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CROI 2006 ABSTRACT #159LB, Grinsztejn

CROI 2006 ABSTRACT #159LB, Grinsztejn. Potent Antiretroviral Effect of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus.

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CROI 2006 ABSTRACT #159LB, Grinsztejn

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

  2. CROI 2006 ABSTRACT #159LB MK-0518A Novel HIV-1 Integrase Inhibitor • HIV integrase inhibition: a new mechanism of action • Potent in vitro activity • IC95 = 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 log10 copies/mL

  3. CROI 2006 ABSTRACT #159LB MK-0518A 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 100 - 800 mg po bid without regard to food • At 100mg b.i.d, mean C12hr > IC95 • Drug interaction studies support dosing of MK-0518 with other ARTs without dose adjustment

  4. 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/mm3 • Endpoints • HIV RNA and CD4 counts • Adverse experiences

  5. 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

  6. CROI 2006 ABSTRACT #159LB Baseline Patients Characteristics * * + OBT; § PSS = Phenotypic sensitivity score; Enfurvitide is not included in the scores since there is no clinical cut-off.

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

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

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

  10. CROI 2006 ABSTRACT #159LB Protocol 005 Safety Most Common Drug-Related Clinical AE (Incidence  5% or 2 pts in at least one treatment group) • MK-0518 safety profile similar to placebo (both with OBT) • Most clinical adverse experiences (AE): mild to moderate * + 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)

  11. Protocol 005 Safety Grade 3/4 Laboratory Abnormalities CROI 2006 ABSTRACT #159LB * + OBT; § n/m = # of pts with Gr 3 or 4/ # of pts with lab test † Isolated hyperbilirubinemia noted only in pts receiving atazanavir

  12. 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

  13. Investigators B. Grinsztejn Brazil C. Katlama France J. Gatell Spain A. Lazzarin Italy D. Vittecoq France C. Gonzalez USA J. Sierra Mexico G. Carosi Italy S. Little USA M. Moroni Italy J. Rockstroh Germany M. Kozal USA R. Liporace USA E. Jones-Lopez USA B. Clotet Spain S. Staszewski Germany Acknowledgements All patients in Protocol 005 D. McMahon USA P. Kumar USA C. Lee Malaysia K. Squires USA M. Opravil Switzerland N. Clumeck Belgium J. Lennox USA J. Eron USA J. Gallant USA M. Nelson UK S. Brown USA K. Tashima USA V. Soriano Spain C. Crumpacker USA D. Kuritzkes USA 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 CROI 2006 ABSTRACT #159LB

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