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Clinical Development of Entecavir for the Treatment of Chronic Hepatitis B
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Reported by Jules Levin
D Dehertogh, R Colonno
Bristol-Myers Squibb, Wallingford, CT
Entecavir is a potent and selective inhibitor of hepatitis B (HBV) and is currently in phase III development worldwide.
The efficacy and safety of entecavir was analyzed across several Phase 2 studies in both naïve and interferon/lamivudine pretreated chronic HBV patients.
The first study evaluated 3 doses of entecavir (0.01, 0.1 and 0.5 mg QD) vs lamivudine 100 mg QD for 24 weeks in 177 nucleoside-naïve patients. Both the 0.5 and 0.1 mg doses of entecavir produced superior reductions in HBV DNA by PCR (mean log10 decrease of 4.7 and 4.3, respectively) compared with 3.4 log10 for lamivudine (p<0.0001). The viral load reduction for 0.5 mg entecavir was superior to that for 0.1 mg (p<0.018). In contrast to lamivudine, entecavir 0.5 mg was highly effective in reducing HBV DNA regardless of baseline ALT. In patients with normal ALT at baseline (ALT<1.25 x ULN), entecavir o.5 mg demonstrated a 4.7 log10 reductioncompared with 2.9 log10 for lamivudine (p<0.0001).
Entecavir also demonstrated potent antiviral activity in a Phase 2 dose-ranging study in 181 patients with lamivudine –refractory chronic HJBV, 87% of whom had detectable YMDD mutations at baseline. Patients who were randomized to switch to entecavir 1.0 mg or 0.5 mg QD achieved superior reductions in HBV DNA by PCR after 48 weeks (5.1 log10 and 4.5 log10 respectively) compared with 1.4 log10 reduction for patients who continued to receive lamivudine. There was no evidence of emergence of entecavir resistance or novel amino acid substitutions associated with viral rebound after 48 weeks of dosing with entecavir 1.0 or 0.5 mg. Among those with abnormal ALT at baseline, entecavir 1.0 and 0.5 mg were superior in normalizing ALT (68% and 59%, respectively) compared to continued lamivudine (6%; p<0.0001). Preliminary data from this trial also suggest that entecavir-treated patients have a more durable response off-treatment, especially in those with HBeAg-negative disease.
The safety of entecavir was evaluated (dose range 0.01 to 1.0 mg QD) for up to 96 weeks, 86 received lamivudine for 52 weeks, and 8 received placebo. There was no dose related increase in the incidence of adverse events across the entecavir doses. The type and incidences of adverse events for entecavir were comparable to that for lamivudine.
Entecavir demonstrated superior antiviral activity and normalization of ALT in both nucleoside-naïve and lamivudine-refractory chronic HBV patients and was well tolerated in Phase 2 trials. These findings must be confirmed in the large ongoing Phase 3 studies of 0.5 mg entecavir for nucleoside-naïve and 1.0 mg for lamivudine-refractory patients.
Rich Colonno from Bristol Myers Squibb presented a report on entecavir resistance at HEP DART.
Infrequent Emergence of Entecavir (ETV) Resistant Variants – Requirement of Prior Lamivudine Resistance
RT (reverse transcriptase) sequences were amplified from serum HBV samples. Antiviral assays used HBV yields from transfected HepG2 cells.
Resistance monitoring of >500 patients in Phase II studies identified 2 heavily pretreated patients who developed resistance to ETV. “Patient A” received 0.5 mg ETV for 52weeks with about 2 log HBV DNA reduction, followed by 0.5 mg ETV + 100 mg lamivudine (LVD) before displaying a rebound at week 133. LVD resistant substitutions L180M, M204V and V173V/L were present at study entry, with substitutions I169T (B Domain) and M250V (E Domain) selected on treatment. Reduced ETV susceptibility required a M250V in addition to LVD substitutions.
Liver transplant “Patient B” failed famciclovir, ganciclovir, foscarnet and LVD therapy and had RT changes S78S/T, L180M, V173V/L, T184T/S and M204V at study entry. Viral rebound occurred after 80 week ETV (1.0 mg) therapy with the additional substitutions A38E, T184G (B Domain) and S202I (C Domain) selected. Significant (>100-fold) phenotypic resistance to ETV occurred only when both the T184G and S202I changes were combined with LVD substitutions.
As part of an extensive search for additional ETV resistant isolates, all patients with LVD-refractory disease in a Phase II Study (A1463-014) were monitored for decreased ETV susceptibility. Of 181 patients treated, 132 (87%) had isolates that harbored LVD substitutions at study initiation, and all 3 doses of ETV (1.0, 0.5, and 0.1 mg) were superior to continued LVD in reducing HBV DNA over 48 weeks. Genotypic analysis of patient HBV isolates monitored the appearance and/or disappearance of LVD-resistant substitutions and any other novel substitutions that emerged on ETV therapy. Results showed no apparent correlation between virologic response on ETV and either LVD-resistant or novel HBV RT substitutions. Analysis of HBV isolates with paired baseline and on treatment samples showed that the majority of patients with LVD-resistant HBV at study entry retained LVD-resistant genotypes over the 48 week study, regardless of the treatment arm, with a small proportion of the patient isolates showing some shifts among their LVD-resistant substitutions. Comparison of the 132 paired isolates (108 ETV and 24 LVD) showed no significant difference in the number of other substitutions that occurred in the HBV RT, either in naturally polymorphic positions or in highly conserved residues. A small number of substitutions at conserved residues did emerge on ETV therapy, but none were correlated with virologic rebounds or reduced susceptibility to ETV.
Colonno concluded emergence of resistance to ETV appears very infrequently, requiring a prolonged ETV treatment period and the presence of multiple RT changes in addition to LVD substitutions.
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