Prothena Corporation plc Overview Jefferies 2014 Global Healthcare Conference

June 3,

2014

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Forward-Looking Statements

This presentation contains "forward-looking" statements that involve risks, uncertainties and assumptions. If the risks or

uncertainties materialize or the assumptions prove incorrect, our results may differ materially from those expressed or implied

by such forward-looking statements. All statements other than statements of historical fact could be deemed forward-looking,

including, but not limited to, any projections of financial performance, business prospects, our product candidates in research

and development, any statements about historical results that may suggest on-going trends for our business, any statements

of the plans, strategies, and objectives of management for future operations, any statements of expectation or belief regarding

future events, potential markets or market size or preclinical, clinical or other developments; and any statements of

assumptions underlying any of the items mentioned. These statements are based on estimates and information available to us

at the time of this presentation and are not guarantees of future performance. Actual results could differ materially from our

current expectations. You should not rely upon forward-looking statements as predictions of future events. Although we believe that

the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee that the future results, levels of

activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. Moreover, we

undertake no obligation to update publicly any forward-looking statements for any reason to conform these statements to actual

results or to changes in our expectations.

We refer you to the documents that we file from time to time with the Securities and Exchange Commission, specifically our

Annual Report on Form 10-K and our Quarterly Reports on Form 10-Q. These documents, including the sections therein

entitled “Risk Factors”, identify important factors that could cause the actual results to differ materially from those contained in

forward-looking statements.

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We target proteins in novel ways to

resolve unmet clinical need in patients

Prothena Vision

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Prothena Overview

• Advancing and developing novel antibodies for diseases

involving protein misfolding or cell adhesion

• Team has track record of discovering and developing

immunotherapy products including abeta immunotherapy

and Tysabri®

• Lead programs in the pipeline (all mABs):

– NEOD001 for AL amyloidosis expected to enter P2/3 in 4Q14

– PRX002, α-synuclein immunotherapy, for Parkinson’s disease in

Phase 1 SAD (worldwide collaboration with Roche)

– PRX003, MCAM antibody, for inflammatory diseases and cancers

• $195M in cash at end of 1Q14

– Additionally, earned $15M clinical milestone (2Q14) from Roche

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Team with Track Record of Bringing Significant Products to Market

SENIOR MANAGEMENT

Dale Schenk, PhD

Chief Executive Officer and Director

Gene Kinney, PhD

Chief Scientific Officer, Head of R&D

Tran Nguyen

Chief Financial Officer

Martin Koller, MD

Chief Medical Officer

Tara Nickerson, PhD, MBA

Chief Business Officer

Bill Homan

Chief Legal Officer

BOARD OF DIRECTORS

Lars Ekman, MD, PhD

Chairman

Richard T. Collier

Director

Shane Cooke

Director

Christopher S. Henney

Director

Dennis J. Selkoe, MD

Director

SELECTED LIFE SCIENCE EXPERIENCE MARKETED PRODUCTS

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2014 Progress and Upcoming Milestones

• NEOD001 for AL Amyloidosis

Dr. Liedtke presented encouraging NT-proBNP results (responses and stabilization) from ongoing Phase 1 clinical trial at ISA in April 2014

Additional Phase 1 data updates expected later in 2014

Initiate Phase 2/3 clinical trial in patients with AL amyloidosis and cardiac involvement in 4Q14

• PRX002 for Parkinson’s disease (worldwide collaboration with Roche)

Initiated Phase 1 SAD study with successful first in human dosing

Earned $15M clinical milestone payment from Roche (April 2014), which is in addition to the $30M upfront payment from Roche (February 2014)

Initiate Phase 1 MAD study in patients with Parkinson’s disease

• PRX003 for inflammatory diseases and cancers

Announce initial indication(s)

Complete IND enabling toxicology studies

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R&D Pipeline for Lead Programs

PROGRAMS 2013 2014 2015+ COMMERCIALIZATION

RIGHTS

NEOD001 Systemic Amyloidosis

PRX002 Parkinson’s Disease

PRX003 Inflammatory Diseases, Cancers

Phase 1a / 1b MAD

Phase 2/3

Preclinical Phase 1

Preclinical IND Phase 1

IND

NEOD001 for Systemic Amyloidosis

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Amyloid Light Chain (AL)

Amyloidosis

• Antibody light chain deposits affect multiple organs (e.g., heart, kidney, etc.)

