Prothena Corporation plc announced positive topline Phase 1 single ascending dose (SAD) study results for PRX005, a potentially best-in-class investigational tri-epitopic antibody for the treatment of Alzheimer's disease that specifically binds with high affinity to the R1, R2, and R3 repeats within the microtubule binding region (MTBR) of tau and targets both 3R and 4R tau isoforms. PRX005 is one of three programs in the global neuroscience research and development collaboration between Prothena and Bristol Myers Squibb. In this first-in-human, randomized, placebo controlled, SAD study, healthy volunteers (n=19) 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. No clinically relevant changes were observed in other safety parameters.

PRX005 also met key pharmacokinetic (PK) and immunogenicity secondary endpoints. 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 (day 29 CSF:Plasma ratio=0.2%), substantial target engagement is expected in the CNS.

PRX005 had a desirable immunogenicity profile with no persistent PRX005-induced antidrug antibodies (ADAs) observed. Prothena plans to present results from the Phase 1 SAD study at an upcoming medical conference. These results support the ongoing Phase 1 MAD trial of PRX005 in patients with Alzheimer's disease.

Topline results from the Phase 1 MAD trial are expected by year end 2023. Tau is a microtubule associated protein, which aggregates and hyper-phosphorylates in the brains of individuals with Alzheimer's disease to form pathological neurofibrillary tangles. Tau tangles, along with amyloid beta plaques represent the pathological hallmarks of Alzheimer's disease.

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 through 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.

PRX005 is designed to be a best-in-class anti-tau antibody that specifically binds with high affinity the R1, R2, and R3 repeats within the MTBR of tau and targets both 3R and 4R tau isoforms. MTBR tau has been shown in preclinical studies to be involved in the pathological spread of tau. Neurofibrillary tangles composed of misfolded tau proteins, along with amyloid beta plaques, are pathological hallmarks of Alzheimer's disease. Cell-to-cell transmission of pathogenic extracellular tau and the accumulation of pathogenic tau also correlate with the progression of symptomatology and clinical decline in patients with Alzheimer's disease.

Recent publications suggest that during the course of Alzheimer's disease progression, tau appears to spread throughout the brain via synaptically-connected pathways; this propagation of pathology is thought to be mediated by tau “seeds” containing the MTBR of tau. Additionally, it has been recently reported that the presence of MTBR fragments in cerebrospinal fluid correlate with dementia stages and tau tangles in Alzheimer's disease to a higher degree than fragments of other tau regions. In preclinical research, antibodies targeting this region of tau were superior in blocking tau uptake and neurotoxicity, which has been associated with efficacy in Alzheimer's disease animal models.

In these preclinical models, PRX005 demonstrated significant reduction of intraneuronal tau pathology and protection against behavioral deficit in a tau transgenic mouse model and complete blockade of neuronal tau internalization in vitro. Alzheimer's disease is a fatal disease and the most common form of dementia causing increasingly serious symptoms, including confusion, disorientation, mood and behavioral changes, and difficulty speaking, swallowing, and walking. Approximately 50 million people worldwide are estimated to be living with Alzheimer's disease or other dementias.

Alzheimer's disease is the most common neurodegenerative disorder. There is an urgent need for therapies that slow the progression and ultimately prevent Alzheimer's disease to address this global healthcare crisis. Prothena's Alzheimer's disease portfolio spans next generation antibody immunotherapy, small molecule, and vaccine approaches, all geared toward building upon first generation treatments to advance the treatment paradigm.