PRX005 Breaks Through Key Clinical Milestone: Novel Anti-Tau Antibody Demonstrates Outstanding Blood-Brain Barrier Penetration

New Directions in Tau Protein Therapy for Alzheimer’s Disease

As the most common neurodegenerative disease worldwide, Alzheimer’s affects approximately 50 million patients. The core pathological features of this deadly disease are the accumulation of two abnormal proteins: amyloid β plaques and Tau tangles. Among them, the spread of Tau protein is particularly critical—scientific evidence indicates that pathological Tau propagates through cell-to-cell transmission in the brain, a process believed to be mediated by Tau “seeds” containing MTBR (microtubule-binding region).

Recent studies have found that levels of MTBR fragments in cerebrospinal fluid (CSF) correlate more strongly with the degree of dementia and Tau tangle burden in Alzheimer’s disease than fragments from other Tau regions. This suggests that the MTBR region may be a key therapeutic target.

Unique Design and Clinical Validation of PRX005

Prothena, in collaboration with Bristol Myers Squibb, developed PRX005, a tri-epitope antibody specifically targeting the R1, R2, and R3 repeat sequences of the Tau protein’s MTBR region, while also targeting both 3R and 4R Tau isoforms. The innovation of this design lies in its ability to block pathological Tau from entering neurons—a feature that is difficult to achieve with antibodies targeting other Tau regions.

In the first human clinical trial, 19 healthy volunteers were randomly assigned to three ascending dose cohorts (low, medium, high) to receive a single intravenous injection of PRX005 or placebo in a 3:1 ratio. The trial included approximately two months of follow-up.

Key Findings from the Trial

Safety and Tolerability

PRX005 was well tolerated across all three dose cohorts. No serious treatment-related adverse events were observed, and other safety parameters showed no clinically relevant changes. This provides a foundation for subsequent multiple-dose studies.

Pharmacokinetics and CSF Penetration

PRX005 plasma concentrations increased proportionally with dose, consistent with expected linear pharmacokinetics. More importantly, CSF exposure levels in the high-dose cohort demonstrated strong central nervous system (CNS) penetration—the CSF-to-plasma ratio reached 0.2% (Day 29), indicating that the antibody can achieve significant target engagement within the CNS.

Immunogenicity Assessment

PRX005 exhibited favorable immunogenicity, with no persistent anti-drug antibody responses observed. This is crucial for the sustainability of long-term treatment.

Scientific Support from In Vitro to Clinical

The development of PRX005 is based on solid preclinical evidence. In vitro and animal models have shown that antibodies targeting the MTBR region are effective in blocking Tau uptake and neurotoxicity. Specifically, PRX005 significantly reduced Tau pathology within neurons in tau transgenic mouse models, protecting animals from behavioral deficits; in vitro systems demonstrated complete inhibition of neuronal Tau uptake. These data provide predictive support for its potential clinical efficacy in Alzheimer’s disease animal models.

Next Steps: Multiple-Dose and Patient Studies

Currently, a first-phase multiple-dose (MAD) trial involving patients is ongoing. This more challenging study will evaluate PRX005’s performance in actual patients, with topline results expected before the end of 2023.

Broader Therapeutic Outlook

Prothena’s Alzheimer’s pipeline is not limited to PRX005. The company is advancing a multi-pronged strategy that includes next-generation antibody immunotherapies, small molecule drugs, and vaccines, aiming to establish new treatment paradigms beyond first-generation therapies. In addition to Alzheimer’s, Prothena’s pipeline covers neurodegenerative diseases such as AL amyloidosis, ATTR amyloidosis, Parkinson’s disease, and other neurodegenerative disorders.

These advances reflect a deeper understanding of protein misfolding and neurofunctional impairment, marking a potential turning point in the treatment of neurodegenerative diseases.