• Median survival < 3 years1

• ~15,000 patients in the US and Europe

Systemic Amyloidoses are Orphan Diseases with Unmet Need and No Approved Therapies

No Approved Therapies

Need for disease modifying

therapies that target organs

and slow damage or

improve function

• Existing AL chemotherapy reduces production, but does not address existing toxic amyloid

1. Palladini G, et al. Amyloid. 2005; 12:120 and Kumar, et al. Am J Hermatol. 2011; 86(3):251-5

Current

Treatment

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AL Represents Majority of Systemic Amyloidoses and NEOD001 Targets AL Amyloid

AL Therapeutic Landscape2

1. van Gameren, I., et al. (2010) Arthritis Care Res, 62: 296–301

2. www.clinicaltrials.gov

• Melph+Dex

• HD Melph

• MLN9708 (P3)

• Pomalyst® (P2)

• Revlimid® (P2)

• Treanda® (P2)

• Velcade® (P2)

• Kyprolis® (P1)

Pla

sm

a c

ell

•NEOD001 (P1)

AL 55%

AA 30%

ATTR 15% A

L A

mylo

id

No A

ppro

ved T

hera

pie

s

Systemic Amyloidoses1

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AL Amyloidosis: Impact of Amyloid Deposits on Cardiac Tissue

1. Modified from http://www.med.uottawa.ca/patho/eng/Public/cardio/lab2.html

2. Seward et al., 2010

Normal Heart1 Amyloidosis2

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Potential NEOD001 MOA: Neutralizes Soluble Toxic Aggregates and Clears AL Amyloid Deposits

Soluble Aggregates

of Amyloid Protein

Monocyte/

Macrophage

Amyloid

Potential Mechanism of Action for NEOD001 Neutralize or facilitate clearance of amyloid protein

Neutralization

Clearance

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Ongoing Phase 1 Trial in AL Amyloidosis Evaluating Safety and Markers of Organ Response

– Evaluate hematologic response (dFLC) and organ response

(e.g., NT-proBNP, proteinuria and alkaline phosphatase)

– Evaluate the safety and tolerability of NEOD001

– Determine maximum tolerated dose or Phase 2/3 recommended

dose of NEOD001

– Evaluate the serum pharmacokinetics (PK) of NEOD001

– Assess immunogenicity of NEOD001

1 Secondary Objectives

Primary Objectives

Exploratory Objectives

2

Data as of 3/11/14, interim, unaudited data

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No Dose-Limiting Toxicity Observed to Date

Preferred Term

NEOD001 (mg/kg)

0.5 1.0 2.0 4.0 8.0 16.0

Dyspnea 1 - 1 1 1 -

Fatigue - - 2 1 - -

Cough - 1 - 1 - -

Diarrhea - 1 - 1 - -

Hyponatremia 1a - 1a - - -

Insomnia 2 - - - - -

Productive cough - 1 - 1 - -

URI 1 1 - - - -

a. Grade 3 severity. TEAE reported by <10% (n = 1) were: dyspnea with exertion, epistaxis, oropharyngeal pain, upper-airway cough syndrome,

wheezing, bronchitis (viral), sinusitis, urinary tract infection, dizziness, headache, peripheral neuropathy, syncope, infusion site reaction, vessel

puncture bruise, dehydration, hyperphosphatemia, hypopotassium, iron deficiency, arthralgia, musculoskeletal pain/stiffness, neck pain,

dyspepsia, gastritis, anxiety, ingrown nail, rosacea, edema, chest pain, atrial fibrillation, QT prolongation, basal cell carcinoma

