Slides
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prothena CORPORATE OVERVIEW August 2026
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2 This overview contains forward-looking statements. These statements relate to, among other things, the sufficiency of our cash position to fund advancement of our pipeline, and the potential to advance, initiate, and complete preclinical and IND enabling studies for our preclinical portfolio, including our TDP-43 CYTOPE and PRX012-TfR programs, and CYTOPE internal targets; the continued advancement of our pipeline, and expected milestones in 2026, 2027, and beyond, including the expected timing of (i) BMS’ decision to continue developing PRX019 by year-end 2026, (ii) completion of the ongoing Phase 2 clinical trial evaluating moponetug in 2027, (iii) completion of the Phase 3 clinical trial for prasinezumab in 2029, and (iv) completion of the Phase 3 clinical trial for coramitug in 2029; whether potential milestones are achieved and amounts we might receive under our partnerships and collaborations with Roche, BMS, and Novo Nordisk; the treatment potential, designs, proposed mechanisms of action, and potential administration of prasinezumab, coramitug, moponetug, TDP-43 CYTOPE, and PRX012-TfR; potential indications and attributes of epitopes and antibodies we have identified in our programs, including their potential for a best-in-class profile; plans for ongoing and future clinical trials of prasinezumab, coramitug, moponetug, and PRX019; the potential to partner our early-stage programs, including PRX012-TfR; and the potential to return capital to shareholders via a share repurchase program or other permissible means. 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 August 6, 2026, and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the SEC. This overview is made as of August 6, 2026, and we undertake no obligation to update publicly any forward- looking statements contained in this overview as a result of new information, future events, or changes in our expectations. Forward-Looking Statements
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3 Our Mission Today We are Focused on Delivering Life-Saving Therapies… …for unmet medical needs caused by diseases of protein dysregulation
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Parkinson’s disease (PD) People living with PD worldwide1 >10 million Neurodegenerative disease1 Fastest increasing In overall economic burden in the US1 $52 billion ATTRv: Hereditary Amyloid Transthyretin; wtATTR: Wild-type ATTR. 1 Parkinson’s Foundation. Understanding Parkinson’s. Statistics. Accessed July 17, 2024. https://www.parkinson.org/understanding-parkinsons/statistics. 2 Gustavsson, A. et al. “Global estimates on the number of persons across the Alzheimer’s disease continuum.” Alzheimer’s & Dementia (2022) 1-13. 3 Long S, Benoist C, Weidner W. World Alzheimer Report 2023: Reducing dementia risk: never too early, never too late. London, England: Alzheimer’s Disease International. Accessed July 18, 2024. https://www.alzint.org/u/World-Alzheimer-Report-2023.pdf. 4 González-Duarte A, Conceição I, Amass L, Botteman MF, Carter JA, Stewart M. Neurol Ther. 2020;9(1):135-149. 5 González-López E, Gagliardi C, Dominguez F, et al. Eur Heart J. 2017;38(24):1895-1904. 6 Tanskanen M, Peuralinna T, Polvikoski T, et al. Ann Med. 2008;40(3):232-239. 7 Kumar S, Dispenzieri A, Lacy MQ, et al. J Clin Oncol. 2012;30(9):989-995 8 Lane T, Fontana M, Martinez-Naharro A, et al. Circulation. 2019;140(1):16-26. 4 We are Addressing Devastating Proteinopathies Affecting Millions of Patients and Families Worldwide RARE PERIPHERAL AMYLOIDNEURODEGENERATIVE DISEASES Alzheimer’s disease (AD) People worldwide living with early symptomatic AD2 >80 million People worldwide living with presymptomatic AD2 >315 million In annual US healthcare costs by 2050 from AD and other dementias3 $1 trillion Transthyretin amyloidosis (ATTR) Estimated number of patients worldwide with wtATTR or ATTRv4-6 450,000 Median overall survival New York Heart Association class III patients with ATTR cardiomyopathy7,8 2.08 years Prasinezumab Phase 3 Coramitug Phase 3 Moponetug Phase 2 PRX012-TfR Preclinical
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Multiple Active Clinical Programs Two partnered Phase 3 programs One partnered Phase 2 program One partnered Phase 1 program Strong Collaborations Established Bristol Myers Squibb Novo Nordisk1 Roche 5 Our Biology-Directed Engine Propels Prothena’s Progress Across our Broad Pipeline Product candidates with best- in-class potential to slow, stop, prevent protein- opathies Targets proteins with the greatest effect on disease, not limited by a single platform or technology Therapeutics engineered to optimally eliminate pathogenic proteins while preserving normal biology Deep expertise in determining optimal epitopes to be targeted for maximal efficacy Disease- Driven Antibody Engineering Expert Epitope Mapping Greater Patient Impact BIOLOGY- DIRECTED ENGINE Pathophysiology Directed Targeting 1 In July 2021 Novo Nordisk acquired coramitug (formerly PRX004) and broader ATTR amyloidosis program and gained full worldwide rights. Prothena is eligible to receive up to $1.23 billion in total consideration.
