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May 2025 CORPORATE OVERVIEW
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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 a broad pipeline; the continued advancement of our discovery, preclinical, and clinical pipeline, and expected milestones in 2025, 2026, and beyond; our goal to continue building a biology-directed engine targeting protein dysregulation; our potential to advance, initiate, and complete IND enabling studies for our discovery and preclinical programs; the treatment potential, designs, proposed mechanisms of action, and potential administration of PRX012, BMS-986446/PRX005, PRX123, prasinezumab, and coramitug/PRX004; 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 PRX012, BMS-986446, prasinezumab, coramitug, and PRX019; the expected timing of reporting data from clinical trials of PRX012, coramitug, BMS-986446, and PRX019, including multiple data readouts starting in August 2025 and continuing throughout the year from our ongoing Phase 1 clinical trials evaluating PRX012; Roche’s plans to work with health authorities to determine next steps for prasinezumab; and amounts we might receive under our partnerships and collaborations with Roche, BMS, and Novo Nordisk. 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 8, 2025, and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the SEC. This overview is made as of May 23, 2025, 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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ATTRv=hereditary amyloid transthyretin; wtATTR=wild-type ATTR. 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 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. 3 Parkinson’s Foundation. Understanding Parkinson’s. Statistics. Accessed July 17, 2024. https://www.parkinson.org/understanding-parkinsons/statistics. 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) Parkinson’s disease (PD) People worldwide living with early symptomatic AD1 >80 million People worldwide living with presymptomatic AD1 >315 million In annual US healthcare costs by 2050 from AD and other dementias2 $1 trillion People living with PD worldwide3 >10 million Neurodegenerative disease3 Fastest increasing In overall economic burden in the US3 $52 billion 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
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Multiple Clinical Programs Ongoing Three partnered Phase 2 programs One partnered Phase 1 program Wholly-owned 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 -Synuclein (C-terminus) Coramitug (PRX004) ATTR-CM Transthyretin (misTTR) BMS-986446 (PRX005) Alzheimer’s disease Tau (MTBR) PRX012 Alzheimer’s disease Aβ (N-terminus) PRX019 Neurodegeneration Undisclosed Target PRX123 Alzheimer’s disease Aβ + Tau Undisclosed AD in Down syndrome Undisclosed Target Aβ, Abeta; AD, Alzheimer’s disease; mAb, monoclonal antibody. 1 Orphan Drug Designation granted by FDA & EMA; 2 FDA Fast Track designation; 3 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 6 Robust R&D Pipeline VaccinemAb Small MoleculeModalities: PROGRAM/ INDICATION PROTEIN TARGET DISCOVERY PRE-CLINICAL PHASE 1 PHASE 2 PHASE 3 GLOBAL PARTNER3 PASADENA (Phase 2) | PADOVA (Phase 2b) ASCENT (Phase 1) Phase 1 IND cleared Phase 2 Phase 2 Fast Track2 Fast Track2 ODD1
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Alzheimer’s Disease
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1 Games, D., Adams, D., Alessandrini, R. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. 1995 Nature; 2 Schenk, D., Barbour, R., Dunn, W. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. 1999 Nature; 3 Rinne et al, C-BiP PET assessment of change in fibrillar amyloid-b load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending –dose study, 2010, 4 Zago W, Schroeter S, Guido T, et al. Vascular alterations in PDAPP mice after anti-Aβ immunotherapy: Implications for amyloid-related imaging abnormalities. 2013 Alzheimers Dement. 5 PRX012 Induces Microglia-Mediated Clearance of Pyroglutamate-Modified and -Unmodified Aß in Alzheimer’s Disease Brain Tissue presented at AAIC 2021; 6 Binding Characteristics of Surrogate PRX012 Demonstrate Potent Engagement of Toxic Abeta Protofibrils and Robust Clearance of Pyroglutamate-Modified Abeta presented at AD/PD 2023 8 OUR LEGACY INCLUDES FOUNDATIONAL DISCOVERIES IN THE UNDERSTANDING OF ALZHEIMER’S DISEASE Our Team has Pioneered Multiple Scientific Advances in Protein Dysregulation Athena Neurosciences founded 1986 Athena acquired by Elan 1996 Prothena spins-out from Elan with a wholly-owned drug discovery platform 2012 Pioneered fundamental discoveries elucidating the roles of beta amyloid (A), gamma secretase and beta secretase play in disease1 First to show that anti-A immunotherapy prevented and cleared amyloid plaques in the brains of transgenic mice2 First to demonstrate plaque clearance by an n-terminus antibody in brains from AD patients3 Discovered biological cause of ARIA and vascular recovery following anti-A immunotherapy4 Developed PRX012, best-in-class anti-A product candidate, with ~10X greater binding potency to fibrillar A vs. aducanumab5 and ~20X greater binding potency against protofibrils vs. lecanemab6
