PRX005 is one of three programs in the global neuroscience research and development collaboration between Prothena and Bristol Myers Squibb (BMS).
The investigational antibody is designed to target a key region within the microtubule binding region (MTBR) of tau to reduce pathogenic tau uptake into neurons, an attribute that has not been similarly achievable with antibodies targeting other regions of tau, according to Gene Kinney, CEO of Prothena.
Results from the single ascending dose (SAD) study in healthy volunteers demonstrated dose-proportional PRX005 concentrations in plasma with robust central nervous system (CNS) penetration of this investigational anti-MTBR-tau antibody, while single doses of PRX005 across three dose cohorts were safe and well tolerated, meeting the primary objective of the study, said the developer.
“For the first time, we have confirmation that PRX005 is safe and well-tolerated in humans and that it crosses the blood-brain barrier with robust central nervous system (CNS) penetration.
“These topline Phase 1 data, together with the mounting scientific evidence suggesting that tau propagation could be mediated by MTBR-tau seeds, underscores the potential of PRX005 in treating Alzheimer’s disease," said Kinney.
Tau pathology
Tau is a microtubule associated protein, which aggregates and hyper-phosphorylates in the brains of individuals with Alzheimer’s disease (AD) to form pathological neurofibrillary tangles. Tau tangles, along with amyloid beta plaques, represent the pathological hallmarks of AD, explained Prothena.
“The presence of tau pathology strongly correlates with neurodegeneration and cognitive impairment in Alzheimer’s disease and its pattern of progression throughout the brain suggests that tau pathology spreads through anatomically connected pathways via cell-to-cell transmission, a hypothesis supported by multiple preclinical studies.
“This propagation of pathology is thought to be mediated by MTBR-tau 'seeds'.
“PRX005 has demonstrated superior ability to bind, intercept and block cellular internalization of pathogenic tau, and mitigate downstream neurotoxicity compared to other anti-tau antibodies in multiple preclinical studies.”
SAD study results - a deeper dive
In the randomized, placebo controlled, SAD study, 19 healthy volunteers were enrolled into three PRX005 dose level cohorts (low, medium or high dose) and randomized in a 3:1 drug to placebo ratio. Study participants received a single dose of PRX0005 or placebo intravenously (IV) and were followed for up to two months.
The results of the study found all three dose level cohorts of PRX005 to be generally safe and well tolerated, meeting the Phase 1 SAD study primary objective. None of the treatment emergent adverse events (TEAE) were serious., and no clinically relevant changes were observed in other safety parameters, reported the company.
PRX005 also met key pharmacokinetic (PK) and immunogenicity secondary endpoints, said the developer.
“Plasma drug concentrations of PRX005 increased in a dose-proportional manner. Furthermore, PRX005 exposure in cerebrospinal fluid (CSF) was measured in the high dose cohort and based on the robust exposure of PRX005 in the CSF, substantial target engagement is expected in the CNS.”
PRX005 had a desirable immunogenicity profile with no persistent PRX005-induced antidrug antibodies (ADAs) observed, it added.
Next steps
Prothena and BSM are combining their expertise to advance the development of PRX005 as quickly as possible, said Kinney.
“We look forward to seeing Phase 1 multiple ascending dose (MAD) results in patients with Alzheimer’s disease later this year.”
That Phase 1 MAD phase of the study is ongoing; the company expects topline results to be released by year end.
"The purpose of the PRX005 Phase 1 MAD trial is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of PRX005 in healthy adults and patients with AD following the administration of multiple doses. We anticipate that these results will help us to determine our path forward, and the appropriate dose or dose levels for subsequent clinical studies," a spokesperson for Prothena told us.
