IAC 2006 Abs# THLB0214 Potent Antiretroviral Effect of MK-0518, a Novel HIV-1 Integrase Inhibitor, as part of Combination ART in Treatment -Naïve HIV-1 infected Patients M. Markowitz 1, B.-Y. Nguyen 2, E. Gotuzzo 3, F. Mendo 4, W. Ratanasuwan 5, C. Kovacs 6, J. Zhao 2, L. Gilde 2, R. Isaacs 2, H. Teppler 2, and the Protocol 004 Part II Study Team 1 Aaron Diamond AIDS Res. Ctr. New York, USA; 2 Merck Res. Labs, West Point, USA; 3 Hosp. Nac. Cayetano Heredia, Lima, Peru; 4 Hosp. Nac. Edgardo Rebagliati, Lima, Peru; 6 Maple Leaf Med. Ctr, Toronto, Canada; 5 Siriraj Hosp., Bangkok, Thailand

IAC 2006 Abs# THLB0214 Protocol 004 Study Team Investigators M. MarkowitzUSA E. Gotuzzo Peru F. Mendo Peru W. Ratanasuwan Thailand C. Kovacs Canada G. Prada Colombia J. Morales-Ramirez Puerto Rico A. AfaniChile D. Cooper Australia J. Perez Chile S. Thitivichianlert Thailand J. Cortes Colombia R. Steigbigel USA M. BlochAustralia S. LittleUSA N. BodsworthAustralia R. SchwartzUSA C TsoukasCanada C. WorkmanAustralia R. LiporaceUSA D. BakerAustralia C. HicksUSA K. TashimaUSA C. CrumpackerUSA P. KumarUSA K. LichtensteinUSA J. Santana-BagurPuerto Rico S. BrownUSA H. Teppler B.-Y. Nguyen R. Isaacs J. Zhao J. Chen L. Gilde L. Wenning M. Miller D. Hazuda J. Vacca M. Rowley V. Summa M. Iwamoto Merck Research Laboratories

IAC 2006 Abs# THLB0214 MK-0518: Strand Transfer Inhibitor of HIV Integrase HIV integrase inhibition: a new mechanism of action MK-0518: potent in vitro activity IC 95 = 33 nM  23 nM in 50% human serum Preclinical evaluation favorable Metabolism primarily via glucuronidation (UGT1A1) Not a potent inhibitor or inducer of CYP3A4 Does not require “ritonavir boosting” Phase I and drug interaction data support: –Dosing mg po bid without regard to food At 100mg b.i.d, mean C 12hr > IC 95 –No dose adjustment when used with other ARTs

Part I cohort Rx-naïve pts stratified and randomized to Integrase monotherapy or placebo for 10 days MK mg bid MK mg bid MK mg bid MK-0518 placebo bid Protocol 004: Study Design MK mg bid + TFV*/3TC MK mg bid+ TFV* /3TC Part I Integrase Monotherapy for 10 days Part II Combination Therapy Interim analysis of Part I before initiating Part II * TFV = tenofovir ~ 8pts ~ 30 pts MK mg bid+ TFV*/ 3TC Efavirenz 600mg** + TFV*/3TC MK mg bid ~ 8pts ~ 30 pts MK mg bid + TFV*/3TC Part II cohort Rx-naïve pts stratified and randomized to combination therapy for 48 weeks Total ~ 38 pts HIV RNA  of 1.7 – 2.2 log 10 copies/mL Morales-Ramirez et al, EACS 2005 IAC 2006 Abs# THLB0214

Protocol 004: Part II Design Part I patients continued at same dose in Part II (pbo→efv) ~150 additional patients randomized for Part II Key inclusion criteria –Susceptible to EFV, 3TC, TFV (by genotype) –No prior ART (<7 days OK) – HIV RNA ≥ 5000 copies/mL baseline stratification for HIV RNA ≤ or > 50,000 copies/mL –CD4 ≥ 100 cells/mm 3 Endpoints –HIV RNA and CD4 counts, Adverse experiences Hypotheses: MK TFV/3TC –will be generally safe and well tolerated –will have similar antiretroviral activity vs efavirenz + TFV/3TC

IAC 2006 Abs# THLB0214 Protocol 004: Baseline Characteristics MK-0518 mg bid* Efavirenz * 600mg qd N= N= N= N= N=40 Age-mean (yrs) %Male %Non-White HIV RNA copies/ml** (log 10 cp/ml) (4.8) (4.8) (4.6) (4.8) (4.8) CD4 – mean (cells/ul) % with AIDS * With TFV/3TC ** = geometric mean

IAC 2006 Abs# THLB0214 Protocol 004: Patient Status at Week 24 Analysis MK-0518*EFV* Description 100 mg n (%) 200 mg n (%) 400 mg n (%) 600 mg n (%) Total Enrolled Treated N = (95) N = (100) N = (100) N = (100) N = (93) Discontinued by Wk 2405 (13)1 (2)2 (5) - due to lack of efficacy 02 (5)000 - due to AE 0001 (3)0 - other03 (8)1 (2)1 (3)2 (5) * + TFV/3TC n = Number of patients in each category; N = Total number of pts enrolled in each group % = n/N for each category in each group

IAC 2006 Abs# THLB0214 Protocol 004: HIV RNA Change from Baseline* (log 10 copies/mL) (95% CI) *assay LoQ 400 copies/mL

IAC 2006 Abs# THLB0214 Protocol Percent (95% CI) of Patients with HIV RNA < 400 copies/mL (NC = F)

IAC 2006 Abs# THLB0214 Protocol 004: Percent (95% CI) of Patients with HIV RNA < 50 copies/mL (NC=F) * P < for MK-0518 at each dose vs. EFV

IAC 2006 Abs# THLB0214 Protocol 004: Change from Baseline in CD4 (cells/mm 3 ) (95% CI)

IAC 2006 Abs# THLB0214 Protocol 004: Common (≥5%) Drug Related Adverse Experiences MK 0518* (all doses) N=160 (%) Efavirenz* N=38 (%) Nausea 1113 Headache924 Dizziness826 Diarrhea711 Insomnia711 Abnormal dreams618 Flatulence6- Additional AEs seen at ≥ 5% in efavirenz group: Nightmare (11%) Vomiting (8%) Malaise (8%) Fatigue (5%) Disturbance in attention (5%) Lethargy (5%) Anxiety (5%) * With TFV/3TC

IAC 2006 Abs# THLB0214 Protocol 004: Safety MK-0518 safety profile was similar to efavirenz (both with TFV/3TC) Most clinical adverse experiences (AE) were mild to moderate 8 serious adverse experiences overall (7/160 or 4% in the 4 MK groups, 1/38 or 3% in EFV group); none considered drug related One discontinuation for increased AST/ALT Grade 3 / 4 lab abnormalities uncommon

IAC 2006 Abs# THLB0214 Conclusion MK-0518 is a promising new strand transfer inhibitor of HIV integrase with potent and durable antiretroviral effect. In treatment naïve patients with HIV RNA ≥ 5000 copies/ml and CD4 ≥ 100/mm 3, MK-0518 at all doses studied for 24 weeks had potent antiretroviral activity » 85-95% with HIV RNA < 50 copies/mL » achieved viral suppression faster than EFV was generally well tolerated