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1 Games D, et al.1995 Nature; 2 Zago W, et al. 2013 Alzheimers Dement; 3 Schenk D, et al. 1999 Nature; 4 Rinne, et al. 2010 Lancet Neurol; 5 Skov M, et al. Preclinical data available at: https://tinyurl.com/3zzpmbxh; 6 Dolan P. Preclinical data available at: https://tinyurl.com/3kf7pvnd. 9 Our Legacy Drives Our Vision to Transform the Care of Alzheimer’s Disease …We’re uniquely positioned to address Alzheimer’s Disease with a best-in-class portfolio BMS-986446 (PRX005), anti-tau candidate, with potential to reduce pathogenic tau spread6 PRX123, dual Aβ/tau vaccine candidate designed for treatment and prevention With unparalleled protein dysregulation expertise… OUR LEGACY Phase 1 IND cleared Phase 2 1-4 PRX012, anti-Aβ candidate with potential best-in-class, highly potent binding; designed for improved patient access via subcutaneous delivery5
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10 Targeting Alzheimer’s Where it Matters COGNITIVE DECLINE TAU NFT ACCUMULATION • Tau hyperphosphorylation • MTBR - Tau transmission • Intracellular tau aggregation and mislocalization • Neurotoxicity A β PLAQUE ACCUMULATION • Vascular dysregulation • APP upregulation and increased β-secretase activity • Calcium dysregulation • Astrocytosis and microgliosis • Neuritic dystrophy • Synaptic loss • Tau hyperphosphorylation Aβ plaque (fibrils) Microglia Neurofibrillary tangles (NFT) Soluble Aβ (oligomers, Protofibrils) Vascular Aβ deposits MTBR - Tau transmission Neuronal Dysfunction Neurodegeneration Inflammation Aβ has been established as a disease modifying target in Alzheimer’s disease Reduction of Aβ plaque associated with clinically meaningful slowing of disease progression Presence of tau pathology strongly correlates with neurodegeneration and cognitive impairment in Alzheimer’s disease
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2020 US FDA ANALYSIS: Aβ has been established as a disease modifying target in AD 2,3 1 Reduction of Amyloid Plaque as measured by SUVr, Standardized Uptake Value Ratio; CDR, Clinical Dementia Rating Scale. 2 ADUHELM [prescribing information]. Cambridge, Massachusetts: Biogen Inc; October 2022; 3 US FDA. Clinical Pharmacology and Pharmacokinetics Review(s). July 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/ 761178Orig1s000ClinPharm_Redacted.pdf. 11 Today’s Clinical Science Validates the Mechanism Designed by Our Team Group Level Mean Difference from Placebo in Reduction of Amyloid Plaque1 Reduction of amyloid plaque Increase of amyloid plaque Group Level Mean Difference from Placebo on CDR Slowing of Progression Disease Progression Mean Difference from Placebo in Reduction of Amyloid Plaque1 and CDR-SB ADUCANUMAB LECANEMAB BAPINEUZUMAB GANTENERUMAB CRENEZUMAB SOLANEZUMAB
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1 Jack, Clifford et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade, 2010 NIH Public Access 12 CHANGING THE TREATMENT PARADIGM THROUGH OUR BIOLOGY-DIRECTED ENGINE Targeting Alzheimer’s Where it Matters Dynamic biomarkers of the Alzheimer’s pathological cascade1
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PRX012 Alzheimer’s Disease
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14 PRX012: Leading a Paradigm Shift in the Treatment of Alzheimer’s Disease 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 AVIDITY to Aβ for extended binding time and opsonization efficiency SLOW OFF RATE / slow & steady dissociation translates to consistent target exposure and potential safety advantages HIGHLY POTENT BINDING, designed for subcutaneous administration PRX012 …potential best-in-class, subcutaneous, once-monthly anti-Aβ product candidate 300+ iterative antibody design and optimization campaigns led to…
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15 PATIENT-CENTRIC DESIGN STRATEGY FOR PRX012 Translating Patient Needs Into Antibody Engineering Maintain From First Generation Antibodies Innovations to Minimize Disease and Treatment Burden ANTIBODY DESIGN ATTRIBUTESTARGET PROFILE Once-monthly dosing Low-volume subcutaneous (SC) delivery At-home administration • Optimize pharmacokinetic profile and immunogenicity • Optimal bioavailability • Optimal biophysical qualities • N-terminal directed • Full effector-function • High binding potency • Stability in high concentrations for single syringe use Effectively clear soluble and insoluble aggregated amyloid OUR MISSION Minimize treatment burden Improve patient outcomes Enable patients and care partners to take anti-Aβ treatment into their own hands Increase accessibility