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Prasinezumab Parkinson’s disease (mAb) α-Synuclein (C-terminus) Coramitug (PRX004) ATTR-CM (mAb) Transthyretin (misTTR) Moponetug (PRX005) Alzheimer’s disease (mAb) Tau (MTBR) PRX019 Neurodegeneration (mAb) Undisclosed target PRECLINICAL PORTFOLIO TDP-43 CYTOPE ® ALS (mAb-CYTOPE) pTDP-43 PRX012-TfR3 Alzheimer’s disease (mAb-TfR) Aβ (N-terminus) CYTOPE® R&D Collaborations4 Ongoing with industry partners in multiple diseases & modalities Undisclosed targets CYTOPE ® Internal Targets4 Multiple diseases and modalities Undisclosed targets mAb: Monoclonal Antibody; TfR: Transferrin Receptor; misTTR: misfolded transthyretin; ATTR-CM: transthyretin amyloid cardiomyopathy; MTBR: microtubule binding region; ALS: amyotrophic lateral sclerosis 1 Orphan Drug Designation granted by FDA & EMA; 2 FDA Fast Track designation; 3 PRX012 combination with TfR technology; 4 Various applications of CYTOPE® technology. 6 Active Research & Development Pipeline PROGRAM PROTEIN TARGET PRECLINICAL PHASE 1 PHASE 2 PHASE 3 GLOBAL RIGHTS3 Phase 3 PARAISO trial ongoing (NCT07174310) Phase 1 completed Phase 2 TargetTau-1 to complete in 1H 2027 (NCT06268886) Phase 3 CLEOPATTRA trial ongoing (NCT07207811) ODD1 Fast Track2 Fast Track2
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7 2026 Strategic Priorities ADVANCE R&D TO SUPPORT RESEARCH COLLABORATIONS & LICENSING DEALS Partnerships provide an efficient path to explore the potential value of early-stage programs • Investing in preclinical CYTOPE® technology and PRX012-TfR • Multiple research collaborations ongoing with industry partners evaluating our CYTOPE® technology • Exploring additional research collaborations and licensing deals for unpartnered programs CAPTURE VALUE EMBEDDED IN PARTNERSHIPS & OPTIMIZE CAPITAL STRUCTURE All partnered assets originated from Prothena’s R&D engine & drive meaningful long -term value Up to $105 MILLION in clinical milestones by YE 2026 $50 MILLION Phase 3 enrollment milestone achieved for coramitug $55 MILLION potential milestone at time of BMS decision to further develop PRX019 $22.3 MILLION worth of shares repurchased in 1H 2026 under Share Repurchase Program1 1 Prothena may repurchase the shares from time to time in open market transactions, which may be structured to occur in accorda nce with the requirements of Rule 10b-18 of the Securities Exchange Act of 1934, as amended. Prothena may also enter into Rule 10b5-1 plans to facilitate repurchases. The timing, number of shares repurchased, and prices paid for the shares under this program will depend on general business and market conditions as well as corporate and regulatory limitations, prevailing share prices, and other considerations. The Share Repurchase Plan allows for up to $100.0 million in share repurchases and will expire on December 31, 2026, may be suspended or discontinued at any time, and does not obligate the company to acquire any amount of ordinary shares. No amount or any amount of outstanding ordinary shares may be acquired by the expiration of the Share Repurchase Plan, at Prothena’s sole discretion.
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Up to ~$3 BILLION aggregate downstream milestones across partnered programs and SALES ROYALTIES from prasinezumab, moponetug, and PRX019 8 Partner Catalysts 1 PRX019 potential milestone could be achieved at time of decision to further develop PRX019 expected in 2026. 2027 2028+ Coramitug ATTR-CM $50 Million Ph 3 Enrollment Milestone (2026) Prasinezumab Parkinson’s disease Ph 3 Trial Completion (2029) Coramitug ATTR-CM Ph 3 Trial Completion (2029) $50 Million Coramitug Milestone Achieved • $55 Million Potential Milestone Related to Decision to Advance PRX019 by YE 20261 2026 PRX019 Neurodegenerative diseases $55 Million BMS Decision (YE 2026) Moponetug Alzheimer’s disease Ph 2 Trial Completion (1H 2027)
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1 Includes $5 million clinical milestone payment for an indication outside of Parkinson’s Disease. 2 Bristol Myers Squibb owns approximately 2.2% of Prothena’s outstanding shares as of March 2, 2026.9 Prothena Partnerships Expected to Generate Meaningful Value Across Programs $150 million paid to date $1.08 billion remaining in sales milestones $135 million paid to date $620 million remaining in regulatory and sales milestones1 Up to double digit teen royalties US co-promote option Up to $755 Million in Total Milestones + Royalties Prasinezumab Phase 3 Parkinson’s disease Coramitug Phase 3 ATTR-CM Up to $1.23 Billion in Total Milestones Up to $1.55 Billion in Total Milestones + Royalties Across Two Clinical Stage Programs Moponetug Phase 2 Alzheimer’s disease PRX019 Phase 1 Neurodegenerative diseases $135 million paid to date $562.5 million remaining in regulatory and sales milestones Up to high teens royalties on a weighted average basis $80 million paid to date $55 million remaining clinical milestone $562.5 million remaining in regulatory and sales milestones Up to high teens royalties on a weighted average basis Upfront Payment + Equity: $150 million2
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Prasinezumab Parkinson’s Disease Phase 3 Worldwide Collaboration with Roche
