Prothena : Corporate Overview

CORPORATE OVERVIEW

May 2024

Forward-Looking Statements

This overview contains forward-looking statements. These statements relate to, among other things, the sufficiency of our cash position to fund advancement of a broad pipeline; the continued advancement of our discovery, preclinical, and clinical pipeline, and expected milestones in 2024, 2025, 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, birtamimab, NNC6019/PRX004, and prasinezumab; potential indications (including prevalence) and attributes of epitopes and antibodies we have identified in our programs; plans for ongoing and future clinical trials of PRX012, BMS-986446/PRX005, PRX123, birtamimab, NNC6019/PRX004, and prasinezumab; the expected timing of reporting data from clinical trials of birtamimab, PRX012, prasinezumab, and NNC6019, including any updates regarding our ongoing Phase 1 clinical trial evaluating PRX012 in 2024 and any topline study results for our Phase 3 AFFIRM-AL clinical trial between 4Q 2024 and 2Q 2025; 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, 2024, and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the SEC. This overview is made as of May 8, 2024, and we undertake no obligation to update publicly any forward-looking statements contained in this press release as a result of new information, future events, or changes in our expectations.

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

NEURODEGENERATIVE DISEASES

RARE PERIPHERAL AMYLOID DISEASES

Alzheimer's

disease (AD)

55 million

People worldwide living with Alzheimer's disease or other dementias1

7th

Leading cause of death in United States6

$1 trillion

In annual US healthcare costs by 2050 from AD and other dementias8

Parkinson's

disease (PD)

10 million

People living with PD worldwide2

Fastest increasing

Neurodegenerative disease7

$52 billion

In overall economic burden in the US9

Amyloid light chain amyloidosis (AL)

60,000-120,000

Patients with Mayo Stage IV AL amyloidosis globally3

5.8 months

Median overall survival in Mayo Stage IV patients with AL amyloidosis4

Transthyretin amyloidosis (ATTR)

450,000

Estimated number of patients worldwide with wtATTR or ATTRv5

2.08 years

Median overall survival New York Heart Association class

1. patients with ATTR cardiomyopathy10

	wtATTR: Wild-Type ATTR. ATTRv: Hereditary amyloid transthyretin.
	1	Alzheimer's Disease International. Dementia Statistics, 2 Parkinson's Foundation. Understanding Parkinson's. Statistics, 3 Kumar N, et al. 2022 Orphanet J Rare Dis; Quock T, et al. 2018 Blood Advances, 4 Levin M, et al. Available at:
	https://www.myamyloidosisteam.com/resources/stages-of-amyloidosis; Kumar S, et al. 2012 J Clin Oncol., 5 Gonzalez-Lopez et al, 2017; Mauer et al, 2016; Gagliardi et al, 2018, 6 2021 Alzheimer's Disease Fact Sheet, National Institute on Aging, NIH,
4	7	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,
	8	Alzheimer's Association Facts and Figures Report 2022, 9 The Economic Burden of Parkinson's Disease - The Michael J. Fox Foundation, 10 Kumar et al 2012, Pinney J et al. 2013; Gonzalez-Lopez E et al. 2017.

Our Biology-Directed Engine Propels Prothena's

Progress Across our Broad Pipeline

Therapeutics engineered to

optimally eliminate pathogenic

proteins while preserving

normal biology

		Disease-
		Driven
		Antibody
		Engineering
Deep
expertise in	Expert	BIOLOGY-	Greater
determining
optimal	Epitope	DIRECTED	Patient
epitopes to	Mapping	ENGINE	Impact
be targeted

for maximal

efficacy

Pathophysiology

Directed

Targeting

Product

candidates with best- in-class potential to slow, stop, prevent protein- opathies

Multiple Clinical Programs Ongoing

Wholly-owned Phase 3 program

Three partnered Phase 2 programs

Wholly-owned Phase 1 program

Two new INDs cleared by FDA

Strong Collaborations Established

Collaborations with Bristol Myers Squibb,

Novo Nordisk1 and Roche

Leveraging our Phase 3 Rare Peripheral Amyloid Disease Program to Support Commercial Buildout

Transition into a fully-integrated commercial biotech through our lead rare disease program

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

5	1	In July 2021 Novo Nordisk acquired NNC6019 (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.

