Safety and pharmacokinetics of the anti-amyloid monoclonal antibody PF-04360365 following a single infusion in patients with mild-to-moderate Alzheimer's disease: Preliminary results

Abstract

PF-04360365 is a humanized anti-amyloid monoclonal antibody (mAb) with several distinct features - an IgG2deltaA that recognizes amino acids 33-40 of the AB1-40 peptide and a requirement for a free carboxy terminus for binding. To date, PF-04360365 has been very well tolerated with no drug-attributed serious adverse events (AEs). Here we further evaluate its safety, as well as its pharmacokinetic (PK) profile. In this double-blind, placebo-controlled, dose-escalation study (0.1-10 mg/kg), patients with mild-to-moderate Alzheimer's disease (AD) were randomized to receive PF-04360365 as a single 2-hour intravenous infusion (N = 26) or placebo (N = 11). The most common AEs (blinded) were upper respiratory tract infection (n = 6), headache (n = 6) and diarrhea (n = 2), all mild-to-moderate in severity. One subject (10 mg/kg cohort) experienced a mild hypersensitivity reaction and another (0.1 mg/kg cohort) demonstrated slight enlargement of a pre-existing midbrain lesion at the time of the 1-year MRI. No clinical or imaging evidence of microhemorrhage, vasogenic edema or encephalitis was noted in any patient. ECG and routine safety laboratory values, including cell counts and cerebrospinal fluid (CSF) protein were unremarkable. No remarkable changes in cognition (ADAS-cog, MMSE) have been noted. The PK profile appeared linear in the studied dose range, with approximately dose-proportional increases in PF-04360365 plasma Cmax and AUC. PK parameters were similar to those of IgG-type mAbs except for a longer elimination half-life (∼6 weeks). Two of eight patients in the 10 mg/kg cohort had measurable PF-04360365 concentrations in CSF (∼0.5% of plasma values) when assessed 29 days post-dosing. Single-dose data indicate PF-04360365 is well-tolerated over the 0.1-10 mg/kg dose range. Plasma PF-04360365 exposure increased in a predictable dose-proportional manner, with evidence of mild central penetration. A multiple-dose study to evaluate PF-04360365 in patients with AD is warranted.