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

Alzheimers Res Ther. 2016 Mar 1;8(1):12. doi: 10.1186/s13195-016-0177-y.


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.

Conclusion: 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / blood*
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / immunology
  • Amyloid beta-Peptides / blood*
  • Amyloid beta-Peptides / immunology*
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects*
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Biomarkers / blood
  • Brain Edema / chemically induced*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Severity of Illness Index


  • Amyloid beta-Peptides
  • Antibodies, Monoclonal, Humanized
  • Biomarkers

Associated data