Results of a Double-Blind, Randomized, Placebo-Controlled Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Anti-Zika Virus Immunoglobulin

Abstract

Zika virus (ZIKV) is transmitted primarily through infected Aedes aegypti or Aedes albopictus mosquitoes. ZIKV infection during pregnancy was linked to adverse fetal/infant outcomes, including microcephaly, brain anomalies, ocular disorders, intrauterine growth restriction, and other congenital malformations. Human anti-Zika virus immunoglobulin (ZIKV-Ig) is being developed for prophylaxis of ZIKV in at-risk populations, including women of childbearing potential and pregnant women. A phase 1 single-center, double-blind, randomized, placebo-controlled study was conducted to assess the safety and pharmacokinetics (PK) of a single 50.0-mL ZIKV-Ig intravenous dose in healthy adult male or non-pregnant female subjects 18 to 55 years of age. Subjects received either ZIKV-Ig (n = 19) or saline placebo (n = 11). Safety was evaluated based on adverse events (AEs), laboratory test results, physical examinations, and vital signs. Overall, there were 11 subjects (36.7%) with treatment-related AEs including eight subjects (42.1%) in the ZIKV-Ig group and three subjects (27.3%) in the placebo group. Of the AEs considered treatment related, three subjects (15.8%) experienced headache (mild). There were no serious AEs, no deaths, and no discontinuations resulting from AEs. Overall, the safety profile of ZIKV-Ig in this study population of healthy adult subjects appeared to be safe and well tolerated. The results of the pharmacokinetic analysis determined that ZIKV-Ig had a maximum observed concentration of 182.3 U/mL (coefficient of variation, 21.3%), the time at which Cmax occurred of 2.3 hours ± 1.0 (SD), an area under the concentration-time curve0-∞ of 77,224 h × U/mL (coefficient of variation, 17.9%), and a half-life of 28.1 days, which is similar to other human-derived commercial Ig intravenous products.

Trial registration: ClinicalTrials.gov NCT03624946.

Figures

Figure 1.

Illustrative representation of the ZK-001 treatment schedule. Group 1A (n = 2), group 1B (n = 2), group and 1C (n = 2) were randomized 1:1 in a double-blind fashion to receive either human anti-Zika virus immunoglobulin (ZIKV-Ig) or placebo. Two subjects per day were dosed at least 3 hours apart and each subgroup was dosed at least 1 day apart over 3 days, with the principal investigator (PI) safety data review occurring between subgroups followed by an overall safety data review of all 6 group 1 subjects prior to group 2 dosing. Groups 2A (n = 2), 2B (n = 2), and 2C (n = 2) were randomized 2:1 in a double-blind fashion to receive either ZIKV-Ig or placebo and were dosed 30 minutes apart on three separate days. An independent Safety Monitoring Committee reviewed safety data for the first 12 dosed subjects (groups A and B) prior to group 3 dosing. Groups 3A (n = 1), 3B (n = 3), and 3C (n = 2) were randomized 2:1 in a double-blind fashion to receive either ZIKV-Ig or placebo and were dosed 30 minutes apart on three separate days. Groups 4A (n = 2), 4B (n = 3), and 4C (n = 1) were randomized 2:1 in a double-blind fashion to receive either ZIKV-Ig or placebo and were dosed 30 minutes apart on three separate days. Group 5 (n = 6) was randomized 2:1 in a double-blind fashion to receive either ZIKV-Ig or placebo and was dosed 30 minutes apart on a single day (group 4C).

Figure 2.

Disposition of volunteers. A total of 309 volunteers were screened for the ZK-001 study. Of these, 279 were screen failures. Thirty subjects met the study eligibility criteria, were randomized, and were administered either human anti-Zika virus immunoglobulin (ZIKV-Ig) (n = 19) or placebo (n = 11). All 19 subjects in the ZIKV-Ig cohort completed the study, whereas 1 of 11 subjects in the placebo cohort was discontinued from the study (lost to follow-up). All 30 subjects were included in the safety population, and 18 out of 19 subjects who received ZIKV-Ig were included in the pharmacokinetics (PK) population.

Figure 3.

Mean (±SD) concentration–time profiles for anti-Zika virus (ZIKV) E-protein binding antibodies on a linear scale (panel A) and a semi-logarithmic scale (panel B) [pharmacokinetic (PK) population). Mean (±SD) concentration–time profiles for anti-ZIKV neutralizing antibodies on a linear scale (panel C) and a semi-logarithmic scales (panel D) (PK population). This figure appears in color at www.ajtmh.org.