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.
EBioMedicine
; 40: 574-582, 2019 Feb.
Article
de En
| MEDLINE
| ID: mdl-30638863
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 65â¯years of age with symptom onset within 72â¯h were randomized 111 to receive a single intravenous infusion of VIS410 4000â¯mg, 2000â¯mg, or placebo. Neuraminidase inhibitor therapy was prohibited. Treatment-emergent adverse events (TEAEs) were evaluated up to 100â¯days post-infusion. Influenza symptoms were assessed daily for 10â¯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 42â¯years; median time from symptom onset to treatment was 42â¯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 4000â¯mg, 2000â¯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 (pâ¯<â¯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 (daysâ¯×â¯log10 TCID50/mL) (3.66 pooled VIS410 vs 4.78 placebo, pâ¯=â¯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, pâ¯=â¯0.009). Kaplan-Meier estimated time to resolution of viral shedding was reduced (1.9 vs 3.6â¯days, pâ¯=â¯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%, pâ¯=â¯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%, pâ¯=â¯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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Antiviraux
/
Virus de la grippe A
/
Grippe humaine
/
Anticorps neutralisants
/
Anticorps monoclonaux
Type d'étude:
Clinical_trials
/
Diagnostic_studies
Limites:
Adult
/
Female
/
Humans
/
Male
Langue:
En
Journal:
EBioMedicine
Année:
2019
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique