Selected Telbivudine Studies
Presented at DDW 2007

By Ronald Baker, PhD

Introduction

Review of Telbivudine Research in 2006

Adefovir Salvage Therapy Results in Consistent HBV Suppression in Telbivudine-treated Patients with Virological Breakthrough

Telbivudine GLOBE Trial at Year 2

Telbivudine Provides Superior HBV Suppression Compared with Adefovir through 76 Weeks

No Pharmacokinetic Drug-drug Interaction between Telbivudine and Tenofovir

Resistance in Patients with Virological Breakthrough after Telbivudine or Lamivudine Therapy

Introduction

The U.S. Food and Drug Administration (FDA) approved telbivudine (Tyzeka) for the treatment of adults with chronic hepatitis B virus (HBV) infection in October 2006. Health authorities in the European Union have also approved telbivudine (marketed as Sebivo in Europe).

Telbivudine is a new molecular entity, a term used by the FDA to describe a medication containing an active substance that has never before been approved for marketing in any form in the United States.

Review of Telbivudine Research in 2006

At the DDW 2007 oral session on Research Highlights from AASLD 2006, Anna Lok, MD, of the University of Michigan reviewed important presentations at last fall’s American Association for the Study of Liver Diseases meeting on hepatitis B, hepatitis C, and cirrhosis [1]. A summary of her comments on telbivudine are outlined below.

In Phase IIb clinical trials that compared telbivudine with lamivudine (Epivir-HBV), patients receiving telbivudine were shown to have a greater degree of viral suppression, and a high proportion had normalized ALT. But in trials combining telbivudine with lamivudine, patients in the combination arm actually fared worse than with those on telbivudine alone, according to Dr. Lok.

Regarding resistance, Dr. Lok noted that telbivudine selects for the M204I mutation but not for the M204V mutation, and it is cross-resistant with lamivudine. In the Phase III GLOBE study comparing telbivudine with lamivudine, resistance developed at 52 weeks. By week 104, there was 22% resistance among HBsAg positive patients and 9% among HBeAg negative patients, compared with 35% and 22%, respectively, with lamivudine, indicating that telbivudine offered a likelihood of resistance 40%-50% that of lamivudine.

In summary, Dr. Lok said that telbivudine has more potent anti-HBV activity than lamivudine and adefovir (Hepsera), but is cross-resistant with lamivudine and has a high rate of drug resistance. “Telbivudine has a limited role as monotherapy and may be best used in combination therapy,” she concluded.

Most of the studies on telbivudine presented at DDW 2007 were also presented at the 42nd annual meeting of the European Association for the Study of the Liver (EASL) held last month in Barcelona, Spain (April 11-15, 2007).

Adefovir Salvage Therapy Results in Consistent HBV Suppression in Telbivudine-treated Patients with Virological Breakthrough [2]

The GLOBE trial is a 2-year Phase III randomized trial of telbivudine versus lamivudine in 1367 patients with chronic hepatitis B. Patients experiencing virological breakthrough while on the GLOBE study were offered adefovir to restore effective viral suppression.

At the time of this analysis, 21 of 22 patients had received ≥ 16 weeks of adefovir salvage treatment. With 16 weeks of adefovir, HBV DNA levels decreased by a mean 4.1 log₁₀ copies/mL, and ALT levels were reduced by 93.1 IU/L. HBV DNA levels decreased by a mean 5.1 log₁₀ copies/mL in the 5 patients who received adefovir in combination with telbivudine, compared to 3.8 log₁₀ copies/mL in the 16 patients who switched to adefovir monotherapy.

In conclusion, the investigators wrote, “Adefovir salvage therapy, administered as follow-on monotherapy or in combination with telbivudine, resulted in consistent viral suppression for telbivudine-treated patients experiencing virologic breakthrough.”

Telbivudine GLOBE Trial at Year 2 [3]

The GLOBE trial enrolled 1367 chronic hepatitis B patients with baseline HBV DNA levels > 6 log₁₀ copies/mL, ALT 1.3-10 x ULN, and compensated liver disease. Patients were randomized 1:1 to oral telbivudine (600 mg/day) or oral lamivudine (100 mg/day) and were pre-stratified for HBeAg status and baseline ALT level.