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Note: Based on preclinical data. Visuals not to scale. 16 PRX012: Promotes Comprehensive Clearance of Amyloid Plaques and Neutralization of Oligomers PRX012 PRX012 elicits microglial-mediated phagocytosis Aβ plaque Microglia Phagocytized Aβ fibrils Both unmodified Aβ fibrils and pyroglutamate-modified Aβ are phagocytized Designed to target and clear toxic aggregated forms of Aβ InsolubleSoluble Low affinity Free/ dispersed Aggregated Aβ Forms PRX012 Selectivity Microglia recognize and engulf PRX012-opsonized Aβ fibrils High affinity
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0 500 1000 1500 0 20 40 60 Time (s) Response (RU) PRX012 AducanumabPRX012 surrogate N3pE-Aβ, pyroglutamate-modified Aβ; SPR, surface plasmon resonance. PRX012s: “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. Aducanumab was generated from a publicly available sequence. 17 PRX012 and Surrogate Demonstrate Equivalent Potent Binding Affinity for Aβ Compound Fibril/Plaque N3pE-Aβ PRX012 0.070a >67b PRX012s 0.054a >67b Affinity for Aβ Species • Potent binding strength of PRX012 and its surrogate (PRX012s) to fibrillar Aβ are equivalent, both demonstrating a very slow rate of dissociation – PRX012 and PRX012s share >99.5% sequence homology • How does binding to protofibrils compare? Data represent KD values from SPRa (nM) or IC50 from ELISAb (nM). Surface Plasmon Resonance (SPR) Aβ Fibrils Dissociation rate Slow off-rate (PRX012 & PRX012s) Fast biphasic off-rate (aducanumab)
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ka, association constant; kd, dissociation constant; KD, equilibrium constant; SPR, surface plasmon resonance. 1 Tucker S, et al. J Alzheimers Dis. 2015;43:575-588. 2 Determined by Prothena. Lecanemab was generated from a publicly available sequence. 18 PRX012s Binds Aβ Protofibrils With Very High Affinity PRX012s binds to Aβ protofibrils with approximately 20-fold greater affinity than lecanemab when tested under the same conditions Greater affinity is driven largely by a slower binding dissociation Antibody Relative Affinity (KD1) Lecanemab1 (Tucker et al., 2015) 1.97 nM Lecanemab2 1.91 nM PRX012s 0.0975 nM ka1 (1/Ms) kd1 (1/s) KD1 Lecanemab1 (Tucker et al., 2015) 6.60E+05 1.30E-03 1.97E-09 Lecanemab2 1.80E+05 3.42E-04 1.91E-09 PRX012s 1.63E+05 1.59E-05 9.75E-11 SPR Binding Kinetics Antibody dissociation Surface Plasmon Resonance Aβ Protofibrils Slower dissociation SPR protofibril binding was performed as described in Tucker et al., 2015 1
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IgG, immunoglobulin; N3pE-Aβ, pyroglutamate-modified Aβ. Donanemab was generated from a publicly available sequence. 19 PRX012s Induced Potent and Robust Clearance of Pyroglutamate-modified Aβ PRX012s facilitates concentration-dependent clearance of pyroglutamate-modified Aβ (N3pE-Aβ) at concentrations that may be relevant for PRX012 clinical exposure PRX012s clears equivalent or more N3pE-Aβ at ~3–8x lower concentrations than donanemab 0 100 200 300 400 500 0 20 40 [antibody], ng/mL % Reduction of N3pE Abeta Donanemab PRX012s Study Conditions Tissue Post-mortem AD brain tissue (same donor used for all conditions) Treatment PRX012s, donanemab, or IgG1 isotype control Microglia Primary mouse microglia (800,000 cells/mL) Culture time 72 hours at 37°C % Reduction of N3pE Aβ [antibody], ng/mL PRX012s Donanemab
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Aβ, amyloid beta; AD, Alzheimer’s disease; IgG, immunoglobulin; N3pE-Aβ, pyroglutamate-modified Aβ. 20 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 hIgG1 PRX012s Microglia (Iba1: green) simultaneously phagocytose Aβ (red) and pyroglutamate-modified Aβ (AβpE3-42: blue) in the presence of PRX012 surrogate, indicating that opsonization of plaques is sufficient to clear both species. Microglia N3pE-Aβ Aβ Merge Arrows indicate examples of phagocytosed Aβ and N3pE-Aβ that co-localize inside microglia cells (immunostained with anti-Iba1 antibody). PRX012s promoted microglia-mediated phagocytosis of Aβ and pyroglutamate- modified Aβ (N3pE-Aβ) simultaneously
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21 PRX012 Phase 1 SAD Design MMSE: Mini Mental State Examination. • Age 20 – 45 years Healthy Volunteer Cohorts 70 mg n ~ 8 (3:1) 200 mg n ~ 8 (3:1) 70 mg n ~ 8 (3:1) 200 mg n ~ 8 (3:1) 400 mg n ~ 8 (3:1) Trial Design • Phase 1, randomized 3:1, double-blind, placebo-controlled, single ascending dose trial • 1 subcutaneous dose of PRX012 or placebo • Evaluate the safety, tolerability, immunogenicity, and pharmacokinetics of PRX012 in healthy volunteers and patients with Alzheimer’s disease • Ages 60 – 85 years • Amyloid PET positive • MMSE ≥ 18 Early Alzheimer’s Disease Cohorts
