title: First-In-Human safety and long-term exposure data for AAB-003 (PF-05236812) and biomarkers after intravenous infusions of escalating doses in patients with mild to moderate Alzheimer's disease.
abstract: BACKGROUND
  In the First-In-Human (FIH), 39-week, randomized, adaptive design study, safety, tolerability, pharmacokinetics and biomarkers were measured in patients with mild-to-moderate Alzheimer's disease (AD) after infusion of a humanized monoclonal antibody to amyloid β, AAB-003 (NCT01193608; registered 19 August 2010). AAB-003 was developed by modifying bapineuzumab to reduce Fc-receptor-mediated effector function as a strategy to reduce the removal of amyloid from vessel walls associated with amyloid-related imaging abnormalities with edema/effusions (ARIA-E) without diminishing overall amyloid clearance.
  
  
  METHODS
  Eighty-eight patients with AD received up to three infusions of AAB-003 (or placebo) 13 weeks apart at doses of 0.5, 1, 2, 4 or 8 mg/kg in the FIH trial. Dose escalation was based on safety data reviews using a Bayesian escalation algorithm. Subjects who completed the FIH study were permitted to enter a 1-year open-label extension trial with four additional intravenous infusions of AAB-003 (NCT01369225; registered 10 May 2011).
  
  
  RESULTS
  Dose-dependent increases in plasma amyloid β and AAB-003 were observed. No significant changes in cerebral spinal fluid biomarkers were observed. Pharmacokinetics elimination half-life (21-28 days) clearance and volume of distribution values were consistent across dose groups indicating linearity. ARIA-E was the most notable safety finding detected by magnetic resonance imaging (MRI) at 8 mg/kg in two patients. Three cases of microhemorrhage were observed. No new safety findings or MRI abnormalities were observed for the 52 subjects who received AAB-003 in the extension trial.
  
  
  CONCLUSIONS
  Based on integrated review of laboratory, electrocardiogram, adverse events, and MRI, AAB-003 was safe and well tolerated up to 8 mg/kg for up to 91 weeks (FIH and extension trials) in patients with mild to moderate AD. Asymptomatic and resolvable ARIA-E was observed after the first or second infusion of AAB-003, similar to bapineuzumab. The AAB-003 dose at which ARIA-E was observed was higher compared to bapineuzumab, supporting the hypothesis that reducing Fc-receptor effector function may reduce the ARIA associated with monoclonal antibodies targeting cerebral amyloid.
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA. marielle.delnomdedieu@pfizer.com.
authors.forename: Marielle
authors.initials: M
authors.lastname: Delnomdedieu
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA. sridhar.duvvuri@pfizer.com.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Duvvuri
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA. David.Li1@pfizer.com.
authors.forename: David Jianjun
authors.initials: DJ
authors.lastname: Li
authors.affiliation: Mass General Hospital, Boston, MA, USA. natassi@mgh.harvard.edu.
authors.forename: Nazem
authors.initials: N
authors.lastname: Atassi
authors.affiliation: Janssen R&D, Spring House, PA, USA. MLu7@its.jnj.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.affiliation: Janssen R&D, Fremont, CA, USA. rbrashea@janimm.com.
authors.forename: H Robert
authors.initials: HR
authors.lastname: Brashear
authors.affiliation: Janssen R&D, Fremont, CA, USA. enchi.liu@comcast.net.
authors.forename: Enchi
authors.initials: E
authors.lastname: Liu
authors.affiliation: Janssen R&D, Fremont, CA, USA. SNess@its.jnj.com.
authors.forename: Seth
authors.initials: S
authors.lastname: Ness
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA. james.w.kupiec@pfizer.com.
authors.forename: James W
authors.initials: JW
authors.lastname: Kupiec
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood* / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001929:Brain Edema / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index
chemical_list: D016229:Amyloid beta-Peptides; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers