Prothena : Corporate Overview

CORPORATE OVERVIEW

May 2026

We are Focused on Delivering Life-Saving Therapies…

…for unmet medical needs caused by

diseases of protein dysregulation

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Our Mission Today

Parkinson's disease (PD)

Alzheimer's disease (AD)

Transthyretin amyloidosis (ATTR)

>10 million

People living with PD worldwide1

Fastest increasing

Neurodegenerative disease1

$52 billion

In overall economic burden in the US1

>80 million

People worldwide living with early symptomatic AD2

>315 million

People worldwide living with presymptomatic AD2

$1 trillion

In annual US healthcare costs by 2050 from AD and other dementias3

450,000

Estimated number of patients worldwide with wtATTR or ATTRv4-6

2.08 years

Median overall survival New York Heart Association class III patients with ATTR cardiomyopathy7,8

Prasinezumab Phase 3

BMS-986446

Phase 2

PRX012-TfR

Preclinical

Coramitug Phase 3

ATTRv: Hereditary Amyloid Transthyretin; wtATTR: Wild-type ATTR.

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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.

We are Addressing Devastating Proteinopathies Affecting Millions of Patients and Families Worldwide

NEURODEGENERATIVE DISEASES

RARE PERIPHERAL AMYLOID

Our Biology-Directed Engine Propels Prothena's Progress Across our Broad Pipeline

Therapeutics engineered to optimally eliminate pathogenic proteins while preserving normal biology

Deep expertise in determining optimal epitopes to be targeted for maximal efficacy

Expert Epitope Mapping

Disease-Driven Antibody Engineering

BIOLOGY-DIRECTED ENGINE

Greater Patient Impact

Product candidates with best-in-class potential to slow, stop, prevent proteinopathies

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

Pathophysiology

Directed Targeting

Roche

Targets proteins with the greatest effect on disease, not limited by a single platform or technology

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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PROGRAM INDICATION (MODALITY)	PROTEIN TARGET	DISCOVERY	PRE-CLINICAL	PHASE 1	PHASE 2	PHASE 3	GLOBAL RIGHTS
Prasinezumab Parkinson's disease (mAb)	α-Synuclein (C-terminus)	Phase 3 PARAISO trial ongoing (NCT07174310)
Coramitug (PRX004) ODD1 Fast ATTR-CM Track2 (mAb)	Transthyretin (misTTR)	Phase 3 CLEOPATTRA trial ongoing (NCT07207811)
BMS-986446 (PRX005) Alzheimer's disease Fast Track2 (mAb)	Tau (MTBR)	Phase 2 TargetTau-1 to complete in 1H 2027 (NCT06268886)
PRX019 Neurodegeneration (mAb)	Undisclosed Target	Phase 1 completed
WHOLLY OWNED PRECLINICAL PROGRAMS
TDP-43 CYTOPE® ALS (mAb-CYTOPE®)	pTDP-43
PRX012-TfR3 Alzheimer's disease (mAb-TfR)	Aβ (N-terminus)

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mAb: Monoclonal Antibody; TfR: Transferrin Receptor; misTTR: misfolded transthyretin.

1 Orphan Drug Designation granted by FDA & EMA; 2 FDA Fast Track designation. 3 PRX012 has completed Phase 1b ASCENT program; PRX012 combination with transferrin receptor technology (PRX012-TfR) is in preclinical development.

Active Development Pipeline

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

• Up to $100 MILLION Share Repurchase Plan for 20261

  
  
  

  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

• Exploring research collaborations and licensing deals for unpartnered programs

• Expanded scientific visibility with additional upcoming congress presentations from preclinical portfolio

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1 Prothena may repurchase the shares from time to time in open market transactions, which may be structured to occur in accordance 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 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.

2026 Strategic Priorities

CAPTURE VALUE EMBEDDED IN PARTNERSHIPS & OPTIMIZE CAPITAL STRUCTURE

Coramitug

ATTR-CM

$50 Million Ph 3 Enrollment Milestone (2026)

PRX019

Neurodegenerative diseases

$55 Million BMS Decision (2026)

BMS-986446

Alzheimer's disease

Ph 2 Trial Completion (2027)

Prasinezumab

Parkinson's disease

Ph 3 Trial Completion (2029)

Coramitug

ATTR-CM

Ph 3 Trial Completion (2029)

Up to ~$3 BILLION aggregate downstream milestones across partnered programs and SALES ROYALTIES from prasinezumab, BMS-986446, and PRX019

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1 PRX019 potential milestone could be achieved at time of decision to further develop PRX019 expected in 2026.

Partner Catalysts

• $50 Million Coramitug Milestone Achieved

• $55 Million Potential Milestone Related to Decision to Advance PRX019 by YE 20261

2026

2027

2028+

Up to $755 Million in Total Milestones + Royalties

Up to $1.23 Billion in Total Milestones

Prasinezumab Phase 3 Parkinson's disease

Coramitug Phase 3 ATTR-CM

PRX019

Phase 1

Neurodegenerative diseases

• $135 million paid to date

• $620 million remaining in regulatory and sales milestones1

• Up to double digit teen royalties

• US co-promote option

• $150 million paid to date

  
  
  
  
  

• $1.08 billion remaining in sales milestones

  • $80 million paid to date

    
    
    

  • $617.5 million remaining in clinical, regulatory,

    and sales milestones

  • Up to high teens royalties on a weighted average basis

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BMS-986446

Phase 2

Alzheimer's disease

• $135 million paid to date

• $562.5 million remaining in regulatory and sales milestones

• Up to high teens royalties on a weighted average basis

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.