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Key Objectives • Evaluate the safety, tolerability, and immunogenicity • Effect on brain amyloid plaque • Incidence of radiographic amyloid-related imaging abnormalities Open-label Extension • Patients may continue into an optional OLE for 12 months, an additional 12 doses (SC 12X Q4W) Trial Overview1 1 Presented at: The 2024 AAIC Annual Meeting; July 28, 2024; Philadelphia, PA. 2 “A” dose cohorts include only APOε4 non-carrier or heterozygous AD patients 3 “B” dose cohorts include only APOε4 homozygous AD patients AD, Alzheimer’s disease; MMSE, Mini-Mental State Examination; PET, positron emission tomography; SC, subcutaneous injection; Q4W, every 4 weeks.22 PRX012 Phase 1 Multiple Dose Design 45 mg A Cohort (n~32) SC 6X Q4W 70 mg A Cohort (n~32) SC 6X Q4W 200 mg A Cohort (n~32) SC 6X Q4W 400 mg A Cohort (n~32) SC 6X Q4W 200 mg Expansion A Cohort (n~99) SC 6X Q4W 45 mg B Cohort (n~12) SC 6X Q4W 70 mg B Cohort (n~12) SC 6X Q4W 200 mg B Cohort (n~12) SC 6X Q4W Randomized 3:1 Active to Placebo (n ~ 263) Dose Escalation: “A” and “B” Cohorts2,3 Dose ExpansionKey Inclusion Criteria • Patients with early AD • Ages 55 – 85 years • Amyloid PET positive • MMSE ≥ 18
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BMS-986446 (formerly PRX005) Alzheimer’s Disease Global Neuroscience Collaboration with Bristol Myers Squibb
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24 BMS-986446: Potential Best-in-Class anti-Tau antibody for Alzheimer’s Disease Phase 2 Trial (NCT06268886): Ongoing • Global, double-blind, placebo-controlled • 475 participants with early AD • Randomized, 3 arms (two doses and placebo) • Primary Endpoint: Mean change from baseline in CDR-SB score at 18 months • Primary completion expected in 2027 Phase 1 Trial: • Phase 1 SAD data in healthy volunteers demonstrated dose-proportional concentrations in plasma with robust CNS penetration • Phase 1 data supportive of Phase 2 • Generally safe and well-tolerated Anti-Tau Mechanism of Action • 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 disease Global Rights Deal for BMS-9864461 • $135 million paid-to-date for global rights • BMS funds all development and commercialization • Up to $563 million in regulatory/sales milestones • Up to high teens royalties on a weighted average basis BMS-986446 Alzheimer’s disease 1 Global Neuroscience Research and Development Collaboration with BMS also included $100 million upfront payment and a $50 mill ion equity investment in Prothena CDR-SB, Clinical Dementia Rating Scale Sum of Boxes Current Status: Phase 2
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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 25 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 thought to be mediated by tau “seeds” containing the MTBR of tau2 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 BMS-986446 Anti-tau mAb BMS-986446: Potential Best-in-Class MTBR-Specific Anti-Tau Antibody to Reduce Pathogenic Tau Spread Tau HSPG LRP1 Microglia
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1 (m)PRX005 = murine form of PRX005 (BMS-986446) 26 BMS-986446 (PRX005): Superior in Blocking Cellular Internalization of Tau and Downstream Neurotoxicity Compared to Other Anti-Tau Antibodies 0 50 100% control Cell Viability (MTT) 50 100 150% control LDH release (m)PRX005 protects rodent primary cortical neurons from tau-induced toxicity (m)PRX005 - + - + - + - + +Tau +Tau * * * p<0.0001 -1 0 1 2 3 0 20 40 60 80 100 [antibody] log nM % tau positive cells PRX005 blocks internalization of tau isotype ctl mPRX005 PRX005 1 10 100 1000 0 25 50 75 antibody concentration (nM) % pHrodo positive cells (m)PRX005 Chimeric Human isotype control Murine isotype control cells only 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 mPRX0051
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(m)PRX005 = murine form of PRX005 (BMS-986446) 27 (m)PRX005 Treatment Reduces Pathological Tau and Ameliorates Behavioral Deficit in Transgenic Tau Mouse Model PBS isotype ctl (m)PRX005 0 1 2 3pTau-199/202 in brainstem (% area) PBS isotype ctl (m)PRX005 0.0 0.5 1.0 pTau-212 in brainstem (% area) Reduction of tau pathological markers * * * * *p<0.05*p<0.05 *p<0.05 3 6 9 9.7 60 80 100 120 Age (months) Latency in Grid-hanging (s) (m)PRX005 PBS isotype ctl 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)
