tetano
Editor, Senior Moderator
EBioMedicine. 2019 Jan 9. pii: S2352-3964(18)30628-5. doi: 10.1016/j.ebiom.2018.12.051. [Epub ahead of print]
[h=1]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.[/h] Hershberger E[SUP]1[/SUP], Sloan S[SUP]1[/SUP], Narayan K[SUP]1[/SUP], Hay CA[SUP]1[/SUP], Smith P[SUP]2[/SUP], Engler F[SUP]2[/SUP], Jeeninga R[SUP]3[/SUP], Smits S[SUP]3[/SUP], Trevejo J[SUP]1[/SUP], Shriver Z[SUP]1[/SUP], Oldach D[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND:[/h] 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.
[h=4]METHODS:[/h] 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.
[h=4]FINDINGS:[/h] 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.
[h=4]SAFETY:[/h] 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.
[h=4]SYMPTOM ANALYSES:[/h] 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.
[h=4]VIROLOGY ANALYSES:[/h] VIS410 was associated with reduced median nasopharyngeal viral load TCID[SUB]50[/SUB] AUC[SUB]Day7[/SUB] (days ? log[SUB]10[/SUB] TCID[SUB]50[/SUB]/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.
[h=4]INTERPRETATION:[/h] VIS410 was safe and well tolerated in adults with uncomplicated influenza A, with favorable effects on symptom resolution and virus replication.
[h=4]TRIAL REGISTRATION:[/h] Clinical Trials: NCT02989194.
[h=4]FUNDING:[/h] 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.
PMID: 30638863 DOI: 10.1016/j.ebiom.2018.12.051
[h=1]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.[/h] Hershberger E[SUP]1[/SUP], Sloan S[SUP]1[/SUP], Narayan K[SUP]1[/SUP], Hay CA[SUP]1[/SUP], Smith P[SUP]2[/SUP], Engler F[SUP]2[/SUP], Jeeninga R[SUP]3[/SUP], Smits S[SUP]3[/SUP], Trevejo J[SUP]1[/SUP], Shriver Z[SUP]1[/SUP], Oldach D[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND:[/h] 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.
[h=4]METHODS:[/h] 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.
[h=4]FINDINGS:[/h] 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.
[h=4]SAFETY:[/h] 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.
[h=4]SYMPTOM ANALYSES:[/h] 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.
[h=4]VIROLOGY ANALYSES:[/h] VIS410 was associated with reduced median nasopharyngeal viral load TCID[SUB]50[/SUB] AUC[SUB]Day7[/SUB] (days ? log[SUB]10[/SUB] TCID[SUB]50[/SUB]/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.
[h=4]INTERPRETATION:[/h] VIS410 was safe and well tolerated in adults with uncomplicated influenza A, with favorable effects on symptom resolution and virus replication.
[h=4]TRIAL REGISTRATION:[/h] Clinical Trials: NCT02989194.
[h=4]FUNDING:[/h] 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.
PMID: 30638863 DOI: 10.1016/j.ebiom.2018.12.051