Data as of 3/11/14, interim, unaudited data

• No related serious adverse events

• No dose-limiting toxicities have been observed

• No anti-drug antibodies detected

15

150

200

250

300

350

Pharmacokinetic Profiles Support 28-Day Cycle Across Dose Levels

Ser

um

NE

OD

001

Co

nce

ntr

atio

n, μ

g/m

L

Time, Days

Data as of 3/11/14, interim, unaudited data

0

10

20

30

40

50

28

0

50

100

150

0 7 14 21 28

0.5 mg/kg Cycle 1 (n=3) 0.5 mg/kg Cycle 3 (n=3)

1.0 mg/kg Cycle 1 (n=3) 1.0 mg/kg Cycle 3 (n=3)

2.0 mg/kg Cycle 1 (n=3) 2.0 mg/kg Cycle 3 (n=3)

4.0 mg/kg Cycle 1 (n=3) 4.0 mg/kg Cycle 3 (n=3)

8.0 mg/kg Cycle 1 (n=3) 8.0 mg/kg Cycle 3 (n=3)

16 mg/kg Cycle 1 (n=3)

16

-90

-60

-30

0

30

60

90

For Patients with Baseline NT-proBNP ≥650 pg/mL

Cardiac Biomarker Response/Progression Criteria1

No response or progression as defined

Decrease in NT-proBNP >30% AND >300 pg/mL

Increase in NT-proBNP >30% AND >300 pg/mL in patients

without progressive renal dysfunction

Response

Progression

Stable

30%

-30%

0

1. Comenzo RL, Reece D, Palladini G, et al. Leukemia. 2012;26:2317–25

Data as of 3/11/14, interim, unaudited data

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NEOD001 Treatment Associated with High Rate of Cardiac Biomarker Response and Stabilization

N=18a

n=1, Progression (11%)

n=1, No Post-BL Data --

n=8, Response or Stable (89%)

a. 12 cardiac patients at diagnosis

Data as of 3/11/14, interim, unaudited data

N=10

N=18 n=6, No Cardiac Involvement (33%)

n=12, Cardiac Involvement (67%)

n=10

NT-proBNP ≥650 pg/mL

NT-proBNP <650 pg/mL

n=8

n=5, Response (56%)

n=3, Stable (33%)

At

Dia

gn

osis

P

er

Pro

toco

l

18

Highlights of Interim Phase 1 Data of NEOD001 in Patients with AL Amyloidosis

• Residual organ dysfunction following plasma cell dyscrasia treatment

remains a significant unmet medical need in patients with AL amyloidosis

• 18 patients in 6 dosing cohorts have received 106 cycles of NEOD001

in the ongoing Phase 1 study

• NEOD001 is safe and well-tolerated, with a PK consistent with dosing

every 28 days, and no hypersensitivity reactions or development of anti-

drug antibodies

• Of the 9 patients with a baseline NT-proBNP value ≥650 pg/mL and a

post-baseline NT-proBNP determination, 8 had cardiac biomarker

response or were stable

• Randomized, placebo-controlled Phase 2/3 study is warranted in

patients with AL amyloidosis who have cardiac involvement

Data as of 3/11/14, interim, unaudited data

PRX002 for Parkinson’s Disease (worldwide collaboration with Roche)

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Parkinson’s is a Neurodegenerative Disease with No Approved Disease-Modifying Therapies

• Parkinson’s disease (PD) is the 2nd most common neurodegenerative

disorder

– Current treatments manage early symptoms, not disease

– There are an estimated 7-10 million Parkinson’s patients worldwide

– Genetic mutations cause early and aggressive disease

• Synuclein pathology strongly implicated in PD

– Also associated with other CNS and peripheral diseases, including some orphan indications

Synuclein is the predominant

component of Lewy bodies found

in Parkinson’s disease and other

synucleinopathies

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Worldwide PRX002 Collaboration with Roche for Parkinson’s Disease

Total Milestones $600M

Upfront and near-term

Clinical, regulatory and first sale

Ex-U.S. sales milestones

U.S. Profit & Loss Split

U.S. Co-Develop

U.S. Co-Promote

Ex-U.S.