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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)1TargetTau-1 1 Presented at: The 2024 AAIC Annual Meeting; July 28, 2024; Philadelphia, PA. 2 Standard bFluid-based biomarkers include total tau, p181tau, p217tau, A β [1-42], Aβ [1-40], neurofilament light chain, and glial fibrillary acidic protein. 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. 28 BMS-986446: TargetTau-1 Phase 2 Trial Design Placebo BMS-986446 low dose IV Q4W Primary Endpoint • Mean change from baseline in CDR-SB score vs. placebo at 76 weeks Secondary Endpoints • Mean change from baseline in brain tau deposition, iADRS, MMSE, ADAS-Cog14, & ADCS-iADL vs. placebo at 76 weeks Open-label Extension • Patients may continue into an optional OLE for 96 weeks Randomized 4:3:3 N = 475 BMS-986446 high dose IV Q4W Key Assessments • Tau PET imaging • Cognitive assessments • AD biomarkers2 • MRI
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PRX123 Alzheimer’s Disease
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PROTHENA IS PIONEERING THE DEVELOPMENT OF DUAL Aβ/TAU VACCINE CANDIDATE PRX123 Vaccine Constructs: Potential Best-in-class Dual Aβ/Tau Vaccine for the Treatment & Prevention of AD • Synergistic mechanism designed for increased efficacy over single-target vaccines – Strong evidence from preclinical models suggests that Aβ and tau may act synergistically in the development of AD – Prothena’s dual Aβ/tau vaccine program aims to induce optimal (quantity and quality) and balanced immune response to both targets, while avoiding cytotoxic t-cell response • Potential treatment & prevention – Dual vaccine constructs were shown to generate balanced titers to Aβ and tau in non-human primates and Guinea pigs as measured by ELISA – The immune animal sera reacted to Aβ and tau, induced Aβ phagocytosis, and blocked tau interaction with a key mediator of cellular release and cell-to-cell transmission • IND cleared by FDA • Fast Track designation granted by FDA Cleavage Site A MTBR of tau Peptide Dual A/Tau Vaccine (CRM Peptide Conjugate) INJECT MOUSE Antigen Presenting Cell The APC internalizes then processes the immunogen and presents peptides to surface B-cells produce anti-A and anti-Tau antibodies B- cell B- cell Helper T-cells Helper T-cells are activated, multiply, differentiate and release cytokines to help B-cells ACTIVE VACCINATION Microgli a β-amyloid Tau Plaque 30
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Preclinical data presentation titles: Development of a Dual Aβ/Tau Vaccine for the Treatment and Prevention of Alzheimer’s Disease presented at ADPD 2022 31 Desirable Attributes of Aβ/Tau Vaccines and Prothena’s Design Strategies RESPONSE Antibody levels, balanced Aβ/tau, persistency Design Strategy Desirable Output • Linear peptides, proprietary cleavable linkers • Optimal carriers, immunization schedule, adjuvant ✓ Optimal antigen presentation with persistent immune response ✓ Overcomes immunodominance and immunosenescence • Optimal A and tau epitopes • Elements for induction of mature TH response ✓ Antibodies bind the right epitopes on pathogenic proteins ✓ IgG switch and affinity maturation • Short A/tau epitopes not recognizable by cytotoxic T-cells • No off-target binding risk based on peptide sequences ✓ No cytotoxic T-cell responses ✓ Specific antibodies Quantity 1 EFFICACY Isotypes, binding, Aβ clearance, tau neutralizationQuality 2 SAFETY Cytotoxic T-cell avoidance, target-specificitySafety 3
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Preclinical data presentation titles: Development of a Dual Aβ/Tau Vaccine for the Treatment and Prevention of Alzheimer’s Disease presented at ADPD 2022 32 Prothena’s Dual Aβ/Tau Vaccines Demonstrate Desirable Quantity, Quality and Safety Unable to induce measurable cytotoxic T-cell activity against Aβ and tau in Non-human primates (ELISpot) ✓ High, balanced, consistent ✓ Epitope, affinity, Aβ clearance, tau neutralization ✓ Avoids T-cell response observed in other vaccines Quantity Quality Safety Aβ Tau Positive Control Prothena’s Dual Vaccine
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Prasinezumab Parkinson’s Disease Worldwide Collaboration with Roche
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MDS-UPDRS: Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale; RWD: Real World Data; P PMI: Parkinson’s Progression Markers Initiative. 1 Jankovic J et al. JAMA Neurol. 2018; 75:1206–1214; 2 Parkinson’s Foundation. Understanding Parkinson’s. Statistics; 3 GBD 2015 Neurological Disorders Collaborator Group (2017) Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol 16, 877-897. 4 Pagano G et al. Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open -label extension of the PASADENA trial. Nat Med (2024) 34 Prasinezumab: Potential First-in-Class Treatment for Parkinson’s Disease Phase 2 Clinical Development Program: • First anti-a-synuclein antibody to slow progression on measures of PD • Consistent positive trends across multiple endpoints observed in both Phase 2b PADOVA (NCT04777331) and Phase 2 PASADENA (NCT03100149) trials • More pronounced efficacy observed in population treated with levodopa in the Phase 2b PADOVA trial (~75% of participants) Next Steps: • Open-label extension studies from both PADOVA and PASADENA ongoing to explore the observed effects • PASDAENA OLE showed slowing of motor progression vs. matched RWD PPMI cohort4 • Roche will continue to evaluate the data and work together with health authorities to determine next steps Anti--synuclein Antibody • Preferentially binds to aggregated -synuclein, designed to reduce pathogenic spread and decrease synuclein pathology1 Rapidly Growing Parkinson’s Patient Population • 10 million patients globally2 • Fastest increasing neurodegenerative disease3 Worldwide Collaboration with Roche • Up to $620 million in additional milestones • $135 million paid-to-date • Up to double-digit teen royalties • US co-promote option Prasinezumab Parkinson’s Disease Current Status: Phase 2b Complete
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Symptoms: Clinical signs or symptoms attributable to neuronal -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. 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. 35 -Synuclein Pathology is Strongly Implicated in Parkinson’s Disease -Synuclein is the predominant component of Lewy bodies found in Parkinson’s disease and other synucleinopathies Accumulation of -Synuclein is a predominant neuropathological feature and follows the topological progression of disease Genetically validated target with evidence favoring a prominent role for -Synuclein in early PD: missense mutations and duplication/triplication Symptoms Functional impairment Dopaminergic neurodegeneration Neuronal -Synuclein Time Biological or Clinical Measures
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1 Proposed mechanism of action. 36 REDUCE NEURONAL TOXICITY AND PREVENT CELL-TO-CELL TRANSMISSION1 Prasinezumab: -Synuclein Immunotherapy Diseased Neuron Protected Neuron Aggregated extracellular -Synuclein Synaptic loss and pathogenic spread Prasinezumab preferentially binds to aggregated -Synuclein to reduce pathogenic spread and decrease synuclein pathology 1 -Synuclein as an extracellular target during pathogenesis • Caudal-rostral staging, host-to-graft transfer, various propagation models
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PADOVA to focus on evaluation of motor progression as measured by MDS-UPDRS Part III PADOVA study population more advanced than the PASADENA population 1 At least 76 weeks and ≥248 events of confirmed motor progression (≥5 point on MDS -UPDRS Part III) 2 7 patients were randomized in PADOVA with H-Y Stage III. Source: Pagano et al. A study to evaluate the efficacy and safety of intravenous prasinezumab in participants with early Parkinson’s disease (PADOV A): Rationale, design, and baseline data. Presented at the AD/PD 2024 International Conference on Alzheimer’s and Parkinson’s Diseases in Lisbon, Spain. March 5-9, 2024. 37 • N=316, randomized 1:1:1 (1500 mg, 4500 mg, placebo), Q4W IV dosing for 52 weeks (Part 1), followed by a 52-week extension (Part 2) • Study Population: Hoehn & Yahr Stage I or II – H&Y Stage I = 24.7% – H&Y Stage II = 75.3% – Age: 40 – 80 years; mean = 59.9 years – Time from diagnosis: ≤ 2 years; mean = 10.1 months – Concomitant medication: Treatment naïve or stable dose of MAO-B inhibitor and not expected to change within 52 wks Primary Endpoint: • Change from baseline at Week 52 in MDS-UPDRS sum of Parts I + II + III vs. placebo Prasinezumab: Clinical Development Program for Early Parkinson’s Disease • N=586, randomized 1:1 (1500 mg, placebo), Q4W IV dosing for at least 76 weeks and confirmed number of events1 • Study Population: Hoehn & Yahr Stage I or II – H&Y Stage I = 13.8% – H&Y Stage II = 85%2 – Age: Age 50 to 85 years; mean = 64.2 years of age – Time from diagnosis: ≤ 3 years; mean = 18.6 months – Concomitant medication: On a stable dose of levodopa or MAO-B inhibitor for ≥3 months prior to baseline Primary Endpoint: • Time to confirmed motor progression event (≥5 point increase in MDS-UPDRS Part III score from baseline) Phase 2 PASADENA (NCT03100149) Phase 2b PADOVA (NCT04777331)
