Hier is wetenschappelijke beschrijving van fase 2A van het HIV onderzoek - op basis waarvan een BLA wordt toegekend voor de hogere dosis.
Phase 2a Study of the CCR5 Monoclonal Antibody PRO 140 Administered Intravenously to HIV-Infected Adults?
Jeffrey M. Jacobson,1,* Jacob P. Lalezari,2 Melanie A. Thompson,3 Carl J. Fichtenbaum,4 Michael S. Saag,5 Barry S. Zingman,6 Paul D'Ambrosio,7 Nancy Stambler,7 Yakov Rotshteyn,7 Andre J. Marozsan,7 Paul J. Maddon,7 Stephen A. Morris,7 and William C. Olson7
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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 log10 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.