Potent Antiretroviral Effect of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus Potent Antiretroviral Effect of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus 1 Grinsztejn, B.; 2 Nguyen, B-Y.; 3 Katlama, C.; 4 Gatell, J.; 5 Lazzarin, A.; 6 Vittecoq, D.; 7 Gonzalez, C.; 2 Chen, J.; 2 Isaacs, R.; Protocol 005 Team 1 Evandro Chagas Clinical Research Institute/ Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 2 Merck Research Laboratories, P.A., USA; 3 Hosp. Pitié Salpêtrière, Paris, France; 4 Univ. of Barcelona, Spain; 5 San Raffaele Sci. Inst., Milan, Italy; 6 Hosp. Paul Brousse, Villejuif, France; 7 New York Univ. School of Medicine, New York, New York CROI 2006 ABSTRACT #159LB, Grinsztejn

MK-0518 A Novel HIV-1 Integrase Inhibitor HIV integrase inhibition: a new mechanism of action Potent in vitro activity IC 95 = 33 nM  23 nM in 50% human serum Active against: –multi-drug resistant HIV-1 –CCR5 and CXCR4 HIV-1 HIV resistant to MK-0518 remain sensitive to other ARTs Synergistic with all ARTs Potent activity in ART-naive patients after 10 days of monotherapy (Morales-Ramirez et al, EACS 2005) HIV RNA  of 1.7 – 2.2 log 10 copies/mL CROI 2006 ABSTRACT #159LB

MK-0518 A Novel HIV-1 Integrase Inhibitor Preclinical evaluation –Predominantly metabolized via glucuronidation (UGT1A1) –Not a potent inhibitor or inducer of CYP3A4 Does not require “ritonavir boosting” –No substantive issues from preclinical studies Phase I –Data support dosing mg po bid without regard to food At 100mg b.i.d, mean C 12hr > IC 95 –Drug interaction studies support dosing of MK-0518 with other ARTs without dose adjustment CROI 2006 ABSTRACT #159LB

Protocol 005 – Study Design Randomized, double-blind –200, or 400, or 600 mg MK-0518 b.i.d. p.o. vs Placebo All in combination with optimized background therapy (OBT) –Baseline stratification Use of T-20 in OBT Degree of HIV resistance to PI at entry –To evaluate potential atazanavir (UGT1A1 inhibitor) effect Sub-study A (non-ATV containing OBT) (hypothesis testing) Sub-study B (ATV containing OBT) Key Inclusion Criteria –Documented genotypic/phenotypic resistance to  1 drug in each of 3 classes (NNRTI + NRTI + PI) –HIV RNA > 5000 copies/mL and CD4 > 50 cells/mm 3 Endpoints –HIV RNA and CD4 counts –Adverse experiences CROI 2006 ABSTRACT #159LB

Protocol 005 – Interim Analysis Similar treatment effect observed across Sub-Study A and B –Data presented are combined from 2 sub-studies All approaches (e.g. Observed data, NC = F) show similar results due to small number of discontinuations –Discontinuations prior to Week 16 1 patient due to lack of efficacy 1 death (suicide)  Observed data are presented CROI 2006 ABSTRACT #159LB

Baseline Patients Characteristics MK-0518*Placebo* 200mg N=40 400mg N=42 600mg N=42N=43 Median Age (yrs) Male83%91% 88% Mean log 10 HIV RNA Mean CD4 Count (/mm 3 ) Median Years of Prior ARTs OBT: Median # of ARTs4444 OBT: # of pts using T-20 (%)13 (33%)16 (38%) PSS § : 0 to all ARTs16 (40%)24 (57%)21 (50%)17 (40%) PSS § : 0 to PI39 (98%)40 (95%)37 (88%)36 (84%) * * + OBT ; § PSS = Phenotypic sensitivity score; Enfurvitide is not included in the scores since there is no clinical cut-off. CROI 2006 ABSTRACT #159LB

