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Subcutaneous Ibalizumab in At-Risk Healthy Subjects
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Reported by Jules Levin
54th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 5-9, 2014, Washington D.C.
J. ERNST1, M. KEEFER2, J. LALEZARI3, P. GOEPFERT4, S. SCHRADER5, J. DEVENTE6, S. VASAN7, N. N. PADTE7, K-L. KUO8, S. WEINHEIMER8, S. LEWIS8
1ACRIA, NY, NY, 2U. Rochester, Rochester, NY, 3Quest Clin. Res., San Francisco, CA, 4U. Alabama-Birmingham, Birmingham, AL, 5Schrader Clin., Houston, TX, 6Living Hope Clin. Fdn., Long Beach, CA, 7Aaron Diamond AIDS Res. Ctr., NY, NY, 8TaiMed Biologics, Irvine, CA
Program Abstract
Background: Long-acting anti-HIV drugs with infrequent dosing may have advantages over once-daily drugs. Ibalizumab is a humanized monoclonal antibody that binds a unique epitope on CD4 and blocks HIV-1 entry. Phase 2 studies demonstrated antiviral activity of intravenous ibalizumab for 48 wks, given every 2 to 4 wks with an optimized background regimen (OBR). A randomized, double-blinded, placebo-controlled, study was conducted to determine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous (SC) ibalizumab in healthy subjects at-risk for HIV-1 infection. Methods: 24 subjects at-risk for acquiring HIV were enrolled (89% male, 65% white, 23% black, mean age 30 years) and randomized (3:1) to 3 sequential dose cohorts (120 mg, 240 mg, 480 mg) receiving 4 weekly SC injections. Safety, PK, CD4 receptor occupancy (RO, % bound by ibalizumab) and CD4 receptor density (RD) were assessed, and subjects were followed for 26 weeks after dosing. Results: Drug exposure increases were greater than dose proportionate. Ibalizumab in serum correlated with CD4 RO; full CD4 RO was observed throughout the 1st dose interval and ≥14 days after the 4th dose in Cohort 3. Reversible declines in CD4 RD were associated with peak ibalizumab levels and high CD4 RO, but CD4+ T-cell counts were not altered. Ibalizumab in serum inhibited HIV infectivity ex vivo; subjects in Cohort 3 had ibalizumab in semen but at 100-500X lower concentrations than in serum. No Serious Adverse Events or discontinuations due to adverse events were reported. No injection site reactions or anti-drug antibodies were observed. Conclusion: Ibalizumab was safe and well tolerated when administered subcutaneously to healthy subjects. PK and PD results support the continued development of long-acting dosing regimens.
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