P1-052: A SINGLE ASCENDING DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF THE ANTI-PHOSPHO-TAU ANTIBODY JNJ-63733657 IN HEALTHY SUBJECTS

Alzheimer's disease (AD) is characterized neuropathologically by extracellular amyloid beta (plaques) and intracellular hyperphosphorylated tau (neurofibrillary tangles). There is evidence for prion-like spread of tau in AD, and anti-tau antibodies are under clinical investigation for disease modification by binding to extracellular tau seeds in the interstitial fluid (ISF). JNJ-63733657 is a humanized IgG1 monoclonal antibody with high affinity for phosphorylated tau (p217+). This antibody depletes toxic tau species in in vitro seeding assays and reduces tau seeding in in vivo models. A sensitive assay has been developed to measure p217+tau fragments in the cerebrospinal fluid (CSF), and changes in CSF levels of p217+ tau may serve as a surrogate for changes in the levels of extracellular tau seed in the ISF following antibody administration. A randomized, double blind, placebo controlled single ascending dose (SAD) study has been conducted in healthy subjects aged 55–75 years. Five cohorts of 8 subjects each were administered placebo or a single dose of JNJ-63733657 intravenously in a dose ranging study. Subjects were followed for 92 days, and serum and CSF samples were collected. Safety, tolerability, pharmacokinetics (PK; serum and CSF), and the effect of JNJ-63733657 on CSF levels of p217+tau fragments (pharmacodynamic (PD) response) were evaluated. Following single dose administration, JNJ-63733657 was generally safe and well-tolerated and demonstrated linear PK in serum. Dose-dependent increases in exposures were observed. CSF exposures were ∼0.2% of serum levels. There were dose dependent reductions in p217+ tau in CSF of healthy subjects following antibody administration. JNJ-63733657 exhibits clearance of toxic tau species in preclinical models and to date shows a favorable clinical profile and biomarker response following single dose administration.