Phase 2 Randomized Trial of the Safety and Efficacy of MHAA4549A, a Broadly Neutralizing Monoclonal Antibody, in a Human Influenza A Virus Challenge Model

Abstract

MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. The safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV challenge model. One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24 to 36 h later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1,200, or 3,600 mg), or a standard oral dose of oseltamivir. Subjects were assessed for safety, pharmacokinetics (PK), and immunogenicity. The intent-to-treat-infected (ITTI) population was assessed for changes in viral load, influenza symptoms, and inflammatory biomarkers. MHAA4549A was well tolerated in all IAV challenge subjects. The 3,600-mg dose of MHAA4549A significantly reduced the viral burden relative to that of the placebo as determined by the area under the curve (AUC) of nasopharyngeal virus infection, quantified using quantitative PCR (98%) and 50% tissue culture infective dose (TCID50) (100%) assays. Peak viral load, duration of viral shedding, influenza symptom scores, mucus weight, and inflammatory biomarkers were also reduced. Serum PK was linear with a half-life of ∼23 days. No MHAA4549A-treated subjects developed anti-drug antibodies. In conclusion, MHAA4549A was well tolerated and demonstrated statistically significant and substantial antiviral activity in an IAV challenge model. (This study has been registered at ClinicalTrials.gov under identifier NCT01980966.).

Keywords: MHAA4549A; influenza A virus; monoclonal antibodies.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Study design (A) and disposition of study subjects (B).

FIG 2

NP virus burden determined by qPCR and TCID50 assays. The AUC of NP viral load was measured by qPCR (A) and TCID50 (B) assays. The calculated AUC for each subject is displayed along with the median and interquartile range for each treatment group. Comparisons between the 400-, 1,200-, and 3,600-mg MHAA4549A groups and the placebo group were performed using the nonparametric Wilcoxon rank sum test. Asterisks indicate statistically significant P values (*, P < 0.05). P values were not adjusted for multiple testing. Oseltamivir data were not plotted due to the small number of infected subjects (n = 2). vps, viral particles.

FIG 3

MHAA4549A serum and NP pharmacokinetics for all dosed subjects and MHAA4549A NP exposure-response relationship for all ITTI subjects. (A) Observed group mean (± standard deviation) MHAA4549A serum concentration versus time profile following single i.v. administration (all dosed subjects); (B) observed group mean (±SD) MHAA4549A NP concentration versus time profile following single i.v. administration (all dosed subjects); (C) time to resolution of viral shedding, stratified by the median of the MHAA4549A NP Cmax, 22.7 μg/ml (ITTI subjects). Mean (±SD) MHAA4549A NP concentrations for all treatment groups at nominal time day 0.33 (∼8 h) were not plotted because more than one-third of the values were below the limit of quantification.

FIG 4

Effects of MHAA4549A on the AUC of NP and serum cytokines. IFN-γ, IP-10, and MCP-1 cytokine levels were measured in the NP-derived samples (upper panels) and sera (lower panels) of all ITTI subjects. Filled circles represent the AUC of each subject. Box plots show the variance, the median (bold line), and the mean (dashed line) for each group and the 25th/75th percentiles. Treatment comparisons against the placebo group were performed using Dunnett's t test; P values are shown only for groups with results that were statistically significant (*, P < 0.05).