Prothena Corporation plc · NASDAQ:PRTA
Prothena — Investor Presentation (August 2025)
46 slides from Prothena's investor presentation, Aug 6, 2025
Slide 1: Corporate Overview August 2025
CORPORATE OVERVIEW August 2025
Slide 2: Forward-Looking Statements
Forward-Looking Statements This overview contains forward-looking statements. These statements relate to, among other things, the sufficiency of our cash position to fund advancement of a broad pipeline; the continued advancement of our pipeline, and expected milestones in 2025, 2026, 2027, and beyo
Slide 3: Our Mission Today
Our Mission Today We are Focused on Delivering Life-Saving Therapies… …for unmet medical needs caused by diseases of protein dysregulation 3
Slide 4: Addressing Devastating Proteinopathies Affecting Millions Worldwide
We are Addressing Devastating Proteinopathies Affecting Millions of Patients and Families Worldwide NEURODEGENERATIVE DISEASES RARE PERIPHERAL AMYLOID Transthyretin Alzheimer’s Parkinson’s amyloidosis disease (AD) disease (PD) (ATTR) >80 million >10 million 450,000 People worldwide living with Peopl
Slide 5: Our Biology-Directed Engine Propels Progress Across Broad Pipeline
Our Biology-Directed Engine Propels Prothena’s Progress Across our Broad Pipeline Therapeutics engineered to optimally eliminate pathogenic proteins while preserving normal biology Disease- Driven Multiple Clinical Programs Ongoing Antibody Two partnered Phase 3 programs Engineering Product Deep can
Slide 6: Robust R&D Pipeline
Robust R&D Pipeline PROGRAM/ GLOBAL PROTEIN TARGET DISCOVERY PRE-CLINICAL PHASE 1 PHASE 2 PHASE 3 INDICATION PARTNER3 Prasinezumab α-Synuclein Roche to initiate Phase 3 development by YE 2025 Parkinson’s disease (C-terminus) Coramitug (PRX004) Transthyretin Novo to initiate Phase 3 development by YE
Slide 7: Potential Value-Creating Milestones
Potential Value-Creating Milestones Up to $105 Million in Clinical Milestones in 2026 Related to the Advancement of Coramitug and PRX0191 PRX012 PRX019 BMS-986446 Prasinezumab Alzheimer’s Coramitug Neurodegenerative Alzheimer’s Parkinson’s disease ATTR-CM diseases disease disease Ph 1 ASCENT Ph 3 Tr
Slide 8: Partnerships Expected to Generate Meaningful Value Across Programs
Prothena Partnerships Expected to Generate Meaningful Value Across Programs Up to $755 Million in Up to $1.23 Billion in Up to $1.55 Billion in Total Milestones + Royalties Total Milestones Total Milestones Across Two Clinical Stage Programs +Royalties Upfront Payment + Equity: $150 million2 Prasi
Slide 9: Prasinezumab
Prasinezumab Parkinson’s Disease Worldwide Collaboration with Roche
Slide 10: Prasinezumab: Potential First-in-Class Treatment for Parkinson's Disease
Prasinezumab: Potential First-in-Class Treatment for Parkinson’s Disease Phase 2 Clinical Development Programs: Prasinezumab Parkinson’s Disease • First anti-α-synuclein antibody to slow progression on measures of PD Status: Phase 3 initiation by YE 2025 • Consistent positive trends across multiple
Slide 11: α-Synuclein Pathology is Strongly Implicated in Parkinson's Disease
α-Synuclein Pathology is Strongly Implicated in Parkinson’s Disease Accumulation of α-Synuclein Neuronal α-Synuclein Dopaminergic neurodegeneration is a predominant Symptoms neuropathological feature and Biological or Clinical Measures Functional impairment follows the topological progression of dis
Slide 12: Prasinezumab: α-Synuclein Immunotherapy
Prasinezumab: α-Synuclein Immunotherapy REDUCE NEURONAL TOXICITY AND PREVENT CELL-TO-CELL TRANSMISSION1 Diseased Neuron Protected Neuron α-Synuclein as an extracellular target during pathogenesis Aggregated • Caudal-rostral staging, extracellular host-to-graft transfer, α-Synuclein various propagati
