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Entecavir: new HBV drug, phase III study in nucleoside-naïve HBeAg-negative patients
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Reported by Jules Levin
Tonite at 6pm Daniel Shouval reported these phase III study results at the AASLD liver meeting. It was a late report and prevented everyone from their dinner plans. But here's NATAP bringing you the most timely reporting. 638 patients were randomized to entecavir 0.5 mg once daily or lamivudine 100 mg once daily in a double-dummy, double-blind study. Patients received paired biopsies, at week 0 and week 48, as the primary study endpoint was histologic improvement. The study continued followup to week 96 but this presentation reports the week 48 results.
SUMMARY-
--histologic improvement: 70% for entecavir, 61% for lamivudine
--viral load reduction: -5.20 log copies/ml for entecavir, -4.66 log copies/ml for lamivudine
--undetectable HBV DNA by PCR: <400 copies/ml- 91% entecavir, 73% lamivudine; <200 copies/ml- 89% entecavir, 70% lamivudine
all differences are statistically significant.
--ALT normalization was similar: 86% vs 81%
--Safety profile was similar
--Entecavir resistance was not observed.
The definition of histologic improvement is Knodell necroinflammatory score (>=2 point decrease) and no worsening of Knodell fibrosis score (worsening >=1 point increase) from baseline.
Other response definitions:
Composite Endpoint Response: HBV DNA
Virologic-only Response: HBV DNA <0.7 MEq/mL by bDNA but ALT >1.25 x ULN
Virologic Non-Response: HBV DNA >0.7 MEq/mL by bDNA
Patients were HBsAg-positive for >24 weeks prior to screening; HBeAg-negative, HBeAb-positive; serum ALT 1.3-10 x ULN; nucleoside (tide) treatment-naïve (<12 weeks therapy); last dose of any anti-HBV therapy >24 weeks prior to randomization; compensated liver function. Patients were excluded for coinfection with HIV, HCV or HDV; other forms of liver disease; hemoglobin <10 g/dL, platelets <75,000 cells/mm3, neutrophils <1500 cells/mm3, creatinine >1.5 mg/dL; pancreatitis within 24 weeks of first dose of study medication; serum alpha fetoprotein >100 ng/mL; other serious medical conditions that might preclude study completion.
The baseline patient demographics were comparable in both arms: 75% male; 44 yrs old; 57% Caucasian, 40% Asian; 7.6 log copies/ml HBV DNA by PCR; mean ALT 141 IU/L.
BASELINE HISTOLOGY
Knodell Necroinflammatory Score (0-18)- mean 8.0 entecavir, 7.7 LAM.
Knodell Fibrosis Score (0-4)- mean 1.9 in both arms
--score >=43% ETV, 41% LAM
--score=4, cirrhosis: 6% ETV, 9% LAM
Ishak Fibrosis score (0-6), mean 2.4 ETV, 2.5 LAM
--score=4: 17% ETV, 19% LAM
--score=6, definite cirrhosis: 2% ETV, 3% LAM
RESULTS
PRIMARY EFFICACY ENDPOINT:
HISTOLOGIC IMPROVEMENT at week 48
70% ETV
61% LAM
p=0.014
NO improvement
19% ETV
26% LAM
SECONDARY HISTOLOGIC ENDPOINT:
Improvement in Ishak Fibrosis Score at week 48
36% ETV
38% LAM
NS
NO CHANGE
41% ETV
34% LAM
% WORSENING
12% ETV
15% LAM
MEAN CHANGE IN HBV DNA
From baseline by PCR, non-completer=failure analysis
ETV -5.20 log copies/ml (n=324 at baseline, n=314 at wk 48)
LAM -4.66 log copies/ml (n=311 at baseline, n=295 at week 48)
P<0.0001
PROPORTION OF PATIENTS with UNDETECTABLE HBV DNA by PCR
<400 copies/ml, non-completer=failure analysis
week 24; 78% ETV, 66% LAM (p=0.001)
week 36: 83% ETV, 69% LAM (p<0.0001)
week 48: 91% ETV, 73% LAM (p<0.0001)
proportion HBV DNA <200 copies/ml
week 24: 69% ETV, 57% LAM (p=0.0021)
week 36: 81% ETV, 67% LAM (p=0.0001)
week 48: 89% ETV, 70% LAM (p<0.0001)
SAFETY PROFILE: similar between arms
ON TREATMENT
Any AE: 75% ETV, 79% LAM
SAE: 6% ETV, 8% LAM
d/c due to AE: 2% ETV, 3% LAM
MOST FREQUENT AEs ON TREATMENT
Headache: 15% ETV, 17% LAM
Upper respiratory infection: 13% ETV, 14% LAM
ALT FLARES
On treatment: 1% ETV, 2% LAM
Off treatment: 5% ETV, 9% LAM
None of the flares resulted in hepatic failure
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