Safety and efficacy of monoclonal antibody VIS410 in adults with uncomplicated influenza A infection: Results from a randomized, double-blind, phase-2, placebo-controlled study

Abstract

Background: VIS410, a broadly neutralizing monoclonal antibody that binds the hemagglutinin stem of influenza A viruses, was safe and efficacious in a human H1N1 virus challenge study. This study evaluated the safety and tolerability of VIS410 in non-hospitalized adult patients with uncomplicated influenza A.

Methods: Patients 18 to 65 years of age with symptom onset within 72 h were randomized 1:1:1 to receive a single intravenous infusion of VIS410 4000 mg, 2000 mg, or placebo. Neuraminidase inhibitor therapy was prohibited. Treatment-emergent adverse events (TEAEs) were evaluated up to 100 days post-infusion. Influenza symptoms were assessed daily for 10 days using the FLU-PRO tool. Nasopharyngeal virus shedding was assessed by quantitative reverse-transcription PCR (qRT-PCR) and viral culture through Day 7.

Findings: Of the 150 patients randomized, 148 received study drug, and 138 were confirmed influenza A positive. Median age was 42 years; median time from symptom onset to treatment was 42 h; 93% had influenza A subtype H3N2.

Safety: TEAEs, most commonly diarrhea of mild severity, were dose-related, occurring in 55%, 35%, and 24% of the 4000 mg, 2000 mg, and placebo patients, respectively. Two serious adverse events occurred, both in placebo patients.

Symptom analyses: Baseline FLU-PRO symptom scores were balanced among groups. Mean scores were lower by Days 3 and 4 in the pooled VIS410 treatment group versus placebo (p < 0.023), with a tendency toward faster resolution by Kaplan-Meier analysis.

Virology analyses: VIS410 was associated with reduced median nasopharyngeal viral load TCID50 AUCDay7 (days × log10 TCID50/mL) (3.66 pooled VIS410 vs 4.78 placebo, p = 0.08) and in the subset of patients with baseline hemagglutination inhibition (HAI) titer ≤40 (overall, 74% of patients) was significantly reduced vs placebo (4.218 pooled VIS410 vs 6.152 placebo, p = 0.009). Kaplan-Meier estimated time to resolution of viral shedding was reduced (1.9 vs 3.6 days, p = 0.03) in VIS410 treated patients. There was a trend toward greater proportion of culture-negative patients by Day 3 (66.7% vs 51.1%, p = 0.11); when this analysis was limited to the subset of patients with positive baseline cultures, this difference became more pronounced (63.2% vs 42.5%, p = 0.053). No differences were observed in nasopharyngeal influenza qRT-PCR profiles, which represent both live and neutralized virus.

Interpretation: VIS410 was safe and well tolerated in adults with uncomplicated influenza A, with favorable effects on symptom resolution and virus replication.

Trial registration: Clinical Trials: NCT02989194.

Funding: This project was funded in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under Contract No. HHSO100201500018C.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1

Trial Profile and Patient Disposition. qRT-PCR = quantitative reverse-transcription PCR; mITT = modified intent-to-treat population.

Fig. 2

Mean Total FLU-PRO Symptom Scores by Treatment Group and Day.

Fig. 3

Time to resolution of viral shedding measured by TCID50 from the end of infusion in days (mITT population). Time to resolution of viral shedding from the end of infusion until resolution of viral load by TCID50 was determined using Kaplan-Meier methods for the pooled VIS410 arms and placebo. Resolution of viral load is considered achieved at the first timepoint with virus BLQ by culture with no subsequent culture result >BLQ. If viral load was still above level of detection at the end of the study, then the last day of viral collection through Day 7 was used. The median Kaplan-Meier estimate of time to resolution of viral shedding by TCID50 from the end of infusion was 1·9 days for the VIS410 total group and 3·6 days in the placebo group (p = 0·03).

Fig. 4

Percentage of subjects with negative virology (TCID50) by study day (subset of subjects with positive cultures at baseline). The analysis subset includes subjects in the mITT group with a positive Baseline TCID50 measurement (>BLQ). Negative viral load by TCID50 is defined as the first timepoint with a TCID50 measurement of BLQ or lower with no samples following that are TCID50-positive. Percentages are calculated based on the number of subjects with a TCID50 measurement at each visit. The percent subjects negative for virus culture by Study Day 3 in the analysis subset was 63·2% for the VIS410 total group and 42·5% for the placebo group (p = 0·053).