• Results from a single ascending dose (SAD) study in healthy volunteers demonstrated dose-proportional PRX005 concentrations in plasma with robust central nervous system (CNS) penetration of this potentially best-in-class investigational anti-MTBR-tau antibody
• Single doses of PRX005 across three dose cohorts were generally safe and well tolerated, meeting the primary objective of the study
• The Phase 1 multiple ascending dose (MAD) portion of the study is ongoing in healthy volunteers and patients with Alzheimer’s disease; topline results are expected by year end 2023

Prothena Corporation plc (NASDAQ:PRTA), a late-stage clinical biotechnology company with a robust pipeline of investigational therapeutics built on protein dysregulation expertise, today 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.

“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. We developed PRX005 to uniquely target a key region within the 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. 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 Gene Kinney, PhD, President and Chief Executive Officer of Prothena. "Working closely with Bristol Myers Squibb, we are combining our expertise to advance the development of PRX005 as quickly as possible, and we look forward to seeing Phase 1 multiple ascending dose (MAD) results in patients with Alzheimer’s disease later this year.”

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.

About Tau

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 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.

About PRX005

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.

About Alzheimer’s Disease

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.

About Prothena

Prothena Corporation plc is a late-stage clinical biotechnology company with expertise in protein dysregulation and a pipeline of investigational therapeutics with the potential to change the course of devastating neurodegenerative and rare peripheral amyloid diseases. Fueled by its deep scientific expertise built over decades of research, Prothena is advancing a pipeline of therapeutic candidates for a number of indications and novel targets for which its ability to integrate scientific insights around neurological dysfunction and the biology of misfolded proteins can be leveraged. Prothena’s pipeline includes both wholly-owned and partnered programs being developed for the potential treatment of diseases including AL amyloidosis, ATTR amyloidosis, Alzheimer’s disease, Parkinson’s disease and a number of other neurodegenerative diseases. For more information, please visit the Company’s website at www.prothena.com and follow the Company on Twitter @ProthenaCorp.

Forward-Looking Statements

This press release contains forward-looking statements. These statements relate to, among other things, the treatment potential, design, proposed mechanism of action, and potential administration of PRX005; attributes of epitopes and PRX005 we have identified; the timing for advancement of our PRX005 program, including the ongoing multiple ascending dose (MAD) portion of the Phase 1 study; the timing for reporting topline and Phase 1 multiple ascending dose (MAD) results in patients with Alzheimer’s disease; and the presentation of results from the Phase 1 SAD study at an upcoming medical conference. These statements are based on estimates, projections and assumptions that may prove not to be accurate, and actual results could differ materially from those anticipated due to known and unknown risks, uncertainties and other factors, including but not limited to those described in the “Risk Factors” sections of our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 3, 2022, and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the SEC. We undertake no obligation to update publicly any forward-looking statements contained in this press release as a result of new information, future events, or changes in our expectations.

View source version on businesswire.com: https://www.businesswire.com/news/home/20230131005981/en/