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Current Status • Roche advanced prasinezumab into the Phase 3 PARAISO clinical trial in ~900 patients with early PD on stable levodopa therapy (NCT07174310) Upcoming Milestones • Phase 3 trial primary completion expected in 2029 Market Opportunity • >$3.5 billion global peak sales per Roche3 Partnership Economics with Roche $135 million paid to date $620 million remaining in regulatory and sales milestones Up to high teen royalties US co-promote option Clear Addressable Unmet Need • > 10 million Parkinson’s patients globally, fastest growing neurodegenerative disease1 Differentiated Mechanism of Action2 • Potential first-in-class disease-modifying anti-α-synuclein antibody • α-synuclein is a known biological driver of PD progression, as supported by preclinical data and two Phase 2 clinical trials Clinical Support • Two Phase 2 clinical trials and OLEs demonstrate consistent effects on slowing of disease progression • Favorable safety and tolerability profile Combination Therapy • Prasinezumab benefits demonstrated on top of symptomatic treatments (e.g., levodopa/carbidopa) 11 Prasinezumab: Potential First-In-Class Treatment for Parkinson’s Disease Slide adapted from Roche’s Pharma Day 2025 Presentation on September 22, 2025. OLE: Open-label Extension; PD: Parkinson’s Disease. 1 Parkinson’s Foundation. Understanding Parkinson’s. Statistics. Accessed July 17, 2024. 2 Jankovic J et al. JAMA Neurol. 2018; 75:1206–1214. 3 Roche states >3B CHF in their 1/29/2026 FY 2025 Earnings presentation; conversion rate of 1 CHF = 1.28 USD (as of January 31, 2026) equates to ~3.85B USD. Prasinezumab
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Chart adapted from: Simuni, Tanya et al. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol 2024. Symptoms: Clinical signs or symptoms attributable to neuronal α Synuclein disease that can be motor or non-motor (e.g., hyposmia, RBD, cognitive impairment, constipation, dysautonomia, depression, and anxiety); Functional Impairment: Degree of impact on activities of daily living. -12 α-Synuclein Pathology is Strongly Implicated in Parkinson’s Disease α-Synuclein is the predominant component of Lewy bodies found in Parkinson’s disease and other synucleinopathies Accumulation of α-Synuclein is a predominant neuropathological feature and follows the topological progression of disease Genetically validated target with evidence favoring a prominent role for α-Synuclein in early PD: missense mutations and duplication/triplication Symptoms Functional impairment Dopaminergic neurodegeneration Neuronal α-Synuclein Time Biological or Clinical Measures Prasinezumab
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1 Proposed mechanism of action. 13 REDUCE NEURONAL TOXICITY AND PREVENT CELL-TO-CELL TRANSMISSION1 Immunotherapy Designed to Selectively Bind Aggregated α-Synuclein Diseased Neuron Protected Neuron Aggregated extracellular α-Synuclein Synaptic loss and pathogenic spread Prasinezumab preferentially binds to aggregated α-Synuclein to reduce pathogenic spread and decrease synuclein pathology 1 α-Synuclein as an extracellular target during pathogenesis • Caudal-rostral staging, host-to-graft transfer, various propagation models Prasinezumab
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Slide adapted from Roche’s Pharma Day 2025 Presentation on September 22, 2025. OLE: Open-label Extension; PD: Parkinson’s Disease. * Roche states >3B CHF in their 9/22/2025 Pharma Day presentation; conversion rate of 1 CHF = 1.26 USD (as of October 22, 2025) equates to ~3.77B USD.14 MULTIPLE ENDPOINTS FROM PHASE 2 STUDIES (PASADENA & PADOVA) AND OLES SUGGEST POTENTIAL TO DELAY MOTOR PROGRESSION Phase 2 Results Support Moving Prasinezumab into Phase 3 in Parkinson’s Disease Peak sales potential >$3.5B (unadjusted)* Prasinezumab
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15 Phase 2 Results Support Moving Prasinezumab into Phase 3 in Parkinson’s Disease Phase 2b PADOVA Primary Endpoint (L-Dopa Subgroup) Prasinezumab showed a trend towards delaying motor progression on top of effective symptomatic therapy Prasinezumab Slide adapted from Roche’s presentation at AD/PD 2026 in Copenhagen, Denmark March 17 -21, 2026. Participants received prasinezumab 1500 mg or placebo Q4W. *Covariates used for adjustment: H&Y stage (1 vs ≥2), DaT-SPECT putamen ipsilateral, age (<60 vs ≥60), sex (male vs female), BL MDS-UPDRS Part III. The intercurrent events of treatment discontinuation and LEDD increase prior to event are handled with the treatment policy strategy; †For descriptive p urposes, nominal p-values are displayed. BL, baseline; CI, confidence interval; DaT-SPECT, dopamine transporter imaging with single-photon emission computed tomography; H&Y, Hoehn and Yahr; HR, hazard ratio; L-DOPA, levodopa; LEDD, levodopa equivalent daily dose; MDS- UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale; Q4W, every four weeks. • Signal of efficacy more pronounced in pre-specified L-DOPA subgroup (~74% of total study population)
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16 Phase 2 Results Support Moving Prasinezumab into Phase 3 in Parkinson’s Disease Phase 2b PADOVA Primary & Secondary Endpoints Consistent trends in favor of prasinezumab across TTE endpoints with clinical signals extending beyond motor signs Prasinezumab Slide adapted from Roche’s presentation at AD/PD 2026 in Copenhagen, Denmark March 17 -21, 2026. Participants received prasinezumab 1500 mg or placebo Q4W. CGI-C, Clinical Global Impression of Change; CI, confidence interval; HR, hazard ratio; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale; PGI-C, Patient Global Impression of Change; Q4W, every four weeks; TTE, time-to-event.
