Entecavir Maintains a High Genetic Barrier to HBV Resistance Through 6 Years in Naïve Patients

Transcription

1 Entecavir Maintains a High Genetic Barrier to HBV Resistance Through 6 Years in Naïve Patients D.J. Tenney 1, K.A. Pokorowski 1, R.E. Rose 1, C.J. Baldick 1, B.J. Eggers 1, J. Fang 1, M.J. Wichroski 1, U. Diva 1, D. Xu 1, R.B. Wilber 1, H. Brett-Smith 1 & U.H. Iloeje 1 1 Research and Development, Bristol-Myers Squibb Company, United States

2 Disclosures I am a full-time employee of Bristol-Myers Squibb; Data presented are from trials in the entecavir development program

3 Primary Factors in Antiviral Resistance Fitness replication capacity of viral variants Impact on viral fitness Genetic Barrier number of substitutions required for resistance Clinical Efficacy Reflects intrinsic drug potency and dose administered Genetic barrier Inherent potency Pharmacologic levels achieved

4 ETV Genotypic Resistance: Population Screening 2 cohorts: Naïve and LVD-refractory All patients with continuous ETV >12 wks Genotype performed:* All baseline specimens If HBV DNA 300 c/ml (50 IU/mL ml) ) at Annual timepoint (Wks 48, 96, 144, 192, 240, 288) End of Dosing If virologic breakthrough while on treatment (confirmed 1 1 log increase in HBV DNA from nadir) * consistent with monitoring recommendations in Pawlotsky et al, Gastroenterology 2008

5 ETV Genotypic Resistance: Rate Calculation Genotypic resistance to ETV requires both: LVD resistance (M204I/V ± L180M), and ETV-specific change (T184, S202 or M250) Cumulative probability* P = 1-(11 (1-n1/N1)(1-n2/N2) n2/n2) (1-nx/Nx) * consistent with monitoring recommendations in Pawlotsky et al, Gastroenterology 2008

6 ETV 6-Year 6 Program: Naïve Patient Flow Years 1-21 Randomized Studies 0.5 mg Years 2-62 ETV-901 Rollover Study 1.0 mg ETV Responders 1 ETV - 022: Naïve HBeAg+ Virologic Responders 1 ETV ETV - 027: Naïve HBeAg- Non-Responders 1. protocol defined response criteria Treatment Gap Time 35 days for resistance cohort

7 Nucleoside-Naïve Cohort (HBeAg+ & HBeAg-): Cumulative Probability of ETV Resistance Through 6 Years ETVr = LVDr (M204V ± L180M) + T184, S202 and/or M250 substitutions Cumulative Probability (%) Years N=663 2 N= N=149 4 N=120 5 N=108 6 N=99 HBV DNA <300 c/ml in 94% of patients in Year-6 (N = 99) HBV DNA <300 c/ml at last on-treatment visit in 89% of those discontinuing

8 Cumulative probability of resistance (%) Cumulative incidence of resistance (%) N= 0 5 Resistance Rates Across Studies in Nucleoside-Na Naïve Patients Genotypic resistance to ETV HBeAg(+) and (-)( ) patients Year of treatment Viral breakthrough with genotypic resistance to LdT 3,4 HBeAg(+) HBeAg(-) 99 6 N= N= NA NA Year of treatment Year of treatment 1. Chang TT, et al. J Gastroenterol Hepatol 2004;19: ; 2. Hadziyannis S, et al. Gastroenterology 2006;131: ; 3. Lai CL, et al. N Engl J Med, 2007;357: ; 4. Liaw YF, et al. Gastroenterology 2009;136: Marcellin P, et al. N Engl J Med 2008;359: ; 6. Snow-Lampart A, et al. Hepatology 2008;48(suppl.): 745A. Incidence of resistance (%) Cumulative probability of resistance (%) N= Genotypic resistance to TDF 5,6 + FTC at Week Year of treatment HBeAg(+) and (-)( ) patients Genotypic resistance to ADV 2 HBeAg(-) ) patients

9 Lamivudine-Refractory Patients

10 Lamivudine Refractory Patient Flow Randomized Studies 1.0 mg Responders 1 Rollover Study 1.0 mg ETV ETV-026 HBeAg+ Virologic Responders 1 ETV mg group ETV-015 Post-Transplant Non-Responders 1 Any Any ETV protocol defined response criteria

11 Lamivudine-Refractory Cohort (HBeAg+): Cumulative Probability of ETV Resistance Through 6 Years ETVr = LVDr (M204V ± L180M) + T184, S202 and/or M250 substitutions Cumulative Probability (%) Years 6 1 N= N= N= N= N= N=29 74/187 (40%) achieved HBV DNA <300 copies/ml 5/74 (7%) with HBV DNA < 300 c/ml had subsequent genotypic ETV resistance

12 Genetic Barrier to Entecavir Resistance Nucleoside-naïve patients ETV rtt184 or rts202 or rtm250 rtm204v/i + rtl180m Wild-type virus LVD-resistant virus ETV-resistant virus Lamivudine-refractory patients LVD then ETV rtm204v/i + rtl180m rtt184 or rts202 or rtm250 rtm204v/i + rtl180m Baraclude (entecavir) Summary of Product Characteristics. Bristol-Myers Squibb Pharma EEIG. January 2008

13 Entecavir Resistance Through 6 Years Nucleoside-Na Naïve: ETV has high potency and high genetic barrier Resistance is rare through 6 years 1.2% genotypic resistance LVD-refractory: ETV potency and genetic barrier are reduced Incremental increase in resistance over time Favorable prognostic subgroups can be identified by early response to treatment and lower baseline HBV DNA (< 10 7 copies/ml)

14 Acknowledgements Bristol-Myers Squibb would like to thank all those who made possible the long-term follow-up of the ETV resistance cohort: >850 patients and >340 investigators from 30 countries Participating in studies: ETV-014, ETV-015, ETV-022, ETV-026, ETV-027 and ETV-901