Phase 2a Study of the CCR5 Monoclonal Antibody PRO 140 Administered Intravenously to HIV-infected Adults.
Antimicrobial agents and chemotherapy 2010 Jul 26; In press
Jacobson J JM, Lalezari J JP, Thompson M MA, Fichtenbaum C CJ, Saag M MS, Zingman B BS, D'Ambrosio P, Stambler N, Rotshteyn Y, Marozsan A AJ, Maddon P PJ, Morris S SA, Olson W WC
Drexel University College of Medicine, Philadelphia, PA; Quest Clinical Research, San Francisco, CA; AIDS Research Consortium of Atlanta, Atlanta, GA; University of Cincinnati, Cincinnati, OH; University of Alabama, Birmingham, AL; Montefiore Medical Cent
The anti-CCR5 antibody PRO 140 has shown potent and prolonged antiretroviral activity in subjects infected with CCR5-tropic (R5) HIV-1. Prior studies have examined single intravenous doses ranging to 5 mg/kg or up to three subcutaneous doses ranging to 324 mg. Here we report results of a randomized, double-blind, placebo-controlled trial that examined the antiviral activity, tolerability and pharmacokinetics of single 5 mg/kg and 10 mg/kg intravenous infusions of PRO 140 in 31 treated subjects. Eligibility criteria included HIV-1 RNA >5,000 copies/mL, CD4(+) cells >300/muL, no antiretroviral therapy for >/=12 weeks, and only R5 HIV-1 detectable in the original Trofile assay. Following post-study testing with an enhanced-sensitivity Trofile assay, one 10 mg/kg subject was reclassified as having dual/mixed-tropic virus at screening and was censored from efficacy analyses. The mean maximum reduction from baseline HIV-1 RNA was 1.8 log10 for both 5 mg/kg and 10 mg/kg doses (P<0.0001 relative to placebo). Viral loads nadired at Day 12 post-treatment and remained significantly (P<0.01) reduced through Day 29 for both PRO 140 dose groups. Treatment was generally well tolerated with no dose-limiting toxicity observed. Peak serum concentrations and overall exposures increased proportionally with dose. In summary, single 5 mg/kg and 10 mg/kg doses of PRO 140 exhibited potent, long-lived antiviral activity and were generally well tolerated. The findings further delineate the safety and antiviral properties of this novel, long-acting antiretroviral agent.