Proportion of patients (95% CI) with HIV RNA < 400 copies/mL CROI 2006 ABSTRACT #159LB

Proportion of patients (95% CI) with HIV RNA < 50 copies/mL CROI 2006 ABSTRACT #159LB

Mean change from baseline (95% CI) in HIV RNA and CD4 cell count (cells/mm3) CROI 2006 ABSTRACT #159LB

Protocol 005 Safety MK-0518 safety profile similar to placebo (both with OBT) Most clinical adverse experiences (AE): mild to moderate MK-0518*Placebo* 200 mg N = mg N = mg N = 44N = 45 Diarrhea2 (5%)1 (2%) 4 (9%) Nausea2 (5%) 5 (11%) Fatigue3 (7%)0 (0%)1 (2%) Injection site reaction1 (2%)3 (7%)4 (9%)1 (2%) Headache4 (10%)0 (0%)2 (5%)2 (4%) Pruritus0 (0%)1 (2%)3 (7%)0 (0%) Most Common Drug-Related Clinical AE (Incidence  5% or 2 pts in at least one treatment group) * + OBT Drug-related SAEs: Acute Pancreatitis after 2 doses, considered 2º to OBT (200 mg) Lacunar infarction by CT (placebo) Lipoatrophy (blinded) Anemia; metabolic acidosis; renal insufficiency; death (blinded) Hepatomegaly tenderness; fever (600 mg) CROI 2006 ABSTRACT #159LB

MK-0518*Placebo* 200 mg N = 42 n/m § (%) 400 mg N = 43 n/m § (%) 600 mg N = 44 n/m § (%) N = 45 n/m § (%)  Neutrophil 0001/43 (2)  Platelet 001/39 (3)0  Cholesterol 0001/29 (3)  Triglycerides 2/26 (8)001/29 (3)  Total bilirubin † 3/39 (8)2/41 (5)3/39 (8)1/43 (2)  AST 1/39 (3)1/41 (2)00  ALT 01/41 (2)00  Alkaline phosphatase 1/39 (3)000  Serum lipase 1/39 (3)1/41 (2)00  Serum pancreatic amylase 002/39 (5)0 Protocol 005 Safety Grade 3/4 Laboratory Abnormalities * + OBT ; § n/m = # of pts with Gr 3 or 4/ # of pts with lab test † Isolated hyperbilirubinemia noted only in pts receiving atazanavir CROI 2006 ABSTRACT #159LB

Conclusions MK-0518 is a promising new HIV integrase inhibitor In patients with advanced HIV infection, failing ARTs with triple-class resistant virus, and with limited active ARTs in OBT, MK-0518 at all doses studied –was generally well tolerated –had potent antiretroviral activity 56-72% with HIV RNA < 50 copies/mL at Wk 16 CROI 2006 ABSTRACT #159LB

Acknowledgements Investigators B. GrinsztejnBrazil C. KatlamaFrance J. GatellSpain A. LazzarinItaly D. VittecoqFrance C. GonzalezUSA J. SierraMexico G. CarosiItaly S. LittleUSA M. MoroniItaly J. RockstrohGermany M. KozalUSA R. LiporaceUSA E. Jones-LopezUSA B. ClotetSpain S. StaszewskiGermany Merck Research Labs B-Y. Nguyen J. Chen R. Isaacs C. Harvey H. Teppler L. Wenning M. Miller D. Hazuda M. Rowley V. Summa J. Vacca D. McMahonUSA P. KumarUSA C. LeeMalaysia K. SquiresUSA M. OpravilSwitzerland N. ClumeckBelgium J. LennoxUSA J. EronUSA J. GallantUSA M. NelsonUK S. BrownUSA K. TashimaUSA V. SorianoSpain C. CrumpackerUSA D. KuritzkesUSA All patients in Protocol 005 CROI 2006 ABSTRACT #159LB