Phase 2a study of the CCR5 monoclonal antibody PRO 140 administered intravenously to HIV-infected adults.

Abstract

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 up to 5 mg/kg of body weight or up to three subcutaneous doses ranging up to 324 mg. Here we report the 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 levels of >5,000 copies/ml, CD4(+) cell counts of >300/μl, no antiretroviral therapy for ≥12 weeks, and detection of only R5 HIV-1 in the original Trofile assay. Following poststudy testing with an enhanced-sensitivity Trofile assay, one subject treated with 10 mg/kg was reclassified as having dual/mixed-tropic virus at screening, and the data for that subject were censored from efficacy analyses. The mean maximum reduction of the HIV-1 RNA level from the baseline level was 1.8 log(10) units for both the 5-mg/kg and 10-mg/kg doses (P < 0.0001 relative to placebo). Viral loads reached their nadir at day 12 posttreatment 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 being 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.

• Authors: Jeffrey M Jacobson, Jacob P Lalezari, Melanie A Thompson, Carl J Fichtenbaum, Michael S Saag, Barry S Zingman, Paul D'Ambrosio, Nancy Stambler, Yakov Rotshteyn, Andre J Marozsan, Paul J Maddon, Stephen A Morris, William C Olson
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 54 Issue 10 Pg. 4137-42 (Oct 2010) ISSN: 1098-6596 [Electronic] United States
• PMID: 20660677 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• CCR5 Receptor Antagonists
• HIV Antibodies
• RNA, Viral
• Receptors, CCR5
• leronlimab

Topics

• Adult
• Antibodies, Monoclonal (administration & dosage, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• CCR5 Receptor Antagonists
• Female
• HIV Antibodies (administration & dosage, therapeutic use)
• HIV Infections (blood, drug therapy)
• Humans
• Injections, Intraventricular
• Male
• Middle Aged
• RNA, Viral (genetics)
• Receptors, CCR5 (metabolism)
• Young Adult