title: 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.affiliation: Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, 245 N 15th St, MS 461, Philadelphia, PA 19104, USA. jeffrey.jacobson@drexelmed.edu
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Jacobson
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Lalezari
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Thompson
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Fichtenbaum
authors.forename: Michael S
authors.initials: MS
authors.lastname: Saag
authors.forename: Barry S
authors.initials: BS
authors.lastname: Zingman
authors.forename: Paul
authors.initials: P
authors.lastname: D'Ambrosio
authors.forename: Nancy
authors.initials: N
authors.lastname: Stambler
authors.forename: Yakov
authors.initials: Y
authors.lastname: Rotshteyn
authors.forename: Andre J
authors.initials: AJ
authors.lastname: Marozsan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Maddon
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Morris
authors.forename: William C
authors.initials: WC
authors.lastname: Olson
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D065100:CCR5 Receptor Antagonists; D005260:Female; D015483:HIV Antibodies / Q000008:administration & dosage / Q000627:therapeutic use*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics; D019713:Receptors, CCR5 / Q000378:metabolism; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D065100:CCR5 Receptor Antagonists; D015483:HIV Antibodies; D012367:RNA, Viral; D019713:Receptors, CCR5; C420063:leronlimab