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17 Phase 2 Results Support Moving Prasinezumab into Phase 3 in Parkinson’s Disease Phase 2b PADOVA Exploratory Endpoints Biomarker evidence suggest impact on underlying disease pathology and potential link to clinical changes Prasinezumab Slide adapted from Roche’s presentation at AD/PD 2026 in Copenhagen, Denmark March 17 -21, 2026. Error bars represent SE; p-values are nominal. *R2 MRI sequence used for imaging. NM, neuromelanin; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale; MRI, magnetic resonance imaging; PD, Parkinson’s disease; r, Pearson correlation; rho, Spearman rank correlation; SE, standard error; SN/PC, substantia nigra pars compacta. • Individuals with slowed decrease of NM-MRI also progressed slower on MDS-UPDRS III • Cross-sectionally, these correlations were not observed • Iron: Prasinezumab treatment was associated with a decrease in substania nigra pars compacta iron (SNpc) and showed significantly reduced iron accumulation in the putamen versus placebo • Structural imaging changes correlated with MDS-UPDRS Part III scores, linking biological impact to clinical motor progression • Neuromelanin (NM): Prasinezumab treatment slowed the loss of NM signal in the SNpc as shown by an increase in NM intensity and volume
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18 Phase 2 Results Support Moving Prasinezumab into Phase 3 in Parkinson’s Disease Prasinezumab Slide adapted from Roche’s presentation at AD/PD 2026 in Copenhagen, Denmark March 17 – 21, 2026. Covariates used for adjustment in MMRM model: medication at baseline (MAO-Bi vs L-DOPA), H&Y stage (1 vs ≥2), DaT-SPECT putamen ipsilateral, age (<60 vs ≥60), sex (male vs female), MDS-UPDRS Part III. BL: Baseline; DaT-SPECT: Dopamine Transporter Imaging with Single-photon Emission Computed Tomography; H&Y: Hoehn & Yahr; L-DOPA: Levodopa; MAO-Bi: Monoamine Oxidase Type B Inhibitor; MDS-UPDRS: Movement Disorder Society- Sponsored Revision of the Unified Parkinson’s Disease Rating Scale; MMRM: Mixed Model for Repeated Measures; OLE: Open -label Extension. Phase 2b PADOVA 6-month OLE (L-DOPA Subgroup) Persistent reduction of motor progression over 2.5 years; mirrors PASADENA results
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19 Prasinezumab Slide adapted from Roche’s presentation at AD/PD 2026 in Copenhagen, Denmark March 17 – 21, 2026. MDS-UPDRS: Movement Disorder Society-Unified Parkinson's Disease Rating Scale; OLE: Open-label Extension; PPMI: Parkinson’s Progression Markers Initiative. • Observed PASADENA outcomes were better than model- predicted progression over time, consistent with a sustained treatment effect • Participants showed ~2 years of ‘time gained’ versus the virtual comparator over 5 years of treatment, suggesting a ~2-year delay in disease progression • A similar effect was observed across both motor and functional domains Phase 2 PASADENA Disease Progression Model PASADENA OLE vs. PPMI-based Virtual Comparator Additional Phase 2 Data Demonstrates Potential for Prasinezumab to Delay Parkinson’s Disease Progression No separation Signal detected
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20 Prasinezumab Key Inclusion Criteria • Early-stage PD on stable L-DOPA monotherapy (excludes MAO-B inhibitors) Primary Endpoint • Time to confirmed motor progression (MDS-UPDRS Part III OFF*) Trial Overview (NCT07174310)PARAISO Phase 3 PARAISO Trial Design Randomized 1:1 N = 900 Placebo Q4W IV infusion Prasinezumab Q4W IV infusion Trial design slide adapted from information available on posting on clinicaltrials.gov. *Practically defined OFF-medication state (≥12 hours since the last dose of L-DOPA). MDS: Movement Disorder Society; OLE: Open-label Extension. Prasinezumab Q4W IV infusion Double-blind treatment Optional OLE 104 weeks minimum treatment duration PARAISO builds on learnings from the PADOVA trial: • Larger sample size ‘n’ of 900 vs. 586 in Phase 2b PADOVA • Longer primary treatment duration of 2 years minimum vs. 18 months in Phase 2b PADOVA • L-DOPA treatment required vs. ~74% on L-DOPA treatment in Phase 2b PADOVA
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Coramitug (formerly PRX004) ATTR Amyloidosis with Cardiomyopathy Phase 3 ATTR Business Acquired by Novo Nordisk
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Current Status • Phase 3 CLEOPATTRA clinical trial ongoing in ~1280 patients with ATTR-CM (NCT07207811); primary completion expected in 2029 • Open-label Phase 1 to evaluate the biodistribution of 89Zr-coramtiug and investigate the effects of coramitug on depleting TTR amyloid deposits in myocardial tissues using PET/CT imaging in ATTR-CM (NCT07448623); primary completion expected in 2027 • Obtained Fast Track Designation from the FDA Market Opportunity • Multi-billion dollar global peak sales potential Partnership Economics with Novo Nordisk $150 million paid to date $1.08 billion remaining in sales milestones 22 Coramitug: Potential Best-in-Class Depleter Treatment for ATTR-CM Coramitug Clear Addressable Unmet Need • 450,000 patients estimated globally with wild-type or hereditary ATTR-CM1-3 Differentiated Mechanism of Action • Potential best-in-class depleter for ATTR-CM • Designed to inhibit fibril formation and specifically deplete pathogenic TTR Clinical Support4-5 • Positive Phase 2 results presented at AHA 2025 • 60 mg/kg reduced NT-proBNP levels from baseline at month 12 and by 48% compared to placebo (p=0.0017) • Favorable safety and tolerability profile Combination Therapy4-5 • Benefits observed in Phase 2 on top of standard of care6 1 González-Duarte A, Conceição I, Amass L, Botteman MF, Carter JA, Stewart M. Neurol Ther. 2020;9(1):135-149. 2 González-López E, Gagliardi C, Dominguez F, et al. Eur Heart J. 2017;38(24):1895-1904. 3 Lane T, Fontana M, Martinez- Naharro A, et al. Circulation. 2019;140(1):16-26. 4 Phase 2 Results Presented During Late-Breaking Session of The American Heart Association Scientific Sessions 2025; November 10, 2025; New Orleans, LA. 5 Phase 2 Results Published in November 10, 2025 Edition of Circulation: https://doi.org/10.1161/CIRCULATIONAHA.125.077304. 6 Standard of care as recommended by their medical health professional; >80% of patients on stabilizers in addition to either coramitug or placebo.