Slide 13: Moving into Phase 3 in Parkinson's Disease
Moving into Phase 3 in Parkinson’s Disease PHASE 2B (PADOVA) AND LONGER FOLLOW-UP DATA SUGGEST CLINICAL BENEFIT IN DELAY OF CONFIRMED MOTOR PROGRESSION Phase 2b (PADOVA) 2.5 years results1 • Multiple endpoints from the PADOVA and OLE study suggest potential clinical benefit of prasinezumab; more pro
Slide 14: Roche's Phase 3 Go Decision Based on Meeting the Bar Criteria
Roche’s Phase 3 Go Decision Based on Meeting the Bar Criteria INSIGHTS FROM PHASE 2B (PADOVA) AND OPEN LABEL EXTENSION WILL INFORM ROCHE’S PH 3 TRIAL DESIGN Peak sales potential >$3B (unadjusted) DMT: Disease modifying therapy; OLE: Open label extension; PD: Parkinson’s disease. 14 Slide adapted fro
Slide 15: Coramitug
Coramitug (formerly PRX004) ATTR Amyloidosis with Cardiomyopathy ATTR Business Acquired by Novo Nordisk
Slide 16: Coramitug: Potential First-in-Class Treatment for ATTR-CM
Coramitug (formerly PRX004): Potential First-in-Class Treatment for ATTR-CM Phase 2 Signal Detection Trial (NCT05442047): Coramitug • Trial complete ATTR amyloidosis with • N = 105 ATTR-CM patients, 3 arms cardiomyopathy (ATTR-CM) • Participants received IV infusion Q4W of 10 mg/kg or 60 Status: Pha
Slide 17: Differentiated Mechanism for ATTR-CM
Differentiated Mechanism for ATTR-CM NON-PATHOGENIC PATHWAY PATHOGENIC PATHWAY HEART Protein Misfolding Restrictive cardiomyopathy Heart failure PERIPHERAL NERVES Loss of sensation LIVER FREE MONOMER, SOLUBLE Loss of reflex TETRAMER AGGREGATE Muscle weakness AMYLOID FIBRILS Coramitug: Current Treatm
Slide 18: Designed to Deplete Amyloid
Designed to Deplete Amyloid SUMMARY OF PRECLINICAL EFFECTS OF mPRX004 mPRX004 (murine Inhibits fibril formation form of PRX004) Specifically binds to pathogenic TTR preclinical results:1 Reacts to amyloid deposits in multiple organs in both wtATTR and ATTRv patients Promotes in vivo ATTR amy
Slide 19: Alzheimer's Disease
Alzheimer’s Disease
Slide 20: Our Team has Pioneered Multiple Scientific Advances in Protein Dysregulation
Our Team has Pioneered Multiple Scientific Advances in Protein Dysregulation OUR LEGACY INCLUDES FOUNDATIONAL DISCOVERIES IN THE UNDERSTANDING OF ALZHEIMER’S DISEASE Pioneered fundamental discoveries elucidating the roles of beta amyloid (Aβ), gamma secretase and beta secretase play in disease1 Firs
Slide 21: Our Legacy Drives Our Vision to Transform Alzheimer's Care
Our Legacy Drives Our Vision to Transform the Care of Alzheimer’s Disease With unparalleled protein …We’re uniquely positioned to address Alzheimer’s dysregulation expertise… Disease with a best-in-class portfolio PRX012, anti-Aβ candidate with potential best-in-class, highly potent binding; designe
Slide 22: Targeting Alzheimer's Where it Matters
Targeting Alzheimer’s Where it Matters Aβ has been established as a disease modifying target Aβ plaque Vascular Aβ deposits (fibrils) in Alzheimer’s disease Microglia Reduction of Aβ plaque MTBR-Tau transmission associated with clinically Neurofibrillary meaningful slowing of tangles (NFT) disease p
Slide 23: Today's Clinical Science Validates the Mechanism Designed by Our Team
Today’s Clinical Science Validates the Mechanism Designed by Our Team Mean Difference from Placebo in Reduction of Amyloid Plaque1 and CDR-SB Progression Group Level Mean Difference Disease from Placebo on CDR Slowing of Progression Reduction of amyloid plaque Increase of amyloid plaque Group Level
Slide 24: Targeting Alzheimer's Where it Matters
