Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults

Abstract

Cytomegalovirus can cause debilitating and life-threatening disease in newborns infected in utero and immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody; n = 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses; n = 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses; n = 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01496755.).

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Phase 1 study design schematic. The first single ascending dose (SAD) cohort (cohort A) enrolled 6 subjects (4:2, RG7667 to placebo) receiving 1 mg/kg of each antibody or placebo, and all other SAD cohorts consisted of 5 subjects each (4:1, RG7667 to placebo) receiving 3, 5, or 10 mg/kg of each antibody or placebo (cohorts B, C, and D, respectively). Both multiple ascending dose (MAD) cohorts enrolled 5 subjects each (4:1, RG7667 to placebo) and received 3 doses (administered on days 1, 29, and 57) of 5 or 10 mg/kg of each antibody or placebo (cohorts E and F, respectively). The multiple dose (MD) expansion stage cohort (cohort G) enrolled 150 subjects (120:30, RG7667 to placebo) and received 3 doses (administered on days 1, 29, and 57) of 10 mg/kg of each antibody or placebo.

FIG 2

MCMV5322A and MCMV3068A target distinct viral antigens required for cellular entry. MCMV5322A binds to the CMV envelope protein glycoprotein H (gH) and neutralizes viral entry into epithelial cells, endothelial cells, macrophages, and fibroblasts. MCMV3068A binds to a neutralizing epitope on the gH/gL/UL128/UL130/UL131 CMV envelope glycoprotein complex required for entry into epithelial cells, endothelial cells, and macrophages but not fibroblasts.

FIG 3

Neutralization of CMV by MCMV5322A and MCMV3068A. (A) MCMV5322A or (B) MCMV3068A was serially diluted and mixed with a fixed amount of virus and added to monolayers of each cell type. The virus was allowed to infect a cell monolayer for 18 h and then was quantitated for viral infection. Duplicates from a representative experiment were log transformed and normalized to infection without antibody, and the mean and standard error of the mean (SEM) were graphed.

FIG 4

Analysis of the interaction between MCMV5322A and MCMV3068A at a 1:1 ratio by the Bliss independence method. MCMV5322A and MCMV3068A were diluted alone or in combination at a 1:1 ratio and mixed with a fixed amount of CMV and added to monolayers of epithelial cells. Duplicates from a representative experiment were log transformed and normalized to infection without antibody, and the mean and standard error of the mean (SEM) were graphed.

FIG 5

Observed group mean (± standard deviation) serum concentration versus time profiles following single-dose and multiple-dose intravenous administration of MCMV5322A and MCMV3068A. SAD, single ascending dose; MAD, multiple ascending dose; MD, multiple dose. (A) SAD for MCMV5322A; (B) SAD for MCMV3068A; (C) MAD for MCMV5322A; (D) MAD for MCMV3068A; (E) MD expansion for MCMV5322A; and (F) MD expansion for MCMV3068A. Data points represent observed group mean serum concentration, and error bars represent standard deviations. n = 4 dosed with MCMV5322A and MCMV3068A in cohorts A, B, C, D, E, and F, and n =120 dosed with MCMV5322A and MCMV3068A in cohort G.