title: Safety and Upper Respiratory Pharmacokinetics of the Hemagglutinin Stalk-Binding Antibody VIS410 Support Treatment and Prophylaxis Based on Population Modeling of Seasonal Influenza A Outbreaks.
abstract: BACKGROUND
  Seasonal influenza is a major public health concern in vulnerable populations. Here we investigated the safety, tolerability, and pharmacokinetics of a broadly neutralizing monoclonal antibody (VIS410) against Influenza A in a Phase 1 clinical trial. Based on these results and preclinical data, we implemented a mathematical modeling approach to investigate whether VIS410 could be used prophylactically to lessen the burden of a seasonal influenza epidemic and to protect at-risk groups from associated complications.
  
  
  METHODS
  Using a single-ascending dose study (n = 41) at dose levels from 2 mg/kg-50 mg/kg we evaluated the safety as well as the serum and upper respiratory pharmacokinetics of a broadly-neutralizing antibody (VIS410) against influenza A (ClinicalTrials.gov identifier NCT02045472). Our primary endpoints were safety and tolerability of VIS410 compared to placebo. We developed an epidemic microsimulation model testing the ability of VIS410 to mitigate attack rates and severe disease in at risk-populations.
  
  
  RESULTS
  VIS410 was found to be generally safe and well-tolerated at all dose levels, from 2-50 mg/kg. Overall, 27 of 41 subjects (65.9%) reported a total of 67 treatment emergent adverse events (TEAEs). TEAEs were reported by 20 of 30 subjects (66.7%) who received VIS410 and by 7 of 11 subjects (63.6%) who received placebo. 14 of 16 TEAEs related to study drug were considered mild (Grade 1) and 2 were moderate (Grade 2). Two subjects (1 subject who received 30 mg/kg VIS410 and 1 subject who received placebo) experienced serious AEs (Grade 3 or 4 TEAEs) that were not related to study drug. VIS410 exposure was approximately dose-proportional with a mean half-life of 12.9 days. Mean VIS410 Cmax levels in the upper respiratory tract were 20.0 and 25.3 μg/ml at the 30 mg/kg and 50 mg/kg doses, respectively, with corresponding serum Cmax levels of 980.5 and 1316 μg/mL. Using these pharmacokinetic data, a microsimulation model showed that median attack rate reductions ranged from 8.6% (interquartile range (IQR): 4.7%-11.0%) for 2% coverage to 22.6% (IQR: 12.7-30.0%) for 6% coverage. The overall benefits to the elderly, a vulnerable subgroup, are largest when VIS410 is distributed exclusively to elderly individuals, resulting in reductions in hospitalization rates between 11.4% (IQR: 8.2%-13.3%) for 2% coverage and 30.9% (IQR: 24.8%-35.1%) for 6% coverage among those more than 65 years of age.
  
  
  CONCLUSIONS
  VIS410 was generally safe and well tolerated and had good relative exposure in both serum and upper respiratory tract, supporting its use as either a single-dose therapeutic or prophylactic for influenza A. Including VIS410 prophylaxis among the public health interventions for seasonal influenza has the potential to lower attack rates and substantially reduce hospitalizations in individuals over the age of 65.
  
  
  BACKGROUND
  Visterra, Inc.
authors.affiliation: Visterra Inc., One Kendall Square, Cambridge, MA 02139, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Wollacott
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: Maciej F
authors.initials: MF
authors.lastname: Boni
authors.affiliation: Visterra Inc., One Kendall Square, Cambridge, MA 02139, USA.
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Szretter
authors.affiliation: Visterra Inc., One Kendall Square, Cambridge, MA 02139, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Sloan
authors.affiliation: Visterra Inc., One Kendall Square, Cambridge, MA 02139, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Yousofshahi
authors.affiliation: Visterra Inc., One Kendall Square, Cambridge, MA 02139, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Viswanathan
authors.affiliation: Visterra Inc., One Kendall Square, Cambridge, MA 02139, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bedard
authors.affiliation: Visterra Inc., One Kendall Square, Cambridge, MA 02139, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Hay
authors.affiliation: d3 Medicine LLC, Parsippany, NJ, USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.affiliation: Visterra Inc., One Kendall Square, Cambridge, MA 02139, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Shriver
authors.affiliation: Visterra Inc., One Kendall Square, Cambridge, MA 02139, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Trevejo
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000008:administration & dosage*; D000080908:Broadly Neutralizing Antibodies; D004196:Disease Outbreaks; D004341:Drug Evaluation; D005260:Female; D006388:Hemagglutinins / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D012621:Seasons
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D006388:Hemagglutinins; C000613160:VIS410 monoclonal antibody
keywords: Epidemic modeling; Influenza; Monoclonal antibody; Prophylaxis