PRX005, a novel anti‐MTBR tau monoclonal antibody: results from a first‐in‐human double‐blind, placebo‐controlled, single ascending dose phase 1 study

Abstract

AbstractBackgroundMultiple lines of evidence indicate that tau protein spreads throughout the brain via synaptically connected pathways and that this propagation could be mediated by tau “seeds” containing the microtubule binding region (MTBR) of tau. In addition, cerebrospinal fluid (CSF) MTBR‐tau levels correlate with tau tangles and clinical stages of Alzheimer’s disease. To block the spread of tau pathology, we developed PRX005, a humanized monoclonal tri‐epitopic antibody that binds with high affinity to the R1, R2, and R3 repeats in the MTBR region of tau, and targets both 3R and 4R tau isoforms.MethodHealthy volunteers were randomly assigned to three dose cohorts and randomized in a 3:1 manner to receive either PRX005 or placebo. Primary endpoint was safety and tolerability with up to 2 months of follow‐up. Secondary endpoints included PRX005 pharmacokinetic parameters in plasma and CSF penetrance.ResultA total of 19 healthy volunteer participants received study drug or placebo. PRX005 was well tolerated and had a pharmacokinetic profile typical of IgG1 antibodies, with dose‐proportional increase in plasma concentration and central nervous system (CNS) penetrance. No persistent drug‐induced anti‐drug antibodies were observed following treatment with PRX005. Additional results from this Phase 1 will be presented.ConclusionIn this first‐in‐human, single ascending dose study, PRX005 was well tolerated and achieved CNS concentrations for pharmacological targeting of MTBR‐tau. Our results support the progression of the clinical development of PRX005 in an ongoing, multiple ascending dose study in patients with Alzheimer’s disease.