Robust R&D Pipeline

FOCUSED ON NEURODEGENERATIVE AND RARE PERIPHERAL AMYLOID DISEASES

PROGRAM/

PROTEIN TARGET

DISCOVERY

PRE-CLINICAL

PHASE 1

PHASE 2

PHASE 3

GLOBAL

INDICATION

PARTNER4,5

Birtamimab

SPA1 ODD2

Fast 3

Kappa & Lambda

AFFIRM-AL (Phase 3)

AL amyloidosis

Light Chain

Track

Prasinezumab

α

-Synuclein

PASADENA (Phase 2) | PADOVA (Phase 2b)

Parkinson's disease

(C-terminus)

NNC6019 (PRX004)

Transthyretin

Phase 2

ATTR amyloidosis

(misTTR)

BMS-986446 (PRX005)

Tau

Phase 2

Alzheimer's disease

(MTBR)

PRX012

Fast

Aβ

ASCENT (Phase 1)

Alzheimer's disease

(N-terminus)

Track3

PRX123

Fast 3

Aβ + Tau

IND cleared

Alzheimer's disease

Track

PRX019

Undisclosed Target

IND cleared

Neurodegeneration

TDP-43

TDP-43

ALS

Undisclosed

Undisclosed Target

AD in Down syndrome

Modalities:

mAb

Small Molecule

Vaccine

Undisclosed

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Aβ, Abeta; AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; mAb, monoclonal antibody.

1 Primary endpoint of all-cause mortality at p≤0.10 under the Special Protocol Assessment (SPA) agreement with FDA; 2 Orphan Drug Designation granted by FDA & EMA; 3 FDA Fast Track designation; 4 In July 2021 Novo Nordisk acquired NNC6019

(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; 5 BMS-986446, PRX019 and TDP-43 are part of a Global Neuroscience Research and

Development Collaboration with Bristol Myers Squibb. BMS has currently opted-in to the global rights for BMS-986446.

Alzheimer's Disease

Our Team has Pioneered Multiple Scientific

Advances in Protein Dysregulation

OUR LEGACY INCLUDES FOUNDATIONAL DISCOVERIES IN THE UNDERSTANDING OF ALZHEIMER'S DISEASE

1986

Athena Neurosciences founded

1996

Athena acquired by Elan

2012

Prothena spins-out

from Elan with a wholly-owned drug discovery platform

Pioneered fundamental discoveries elucidating the roles of beta amyloid (Aβ), gamma secretase and beta secretase play in disease1

First to show that anti-Aβ immunotherapy prevented and cleared amyloid plaques in the brains of transgenic mice2

First to demonstrate plaque clearance by an n-terminusantibody in brains from AD patients3

Discovered biological cause of ARIA and

vascular recovery following anti-Aβ immunotherapy4

Developed PRX012, best-in-classanti-Aβ product candidate, with ~10X greater binding potency to fibrillar Aβ vs. aducanumab5 and ~20X greater binding potency against protofibrils vs. lecanemab6

	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,
8	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

Our Legacy Drives Our Vision to Transform

the Care of Alzheimer's Disease

With unparalleled protein	…We're uniquely positioned to address Alzheimer's
dysregulation expertise…	Disease with a best-in-class portfolio

PRX012, anti-Aβ candidate with potential
best-in-class, highly potent binding;
designed for improved patient access via	Phase 1

subcutaneous delivery5

BMS-986446(PRX005), anti-tau candidate, with potential to reduce pathogenic tau spread6

PRX123, dual Aβ/tau vaccine candidate

designed for treatment and prevention

Phase 2

OUR LEGACY 1-4

IND cleared

9	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.