Biotech Values

[kcalt]

IDIX HBV abstracts from DDW
http://ddw2006.abstractcentral.com/planner#

1)
ID#
479

Location:
409 A/B (LA Convention Center)

Time of Presentation:
May 23 9:00 AM - 9:15 AM

A Randomized Trial of Telbivudine (LdT) vs. Adefovir for HBeAg-Positive Chronic Hepatitis B: Results of the Primary Week 24 Analysis
E. Heathcote1; H. L. Chan2; M. Cho3; C. Lai4; Y. Moon5; Y. Chao6; R. Myers7; G. Minuk8; P. Marcellin9; L. Jeffers10; W. Sievert11; R. Kaiser12; G. Chao12; N. Brown12; 0. Study Group12
1. Toronto Western Hospital, Toronto, ON, Canada.
2. Prince of Wales Hospital, Hong Kong, China.
3. University of Hong Kong, Hong Kong, China.
4. Pusan National University Hospital, Pusan, South Korea.
5. Severance Hospital, Seoul, South Korea.
6. Tri-Service General Hospital, Taipei, Taiwan.
7. University of Calgary, Calgary, AB, Canada.
8. University of Manitoba, Winnipeg, MB, Canada.
9. Hopital Beaujon, Clichy, France.
10. University of Miami, Miami, FL, USA.
11. Monash Medical Center, Clayton, VIC, Australia.
12. Idenix Pharmaceuticals, Cambridge, MA, USA.

Background: For optimizing patient management with the current antiviral armamentarium for hepatitis B, additional comparative studies are needed. Adefovir dipivoxil has significantly greater efficacy than placebo treatment but has not been evaluated in comparative trials. Telbivudine exhibited superior antiviral activity vs lamivudine in a large phase III trial, and those study results indicated that optimal viral suppression and clinical efficacy (ALT normalization, HBeAg loss/seroconversion) at 1 year were associated with maximal HBV DNA reductions in the first 6 months of treatment.
Methods: This ongoing 1-year international trial is comparing the antiviral efficacy and safety of telbivudine vs adefovir. The enrolled ITT population is 133 adults with HBeAg-positive chronic hepatitis B. Key entry criteria were HBsAg+, HBeAg+, HBV DNA >6 log10 copies/mL by COBAS Amplicor PCR assay, ALT 1.3-10 xULN, and compensated liver disease. Patients were randomized (2:1) to treatment with adefovir 10 mg/d or telbivudine 600 mg/d; at Week 24, half the adefovir cohort is secondarily randomized to switch to telbivudine. Completion of study treatment is at Week 52. The primary endpoint defined by the study protocol is HBV DNA reduction at Week 24, with secondary antiviral and clinical efficacy and safety endpoints assessed at Weeks 24 and 52.
Results: Treatment groups were well-matched at baseline. Telbivudine was superior to adefovir on the primary efficacy endpoint (HBV DNA reduction at Week 24) and all other measures of direct antiviral efficacy (Table). ALT normalization was similar at Week 24. Both treatments have been well-tolerated to date.
Conclusion: After 24 weeks, telbivudine exhibited significantly greater and more consistent antiviral efficacy than adefovir in HBeAg+ patients with chronic hepatitis B. One-year data, to be presented at the meeting, will assess the association of this difference in antiviral effect with subsequent clinical efficacy outcomes.


N Log10
HBV DNA ↓ % HBV DNA
< 5 log10† % HBV DNA
PCR-neg‡ % ALT
normalized % HBeAg loss
Telbivudine 44 6.37* 95%* 38.6%* 61.4% 16%
Adefovir 89 5.11 58% 12.4% 62.9% 10%
† percent of patients with HBV DNA level < 5 log10 (AASLD & APASL guideline) ‡ COBAS PCR assay limit ≤300 copies/mL * p < 0.01, telbivudine vs. adefovir

2)

ID#
482

Location:
409 A/B (LA Convention Center)