Targeting Alzheimer’s Where it Matters CHANGING THE TREATMENT PARADIGM THROUGH OUR BIOLOGY-DIRECTED ENGINE Dynamic biomarkers of the Alzheimer’s pathological cascade1 24 1 Jack, Clifford et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade, 2010 NIH Public Access
Slide 25: PRX012
PRX012 Alzheimer’s Disease
Slide 26: PRX012: Leading a Paradigm Shift in Treatment of Alzheimer's Disease
PRX012: Leading a Paradigm Shift in the Treatment of Alzheimer’s Disease 300+ iterative antibody design and optimization campaigns led to… Key Antibody Design Attributes HUMANIZED IgG1 monoclonal antibody with low immunogenicity TARGETS a key epitope at the N-terminus of Aβ protein HIGH AFFINITY AND
Slide 27: Translating Patient Needs Into Antibody Engineering
Translating Patient Needs Into Antibody Engineering PATIENT-CENTRIC DESIGN STRATEGY FOR PRX012 TARGET PROFILE ANTIBODY DESIGN ATTRIBUTES OUR MISSION Maintain From First Effectively clear soluble and • N-terminal directed Generation insoluble aggregated amyloid Improve patient outcomes • Full effecto
Slide 28: PRX012: Promotes Comprehensive Clearance of Amyloid Plaques
PRX012: Promotes Comprehensive Clearance of Amyloid Plaques and Neutralization of Oligomers Designed to target and clear toxic aggregated forms of Aβ Free/ dispersed Aggregated Microglia PRX012 Aβ plaque Aβ Forms PRX012 elicits microglial-mediated phagocytosis Both unmodified Aβ fibrils and Phagocyt
Slide 29: PRX012 and Surrogate Demonstrate Equivalent Potent Binding Affinity for Aβ
PRX012 and Surrogate Demonstrate Equivalent Potent Binding Affinity for Aβ Surface Plasmon Resonance (SPR) Affinity for Aβ Species Aβ Fibrils Compound Fibril/Plaque N3pE-Aβ 60 Slow off-rate (PRX012 & PRX012s) PRX012 0.070a >67b Response (RU) 40 PRX012s 0.054a >67b Fast biphasic off-rate (aducanumab)
Slide 30: PRX012s Binds Aβ Protofibrils With Very High Affinity
PRX012s Binds Aβ Protofibrils With Very High Affinity Surface Plasmon Resonance Antibody Relative Affinity (KD1) Aβ Protofibrils Lecanemab1 1.97 nM (Tucker et al., 2015) Lecanemab2 1.91 nM dissociation Slower PRX012s 0.0975 nM SPR Binding Kinetics Antibody dissociation ka1 (1/Ms) kd1 (1/s) KD1 Lecan
Slide 31: PRX012s Induced Potent and Robust Clearance of Pyroglutamate-modified Aβ
PRX012s Induced Potent and Robust Clearance of Pyroglutamate-modified Aβ PRX012s PRX012s Abeta Aβ Donanemab Donanemab 40 Reduction %%Reduction ofof N3pE N3pE 20 Study Conditions Post-mortem AD brain tissue (same donor used for Tissue all conditions) Treatment PRX012s, donanemab, or IgG1 isotype cont
Slide 32: PRX012s Promotes Simultaneous Microglia-Mediated Phagocytosis of Aβ and N3pE-Aβ
PRX012s Promotes Simultaneous Microglia-Mediated Phagocytosis of Aβ and N3pE-Aβ in Post-mortem Brain Tissue From AD Subjects Microglia (Iba1) Aβ N3pE-Aβ Merge Microglia Aβ N3pE-Aβ Merge hIgG1 PRX012s Microglia (Iba1: green) simultaneously phagocytose Aβ (red) and pyroglutamate-modified Aβ (AβpE3-42:
Slide 33: PRX012 Phase 1 SAD Design
PRX012 Phase 1 SAD Design Healthy Volunteer Cohorts Trial • Age 20 – 45 years Design 70 mg 200 mg • Phase 1, randomized 3:1, double-blind, placebo-controlled, n~8 n~8 single ascending dose trial (3:1) (3:1) • 1 subcutaneous dose of PRX012 or placebo • Evaluate the safety, tolerability, Early Alzheim
Slide 34: PRX012 Phase 1 Multiple Dose Design
PRX012 Phase 1 Multiple Dose Design Trial Overview1 Key Inclusion Dose Escalation: “A” and “B” Cohorts2,3 Dose Expansion Key Objectives Criteria • Evaluate the safety, 45 mg A Cohort (n~32) • Patients with tolerability, and SC 6X Q4W early AD immunogenicity 70 mg A Cohort (n~32) • Effect on brain •
Slide 35: BMS-986446
