Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. 8 th International Workshop on Clinical Pharmacology of Hepatitis Therapy June 2013

Transcription

1 Relationship Between Transaminase Levels and Plasma Pharmacokinetics Following Administration of with Pegylated Interferon Alfa-2b and Ribavirin to G1 Treatment-Naïve HCV Patients Luzelena Caro, Lihong Du, Shelby Huang, Larissa Wenning, Jing Su, Peggy Hwang, Robert Valesky, Christopher Gilbert, Jacqueline Gress, Frank Klaassen, Isaias Noel Gendrano, Joann Brunhofer, Michael Cooreman, Jan Huisman, Niloufar Mobashery Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA 8 th International Workshop on Clinical Pharmacology of Hepatitis Therapy June 2013

2 Background is a potent, once-daily, next-generation NS3/4A protease inhibitor with a high barrier to resistance Potent in vitro activity against a broad enzyme panel including major HCV genotypes 1 D81 In vitro activity against resistanceassociated variants found in patients who failed therapy with firstgeneration protease inhibitors (boceprevir, telaprevir, and TMC-435) 2 R155 A156 H57 S139 5 log 10 drop in HCV RNA levels following monotherapy with ( 30 mg once daily) for 7 days in patients with HCV G1 infection 3 D Summa V, et al. Antimicrob Agents Chemother 2012;56: Graham D, et al. Hepatology 2011;54(suppl):139A (abs #370). 3. Petry A, et al. Hepatology 2011;54(suppl):531A (abs #346).

3 Phase II Study Design: Multicenter, Double-Blind, Randomized, Active-Controlled, Dose-ranging, Response- Guided Trial Arm mg QD + Arm mg QD + Arm mg QD + Arm mg QD + Arm 5: BOC+ BOC+ Week 4 Interim Analysis Week 12 Assess Futility Week 16 Primary Analysis Week 24 Assess Futility Week 36 Week 48 Week 72 Arms 1-4: + peginterferon and ribavirin () for 12 weeks, then 12 or 36 weeks TW4 HCV-RNA target not detected (TND): 12 additional weeks of TW4 HCV-RNA target detected quantifiable (TD(q)) or target detected unquantifiable (TD(u)): 36 more weeks Arm 5: Boceprevir (BOC) + response-guide therapy per product circular Patients in PK sub-study provided plasma samples through Week 12 for assessment of plasma 3 concentrations

4 Virologic Response Outcomes and Patients With Late Transient ALT/AST Elevations Interim Analysis Parameter 100 mg QD + (N=66) 200 mg QD + (N=68) 400 mg QD + (N=67) 800 mg QD + (N=65) Once-Daily + therapy was efficacious in treatment-naïve, G1 HCV Patients, with high SVR24 rates Efficacy for 100 mg QD of was similar to that achieved at higher doses BOC + (N=66) TND at the Last Visit on 92% 99% 96% 98% 67% Record SVR24 (%) 86% 92% 91% 87% 54% Patients with Late ALT/AST >2xULN 1 (2%) 6 (9%) 13 (19%) 15 (23%) 1 (2%) >5xULN, 0 (0%) 1 (1%) 4 (6%) 6 (9%) 0 (0%) N is total number of patients in the tratment arm. 31.3% of patients had a baseline ALT >2x ULN. 2.4% of patients had a baseline ALT >5x ULN. Late ALT/AST >5 ULN category represents subset of patients in late ALT/AST >2 ULN category 254 of 266 (95%) patients reached follow-up week 24 or discontinued before follow-up week 24 Transient, transaminase elevations of 2X and 5X ULN occurred after TW4 in minority of patients in a dose-dependent manner Frequency of transaminase increase similar for control and 100 mg +

5 Pharmacokinetic/Safety Analysis: Objective & Methods Objectives: Explore relationship between plasma pharmacokinetics (PK) and late ALT/AST elevations following administration of + to HCV G1 Treatment-Naïve Patients to guide program dose selection by minimizing the probability of elevated liver transaminase occurrences Steady-State PK Endpoints: C trough: Predose samples collected at ~24 hrs postdose C 2hr: Representative of Cmax (actual Cmax is at ~3-4 hrs) Safety Endpoints: Criterion 1: ALT/AST stabilized by Week 4, followed by an increase in ALT or AST > 2X ULN Criterion 1A: ALT/AST stabilized by Week 4, followed by an increase in ALT or AST > 5X ULN Logistic PK/safety regression analyses conducted to assess probability of Criterion 1 or 1A occurring at a given PK parameter value

6 Mean Plasma PK Exposures versus Dose e+5 SS C trough (nm) (log-scale) 100 SS C 2hr (nm) (log-scale) 1e+4 1e+3 GM and 90% CI QD Dose (mg) SS: Steady-State; GM: Geometric Mean; CI: Confidence Interval 1e QD Dose (mg) GM and 90% CI Greater than dose-proportional PK at doses of mg QD, which is more evident at high doses ( 200 mg) Clear difference in PK across doses, with non-overlapping variability, is consistent with dose-dependent trend of transaminase elevations

7 PK/Safety Logistic Regression Plot: Criterion 1 (>2X ULN) vs. GM Ctrough and GM C2hr GM Ctrough and GM C2hr have a statistically significant relationship with Criterion 1 (>2X ULN) and Criterion 1A (> 5X ULN) Probability of ALT/AST elevations >2X ULN occurring increased with increasing GM Ctrough and GM C2hr values Probability threshold specified: <10% probability of ALT/AST >2XULN PK Values corresponding to the specified threshold: GM Ctrough ~ 56 nm; GM C2hr ~ 1.47 um

8 PK/Safety Logistic Regression Plot: Criterion 1A (>5X ULN) vs. GM Ctrough and GM C2hr Probability of ALT/AST elevations >5X ULN occurring increased with increasing GM Ctrough and GM C2hr values Probability threshold specified: <5% probability of ALT/AST >5XULN PK Values corresponding to the specified threshold: GM Ctrough ~ 128 nm GM C2hr ~ 4.68 um

9 Predictability of PK Thresholds using Negative Predictive Values (NPV) High NPV (closest to 100%): PK thresholds are effective differentiators for not having Criterion 1 and Criterion 1A Criterion 1A (>5X ULN) GM Ctrough 128 nm resulted in a 98% NPV GM C2hr 4675 nm resulted in a 100% NPV Criterion 1 (>2X ULN) GM Ctrough 56 nm resulted in a 93% NPV GM C2hr 1470 nm resulted in a 95% NPV Results confirm that GM Ctrough and GM C2hr thresholds provide a good differentiator for not having Criterion 1 or Criterion 1A

10 Discussion & Conclusions + generally well tolerated, but dose-related transaminase elevations noted PK/Safety analysis shows correlation between plasma PK and risk for of ALT/AST increases, supports low risk for a hepatic safety signal at 100 mg QD Criterion 1 (>2X ULN): GM Ctrough and GM C2hr associated with 10% probability of Criterion 1 provide ~1.8-fold and ~4-fold margin to upper 90% CI for the 100 mg PK, respectively Criterion 1A (>5X ULN): GM Ctrough and GM C2hr associated with 5% probability of Criterion 1A provide a ~4-fold and ~13-fold margin to upper 90% CI for the 100 mg PK, respectively Additional clinical studies will evaluate at oral daily doses of 100 mg Safety margins allows for exposure increases from DDIs and/or special populations High SVR rates at 100 mg QD, with similar efficacy as higher doses Frequency of late transaminase increase for 100 mg+ same as control

11 Acknowledgements Our gratitude to the patients and study sites participating in this study 11

12 Disclosures All authors are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ 12