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Protein Misfolding MONOMER, SOLUBLE AGGREGATE AMYLOID FIBRILS LIVER FREE TETRAMER HEART Restrictive cardiomyopathy Heart failure PERIPHERAL NERVES Loss of sensation Loss of reflex Muscle weakness Coramitug: Amyloid depletion Uniquely designed for patients at high risk of early mortality PATHOGENIC PATHWAY Current Treatment Approach: Reduce new protein entering pathogenic pathway NON-PATHOGENIC PATHWAY Preclinical studies of mPRX004, the murine form of PRX004; Higaki JN et al. Amyloid, 2016; Suhr OB et al., Amyloid, 2025. 23 Differentiated Mechanism for ATTR-CM Coramitug: Depleter MoA May Provide a New Treatment Paradigm for Patients at High-risk of Early Mortality Due to Amyloid Deposition Coramitug
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Preclinical studies of mPRX004, the murine form of PRX004; Higaki JN et al. Amyloid, 2016; 1 mPRX004: murine form of PRX004 (coramitug). Suhr OB et al., Amyloid, 2025.24 SUMMARY OF PRECLINICAL EFFECTS OF mPRX004 Designed to Deplete Amyloid mPRX004 (murine form of PRX004) preclinical results:1 Inhibits fibril formation Specifically binds to pathogenic TTR Engages amyloid deposits in multiple organs in both wtATTR and ATTRv patients Promotes in vivo ATTR amyloid clearance Clearance of amyloid Inhibition of amyloid formation Specific binding to amyloid Percentage of cells with internalized ATTR V122I WT-ATTR Heart V30M Sciatic Nerve GI Tract V30M control mPRX0042 Coramitug
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25 Phase 2 Results Support Moving Coramitug into Phase 3 in ATTR-CM • Coramitug 60 mg/kg showed a treatment difference of 13.45 m in 6MWT vs. placebo at 12 months • Coramitug 60 mg/kg was associated with improvements versus placebo across a wide range of echocardiogram parameters suggestive of favorable cardiac remodeling at 12 months • Improved measures include LV and RV systolic function, diastolic function, and estimated pulmonary arterial pressures • Favorable safety and tolerability profile LV: Left Ventricle; NT-proBNP: N-terminal Pro-B-type Natriuretic Peptide; RV: Right Ventricle; TTR: Transthyretin; 6MWT: 6-Minute Walk Test. 1 Phase 2 Results Presented During Late-Breaking Session of The American Heart Association Scientific Sessions 2025; November 10, 2025; New Orleans, LA. 2 Phase 2 Results Published November 10, 2025. Edition of Circulation: https://doi.org/10.1161/CIRCULATIONAHA.125.077304. Coramitug 60 mg/kg reduced NT-proBNP levels from baseline at 12 months and by 48% vs. placebo p=0.0017 Phase 2 Results1-2 105 patients / 3-arms / 12 months Coramitug
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26 Key Inclusion Criteria • 18 years and older • Diagnosis of ATTR-CM1 • Demonstrated cardiac amyloid infiltration • Increased LV wall thickness ≥12 mm • Chronic heart failure (NYHA Class I – IV) requiring ongoing treatment with a loop diuretic Trial Overview (NCT07207811) (NCT07207811)CLEOPATTRA Phase 3 CLEOPATTRA Trial Design Primary Endpoint • Number of occurrences of composite endpoint of CV deaths and recurrent CV events (CV hospitalizations and urgent heart failure visits) from baseline to end of study • Duration: up to ~4 years SOC: everyone in the study will continue receiving their usual heart treatments as recommended by their doctor Randomized 1:1 N = 1280 Placebo + SOC IV infusion Coramitug + SOC IV infusion Trial design slide adapted from information available on posting on clinicaltrials.gov. CV: Cardiovascular; NYHA: New York Heart Association; SOC: Standard of Care (as recommended by their medical health professio nal). 1 ATTR-CM includes wild-type ATTR (ATTRwt) or variant ATTR (ATTRv); target ATTRv resruitment is ~15% of the study population. Coramitug
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Moponetug (formerly BMS-986446/PRX005) Alzheimer’s Disease Phase 2 Global Neuroscience Collaboration with Bristol Myers Squibb
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28 Moponetug: Potential First-In-Class anti-Tau mAb for Alzheimer’s Disease Moponetug Clear Addressable Unmet Need • > 80 million Alzheimer’s patients globally1 Differentiated Mechanism of Action • Potential first-in-class anti-tau antibody • Designed to specifically bind with high affinity to a key epitope within the microtubule binding region (MTBR) of tau, a protein implicated in the causal pathophysiology of Alzheimer’s Clinical Support • Phase 1 MAD data presented at CTAD 2025 • Phase 1 data presented at AD/PD 2026 • Open-label single-dose Phase 1 study to assess a subcutaneous administration conducted in 2025 • Favorable safety and tolerability profile Current Status • Phase 2 TargetTau-1 clinical trial in ~310 patients with early Alzheimer’s disease is fully enrolled (NCT06268886) • Obtained Fast Track Designation from the FDA Upcoming Milestones • Phase 2 trial primary completion expected in 2027 Market Opportunity • Multi-billion dollar global peak sales potential Partnership Economics with BMS2 $135 million paid to date $562.5 million remaining in regulatory and sales milestones Up to high teen royalties on a weighted average basis MAD: Multiple Ascending Dose. 1 Gustavsson, A. et al. “Global estimates on the number of persons across the Alzheimer’s disease continuum.” Alzheimer’s & Dementia (2022) 1-13. 2 Global Neuroscience Research and Development Collaboration with BMS also included $100 million upfront payment and a $50 million equity investment in Prothena.
