prolonged Efficacy and Safety of 3 Years of Continuous Telbivudine Treatment in Pooled Data from Globe and 015 Studies in Chronic Hepatitis B Patients. EASL 2009. Copenhagen, Denmark. April 22-26, 2009. Abstract 911.

K Wursthorn, M Jung, M Manns, and others. Kinetics Of HBaGDecline In HBeAg+ Chronic Hepatitis B Patients with 3 Years of Telbivudine Treatment during the Globe Study. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009. Abstract 17.

J Goncalves, R Laeufle, and C Avila. Increased risk with combination of telbivudine and pegylated-interferon alfa-2a in study CLDT600A2406, compared to uncommon rate with telbivudine monotherapy from the Novartis global database. EASL 2009. Copenhagen, Denmark. April 22-26, 2009. Abstract 907.

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15th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
Coverage by HIV and Hepatitis.com - February 8 - 11, 2009, Montreal
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