• Data from PRX012, PRX005 and PRX123 programs showcase promise of Prothena’s pipeline and commitment to transform the care of patients with Alzheimer's disease

DUBLIN / Jul 17, 2023 / Business Wire / Prothena Corporation plc (NASDAQ:PRTA), a late-stage clinical biotechnology company with a robust pipeline of investigational therapeutics built on protein dysregulation expertise, today shared data on three investigational product programs for the treatment and prevention of Alzheimer’s disease, PRX005, PRX012 and PRX123, at the Alzheimer’s Association International Conference^® 2023 (AAIC^®) being held July 16-20, 2023 in Amsterdam, Netherlands and virtually.

“Ending Alzheimer’s disease with cutting-edge science is our mission. Our posters at AAIC exemplify our multiple efforts to continue bringing innovation to the Alzheimer’s disease field,” said Wagner Zago, Ph.D., Chief Scientific Officer, Prothena. “From two next-generation antibodies with best-in-class potential, PRX012 and PRX005, to our vaccine, PRX123, our goal is to deliver better outcomes for the millions of patients with this devastating disease and ultimately eradicate it altogether.”

PRX005 Phase 1 Clinical Trial, Single Ascending Dose (SAD) Portion

Poster 74181: PRX005, A Novel Anti-MTBR Tau Humanized Monoclonal Antibody: Results from the Single Ascending Dose Portion of a First-in-Human Double-Blind, Placebo-Controlled, Phase 1 Clinical Trial

The results of the Phase 1 clinical trial SAD portion showed that all three dose level cohorts (low, medium, high) of PRX005 were considered generally safe and well tolerated, meeting the Phase 1 clinical trial SAD portion primary objective and supporting evaluation of doses in the MAD portion of the ongoing Phase 1 clinical trial. PRX005 also met key pharmacokinetic (PK) and immunogenicity secondary endpoints. Plasma drug concentrations of PRX005 increased in a dose-proportional manner. As planned, cerebral spinal fluid (CSF) drug levels were measured in the high dose cohort and reached sufficient CSF concentrations to predict pharmacological targeting of MTBR tau in the central nervous system (CNS) (day 29 CSF:plasma ratio=0.2%).

On July 10, 2023, Prothena announced that Bristol Myers Squibb exercised its $55 million option under the global neuroscience research and development collaboration to obtain the exclusive worldwide commercial rights for PRX005. Bristol Myers Squibb will be responsible for the development, manufacturing, and commercialization of PRX005. All program updates, including results from ongoing and any future PRX005 clinical studies, will be reported by Bristol Myers Squibb going forward.

PRX123 Preclinical Study Results

Poster #82687: Immunological response to dual Aβ/Tau vaccine PRX123 surrogate and effects on brain amyloid plaques in rapidly depositing transgenic animal model

Preclinical results demonstrated that a PRX123 vaccine surrogate elicited robust antibody responses that bound with high avidity to Aβ plaques in Alzheimer’s disease brain ex vivo and significantly reduced Aβ brain plaques in a transgenic mouse model of Alzheimer’s disease pathology. The results support the continued development of PRX123, a dual Aβ-tau conjugated linear peptide vaccine designed to treat and/or prevent Alzheimer’s disease, and represent the first time that a dual target vaccine for Alzheimer’s disease has been shown to reduce pathology in a transgenic animal model.

PRX012 Preclinical Study Results (encore presentation)

Poster #74811: Binding Characteristics of Surrogate PRX012 Demonstrate Potent Engagement of Toxic Aβ Protofibrils and Robust Clearance of Pyroglutamate-Modified Aβ

Results from two preclinical studies were presented comparing a PRX012-surrogate^* (PRX012s) to lecanemab and donanemab^†. In the first study, Surface Plasmon Resonance (SPR) was used to compare PRX012s to lecanemab and showed that PRX012s had approximately 20-fold higher affinity to Aβ protofibrils when compared to lecanemab, tested under the same conditions. In the second study, ex vivo using post-mortem Alzheimer’s disease brain tissue, PRX012s demonstrated to robustly clear pyroglutamate-modified Aβ deposited in plaques more potently than donanemab.

About PRX005

PRX005 is designed to be a best-in-class anti-tau antibody that specifically binds with high affinity to 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 the Global Neuroscience R&D Collaboration

This global neuroscience research and development collaboration is focused on three proteins implicated in the pathogenesis of several neurodegenerative diseases, including tau, TDP-43 and an undisclosed target. PRX005 is designed to be a best-in-class anti-tau, MTBR-specific antibody for the potential treatment of Alzheimer’s disease and is the first program to advance to the clinic from this collaboration. Prothena is eligible to receive up to an additional $160 million for U.S. rights, up to $110 million for global rights, and up to $1.7 billion for regulatory and commercial milestone payments for a total of up to $2.2 billion, which also includes amounts received to date.

About PRX123

PRX123, a potential first-in-class investigational dual Aβ/tau vaccine designed for the treatment and prevention of Alzheimer's disease, is a dual-target vaccine targeting key epitopes within the N-terminus of Aβ and MTBR-tau to simultaneously promote amyloid clearance and blockade of pathogenic tau.

About PRX012

PRX012, an investigational next-generation anti-Aβ antibody, was designed as a subcutaneous IgG1 mAb to target aggregated forms of Aβ, including protofibrils and plaques, with high binding affinity. PRX012 is currently being investigated in a Phase 1 clinical trial for the treatment of Alzheimer’s disease. Preclinical data have demonstrated binding of PRX012 to beta amyloid plaques and oligomers with high affinity, allowing effective Aβ plaque occupancy and removal at relatively lower dose ranges, optimal for subcutaneous delivery. Preclinical data have also demonstrated clearance of both pyroglutamate modified and unmodified Aβ plaque in brain tissue at concentrations of PRX012 estimated to be clinically achievable in the central nervous system with subcutaneous delivery.

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 55 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, 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, designs, proposed mechanisms of action, and potential administration of PRX005, PRX012, and PRX123; and amounts we might receive under our collaboration with BMS. 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 May 4, 2023, 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.

^* “Surrogate” is defined as an antibody with >99.5% homology, the same binding epitope and equivalent binding profile to different forms of Aβ where directly compared.

^† Lecanemab and donanemab were generated from publicly available sequences