BMS-986446 (formerly PRX005) Alzheimer’s Disease Global Neuroscience Collaboration with Bristol Myers Squibb
Slide 36: BMS-986446: Potential Best-in-Class anti-Tau antibody for Alzheimer's Disease
BMS-986446: Potential Best-in-Class anti-Tau antibody for Alzheimer’s Disease Phase 2 Trial (NCT06268886): Ongoing BMS-986446 Alzheimer’s disease • Global, double-blind, placebo-controlled Status: Phase 2, completion 2027 • 310 participants with early AD Anti-Tau Mechanism of Action • Randomized, 3
Slide 37: BMS-986446: MTBR-Specific Anti-Tau Antibody
BMS-986446: MTBR-Specific Anti-Tau Antibody BMS-986446, a differentiated tau antibody that targets an optimal tau region within the MTBR • Recent publications strongly suggest that tau appears to spread throughout the brain via synaptically-connected pathways1 • This propagation of pathology is thou
Slide 38: BMS-986446: Superior in Blocking Cellular Internalization of Tau
BMS-986446 (PRX005): Superior in Blocking Cellular Internalization of Tau and Downstream Neurotoxicity Compared to Other Anti-Tau Antibodies Repeats 1 and 2 defined as the strongest inhibitory regions in screening with cellular internalization and neurotoxicity assays mPRX0051 • Panel of Prothena an
Slide 39: (m)PRX005 Treatment Reduces Pathological Tau in Transgenic Mouse Model
(m)PRX005 Treatment Reduces Pathological Tau and Ameliorates Behavioral Deficit in Transgenic Tau Mouse Model All values are mean ± SE (n=15-20) Reduction of tau pathological markers Delay of behavioral deficit *p<0.05 *p<0.05 * * Chronic dosing start * * *p<0.05 • PS19 transgenic mice overexpressin
Slide 40: BMS-986446: TargetTau-1 Phase 2 Trial Design
BMS-986446: TargetTau-1 Phase 2 Trial Design TargetTau-1 Trial Overview (NCT06268886)1 Key Inclusion Criteria Primary Endpoint • Ages 50 – 80 years Placebo • Change from baseline in brain tau deposition as measured • MCI due to AD or by tau PET at 76 weeks mild AD dementia Randomized BMS-986446 Seco
Slide 41: PRX123
PRX123 Alzheimer’s Disease
Slide 42: Vaccine Constructs: Potential Best-in-class Dual Aβ/Tau Vaccine
Vaccine Constructs: Potential Best-in-class Dual Aβ/Tau Vaccine for the Treatment & Prevention of AD PROTHENA IS PIONEERING THE DEVELOPMENT OF DUAL Aβ/TAU VACCINE CANDIDATE PRX123 • Synergistic mechanism designed for increased efficacy over single-target vaccines Cleavage Site Aβ MTBR of tau – Stron
Slide 43: Desirable Attributes of Aβ/Tau Vaccines and Prothena's Design Strategies
Desirable Attributes of Aβ/Tau Vaccines and Prothena’s Design Strategies Design Strategy Desirable Output • Linear peptides, proprietary Optimal antigen presentation RESPONSE cleavable linkers with persistent immune response 1 Antibody levels, balanced • Optimal carriers, immunization Overcomes
Slide 44: Prothena's Dual Aβ/Tau Vaccines Demonstrate Desirable Quantity, Quality and Safety
Prothena’s Dual Aβ/Tau Vaccines Demonstrate Desirable Quantity, Quality and Safety Quantity Quality Safety Unable to induce measurable cytotoxic T-cell activity against Aβ and tau in Non-human primates (ELISpot) Prothena’s Dual Vaccine Positive Control Aβ Tau Epitope, affinity, Aβ clearance, Avo
Slide 45: PRX019
PRX019 Neurodegenerative Diseases Global Neuroscience Collaboration with Bristol Myers Squibb
Slide 46: PRX019: Potential Treatment of Neurodegenerative Diseases
PRX019: Potential Treatment of Neurodegenerative Diseases Phase 1 Trial: Ongoing PRX019 Neurodegenerative diseases • Phase 1 clinical trial being conducted by Prothena Status: Phase 1, completion 2026 • Single ascending dose and multiple ascending dose in healthy adults Global Rights Deal for PRX019