Safety and Pharmacokinetics Following a Single Infusion of the Anti-amyloid Monoclonal Antibody Ponezumab (pf-04360365) in Patients With Mild-to-moderate Alzheimer's Disease: Final Results

Ponezumab (PF-04360365) is a humanized anti-amyloid β monoclonal antibody in clinical development as a therapeutic agent to reduce brain amyloid burden and improve clinical outcomes in patients with Alzheimer's disease (AD). This randomized, double-blind, placebo-controlled, single-dose-escalation study (0.1-10 mg/kg) in 37 patients with mild-to-moderate AD examined the safety and pharmacokinetics of ponezumab following 2-hour intravenous infusion. Patients enrolled into one of five dosing cohorts, mg/kg (n, ponezumab/placebo): 0.1 (4/2); 0.3 (4/2); 1 (4/2); 3 (6/2); 10 (8/3). Those receiving 1 or 10 mg/kg underwent optional lumbar punctures at baseline and Day 29 post-dose. All patients completed this 1-year trial. Ponezumab was well tolerated with no drug-attributed SAEs. The most common AEs were URTIs (n = 6 ponezumab; n = 4 placebo), headaches (n = 8 ponezumab; n = 5 placebo) and GI upset (n = 6 ponezumab), all mild-to-moderate. No AEs were dose-related. One subject (10 mg/kg) experienced a mild hypersensitivity reaction. Another (0.1 mg/kg) demonstrated slight enlargement of a pre-existing midbrain lesion. ECGs and routine safety laboratory values including CSF measures were unremarkable. No evidence of new microhemorrhage, vasogenic edema or encephalitis was noted. The pharmacokinetic profile of ponezumab was linear across the 0.1-10 mg/kg range with mean terminal half-lives of ˜6 weeks. Two 10 mg/kg patients had low CSF ponezumab concentrations (˜0.5% of plasma values) at Day 29. A dose-dependent increase in plasma Aβ1-x response and mean 38% increase from baseline at Day 29 in CSF Aβ1-x (p = 0.002 vs placebo) for the 10 mg/kg dose were observed. Single-dose ponezumab is well tolerated over the 0.1-10 mg/kg dose range in patients with mild-to-moderate AD. The pharmacokinetic profile of ponezumab is linear with limited evidence for central penetration. A dose-dependent increase in plasma Aβ1-x is consistent with the hypothesized mechanism of action, with effect also seen on CSF Aβ1-x. Multiple-dose studies are ongoing.