Prothena Partnerships Expected to Generate Meaningful Value Across Programs

Up to $1.55 Billion in Total Milestones + Royalties Across Two Clinical Stage Programs

• Upfront Payment + Equity: $150 million2

Prasinezumab

Parkinson's Disease Phase 3

Worldwide Collaboration with Roche

Prasinezumab

Prasinezumab: Potential First-In-Class Treatment for Parkinson's Disease

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)

  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

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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.

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

α-Synuclein Pathology is Strongly Implicated in Parkinson's Disease

Accumulation of α-Synuclein is a predominant neuropathological feature and follows the topological progression of disease

Neuronal α-Synuclein Dopaminergic neurodegeneration

Symptoms

Biological or Clinical Measures

Functional impairment

Genetically validated target with evidence favoring a prominent role for

α-Synuclein in early PD: missense mutations and duplication/triplication

Time

α-Synuclein is the predominant component of Lewy bodies found in Parkinson's disease and other synucleinopathies

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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.

Diseased Neuron

Protected Neuron

Aggregated extracellular α-Synuclein

Prasinezumab

preferentially binds to aggregated

α-Synuclein to reduce pathogenic spread and decrease synuclein pathology1

Prasinezumab

Immunotherapy Designed to Selectively Bind Aggregated α-Synuclein

REDUCE NEURONAL TOXICITY AND PREVENT CELL-TO-CELL TRANSMISSION1

α-Synuclein as an extracellular target during pathogenesis

Synaptic loss and pathogenic spread

• Caudal-rostral staging, host-to-graft transfer, various propagation models

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  1 Proposed mechanism of action.

  
  
  

  Peak sales potential >$3.5B (unadjusted)*

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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.

  Prasinezumab

  Phase 2 Results Support Moving into Phase 3 in Parkinson's Disease

  MULTIPLE ENDPOINTS FROM PHASE 2 STUDIES (PASADENA & PADOVA) AND OLE SUGGEST POTENTIAL TO DELAY MOTOR PROGRESSION

  
  
  

  ~40% relative reduction in progression at week 104 vs. placebo p=0.01771

• More pronounced effect in L-DOPA treated patients (~75% of population)

• Results consistent across both PADOVA and PASADENA Phase 2 trials and OLEs

• Phase 3 trial design incorporates:

  • Larger sample size 'n' (~900)

  • Longer duration (2 years)

  • L-DOPA population

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Slide adapted from Roche's presentation at AD/PD 2025 in Vienna, Austria April 1-5, 2025.

MDS-UPDRS: Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale; OFF: Practically defined OFF state; OLE: Open-label Extension.

1 For descriptive purposes, nominal p-values are displayed for 2-year, double-blind data for L-DOPA-treated population.

Prasinezumab

Phase 2 Results Support Moving into Phase 3 in Parkinson's Disease

Phase 2b PADOVA 2 Year Results

L-DOPA-treated population

Prasinezumab

Phase 3 PARAISO Trial Design

PARAISO

Trial Overview (NCT07174310)

Key Inclusion Criteria

• Ages 50 - 85 years

• Diagnosis of idiopathic Parkinson's disease based on MDS criteria

• Hoehn & Yahr Stage I or II

• On stable symptomatic monotherapy with levodopa

Randomized 1:1

N = 900

Primary Endpoint

Prasinezumab

IV infusion

• Time to Confirmed Motor Progression Event on Movement Disorder Society -Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III Score

  Placebo

  IV infusion

• Duration: at least 104 weeks (~2 years)

  Open-label Extension

• Patients may continue into an optional OLE

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  Trial design slide adapted from information available on posting on clinicaltrials.gov. MDS: Movement Disorder Society; OLE: Open-label Extension.

  
  
  

• 6-month PADOVA OLE data shows persistent reduction of motor progression

• Consistently stronger signal in L-DOPA subgroup over 2.5 years, mirroring PASADENA results

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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.

Prasinezumab

Additional Phase 2 Data Demonstrates Potential to Delay Parkinson's Progression

Phase 2b PADOVA 2.5 Year Results (6-month OLE)

L-DOPA-treated population

p=0.0025

p=0.1903

Iron (N=202)

Neuromelanin (N=194)

• PADOVA biomarker data suggests prasinezumab is biologically active and slows neurodegenerative processes in early PD

  • 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

    p=0.079

    p=0.1566

    
    
    

  • Neuromelanin (NM): Prasinezumab treatment slowed the loss of NM signal in the SNpc as shown by an increase in NM intensity and volume

• Structural imaging changes correlated with MDS-UPDRS Part III scores, linking biological impact to clinical motor progression

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Slide adapted from Roche's poster presentation at AD/PD 2026 in Copenhagen, Denmark March 17 - 21, 2026. MDS-UPDRS: Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

Prasinezumab

Additional Phase 2 Data Demonstrates Potential to Delay Parkinson's Progression

Phase 2b PADOVA 1.5 Year Biomarker MRI Results

No separation Signal detected

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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

Prasinezumab

Additional Phase 2 Data Demonstrates Potential to Delay Parkinson's Progression

Phase 2 PASADENA Disease Progression Model

PASADENA OLE vs. PPMI-based Virtual Comparator

Coramitug (formerly PRX004) ATTR Amyloidosis with Cardiomyopathy Phase 3

ATTR Business Acquired by Novo Nordisk