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Antiviral effects and tolerability of the CCR5 monoclonal antibody PRO 140: a proof of concept study in HIV-infected individuals
Presented by W.C. Olson, .
Saag M.S.1, Jacobson J.M.2, Thompson M.3, Fischl M.4, Liporace R.5, Reichman R.C.6, Redfield R.R.7, Fichtenbaum C.J.8, Zingman B.S.9, Patel M.C.10, D'Ambrosio P.11, Michael M.11, Kroger H.11, Ly H.11, Rotshteyn Y.11, Stavola J.J.11, Maddon P.J.11, Kremer A.B.11, Olson W.C.11
1University of Alabama, UAB Center for AIDS Research, Birmingham, United States, 2Drexel University, Philadelphia, United States, 3AIDS Research Consortium of Atlanta, Atlanta, United States, 4University of Miami, Miami, United States, 5Albany Medical Center, Albany, United States, 6University of Rochester, Rochester, United States, 7University of Maryland, Baltimore, United States, 8University of Cincinnati, Cincinnati, United States, 9Montefiore Medical Center and the Einstein/Montefiore Center for AIDS Research, Bronx, United States, 10Jacobi Medical Center, Bronx, United States, 11Progenics Pharmaceuticals, Inc., Tarrytown, United States
Background: PRO 140 is a humanized CCR5 monoclonal antibody that potently inhibits wild-type and drug-resistant HIV in vitro, including viruses resistant to small-molecule CCR5 antagonists. Single-dose PRO 140 demonstrated favorable tolerability and pharmacokinetic (PK) profiles in healthy volunteers, and the present study is the first to evaluate this new agent in HIV-infected individuals.
Methods: A randomized, double-blind, placebo-controlled, single-dose, dose-ascending study was conducted in 39 HIV-infected individuals with CD4 > 250 cells/µl, HIV RNA > 5,000 copies/mL, only CCR5-tropic virus, and no antiretroviral therapy for at least 3 months. Patients were randomized 10:3 to receive single intravenous infusions of PRO 140 (0.5, 2 or 5 mg/kg nominal doses) or placebo in sequential dose-ascending cohorts. Serial HIV RNA, PK and safety assessments were performed through Day 59.
Results: PRO 140 was generally well tolerated, and no drug-related serious adverse events or obvious pattern of toxicity was observed. Mean maximum log10 HIV RNA changes of -0.39, 0.58, -1.20 (P=0.0002), and -1.83 (P<0.0001) were observed for the placebo, 0.5 mg/kg, 2 mg/kg and 5 mg/kg groups, respectively; and a >10-fold decrease in HIV RNA was observed in 0/9, 1/10, 6/10 (P=0.01) and 10/10 (P<0.0001) patients in these respective treatment groups. Antiviral effects were correlated with PRO 140 serum concentrations and CCR5 receptor occupancy as assessed by flow cytometry.
Conclusions: Single-dose PRO 140 demonstrated favorable tolerability and potent, dose-dependent antiviral activity in HIV-infected individuals. The study provides proof of concept for PRO 140 as a potent and long-acting antiretroviral agent.
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