After 1 year, telbivudine demonstrated greater antiviral efficacy than lamivudine. In the current study, the authors report results from GLOBE after 2 years, including efficacy, safety, and relationships between viral load at week 24 and outcomes at week 104.

Telbivudine was superior to lamivudine for the primary efficacy measure, therapeutic response (HBV DNA < 5log10 cps/mL and ALT normalization or HBeAg loss. 63% vs 48% were HBeAg positive; 78% vs 66% were HBeAg negative).

Telbivudine was superior to lamivudine for other direct measures of antiviral efficacy:

• mean log₁₀ HBV DNA reduction: -5.7 vs -4.4 HBeAg+, -5.0 vs 4.2 HBeAg-;
• PCR negativity: 56% vs 39% HBeAg+, 82% vs 57% HBeAg-;
• viral breakthrough: 19% vs 33% HBeAg+, 8% vs 16% HBeAg-;
• primary treatment failure (HBV DNA never < 5log₁₀ copies/mL): 4% vs 12% HBeAg+, 0% vs 3% HBeAg-).

Telbivudine also produced significantly greater ALT normalization compared with lamivudine (70% vs 62% HBeAg+, 78% vs 70% HBeAg-) and proportionally higher rates of HBeAg loss (35% vs 29%) and seroconversion (30% vs 25%).

Significantly more patients receiving telbivudine than lamivudine had undetectable HBV DNA by PCR at week 24 (45% vs 32%; P<0.05).

Viral suppression at week 24 predicted efficacy outcomes at 2 years. Two-year response rates were highest for patients with HBV DNA undetectable by PCR at week 24. Both treatments were well tolerated with similar adverse event profiles.

The investigators concluded, “Telbivudine exhibited significantly greater antiviral and clinical efficacy vs lamivudine in HBeAg positive and HBeAg negative patients at 2 years. Better viral suppression at week 24 predicted greater efficacy responses at 2 years. Observed relationships between week 24 viral load and subsequent efficacy support the potential of early virologic response for optimizing treatment outcomes.”

Telbivudine Provides Superior HBV Suppression Compared with Adefovir through 76 Weeks [4]

In this multinational study, researchers compared telbivudine vs adefovir over 52 weeks, the effects of switching from adefovir to telbivudine in patients with suboptimal initial response to adefovir, and analyzed the relationship of early virologic responses to subsequent efficacy outcomes.

At Week 24, mean HBV DNA reduction from baseline was significantly greater with telbivudine vs adefovir (-6.30 vs -4.97 log₁₀ copies/mL; P<0.01). Viral load decreased sharply in adefovir-treated patients after switching to telbivudine at Week 24. 78% (70 of 90) of patients in the adefovir group had suboptimal response at Week 24; those switched to telbivudine (n=36) displayed an additional 2.1 log₁₀ mean reduction between Week 24 and Wekk 52 vs 0.9 log₁₀ for patients who remained on adefovir.

Similarly, 59% (26 of 44) of adefovir recipients had persistent suboptimal response at Week 52 and a 2.1 log₁₀ decrease in viral load occurred between Week 52 and Week 76 in patients who switched to telbivudine (n=20).

In patients receiving continuous telbivudine, mean HBV DNA reductions from baseline was 6.3 log₁₀, 6.8 log₁₀, and 7.2 log₁₀ at weeks 24, 52, and 76, respectively.

At Week 24, HBV DNA levels were reduced to <3 log₁₀ copies/mL in significantly more telbivudine recipients vs adefovir recipients (49% vs 22%, P<0.01). Efficacy results at Week 52 correlated with HBV DNA level at Week 24.

In patients with viral breakthrough at 1 year (2 telbivudine, 1 adefovir), HBV DNA levels were > 4 log₁₀ cp/mL at Week 24.

The researchers concluded, “For patients with suboptimal initial response to adefovir, switching from adefovir to [telbivudine] after 24 or 52 weeks provided substantial additional reduction of serum HBV DNA that persisted through week 76. HBV DNA level after 24 weeks of treatment with [telbivudine] or adefovir correlated with efficacy outcomes and viral breakthrough at one year.”