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Rationale for Targeting Microtubule Binding Region (MTBR) of Tau: • Pathology: MTBR is central to fibril formation, seeding and cell-to-cell transmission of tau pathology1-2 • Biomarkers: MTBR-tau243 highly correlated with tau-PET and disease progression3-4 • Preclinical: MTBR-targeting antibodies have demonstrated blocking of internalization and spread of tau, leading to the reduction of tau pathology5,6 • Clinical: Trials ongoing, early clinical data from MTBR-targeting antibodies has shown positive trends on biomarkers including MTBR-tau243 and tau-PET 7 29 Microtubule Binding Region (MTBR) of Tau N1 N2 Proline-rich domain R1 R2 R3 R4 1 45 104 151 244 275 306 338 371 N-terminus Microtubule-binding domain C-terminus 441 Moponetug N1/N2 = represent the two n-terminal domains; R1-R4 represents the four MTBR domains. 1 Holmes BB, Diamond MI et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. 2013 Proc Natl Acad Sci U S A. 2 Annadurai N, et al. Tau R2 and R3 are essential regions for tau aggregation, seeding and propagation. 2022 Biochimie.3 Horie K, Bateman RJ et al. CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer's disease. 2023 Nat Med. 4 Horie K, Bateman RJ et al. Plasma MTBR-tau243 biomarker identifies tau angle pathology in Alzheimer’s disease. 2025 Nat Med. 5 Roberts M, de Silva R et al. Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease. 2020 Acta Neuropathol Commun. 6 Prothena data on file. 7 Eisai presentation on E2814 at CTAD 2025.
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1 Ahmed, Z., Cooper, J.. et al. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle patholo gy: the pattern of spread is determined by connectivity, not proximity. 2014 Acta Neuropathol; 2 Horie, k., Barthelemy, H., Bateman, R.J. CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer’s disease. 2021 Brain 30 MTBR-Specific Anti-Tau Antibody Moponetug, 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 pathways 1 • This propagation of pathology is thought to be mediated by tau “seeds” containing the MTBR of tau 2 Potential for best-in-class efficacy • Preclinical evaluation of our antibodies in our AD models demonstrated that MTBR-specific antibodies are superior to non-MTBR tau antibodies in blocking tau uptake and neurotoxicity • Demonstrated significant inhibition of cell-to-cell transmission and neuronal internalization in vitro and in vivo and slowed pathological progression in a tau transgenic mouse model Moponetug Anti-tau mAb Moponetug: Potential Best-in-Class MTBR-Specific Anti-Tau Antibody to Reduce Pathogenic Tau Spread Tau HSPG LRP1 Microglia Moponetug
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1 (m)PRX005: murine form of PRX005 (moponetug/BMS-986446). Prothena data on file. 31 Superior in Blocking Cellular Internalization of Tau and Downstream Neurotoxicity Repeats 1 and 2 defined as the strongest inhibitory regions in screening with cellular internalization and neurotoxicity assays • Panel of Prothena antibodies targeted throughout the tau molecule were screened for optimal affinity and epitope • These were tested in vitro for their ability to block internalization and toxicity (m)PRX0051 Moponetug
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(m)PRX005: murine form of PRX005 (moponetug/BMS-986446). Prothena data on file. (m)PRX005 Reduces Pathological Tau and Ameliorates Behavioral Deficit in Transgenic Tau Mouse Model Reduction of tau pathological markers * * * * *p<0.05*p<0.05 *p<0.05 Delay of behavioral deficit Chronic dosing start • PS19 transgenic mice overexpressing tau mutation (P301S) cause high levels of neuronal tau pathology and resultant behavioral deficits • Initiation of treatment (weekly i.p.) at the onset of pathological development (treatment mode) with (m)PRX005 delays brainstem tau pathology and consequent behavioral deficits All values are mean ± SE (n=15-20) 32 Moponetug
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Key Inclusion Criteria • Ages 50 – 80 years • MCI due to AD or mild AD dementia • Objective episodic memory impairment • MMSE score 22–30 • AD pathology confirmed by plasma biomarkers and positive tau PET imaging Trial Overview (NCT06268886)TargetTau-1 33 Phase 2 TargetTau-1 Trial Design Primary Endpoint • Change from baseline in brain tau deposition as measured by tau-PET at 76 weeks Secondary Endpoints • Change from baseline in CDR-SB, iADRS, ADASCog14, ADCS-iADL, and MMSE score vs. placebo at 76 weeks Open-label Extension • Patients may continue into an optional OLE for 96 weeks Randomized 4:3:3 N = 310 Placebo Moponetug low dose IV Q4W Moponetug high dose IV Q4W Key Assessments • Tau PET imaging • Cognitive assessments • AD biomarkers1 • MRI Trial design slide adapted from presentation at The 2024 AAIC Annual Meeting (July 28, 2024) and clinicaltrials.gov. AD: Alzheimer’s Disease; ADAS-Cog14: 14-item Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-iADL: Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living Scale; CDR-SB: Clinical Dementia Rating Scale Sum of Boxes; iADRS: Integrated Alzheimer’s Disease Rating Scale; IV: Intravenous; MMSE: Mini-Mental State Examination; MRI: Magnetic resonance imaging; OLE: Open-label Extension; PET: Positron Emission Tomography; Q4W: Every 4 weeks. 1 Standard Fluid-based biomarkers include total tau, p181tau, p217tau, A β [1-42], Aβ [1-40], neurofilament light chain, & glial fibrillary acidic protein. Moponetug
