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Entecavir: new hepatitis B drug-phase III study results of 48-weeks therapy in HBeAg+ nucleoside-naïve patients
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Written by Jules Levin
Results from 3 large phase III studies of entecavir are being presented at this conference (55th Annual American Association for the Study of Liver Diseases), as well as a number of substudies. At today's late afternoon oral sessions, Robert Gish reported results from ETV-022, a study in 700 patients comparing entecavir 0.5 mg once daily to lamivudine 100 mg once daily. This is an international randomized, double-dummy, double-blind study. Liver biopsies were performed within 52 weeks of randomization and at week 48.
BRIEF SUMMARY: ETV showed superiority with histolpgic improvement (72% vs 62%; mean viral load reduction by PCR; -6.98 vs -5.46 log; undetectable HBV DNA by PCR: 69% vs 38%; ALT normalization: 78% vs 79% <400 c/ml; (all significant). Loss of HBeAg & seroconversion were similar for both groups; safety profile was similar for both; fewer discontinuations due to adverse events for ETV; fewer ALT flares observed both on & off treatment for ETV; entecavir resistance was not observed. Up to 14 log viral load reductions were observed.
Patients were HBsAg+ for >24 weeks prior to screening for study; HBeAg-positive; HBV DNA >3 MEq/mL (by DNA); serum ALT 1.3-10 x ULN; compensated liver function; nucleoside-naïve (<12 weeks of therapy); last dose of anti-HBV therapy >24 weeks prior to randomization; I think Gish said 13% of patients had previously used IFN.
75% were men. Mean 35 yrs old. 40% Caucasian, 57% Asian. REGION: 24% Europe; 48% Asia; 13% North America; 13% South America.
BASELINE HISTOLOGY: comparable between arms
Knodell Necroinflammatory Score (0-18) Mean:
--Entecavir 7.8
--Lamivudine 7,7
Knodell Fibrosis Score (0-4)
Mean: ETV 1.7, LAM 1.7
score >=3
--entecavir 34%
--lamivudine 32%
score=4, cirrhosis
--entecavir 8%
--lamivudine 8%
Ishak Fivbrosis Score (0-6) Mean
Score >=5, cirrhosis
--entecavir & LAM: 8%
HISTOLOGIC IMPROVEMENT (primary efficacy endpoint) Week 48
Improvement in Knodell necroinflammatory score by at least two points, plus no worsening of Knodell fibrosis score
IMPROVEMENT
ETV (n=314): 72%
LAM (n=314): 62%
P=0.0085
NO IMPROVEMENT
ETV: 21%
LAM: 24%
IMPROVEMENT IN ISHAK FIBROSIS SCORE Week 48
Secondary Histologic Endpoint
ETV: 39%
LAM: 35%
NS
NO CHANGE
ETV: 46%
LAM: 40%
PROPORTION OF PATIENTS WORSENED
ETV: 8%
LAM: 10%
MEAN CHANGE in HBV DNA from baseline by PCR
ETV: -6.98 log copies/ml
LAM: -5.46 log copies/ml
P<0.0001
PROPORTION OF PATIENTS with HBV DNA <400 Copies/ml at Week 48
ETV: 69%
LAM: 38%
P<0.0001
PROPORTION of PATIENTS with ALT NORMALIZATION (<1.25 x ULN)
ETV: 78%
LAM: 70%
P=0.014
LOSS of HBeAg & SEROCONVERSION at week 48
LOSS OF HBeAg
ETV: 22%
LAM: 20%
NS
SEROCONVERSION
ETV: 21%
LAM: 18%
NS
MOST FREQUENT ADVERSE EVENTS ON TREATMENT
Comparable across arms
Headache 21%
URI 17-20%
Cough 12-15%
Nasopharyngitis 14%
Abdominal pain, upper 10%
Fatigue 10%
Fever 10-9%
CUMULATIVE SAFETY PROFILE
| ETV | LAM | | Any AE | 85% | 83% | | SAE | 7% | 7% | | G3/4 AE | 13% | 15% | | D/C AE | <1% | 3% | | Deaths | 0 | 1% |
ALT FLARES
12 (3%) patients treated with ETV had on treatment ALT flares: 9/12 occurred between day 9 & 98 of treatment; 11/12 were self-limiting on continued therapy, resolving in 2 to 7 weeks. None of the ETV-treated patients had hepatic decompensation. 2 off treatment ALT flares.
20 (6%) patients treated with LAM had on-treatment ALT flares. 8 off treatment ALT flares.
On treatment ALT flare: ALT >2 x baseline and >10 x ULN
Off treatment ALT flare: ALT >2 reference (minimum of baseline and dosing) and >10 x ULN
PATIENT ENDPOINT MANAGEMENT
Complete Virologic Response
HBV DNA <0.7 q/mL by bDNA & loss of HBeAg
ETV: 21%
LAM: 19%
Virologic response Only
HBV DNA <0.7 MEq/mL by
bDNA but positive for HBeAg
ETV: 70%
LAM: 46%
Virologic Non-response
HBV DNA >0.7 MEq/mL by bDNA
ETV: 5%
LAM: 26%
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