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 AUC_Day7 (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.

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).