Background

Ponezumab (PF-04360365) is a passive immunotherapy treatment originally developed by Rinat Neuroscience. It is a humanized IgG2δA monoclonal antibody that binds the free carboxy terminal amino acids 33-40 of the Aβ 1-40 peptide (see La Porte et al. 2012). This antibody drew widespread attention in 2006, when Pfizer acquired its original developer, the small biotech company Rinat Neuroscience, for a reported several hundred million dollars. 

Findings

Five Phase 1 trials tested ponuzemab's safety and pharmacokinetics in Western and Japanese patients with mild to moderate disease. They showed acceptable safety without findings of antibody-induced microhemorrhage, amyloid-related imaging abnormalities (ARIA), or encephalitis, but only a small proportion of the antibody was detectable in the CSF. Two Phase 2 trials concluded in 2011. One study of 198 patients with mild to moderate Alzheimer's confirmed adequate safety and showed a plasma Aβ40 increase with treatment, suggesting a peripheral sink effect. A second trial of 36 patients with mild to moderate AD, however, showed no effect on the primary endpoints of change in brain or CSF Aβ burden. Development of ponezumab for Alzheimer's disease was discontinued. Pfizer is, however, conducting a Phase 2 study of ponezumab in patients with cerebral amyloid angiopathy (CAA). For all ponezumab trials, see clincialtrials.gov. 

Clinical Trial Timeline