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Protocol 004 Study Team

Potent Antiretroviral Effect of MK-0518, a Novel HIV-1 Integrase Inhibitor, as part of Combination ART in Treatment -Naïve HIV-1 infected Patients.

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Protocol 004 Study Team

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  1. 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. Markowitz1, B.-Y. Nguyen2, E. Gotuzzo3, F. Mendo4, W. Ratanasuwan5, C. Kovacs6, J. Zhao2, L. Gilde2, R. Isaacs2, H. Teppler2, and the Protocol 004 Part II Study Team 1Aaron Diamond AIDS Res. Ctr. New York, USA; 2Merck Res. Labs, West Point, USA; 3Hosp. Nac. Cayetano Heredia, Lima, Peru; 4Hosp. Nac. Edgardo Rebagliati, Lima, Peru; 6Maple Leaf Med. Ctr, Toronto, Canada; 5Siriraj Hosp., Bangkok, Thailand

  2. Protocol 004 Study Team Merck Research Laboratories Investigators M. Markowitz USA E. Gotuzzo Peru F. Mendo Peru W. Ratanasuwan Thailand C. Kovacs Canada G. Prada Colombia J. Morales-Ramirez Puerto Rico A. Afani Chile D. Cooper Australia J. Perez Chile S. Thitivichianlert Thailand J. Cortes Colombia R. Steigbigel USA M. Bloch Australia S. Little USA N. Bodsworth Australia R. Schwartz USA C Tsoukas Canada C. Workman Australia R. Liporace USA D. Baker Australia C. Hicks USA K. Tashima USA C. Crumpacker USA P. Kumar USA K. Lichtenstein USA J. Santana-Bagur Puerto Rico S. Brown USA 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

  3. MK-0518: Strand Transfer Inhibitor of HIV Integrase • HIV integrase inhibition: a new mechanism of action • MK-0518: potent in vitro activity • IC95 = 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 100 - 800 mg po bid without regard to food • At 100mg b.i.d, mean C12hr > IC95 • No dose adjustment when used with other ARTs

  4. Protocol 004: Study Design Interim analysis of Part I before initiating Part II Part II Combination Therapy Part I Integrase Monotherapy for 10 days Total ~ 8pts ~ 30 pts ~ 38 pts MK-0518 600mg bid MK-0518 600mg bid + TFV*/3TC ~ 30 pts ~ 38 pts ~ 8pts MK-0518 400mg bid MK-0518 400mg bid+ TFV* /3TC ~ 30 pts ~ 38 pts ~ 8pts MK-0518 200mg bid MK-0518 200mg bid+ TFV*/ 3TC ~ 30 pts ~ 8pts ~ 38 pts MK-0518 100mg bid MK-0518 100mg bid + TFV*/3TC ~ 30 pts ~ 8pts ~ 38 pts MK-0518 placebo bid Efavirenz 600mg** + TFV*/3TC Part I cohort Rx-naïve ptsstratified and randomized to Integrase monotherapy or placebo for 10 days Part II cohort Rx-naïve ptsstratified and randomized to combination therapy for 48 weeks *TFV = tenofovir • HIV RNA  of 1.7 – 2.2 log10 copies/mL • Morales-Ramirez et al, EACS 2005 IAC 2006 Abs# THLB0214

  5. 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/mm3 • Endpoints • HIV RNA and CD4 counts, Adverse experiences • Hypotheses: MK-0518 + TFV/3TC • will be generally safe and well tolerated • will have similar antiretroviral activity vs efavirenz + TFV/3TC

  6. Protocol 004: Baseline Characteristics * With TFV/3TC ** = geometric mean

  7. Protocol 004: Patient Status at Week 24 Analysis *+ 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

  8. Protocol 004: HIV RNA Change from Baseline* (log10 copies/mL)(95% CI) *assay LoQ 400 copies/mL

  9. Protocol 004 - Percent (95% CI) of Patients with HIV RNA < 400 copies/mL (NC = F)

  10. Protocol 004: Percent (95% CI) of Patients with HIV RNA < 50 copies/mL (NC=F) * P < 0.001 for MK-0518 at each dose vs. EFV

  11. Protocol 004: Change from Baseline in CD4 (cells/mm3) (95% CI)

  12. Protocol 004: Common (≥5%) Drug Related Adverse Experiences 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

  13. 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

  14. 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/mm3, 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

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