No Pharmacokinetic Drug-drug Interaction between Telbivudine and Tenofovir [5]

Clinical outcomes may be improved by combining anti-HBV drugs, including nucleoside and nucleotide analogs. In the current study of 16 healthy (HBV uninfected) individuals, researchers evaluated pharmacokinetic (PK) interactions between 2 potent antivirals: the nucleoside analog telbivudine and the nucleotide analog tenofovir (Viread).

Plasma PK parameters of telbivudine at steady-state were similar when telbivudine was administered alone or in combination with tenofovir. Similarly, steady-state PK parameters of tenofovir were also comparable when tenofovir was administered alone or in combination with telbivudine. In general, both drugs were well tolerated when administered in combination.

Based on these results, the investigators concluded, “There is no appreciable PK drug-drug interaction between telbivudine and tenofovir in healthy human subjects, providing pharmacokinetic support for assessing combination anti-HBV treatment regimens involving these two drugs.”

Resistance in Patients with Virological Breakthrough after Telbivudine or Lamivudine Therapy [6]

Researchers at Idenix evaluated resistance to telbivudine and lamivudine at week 48 of therapy in the GLOBE study, which enrolled 1367 patients with chronic hepatitis B who were randomized (1:1) to receive 600 mg telbivudine or 100 mg lamivudine daily.

131 patients met the breakthrough definition; 32 were on telbivudine and 99 on lamivudine. Genotypic resistance, all based on rtM204 variants, was confirmed in 28 of 32 telbivudine and 75 of 93 lamivudine patients; the remaining genomes were essentially wild-type.

Of the 28 telbivudine-resistant patients, 27 exhibited the M204I mutation alone (10) or in combination with rtL80I/V substitutions (17). Of the 75 lamivudine resistant patients, 34 were due to M204I, 25 to M204V/L180M, and 16 were mixed M204M/I/V mutants.

No telbivudine-related M204V or M204/L180M mutants or novel resistance mutants were seen in association with breakthrough, without a detectable M204I mutation.

Analysis of year 2 data is ongoing, but to date, M204I-mutant HBV strains continue to be the basis of genotypic resistance with virological breakthrough for telbivudine. In vitro phenotypic testing revealed that M204I and M204I/L80I variants were resistant to telbivudine (>1300 fold), but sensitivity to adefovir or tenofovir was only reduced 3- to 5-fold.

“In the GLOBE trial,” concluded the Idenix researchers, “genotypic HBV resistance with virologic breakthrough on telbivudine is based on the M204I mutation, confirming our earlier findings (Standring et al., EASL 2005).”

Further, they noted, “Based on our in vitro data, the best agents for therapy of telbivudine resistant M204I and M20I/L80I mutant HBV strains would appear to be adefovir or tenofovir.”

05/22/07

References

1. A Lok. American Association for the Study of the Liver - Research Highlights. Digestive Disease Week 2007 (DDW 2007) email Update. May 20, 2007.

2. E Heathcote, E J Gane, C Lai, and others. Salvage Therapy with Adefovir for Virologic Breakthrough in Telbivudine-treated Patients from the GLOBE Study. DDW 2007. Washington, DC. May 19-24, 2007. Abstract S1776.

3. S Han, C Lai, E J Gane, and others. Telbivudine Globe Trial at Year Two: Efficacy, Safety, and Predictors of Outcome in Patients with Chronic Hepatitis B. DDW 2007. Abstract S1777.

4. N Bzowej, P, Marcellin, H Chan, and others. A Randomized Trial of Telbivudine vs Adefovir for HBeAg-Positive Chronic Hepatitis B: Efficacy through Week 76, Predictors of Response and Effects of Switching to Telbivudine. DDW 2007. DDW 2007. Abstract S1774.

5. X. Zhou¹; K. Pietropaolo¹; M. Becker, and others. Absence of Pharmacokinetic Drug-Drug Interaction between Telbivudine and Tenofovir. DDW 2007. DDW 2007. Abstract S1782.

6. Resistance Determination in Patients Experiencing Virologic Breakthrough Following Telbivudine or Lamivudine Therapy in the International GLOBE Trial. D N Standring, A Patty, C Chapron, and others. DDW 2007. Abstract S1781.

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