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Durability of Response and Rate of Re-emergence of Wild Type at Boceprevir BOC Resistance-Associated Variant RAV Loci i

Summary of Boceprevir. Boceprevir is a NS3 protease inhibitor that has completed phase 3 clinical trialsRESPOND-1; Phase 2 Dose finding-study in previous null responders IFN /- RBVSPRINT-1; Phase 2 Safety/Efficacy Study in treatment na

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Durability of Response and Rate of Re-emergence of Wild Type at Boceprevir BOC Resistance-Associated Variant RAV Loci i

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    1. Durability of Response and Rate of Re-emergence of Wild Type at Boceprevir (BOC) Resistance-Associated Variant (RAV) Loci in Genotype 1a and 1b Patients: Interim Analysis of Long-Term Follow-Up of Patients Treated With Boceprevir + PegIntron +/-Ribavirin Richard J.O. Barnard, John Howe, Donald J. Graham, Robert A. Ogert, Jianmin A. Long, Navdeep Boparai, Patricia Mendez, Clifford Brass, Janice Albrecht, Robert Ralston

    2. Summary of Boceprevir Boceprevir is a NS3 protease inhibitor that has completed phase 3 clinical trials RESPOND-1; Phase 2 Dose finding-study in previous null responders + IFN +/- RBV SPRINT-1; Phase 2 Safety/Efficacy Study in treatment naļve patients +IFN/RBV SPRINT-2; Phase 3; Response-guided therapy vs 48-week therapy study + IFN/RBV in treatment naļve patients (800mg BOC TID) RESPOND-2; Phase 3; Response-guided therapy vs 48-week therapy study + IFN/RBV in previously treated patients (800mg BOC TID) SVR rates were superior to control arms in RESPOND-2, (59-66% vs 21%) and SPRINT-2 (63-66% vs 38%) Resistant Associated amino acid Variants (RAVs) were detected in 53% of non-SVR patients in SPRINT-2/RESPOND-2 studies As HCV does not integrate into the human genome, the issue of the longevity of RAVs selected in non-SVR patients is unknown

    3. In vitro Characterization of Boceprevir NS3 RAVs in Enzymatic Studies

    4. Long-Term Follow-Up Study These analyses were undertaken to characterize the rates of re-emergence of wild-type at boceprevir resistant loci in non-SVR patients with detectable RAVs Study Description Patients are being monitored for at least 3.5 years post-therapy Resistance variants were detected by population sequencing of the NS3 protease region (aa codons 1-181)

    5. Objectives and Criteria for the Interim Analysis of Resistance Initial aim was to characterize the presence of boceprevir RAVs over time by population sequencing (~20-25% Sensitivity) Patients in interim analysis had to have viruses with at least one of the majority RAVs (detected in =25% of non-SVR patients) V36M, T54A/S and/or R155K Patients had to have viruses that were wild-type at that position prior to receiving boceprevir Patients had to have at least two years of follow-up data (183 patients in this interim analysis); majority of patients from RESPOND-1

    6. Baseline Demographic and Disease Characteristics Demographic and baseline characteristics of age, sex, race, ethnicity, weight,  BMI and  viral load are consistent with previously studies in HCV patients Patients enrolled in the long-term follow up study were typically white males; average age was 49 to 52  years  The distribution of genotypes was similar among the patient groups The average length of time since probable exposure to HCV was 25 to 30 years

    7. Return of Wild-Type at Individual RAV Loci by Population Sequencing

    8. Median Rates of Return of Wild-Type at Specific RAV Loci

    9. Individual Viral Load Plots from Patients infected with Genotype 1b Virus

    10. Viral Load Plot from a Patient infected with Genotype 1a Virus Here is an example of a 1A patient with two RAVs that were linked, that decline at different ratesHere is an example of a 1A patient with two RAVs that were linked, that decline at different rates

    11. Conclusions Different RAVs are selected in genotype 1a and 1b viruses WT at each RAV loci re-emerged at different rates depending on the specific RAV selected WT re-emerged most rapidly in genotype 1a or 1b viruses with V36M or T54A, as compared to viruses with either T54S or R155K Variation in the appearance of resistance and rates of re-emergence of WT at each loci reflects relative fitness of the specific RAVs in the specific genetic background In patients that fail with multiple RAVs, individual RAVs can decline at different rates Studies are ongoing to analyze the linkage in viruses with multiple RAVs The majority of patients in this interim analysis are from phase 2 studies Make point in the last bullet that we don’t know what the Ph3 data will look like.Make point in the last bullet that we don’t know what the Ph3 data will look like.

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