Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses for Raltegravir in Phase II and III Studies in Treatment Experienced HIV-Infected Patients L. Wenning, B.-Y. Nguyen, X. Sun, E. Hwang, Y. Chen, H. Teppler, C. Harvey, R. Rhodes, D. Ryan, N. Azrolan, J. Stone 9 th International Workshop on Clinical Pharmacology of HIV 8-April-2008

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved2 Raltegravir Background  HIV Integrase Strand Transfer Inhibitor  In vitro IC 95 ~ 33 nM  Metabolism and excretion  Major mechanism of clearance is glucuronidation (UGT1A1)  Minor component of renal elimination  Raltegravir pharmacokinetics support BID dosing  Terminal t ½ ~9 hrs with a shorter α-phase t ½ ~1 hr  Slight degree of accumulation in C 12hr with multiple doses  Pharmacokinetics similar across  Gender, race, age (adults), HIV infection status, hepatic function, renal function, and body mass index

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved3 Background: Raltegravir PK  Relatively large degree of interoccasion variability in absorption  Development of a population PK model was problematic Representative Raltegravir Plasma Concentration Profiles from Phase I Studies with Population Mean Predicted Line Overlaid

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved4 Sparse Raltegravir PK Sampling Included in Phase II and III Studies Raltegravir Plasma Concentrations from Phase III Studies (400 mg BID + OBT)

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved5 Individual PK Parameters Assessed in PK/PD Analyses of Phase II/III Studies  Non-model based parameters: from concentration data obtained from sparse sampling in Phase II/III  Original Analysis:  Geometric mean (GM) of observed C 12hr [Primary]  GM of all concentrations in individual collected between 11 and 13 hrs post-dose  Median of 2 samples/patient; ~60% of patients have value  Minimum of observed C 12hr  Supplemental Analysis (Phase III studies only):  Geometric mean of all observed concentrations (GM All)  Median of 4 samples/patient; 457 of 462 patients have value  Minimum of all observed concentrations (C min )

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved6 Geometric Mean of All Concentrations (GM All)  Best currently available measure of overall long- term exposure to raltegravir during Phase III studies  For full profiles, GM All is well correlated with AUC, but interpretation less clear in context of sparse sampling  Approximately 60% of the Phase III subjects had samples that spanned at least 8 of the 12 hours of the dosing interval

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved7 Efficacy Parameters Evaluated in PK/PD Analyses  Pharmacodynamic parameters examined at times below :  HIV RNA <400 copies/mL  HIV RNA <50 copies/mL  Virologic failure  Mutation in integrase gene at amino acid 148 and/or  Mutation in integrase gene at amino acid 155  Change from baseline in HIV RNA  Phase II data (Week 24) in 124 treatment-experienced patients from Protocol 005  Phase II data (Week 48) in 150 treatment-naïve patients from Protocol 004  Pooled Phase II/III data (Week 16) in 579 treatment- experienced patients from Protocols 005, 018, and 019  For supplemental analysis: 457 patients from Phase III only

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved8 Raltegravir PK/PD Analysis: Results (1)  No statistically significant relationships identified between GM C 12hr and any PD endpoint in Phase II or III studies  Treatment response does not appear reduced in patients with GM C 12hr < IC 95  BQL values excluded from analysis  Response may be lower in patients with BQL values, but this may reflect compliance rather than PK

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved9 Quartile Analysis of Potential Relationship Between GM C 12hr and HIV RNA<400  A similar percentage of patients had HIV RNA <400 at treatment week 16 in each quartile of observed raltegravir C 12hr values  16 out of 332 patients had GM observed C 12hr values <33 nM (~in vitro IC 95 )  These patients had a similar rate of treatment success compared to patients with other GM observed C 12hr values GM Observed C 12hr <33 nM

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved10 Raltegravir PK/PD Analysis: Results (2)  Statistically significant relationships identified between many PD endpoints and GM All at Week 16 of treatment in Phase III studies  HIV RNA <400 copies/mL  HIV RNA <50 copies/mL  Virologic failure  Change from baseline in HIV RNA  PK appears less influential than other covariates (e.g. baseline HIV RNA; use of other active agents in OBT)

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved11 Treatment-experienced patients (P018, P019 Combined) HIV RNA <50 copies/mL in 282 out of 442 patients with PK and efficacy data Odds ratio (95% CI) = 2.09 (1.24, 3.51), p=0.005 Relationship Between GM All and HIV RNA <50 Copies/mL

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved12 Pearson’s Correlation = ; p=0.001 Spearman’s Rank Correlation = ; p=0.006 Relationship Between GM All and Change from Baseline in HIV RNA

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved13 How Does Impact of Raltegravir PK Compare to Other Factors?  Baseline HIV RNA level and use of other active agents in OBT have more influence over treatment outcome than PK Naïve darunavir use = yes:Naïve darunavir use = no:

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved14 Conclusions  No statistically significant relationships identified between GM C 12hr and any PD endpoint in Phase II or III studies (Week 16 of treatment)  Statistically significant relationships identified between many PD endpoints (Week 16 of treatment) and GM All  PK appears to have less influence on treatment outcome than other covariates (e.g. baseline HIV RNA; use of other active agents in OBT)  No threshold concentrations identified

L. Wenning et al. PK/PD of Raltegravir Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved15 Acknowledgements  The Patients and Investigators of P004, P005, P018 and P019  Merck & Co., Inc.  Department of Clinical PK/PD  Department of Clinical Research  Department of Biostatistics  Department of Antiviral Research  Department of Clinical Pharmacology  Cognigen Corporation