Phase 2 Randomized Trial of the Safety and Efficacy of MHAA4549A, a Broadly Neutralizing Monoclonal Antibody, in a Human Influenza A Virus Challenge Model

Abstract

MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. The safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV challenge model. One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24 to 36 h later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1,200, or 3,600 mg), or a standard oral dose of oseltamivir. Subjects were assessed for safety, pharmacokinetics (PK), and immunogenicity. The intent-to-treat-infected (ITTI) population was assessed for changes in viral load, influenza symptoms, and inflammatory biomarkers. MHAA4549A was well tolerated in all IAV challenge subjects. The 3,600-mg dose of MHAA4549A significantly reduced the viral burden relative to that of the placebo as determined by the area under the curve (AUC) of nasopharyngeal virus infection, quantified using quantitative PCR (98%) and 50% tissue culture infective dose (TCID) (100%) assays. Peak viral load, duration of viral shedding, influenza symptom scores, mucus weight, and inflammatory biomarkers were also reduced. Serum PK was linear with a half-life of ∼23 days. No MHAA4549A-treated subjects developed anti-drug antibodies. In conclusion, MHAA4549A was well tolerated and demonstrated statistically significant and substantial antiviral activity in an IAV challenge model. (This study has been registered at ClinicalTrials.gov under identifier NCT01980966.).

The human viral challenge model: accelerating the evaluation of respiratory antivirals, vaccines and novel diagnostics

“…Short duration proof of concept studies, which incorporate the HVC model, typically include small numbers of subjects. The resulting safety and, particularly, efficacy data can more accurately guide decisions on whether to expose a larger number of subjects to promising candidate therapeutics in field studies than conventional phase 1 safety data alone otherwise might protein [155,156] the conserved stalk of the HA [157] and small molecule antiviral drugs that target the viral polymerase, e.g. favipiravir [158].…”

Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

“…Although detection of viruses that exhibit reduced susceptibility to NA inhibitors or baloxavir marboxil in immunocompetent patients has frequently been reported 1,[4][5][6][7][8][9] , such viruses usually do not dominate susceptible viruses with the exception of the worldwide spread of oseltamivir-resistant H1N1 virus in the 2007-2008 season. Recently, broadly protective human monoclonal antibodies (mAbs) against conserved regions of HA, including the receptorbinding site (RBS) and stem region, have been evaluated [10][11][12][13][14][15][16] and studies for their clinical application are being conducted [17][18][19][20] . However, no human mAbs are currently available for clinical use.…”

Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference

“…MHAA4549A is a human immunoglobulin G1 (IgG1) monoclonal antibody that binds to a highly conserved epitope on the stalk of influenza A HA (Gupta et al, 2016). In a Phase 2 human influenza A virus challenge study MHAA4549A showed significant reduction in clinical symptoms and viral burden relative to placebo (McBride et al, 2017). Two additional Phase 2 randomized, double-blind, placebo-controlled trials for treatment of influenza A infection utilizing MHAA4549A were conducted.…”