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PRX019 Neurodegenerative Diseases Phase 1 Global Neuroscience Collaboration with Bristol Myers Squibb
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35 PRX019: Potential Treatment of Neurodegenerative Diseases PRX019 Current Status • Phase 1 clinical trial conducted by Prothena is complete (NCT06699680) • Single ascending dose and multiple ascending dose in healthy adults • Phase 1 trial to evaluate: • Safety • Tolerability • Immunogenicity • Pharmacokinetics • Pharmacodynamics Upcoming Milestones • Eligible for $55 million potential milestone at time of BMS decision to further develop PRX019 expected by YE 2026 Partnership Economics with BMS1 $80 million paid to date $55 million remaining clinical milestone $562.5 million remaining in regulatory and sales milestones Up to high teen royalties on a weighted average basis 1 Global Neuroscience Research and Development Collaboration with BMS also included $100 million upfront payment and a $50 million equity investment in Prothena.
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TDP-43 CYTOPE® ALS Preclinical Unpartnered Program
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37 CYTOPE®: A Breakthrough in Intracellular Therapeutics CYTOPE® is an innovative intracellular drug targeting technology designed at Prothena to reach virtually any cell-type, enable precise targeting of intracellular disease pathways, and to unlock therapeutic access to targets where conventional modalities fall short Fab: Fragment antigen-binding region. 1 Poster presentation at Society for Neuroscience (SfN) November 2025 titled: Treatment with a Cell-Internalizing CYTOPE ® Targeting pTDP-43 Reduces Intraneuronal Pathology in a Mouse Model of ALS . Proprietary Cell Internalizing Technology • Demonstrated to efficiently target intracellular disease pathways in multiple cell-types & tissues, to cross the blood-brain-barrier, and to achieve activity in brain & periphery with infrequent, systemic administration1 • Utilizes endosomal escape mechanism for cytosolic delivery while preserving membrane and vesicle integrity (non-endolytic) designed for safety & performance CYTOPE Elements + Compatibility with Add-on Elements • Compatible with add-on elements such as a receptor-mediated technology to enable delivery to specific cells / tissues CYTOPE® +/- Macromolecule (e.g., mAb) Receptor binding Fab fragment Delivery Element Targeting Element Optional Elements
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38 pTDP-43 is a Core Driver of ALS Pathogenesis that is an Undruggable Target with Current Modalities • ~97% of ALS cases show TDP-43 nuclear-to-cytoplasmic mislocalization where it forms toxic aggregates • pTDP-43 aggregates trigger both toxic gain-of- function and loss-of-function consequences Antibodies cannot reach pTDP-43 aggregates are cytosolic Small Molecules cannot bind pTDP-43 aggregates lack specific binding pockets ASOs/siRNAs lack specificity Targeting only pTDP-43 without wildtype knockdown is not feasible (post-translational modification) Loss-of-FunctionToxic Gain-of-Function Graphic modified from Tamaki et al. Int. J. Mol. Sci. 2022. Toxic pTDP-43 aggregation in cytoplasm leads to neuron death Loss of normal nuclear TDP-43 leads to aberrant RNA splicing pTDP-43: Hallmark of ALS Pathology Challenges in Targeting pTDP-43 • Delivery: Intracellular target expressed broadly in CNS & periphery • Specificity: Targeting pTDP-43 is critical; broad TDP-43 KD disrupts global RNA processing, leading to cell death CYTOPE® KD: Knockdown. Ling et al. Neuron. 2013; Tamaki et al. Int. J. Mol. Sci. 2022. Autophagy Proteasome Proteolysis dysfunction -Impaired UPS -Impaired autophagy ER stress Oxidative stress Inflammation Axonal transport impairment Mitochondrial dysfunction -Mitochondrial localization of TDP-43 -TDP-43 acetylation -Impaired stress granule dynamics -Liquid-liquid phase separation Aggregation -Oligomerization -Hyperphosphorylation -Ubiquitination -C-terminal fragmentation Cytoplasmic mislocalization Prion-like propagation Nucleocytoplasmic transport dysfunction Nuclear depletion Mutation Dysregulation of RNA metabolism
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39 TDP-43 CYTOPE® is Designed to Address Toxic Gain-of-Function and Loss-of-Function Pathology Graphic modified from Tamaki et al. Int. J. Mol. Sci. 2022. CYTOPE® Toxic Gain-of-Function Loss-of-Function Specifically degrades pTDP-43 aggregates in the cytoplasm, addressing toxic gain-of-function pathology 1 Restores normal TDP-43 activity in the nucleus, addressing loss-of-function 2 TDP-43 CYTOPE® TDP-43 CYTOPE was designed to specifically bind to and degrade intracellular pTDP-43 aggregates that are central to ALS pathology TDP-43 CYTOPE
