Abstract

Background: Effective, long-acting prevention approaches are needed to reduce human immunodeficiency virus (HIV) incidence. We evaluated the safety and pharmacokinetics of VRC07-523LS and PGT121 administered subcutaneously alone and in combination as passive immunization for young women in South Africa.

Methods: CAPRISA 012A was a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 trial. We enrolled 45 HIV-negative women into 9 groups and assessed safety, tolerability, pharmacokinetics, neutralization activity, and antidrug antibody levels. Pharmacokinetic modeling was conducted to predict steady-state concentrations for 12- and 24-weekly dosing intervals.

Results: VRC07-523LS and PGT121, administered subcutaneously, were safe and well tolerated. Most common reactogenicity events were injection site tenderness and headaches. Nine product-related adverse events were mild and transient. Median VRC07-523LS concentrations after 20 mg/kg doses were 9.65 μg/mL and 3.86 μg/mL at 16 and 24 weeks. The median week 8 concentration after the 10 mg/kg PGT121 dose was 8.26 μg/mL. Modeling of PGT121 at 20 mg/kg showed median concentrations of 1.37 μg/mL and 0.22 μg/mL at 16 and 24 weeks. Half-lives of VRC07-523LS and PGT121 were 29 and 20 days. Both antibodies retained neutralizing activity postadministration and no antidrug antibodies were detected.

Conclusions: Subcutaneous administration of VRC07-523LS in combination with optimized versions of PGT121 or other antibodies should be further assessed for HIV prevention.

Abstract

Background:

Human monoclonal antibodies that potently and broadly neutralize HIV-1 (bnMAbs) are under development to prevent and treat HIV-1 infection. We performed a phase 1 clinical trial to determine the safety, tolerability, and pharmacokinetic profile of the bnMAb VRC07–523LS, an engineered variant of VRC01 that targets the CD4 binding-site of the HIV-1 Env protein.

Methods:

This phase 1, open-label, dose-escalation clinical trial was done at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Individuals were recruited from the greater Washington, DC, area by IRB-approved written and electronic media. We enrolled healthy, HIV-1-negative adults aged 18–50 years. Inclusion criteria were good general health, measured through clinical laboratory tests, medical history, and physical examination. Participants self-selected into one of seven open groups during enrollment without randomization. Four groups received a single intravenous dose of 1, 5, 20, or 40 mg/kg of VRC07–523LS, and one group received a single 5 mg/kg subcutaneous dose. Two groups received three doses of either 20 mg/kg intravenous VRC07–523LS, or 5 mg/kg subcutaneous VRC07–523LS at 12-week intervals. The primary outcome was the safety and tolerability of VRC07–523LS, assessed by dose, route, and number of administrations. This study is registered with ClinicalTrials.gov, NCT03015181.

Findings:

Between Feb 21, 2017, and September 13, 2017, we enrolled 26 participants, including 11 (42%) men and 15 (58%) women. Two (8%) participants withdrew from the study early: one participant in group 1 enrolled in the study but never received VRC07–523LS, and one participant in group 6 chose to withdraw after a single administration. One (4%) participant in group 7 received only one of the three scheduled administrations. 17 participants received intravenous administrations and 8 participants received subcutaneous administrations. Local and systemic reactogenicity were mild to moderate when reported. The most commonly reported symptoms following IV administration included malaise or myalgia in three participants (18%) and headache or chills in two participants (12%). Following SC administration, the most commonly reported symptoms included pain and tenderness in four participants (50%) and malaise or headache in three participants (38%). No serious adverse events or dose-limiting toxicities occurred.

Interpretations:

We found VRC07–523LS to be safe and well tolerated. These qualities make VRC07–523LS a strong and practical candidate for inclusion in HIV-1 prevention and therapeutic strategies. The results from this trial also indicate that an HIV-1 bnMAb engineered to improve pharmacokinetic properties and neutralization activity can be safe for clinical use.