Safety and pharmacokinetics of VRC07-523LS administered via different routes and doses (HVTN 127/HPTN 087): A Phase I randomized clinical trial

Abstract

Background: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV.

Methods and findings: Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions were reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 μg/mL (25.2, 33.4), 58.5 μg/mL (49.4, 69.3), and 257.2 μg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 μg/mL (8.8, 13.3) and 22.8 μg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 μg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 μg/mL (2.5, 4.6), 6.5 μg/mL (5.6, 7.5), and 27.2 μg/mL (23.9, 31.0) with IV dosing; 0.97 μg/mL (0.65, 1.4) and 3.1 μg/mL (2.2, 4.3) with SC dosing, and 2.6 μg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days).

Conclusions: VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens.

Trial registration: ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).

Fig 1

CONSORT diagram (A) and study schema (B).

Fig 2. Solicited AEs reported by participants after product administration.

Local (A) and systemic (B) solicited AEs were collected for 3 days following each administration of VRC07-523LS or placebo. P6 = placebo IM; T1 = 2.5 mg/kg IV; T2 = 5 mg/kg IV; T3 = 20 mg/kg IV; T4 = 2.5 mg/kg SC; T5 = 5 mg/kg SC; T6 = 2.5 mg/kg IM. AE, adverse event; IM, intramuscular; IV, intravenously; SC, subcutaneous.

Fig 3. VRC07−523LS serum concentration (μg/mL) following first SPA.

GMs and 95% CIs are presented, by treatment group and target day. CI, confidence interval; GM, geometric mean; SPA, study product administration.

Fig 4. VRC07-523LS concentrations measured after product administration every 4 months at specified doses and routes.

Peak levels were only assessed after the first dose. Levels following the second and subsequent doses were assessed by binding antigen multiplex assay (BAMA).

Fig 5. Measured serum concentrations of VRC07-523LS vs. concentrations predicted by a 2-compartment pharmacokinetic model. Spearman’s rank correlation coefficient: rho = 0.99.

Fig 6. Neutralization activity of participant serum 8 weeks following their first VRC07-523LS administration against seven HIV-1 isolates collected from incident HIV-1 acquisition events in placebo recipients in the AMP trials.

ID₈₀ titer is shown.

Fig 7. MB curves for participant serum following VRC07-523LS administration against a panel of HIV-1 isolates collected from incident HIV-1 acquisition in placebo recipients in the AMP trials.

ID₈₀ titer is shown at Week 8 (A) and Week 72 (B). AMP, Antibody Mediated Prevention; MB, magnitude-breadth.