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38 PRASINEZUMAB IN EARLY PARKINSON’S DISEASE • First anti--synuclein antibody to slow progression on measures of PD ✓ Prasinezumab showed potential clinical effect in the primary endpoint of time to confirmed motor progression with a HR=0.84 [0.69-1.01] and p=0.0657 ✓ The effect of prasinezumab was more pronounced in a pre-specified analysis in the population treated with levodopa (75% of participants), HR=0.79 [0.63-0.99] and nominal p=0.0431 ✓ Pre-specified supplementary covariate-adjusted1 analyses of these endpoints demonstrated nominally significant effects: • Primary endpoint (HR=0.81 [0.67-0.98]; nominal p=0.0334) • Primary endpoint/levodopa subgroup (HR=0.76 [0.61-0.95]; nominal p=0.0175) ✓ Consistent positive trends across multiple secondary and exploratory endpoints were also observed • Prasinezumab generally safe and well-tolerated Phase 2b PADOVA Trial Summary of Results Results support the potential of prasinezumab to slow underlying disease pathophysiology and clinical decline in patients with PD 1 Covariates used for adjustment: Medication at baseline, H&Y stage, DaT-SPECT, Age, Sex, Baseline dependent parameter
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1 Primary Endpoint: Change from baseline at Week 52 in MDS-UPDRS sum of Parts I + II + III vs. placebo; Pagano et al. N Engl J Med 2022;387:421-32. 2 Pagano, G., Taylor, K.I., Anzures Cabrera, J. et al. Nat Med 30, 1096–1103 (2024). 3 Pagano et al. Delayed start analysis of PASADENA: A randomised Phase II study to evaluate the safety and efficacy of prasinezumab in early Parkinson’s disease; Part 2 Week 104 results. Presented at the AD/PD 2022 International Conference on Alzheimer’s and Parkinson’s Diseases in Barcelona, Spain. March 15-20, 2022. 4 Compared prasinezumab population with a propensity score-balanced cohort of real-world data (RWD) Parkinson’s Progression Markers Initiative (PPMI); Source: Pagano et al. PASADENA long-term open-label extension continue to show reduced motor and functional progression in prasinezumab-treated individuals with early-stage Parkinson’s disease compared to a real-world data arm. Presented at the AD/PD 2024 International Conference on Alzheimer’s and Parkinson’s Diseases in Lisbon, Spain. March 5-9, 2024. 39 PRASINEZUMAB IN EARLY PARKINSON’S DISEASE • First anti--synuclein antibody to slow progression on measures of PD ✓ Part 1: 35% less progression vs. placebo at 1 year on MDS-UPDRS Part III1 • Greater slowing of motor progression in subpopulations of individuals with rapidly progressing disease2 ✓ Part 2: Less progression on MDS-UPDRS Part III in early-start vs. delayed-start group at 2 years3 ✓ OLE: 65% less progression vs. matched RWD PPMI cohort at 4 years on MDS-UPDRS Part III (OFF state) with early-start treatment group3 ✓ OLE: 118% less progression vs. matched RWD PPMI cohort at 4 years on MDS-UPDRS Part III (ON state) with early-start treatment group3 • Prasinezumab generally safe and well-tolerated Phase 2 PASADENA Trial Summary of Results Results support the potential of prasinezumab to slow underlying disease pathophysiology and clinical decline in patients with PD
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40 PRASINEZUMAB CONTINUED TO SLOW PROGRESSION OF MOTOR DEFICITS IN EARLY-STAGE PD PASADENA Open-Label Extension 4-year change from baseline on MDS UPDRS Part III OFF score1 1 CI, confidence interval; MDS-UPDRS, Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale; PPMI, Parkinson’s Progression Markers Initiative; RWD, real-world data. Data from ongoing 5 year open-label extension trial with patients receiving 1500 mg dose of Prasinezumab Q4W IV dosing. Source: Pagano G et al. Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open -label extension of the PASADENA trial. Nat Med (2024) PASADENA: Open-Label Extension Compared prasinezumab population with a propensity score-balanced cohort of real-world data (RWD) Parkinson’s Progression Markers Initiative (PPMI) The data suggests that prasinezumab slowed the progression of motor deficits (MDS-UPDRS Part III OFF score) in early-stage Parkinson’s disease
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41 PRASINEZUMAB CONTINUED TO SLOW PROGRESSION OF MOTOR DEFICITS IN EARLY-STAGE PD PASADENA Open-Label Extension 4-year change from baseline on MDS UPDRS Part III ON score1 1 CI, confidence interval; MDS-UPDRS, Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale; PPMI, Parkinson’s Progression Markers Initiative; RWD, real-world data. Data from ongoing 5 year open-label extension trial with patients receiving 1500 mg dose of Prasinezumab Q4W IV dosing. Source: Pagano G et al. Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open -label extension of the PASADENA trial. Nat Med (2024) PASADENA: Open-Label Extension The data suggests that prasinezumab slowed the progression of motor deficits (MDS-UPDRS Part III ON score) in early-stage PD patients when receiving benefit from symptomatic treatment
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Coramitug (formerly PRX004) ATTR Amyloidosis with Cardiomyopathy ATTR Business Acquired by Novo Nordisk
