A Randomized, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of VIR-2482 in Healthy Adults for Prevention of Influenza A Illness (PENINSULA).

BACKGROUND: Influenza A results in significant morbidity and mortality. VIR-2482, an engineered human monoclonal antibody with extended half-life, targets a highly conserved epitope on the stem region of influenza A hemagglutinin, and may protect against seasonal and pandemic influenza. METHODS: This double-blind, randomized, placebo-controlled, phase 2 study examined the safety and efficacy of VIR-2482 for seasonal influenza A illness prevention in unvaccinated healthy adults. Participants (N = 2977) were randomized 1:1:1 to receive VIR-2482 450 mg, VIR-2482 1200 mg, or placebo via intramuscular (IM) injection. Primary and secondary efficacy endpoints were the proportions of participants with reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed influenza A infection and either protocol-defined influenza-like illness (ILI) and Centers for Disease Control and Prevention (CDC)-defined ILI or World Health Organization (WHO)-defined ILI, respectively. RESULTS: VIR-2482 450 mg and 1200 mg prophylaxis did not reduce the risk of protocol-defined ILI with RT-PCR-confirmed influenza A versus placebo (relative risk reduction [RRR], 3.8% [95% CI: -67.3, 44.6] and 15.9% [95% CI: -49.3, 52.3], respectively). At the 1200 mg dose, the RRRs in influenza A illness were 57.2% [95% CI: -2.5, 82.2] using CDC-ILI and 44.1% [95% CI: -50.5, 79.3] using WHO-ILI definitions, respectively. Serum VIR-2482 levels were similar regardless of influenza status; variants with reduced VIR-2482 susceptibility were not detected. Local injection-site reactions were mild and similar across groups. CONCLUSION: VIR-2482 1200 mg IM was well tolerated but did not significantly prevent protocol-defined ILI. Secondary endpoint analyses suggest this dose may have reduced influenza A illness.

A phase 1 study in healthy volunteers to investigate the safety, tolerability, and pharmacokinetics of VIR-2482: a monoclonal antibody for the prevention of severe influenza A illness.

The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of VIR-2482 in healthy adult subjects. A phase 1, first-in-human, randomized, double-blind, placebo-controlled dose-escalation study was conducted. One hundred participants were allocated to four cohorts (60 mg, 300 mg, 1,200 mg, and 1,800 mg). In each cohort, participants were randomized in a 4:1 ratio (active:placebo) to receive either VIR-2482 or volume-matched placebo by gluteal intramuscular injection. Participants remained at the investigative site under observation for 48 h, and adverse events (AEs) were collected for 56 days. PK and immunogenicity were measured up to 52 weeks post-dose. VIR-2482 was well tolerated at all doses studied. The overall incidence of AEs was comparable between VIR-2482 (68.8%) and placebo (85.0%). Nineteen VIR-2482 (23.8%) and six placebo (30.0%) recipients had Grade 1 or 2 AEs that were considered to be related to the study intervention. There were no treatment-related serious AEs. Injection-site reactions (ISRs) were reported in six (7.5%) VIR-2482 recipients, while no such reactions were reported among the placebo recipients. All ISRs were Grade 1, and there was no relationship with the dose. Median VIR-2482 serum elimination half-life ranged from 56.7 to 70.6 days across cohorts. The serum area under the curve and Cmax were dose-proportional. Nasopharyngeal VIR-2482 concentrations were approximately 2%-5% of serum levels and were less than dose-proportional. The incidence of immunogenicity across all cohorts was 1.3%. Overall, the safety, tolerability, and pharmacokinetic profile of VIR-2482 at doses up to 1,800 mg supported its further investigation as a long-acting antibody for the prevention of influenza A illness. This study has been registered at ClinicalTrials.gov under identifier NCT04033406.

Effect of Bamlanivimab as Monotherapy or in Combination with Etesevimab or Sotrovimab on Persistently High Viral Load in Patients with Mild-to-Moderate COVID-19: A Randomized, Phase 2 BLAZE-4 Trial.

INTRODUCTION: Treatment with monoclonal antibodies provides rapid, passive immunity and may stop COVID-19 disease progression. The study evaluated the effect of bamlanivimab (BAM) or BAM + etesevimab (ETE)/sotrovimab compared to placebo on SARS-CoV-2 viral load in patients with COVID-19. METHODS: The phase 2, randomized, single-dose study included patients aged between ≥ 18 and < 65 years, not hospitalized at the time of randomization, and had ≥ 1 mild or moderate COVID-19 symptoms. Study included arms 1-6 (placebo, BAM 175 mg + ETE 350 mg, BAM 700 mg + ETE 1400 mg, BAM 2800 mg + ETE 2800 mg, BAM 700 mg alone, and BAM 350 mg + ETE 700 mg, respectively), BAM 700 mg + ETE 700 mg unintentional dosing; and arms 7 and 8 (BAM 700 mg + sotrovimab 500 mg and placebo, respectively). The primary endpoint was proportion of patients with SARS-CoV-2 log viral load > 5.27 on day 7 (persistently high viral load [PHVL]) who received BAM or BAM + (ETE or sotrovimab). RESULTS: A total of 725 patients, mean age 39.6 years (range 18-75 years), 50.2% male were randomized and infused with study drug in arms 1-6; and a total 202 patients, mean age 38 years (range 18-63 years), 53.5% female were randomized and infused with study drug in arms 7 and 8. A significantly lower proportion of patients in arms 2-6 and arm 7 experienced PHVL on day 7 compared to placebo. On day 7, patients in arms 2, 3, and 6 consistently experienced significantly greater reduction in viral load than placebo. Significant improvement was observed in time to viral load clearance and time to symptom improvement by day 29 in some arms compared to placebo. No new safety concerns were observed with drug combinations. CONCLUSION: The study demonstrated that a significantly lower proportion of patients with mild-to-moderate COVID-19 treated with BAM or BAM + (ETE or sotrovimab) experienced a PHVL at day 7. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04634409.