45M

380M

175M

30%

Ability to opt-out1 Will lead the clinical development

Ability to opt-in Will lead the commercialization

Up to double digit royalties

Sole responsibility to develop and commercialize

--

70%

--

--

--

• Total milestones

expected to more

than fully fund U.S.

clinical development

of PRX002

– Continue to

participate through

Joint Steering

Committee

• $45M already

earned in 2014

• Retain significant

financial upside

• Ability to build U.S.

specialty sales force

1. Upon opting out of the co-development and cost and profit sharing on any co-developed Licensed Products, Prothena instead

would receive U.S. commercial sales milestones totaling up to $155.0 million and tiered, single-digit to high double-digit royalties

in the teens based on U.S. annual net sales, subject to certain adjustments

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Synuclein Immunotherapy may Reduce Neuronal Toxicity and Prevent Cell-to-Cell Transfer

Synaptic Loss

and Pathogenic

Spread

Antibodies

Reduce

Pathogenic

Spread and

Decrease

Synuclein

Pathology

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PRX002 Phase 1 SAD Study Underway

• Initiated Phase 1 SAD study in April 2014

• Initiate Phase 1 MAD study in patients with

Parkinson’s disease

• Biomarkers from CNS and periphery anticipated to

guide Phase 2 dose selection

• Potential development of follow-on antibodies for

other orphan synucleinopathies

PRX003 for Inflammatory Diseases and Cancers

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MCAM Blockade Potentially More Effective Approach for Treating Inflammation Compared to anti-IL17 Therapies

TH1 cell

TH2 cell

TReg cell

TH17 cell

IL-12

IL-4

TGFß and IL-6

(IL-1 and IL-23)

TCR

DC

Peptide-MHC

molecule

TGFß

Naïve

T cell

(IL6)

(TNF)

RORgt

IL17

IL22

CCL20

IL26

(IFNg)

Figure modified from: Zou & Restifo, Nature Reviews Immunology10: 248-256 (2010)

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PRX003 Clinical Trial Expected to Initiate in 2015

• Lead candidate, PRX003, identified and

CMC initiated

• Announce initial indication(s)

• Expect to file IND and initiate Phase 1

trial(s) in 2015

Corporate Information

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Financial Overview

SUMMARY INFORMATION

Cash and cash equivalents (March 31, 2014)1 $195M

Shares outstanding (April 25, 2014)2 21.9M

Full-time employees (December 31, 2013) 39

2014 GUIDANCE

Cash burn range3 $7 to $12M

Net loss range3 $13 to $18M

Projected year-end cash position (mid-point) ~$167M

1. Does not include $15M clinical milestone earned in 2Q14 from Dec-13 Roche collaboration

2. Does not include 2.4mm ordinary shares underlying options with a weighted average strike price of $12.19

3. Accounts for the $30M in upfront (1Q14) and $15M near-term clinical milestone (2Q14) from Dec-13 Roche collaboration

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Upcoming Key Milestones

Timing Key Milestone Program

2013 PRX002 collaboration with Roche Parkinson’s Disease

2014 Initiate Phase 1 SAD trial of PRX002 Parkinson’s Disease

2014 Communicate interim data from ongoing Phase 1 trial of NEOD001 at ISA

AL Amyloidosis

2014 Initiate Phase 1 MAD trial of PRX002 Parkinson’s Disease

2014 Initiate Phase 2/3 trial of NEOD001 in 4Q14 AL Amyloidosis

2014 Communicate additional data from ongoing Phase 1 trial of NEOD001

AL Amyloidosis

2015 Initiate Phase 1 trial(s) of PRX003 Inflammation and cancers

Prothena Corporation plc June 3,

2014