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Phase 2 Signal Detection Trial (NCT05442047): Ongoing • N = ~99 ATTR-CM patients, 3 arms • Participants receive IV infusion Q4W of 10 mg/kg or 60 mg/kg of coramitug or placebo added to SOC until week 52 • Co-primary Endpoints: Change from baseline in 6MWT and in NT-proBNP levels • Trial completion expected in 1H 2025; results expected in 2H 2025 Phase 1 Trial: • All six dose levels of coramitug found to be generally safe and well-tolerated • Positive results on neuropathy and cardiac function • Data supportive of advancing to Phase 2 43 Coramitug (formerly PRX004): Potential First-in-Class Treatment for ATTR-CM Differentiated Depleter Mechanism of Action • Designed to inhibit fibril formation and specifically bind to pathogenic TTR1 • Uniquely designed for patients at high risk of early mortality due to amyloid deposition Worldwide Collaboration with Novo Nordisk • $1.13 billion in potential additional milestones • $100 million paid-to-date Coramitug ATTR amyloidosis with cardiomyopathy (ATTR-CM) 1 Higaki JN et al. Amyloid, 2016; Preclinical studies of mPRX004, the murine form of PRX004. Current Status: Phase 2
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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 Higaki JN et al. Amyloid, 2016; Preclinical studies of mPRX004, the murine form of PRX004 44 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
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1 Higaki JN et al. Amyloid, 2016; Preclinical studies of mPRX004, the murine form of PRX004 2 mPRX004 = murine form of PRX004 (coramitug) 45 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 ✓ Reacts to amyloid deposits in multiple organs in both wtATTR and ATTRv patients ✓ Promotes in vivo ATTR amyloid clearance V122I WT-ATTR Heart V30M Sciatic Nerve GI Tract Clearance of amyloid Inhibition of amyloid formation Specific binding to amyloid 27/1 14G8 0 20 40 60 Phrodo-ATTR+ Phagocytes (%) p<0.001 Percentage of cells with internalized ATTR V30M control mPRX0042
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Upcoming Milestones
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47 Meaningful Clinical Catalysts Ahead Wholly-owned Programs PRX012 Alzheimer’s disease August 2025 to YE25 Multiple data readouts starting August 2025 and continuing throughout the year from PRX012 Phase 1 ASCENT clinical trials PRX123 Alzheimer’s disease portfolio 2025 Update on PRX123 clinical development Partnered Programs Coramitug (PRX004) ATTR-CM 2025 Completion and results of ongoing Phase 2 trial (NCT05442047) Prasinezumab Parkinson’s disease Mid-25 Roche to determine next steps BMS-986446 (PRX005) Alzheimer’s disease 2027 Completion of ongoing Phase 2 trial (NCT06268886) PRX019 Neurodegeneration 2026 Completion of ongoing Phase 1 trial
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APPENDIX: Partnership and Collaboration Details
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BMS Collaboration1: Up to $1.55 Billion + Royalties $365 million earned to date (includes $100 million upfront and $50 million equity purchase) $1.18 billion in additional milestones available ($562.5 million for BMS-986446 and $617.5 million for PRX019) 1 BMS = Bristol Myers Squibb collaboration following its acquisition of Celgene in November 2019; total of up to $1.55 billion, including upfront payment and equity investment, future potential development, regulatory and commercial milestones, plus potential additional U.S. and global product sales royalties 2 Future milestone and royalty payments would be reduced in the case where BMS is successful in developing a modified version of PRX019 that achieves certain specified improved metrics 49 Bristol Myers Squibb Collaboration: Advancing Two Clinical Stage Programs $135 million in option payments received $562.5 million in potential regulatory and commercial milestones Up to high teens royalties on a weighted average basis $80 million option exercised $242.5 million in potential development and regulatory milestones $375 million in potential commercial milestones Up to high teens royalties on a weighted average basis BMS-986446 (PRX005) Status: Phase 2 Ongoing PRX0192 Status: Phase 1 Ongoing BMS leading and funding further development and commercial Prothena conducting ongoing Phase 1 trial
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1 Includes $60 million milestone announced in May 2021 from Roche as earned (received in June 2021) 50 Worldwide Collaboration with Roche $755 millionTotal Milestones ✓ Upfront, P1, P2 and P2b milestones Clinical, regulatory & first sale U.S. sales milestones Ex-U.S. sales milestones • U.S. • U.S. co-promote • Ex-U.S. $135 million1 $290 million $155 million $175 million • Up to double digit teen royalties • Ability to opt-in • Up to double digit teen royalties • Leads clinical development • Will lead commercialization • Sole responsibility to develop and commercialize $-- -- -- -- –