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40 TDP-43 CYTOPE® Preclinical Data Demonstrates Potential of CYTOPE Technology TDP-43 CYTOPE® significantly reduced brain & muscle pathology in a severe ALS mouse model after systemic administration • These findings are particularly compelling given rapid, persistent, and aggressive accumulation of pathogenic aggregates in the rNLS8 transgenic mouse model of ALS Addresses Toxic Gain-of-Function: Significantly Reduced pTDP-43 Aggregates Motor Cortex Skeletal Muscle Human Neuronal Cells rNLS8 Mice (Left) % Total pTDP-43 staining in motor cortex of rNLS8 nice after 4 weekly IV doses of TDP -43 CYTOPE. *p<0.05. (Right) % Untreated pTDP-43 staining in skeletal muscle of rNLS8 mice 72 hours post treatment with a single IV dose of TDP-43 CYTOPE; sample size (n) did not support statistical analysis. (Left) SH-SY5Y cells transfected with mutant TDP-43 to induce cytoplasmic aggregates for 24h; cells treated with indicated antibodies for an additional 24h. **UNC13A levels were undetectable in transfected and TDP -43 treated samples; values normalized to transfected samples. (Right) 4-week treatment of rNLS8 mice with TDP-43 CYTOPE. *p<0.05. TDP-43 CYTOPE attenuated RNA mis-splicing caused by cytoplasmic pTDP-43 aggregates in human neurons & mice • Species-specific splicing necessitates analysis in both human cells & mice; rNLS8 mice do not replicate human ALS splicing defects, but they do express dysregulated transcriptomics due to pTDP-43 pathology (↑Csn2a; ↓Rpl15 mRNA)1,2 Addresses Loss-of-Function: Attenuated ALS-Related Splicing Defects 1 2 CYTOPE® Poster presentation at Society for Neuroscience (SfN) November 2025 titled: Treatment with a Cell-Internalizing CYTOPE ® Targeting pTDP-43 Reduces Intraneuronal Pathology in a Mouse Model of ALS . 1 Eck et al., 2025; 2 Riemenschneider et al., 2023.
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PRX012-TfR Alzheimer’s Disease Preclinical Unpartnered Program
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Rationale for Transferrin Receptor Technology: • The addition of transferrin targeting to gantenerumab has been demonstrated to: • Significantly decrease the time required to achieve meaningful amyloid reduction • Substantially lower risk of ARIA-E associated with amyloid-targeting antibodies Potential of TfR for PRX012 42 Gantenerumab1 Phase 3 GRADUATE I and II Trontinemab2,3 Phase 1b/2 Dose level (monthly) ~15mg/kg4 3.6 mg/kg Subjects amyloid negative (<24 CL) ~27-28% ~91% Timepoint 116 weeks 28 weeks ARIA-E incidence 24.9% <5% Roche effectively improved the profile of its anti-Aβ mAb with its TfR-1 technology: PRX012-TfR ARIA: Amyloid-Related Imaging Abnormalities; CL: Centiloid; PET: Positron Emission Tomography. 1 Bateman RJ et al. Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease. 2023 NEJM. M 2 Roche 2025 Pharma Day presentation: https://www.roche.com/investors/events/roche-pharma-day-2025. 3 Trontinemab administered intravenously every four weeks: Kulic L et al., AAIC 2025. 4 During the double-blind treatment period, the gantenerumab dose was increased over a period of 36 weeks to a target level of 510 mg every 2 weeks, 1020 mg every 4 weeks or roughly 15mg/kg per month.
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PRX012-TfR PRX012-TfR for Alzheimer’s Disease 43 PRX012 Antibody Profile • Phase 1 ASCENT top-line results1 support once- monthly, subcutaneous PRX012 with dose- and time-dependent reductions in amyloid plaque • At the 400 mg dose level, PRX012 demonstrated a mean reduction in amyloid PET to: • 27.5 mean centiloids (CL) at month 12 • 16.0 mean CL at month 18 • 9 of 12 participants reached amyloid negativity (<24.1 CL) within 18 months • ARIA-E rates were non-competitive relative to FDA approved anti-Aβ antibodies PRX012-TfR Antibody • PRX012-TfR may lower the risk of ARIA, lower dose level of PRX012, and more rapidly reduce amyloid plaque with a once- monthly subcutaneous administration • Initial preclinical studies demonstrated 2: • Substantially increased brain exposure • Facilitated rapid targeting of Aβ plaques • Additional preclinical studies ongoing to further elucidate the potential of PRX012-TfR Prothena is exploring partnership interest in the program ARIA: Amyloid-Related Imaging Abnormalities; CL: Centiloid; PET: Positron Emission Tomography. 1 Prothena data on file. Preliminary top-line results reported above. 12 and 18 months mean CL top-line data includes only participants who were randomized to PRX012 in ASCENT-2 and rolled over to ASCENT-3 (OLE) as those participants had the opportunity to reach month 12 and only those participants had the opportunity to reach month 18 dosing. 2 Prothena data on file for surrogate Aβ-transferrin receptor antibody in an APP/PS1 transgenic mouse model.