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

Topic: Drug trials: efficacy and safety

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.

Key findings

• 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.
• Results Dose-dependent increases in plasma amyloid β and AAB-003 were observed.
• No significant changes in cerebral spinal fluid biomarkers were observed.
• 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.

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Study details

• Study designopen-label trial
• Participants52
• Evidence strengthHigh

Read the original

• DOI: 10.1186/s13195-016-0177-y
• PubMed: 26925577
• Original source →

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@article{delnomdedieu2016-26925577,
  author  = {Delnomdedieu, M. and Duvvuri, S. and Li, D. J. and Atassi, N. and Lu, M. and Brashear, H. R. and Liu, E. and Ness, S. and others},
  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}},
  journal = {Alzheimer's research \& therapy},
  year    = {2016},
  doi     = {10.1186/s13195-016-0177-y},
  pmid    = {26925577},
  url     = {https://doi.org/10.1186/s13195-016-0177-y}
}

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