Time of Presentation:
May 23 9:45 AM - 10:00 AM




Phase III Comparison of Telbivudine vs Lamivudine in Patients with Chronic Hepatitis B: Efficacy, Safety, and Predictors of Response at 1 Year
N. Bzowej1; C. Lai2; E. Gane3; Y. Liaw4; S. Thongsawat5; Y. Wang6; Y. Chen7; J. Heathcote8; J. Rasenack9; N. Naoumov10; G. Chao11; B. Fielman11; N. Brown11
1. Sutter Health, San Francisco, CA, USA.
2. University of Hong Kong, Hong Kong, Hong Kong.
3. Middlemore Hospital, Auckland, New Zealand.
4. Chang Gung University and Memorial Hospital, Taipei, Taiwan.
5. Ching Mai University, Ching Mai, Thailand.
6. Military Medical University, Chongqing, China.
7. Zeijiang University College of Medicine, Hangzhou, China.
8. Toronto Western Hospital, Toronto, ON, Canada.
9. Albert Ludwigs Universitat, Freiburg, Germany.
10. University College, London, United Kingdom.
11. Idenix Pharmaceuticals, Cambridge, MA, USA.



Background: The GLOBE trial is a 2-year phase III randomized comparison of telbivudine (LdT) vs lamivudine (lam) in 921 HBeAg +ve and 446 HBeAg -ve adults with compensated chronic hepatitis B. We report primary efficacy and safety results at 52 weeks (wks) and preliminary results at 76 wks and determine predictors of efficacy.
Methods: Key entry criteria were HBsAg+, HBeAg+ or HBeAg-, HBV DNA >6 log10 by PCR assay, and ALT 1.3-10 xULN. Outcomes were assessed according to baseline demography (age, gender, ethnicity) and disease factors (HBV genotype, HBV DNA and ALT levels), and early on-treatment responses (HBV DNA and ALT levels at Wks 12 and 24).
Results: At Wk 52, LdT was superior to lam on all measures of direct antiviral efficacy in both HBeAg+ and HBeAg- pts (log10 HBV DNA reduction, % PCR -ve, resistance, treatment failure). HBeAg loss was higher in HBeAg+ pts with baseline ALT >2xULN (“interferon eligible” pts): 32% and 49% for LdT at Wks 52 and 76 respectively, vs. 27% and 29% for lam. Univariate analyses revealed that lower ALT and HBV DNA levels at wks 12 and 24, younger age, and Asian ethnicity were associated with improved 1-year efficacy outcomes. Multivariate analysis revealed that lower HBV DNA at Wk 24 was the best predictor of greater efficacy and less resistance at 1-year. Positive predictive values were high for pts who were PCR -ve at Wk 24: at 1 year, 36% of this group seroconverted HBeAg (HBeAg+ pts), and <1% developed resistance (both HBeAg+ and HBeAg-). For pts with HBV DNA >4 log10 at Wk 24, the negative predictive value for failure to HBeAg seroconvert was 93%. Clinical adverse events were similar for LdT and lam.
Conclusions: After 1 year, LdT showed significantly greater direct antiviral efficacy than lam in HBeAg +ve and HBeAg -ve pts with chronic hepatitis B, with less treatment failure and resistance. Early HBV DNA response was the strongest predictor of 1-year efficacy outcomes.


HBeAg (+) HBeAg (-)
Week 52 Week 76 Week 52 Week 76
Response LdT Lam LdT Lam LdT Lam LdT Lam
n 458 463 458 463 163 165 163 165
log10 HBV DNA ↓ 6.5* 5.5 6.6* 5.2 5.2* 4.4 5.3 4.7
% PCR neg 60* 40 69* 41 88* 71* 84* 67
% Histologic Resp 65* 56 - - 67 66 - -
% ALT normalized 77 75 78* 68 74 79 76 64
% Therapeutic Resp‡ 75* 67 75- 58 75 77 75 70
% HBeAg loss 26 23 40* 26 - - - -
% HBV resist. 3* 8 - - 2* 9 - -
% 1° Treatment Failure† 5* 13 - - <1 3 - -
† HBV DNA never <5 log10 copies/mL ‡ HBV DNA <5 log10 plus ALT normalization or HBeAg loss * p<0.01, telbivudine vs lamivudine