VRC01 is a monoclonal antibody (mAb) directed at the CD-4 binding site that neutralized most HIV isolates that it was tested against in vitro, protected simians from retroviral challenges, decreased HIV plasma RNA in treatment-naïve HIV-infected participants (ppt), and offers the potential to prevent HIV transmission in humans.
In HVTN 104, 88 low risk, healthy men (n=44) and women (n=44) were enrolled and assigned to receive either a 40 mg/kg IV loading dose, followed by 20 mg/kg IV every 4 weeks (Group 1), or 10, 30 or 40 mg/kg of VRC01 administered intravenously (IV) every 8 weeks (Groups 2, 4, or 5), or a 40 mg/kg IV loading dose, followed by 5 mg/kg subcutaneously, every 2 weeks for 5.5 months (Group 3, which included a placebo arm). Safety and tolerability were evaluated by site clinicians and reviewed weekly by the protocol safety team. VRC01 drug levels in serum were measured by a VRC01 anti-idiotype ELISA binding antibody assay. Safety data from all 5 groups and pharmacokinetic data from groups 1 to 3 are presented here.
The median age of enrollees was 27 yrs (range: 18-50); 46.5% were non-White; 11.4% were Hispanic. Infusions and injections were generally well-tolerated, with 28% of infusions and 14% of injections resulting in mild pain/tenderness reactions, and very few erythema/induration reactions. 57% of participants had a systemic reaction, and of the 3 that were severe, 2 had concurrent viral infections, and 1 had malaise lasting 1 day. Most participants (72.7%) reported at least 1 adverse event, 73.6% of these events were graded as mild; with only 6.2% deemed product-related, and all of those were mild. Study product was discontinued after AEs in 3 ppt, out of caution. As of Sept. 4, 2015, 226 infusions and 167 injections were completed. Median peak levels after a 40 mg/kg infusion generally exceeded 300 mcg/mL and median VRC01 levels at 112 days were ~30 mcg/mL whether VRC01 was administered at 20 mg/kg at 28 days, 40 mg/kg at 56 days, or 5 mg/kg SC every 2 weeks. Drug levels from the first 3 groups are depicted in the acompanying figure.
VRC01 administered IV or SC was well-tolerated. Product-related AEs were generally transient and mild. After a 40 mg/kg IV loading dose, VRC01 levels could be maintained >30 mcg/mL for several months through either IV or SC administration. These findings support the rationale that VRC01 administered every 2 weeks SC or 2 months IV should be evaluated for HIV immunoprophylaxis