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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 MK-0518 A Novel HIV-1 Integrase Inhibitor CROI 2006 ABSTRACT #159LB • 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 MK-0518 A Novel HIV-1 Integrase Inhibitor CROI 2006 ABSTRACT #159LB • 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 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 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=42 N=43 43 44 44 43 83% 91% 91% 88% Mean log10HIV RNA 4.6 4.8 4.7 4.7 Mean CD4 Count (/mm3) 244 220 226 283 Median Years of Prior ARTs 9 11 9 10 OBT: Median # of ARTs 4 4 4 4 Median Age (yrs) Male OBT: # of pts using T-20 (%) 13 (33%) 16 (38%) 16 (38%) 16 (38%) PSS§: 0 to all ARTs 16 (40%) 24 (57%) 21 (50%) 17 (40%) PSS§: 0 to PI 39 (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 Percent of Patients With HIV RNA <400 Copies/mL Proportion of patients (95% CI) with HIV RNA < 400 copies/mL 100 80 60 40 20 0 0 MK-0518 200 mg MK-0518 400 mg MK-0518 600 mg OBT Alone 2 4 8 Week 12 16 40 42 42 43 39 39 40 43 35 36 35 36 31 32 33 31 25 28 28 27 m518p5.r400.1 Jan. 12, 2006 CROI 2006 ABSTRACT #159LB Percent of Patients With HIV RNA <50 Copies/mL Proportion of patients (95% CI) with HIV RNA < 50 copies/mL 100 80 60 40 20 0 0 MK-0518 200 mg MK-0518 400 mg MK-0518 600 mg OBT Alone 2 4 8 Week 12 16 40 42 42 43 38 39 40 43 35 36 35 36 31 31 32 31 25 27 28 27 m518p5.r50.1 Jan. 12, 2006 CROI 2006 ABSTRACT #159LB MK-0518 200 MK-0518 400 200 MK-0518 600 OBT Alone 150 100 Change from Baseline in HIV RNA (Log10 Copies/mL) 50 0 0 -1 -2 -3 0 2 4 8 12 Week m518p5.cdr1.rna.1 Jan. 10, 2006 16 Change from Baseline in CD4 Cell Count Mean change from baseline (95% CI) in HIV RNA and CD4 cell count 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 Most Common Drug-Related Clinical AE (Incidence 5% or 2 pts in at least one treatment group) MK-0518* Diarrhea Nausea Fatigue Injection site reaction Headache Pruritus 200 mg N = 42 2 (5%) 2 (5%) 3 (7%) 1 (2%) 4 (10%) 0 (0%) 400 mg N = 43 1 (2%) 2 (5%) 0 (0%) 3 (7%) 0 (0%) 1 (2%) Placebo* 600 mg N = 44 1 (2%) 5 (11%) 1 (2%) 4 (9%) 2 (5%) 3 (7%) N = 45 4 (9%) 5 (11%) 1 (2%) 1 (2%) 2 (4%) 0 (0%) * + 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) Protocol 005 Safety Grade 3/4 Laboratory Abnormalities CROI 2006 ABSTRACT #159LB 200 mg N = 42 n/m§ (%) 0 MK-0518* 400 mg N = 43 n/m§ (%) 0 600 mg N = 44 n/m§ (%) 0 N = 45 n/m§ (%) 1/43 (2) Platelet 0 0 1/39 (3) 0 Cholesterol 0 0 0 1/29 (3) Triglycerides 2/26 (8) 0 0 1/29 (3) Total bilirubin† 3/39 (8) 2/41 (5) 3/39 (8) 1/43 (2) AST 1/39 (3) 1/41 (2) 0 0 ALT 0 1/41 (2) 0 0 Alkaline phosphatase 1/39 (3) 0 0 0 Serum lipase 1/39 (3) 1/41 (2) 0 0 0 0 2/39 (5) 0 Neutrophil Serum pancreatic amylase Placebo* * + OBT ; § n/m = # of pts with Gr 3 or 4/ # of pts with lab test † 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 Acknowledgements All patients in Protocol 005 Investigators B. Grinsztejn C. Katlama J. Gatell A. Lazzarin D. Vittecoq C. Gonzalez J. Sierra G. Carosi S. Little M. Moroni J. Rockstroh M. Kozal R. Liporace E. Jones-Lopez B. Clotet S. Staszewski Brazil France Spain Italy France USA Mexico Italy USA Italy Germany USA USA USA Spain Germany D. McMahon P. Kumar C. Lee K. Squires M. Opravil N. Clumeck J. Lennox J. Eron J. Gallant M. Nelson S. Brown K. Tashima V. Soriano C. Crumpacker D. Kuritzkes USA USA Malaysia USA Switzerland Belgium USA USA USA UK USA USA Spain USA 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