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.

Autor: Hershberger E; Visterra Inc, 275 2nd Avenue, Waltham, MA 02451, USA., Sloan S; Visterra Inc, 275 2nd Avenue, Waltham, MA 02451, USA., Narayan K; Visterra Inc, 275 2nd Avenue, Waltham, MA 02451, USA., Hay CA; Visterra Inc, 275 2nd Avenue, Waltham, MA 02451, USA., Smith P; Certara, Princeton, NJ, USA., Engler F; Certara, Princeton, NJ, USA., Jeeninga R; Viroclinics Biosciences, Rotterdam, the Netherlands., Smits S; Viroclinics Biosciences, Rotterdam, the Netherlands., Trevejo J; Visterra Inc, 275 2nd Avenue, Waltham, MA 02451, USA., Shriver Z; Visterra Inc, 275 2nd Avenue, Waltham, MA 02451, USA., Oldach D; Visterra Inc, 275 2nd Avenue, Waltham, MA 02451, USA. Electronic address: doldach@visterrainc.com.
Jazyk: angličtina
Zdroj: EBioMedicine [EBioMedicine] 2019 Feb; Vol. 40, pp. 574-582. Date of Electronic Publication: 2019 Jan 09.
DOI: 10.1016/j.ebiom.2018.12.051
Abstrakt: 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 TCID 50 AUC Day7 (days × log 10 TCID 50 /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.)
Databáze: MEDLINE
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