Prothena Corporation plc R&D Day. November 16, 2017

Transcription

1 Prothena Corporation plc R&D Day November 16, 2017

2 Gene Kinney, PhD President & Chief Executive Officer

3 Forward-Looking Statements This presentation contains forward-looking statements. These statements relate to, among other things: the strength of our cash position; the potential of our pipeline; the designs, proposed mechanisms of action and possible clinical benefits of NEOD001, PRX002 and PRX004; the design and powering of our Phase 2b PRONTO and Phase 3 VITAL studies of NEOD001; the predictive value of NT-proBNP as a biomarker; the design of the Phase 2 PASADENA study of PRX002/RG7935; potential CNS misfolding protein targets for immunotherapy; our confidence in the development strategy for NEOD001; the expected timing of announcing data from our Phase 2b PRONTO study of NEOD001; the mortality rates in and the projected timing of the final event in the Phase 3 VITAL study of NEDO001; the expected timing of beginning clinical development of PRX004; our ability to advance a growing pipeline of novel first-in-class therapies in neuroscience and orphan diseases; and the potential targeting of novel epitopes we have identified on misfolded forms of tau protein and on misfolded forms of LECT2 protein. These forward-looking 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 the risks, uncertainties and other factors described in the Risk Factors sections of our Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) on February 27, 2017 and our subsequent Quarterly Reports on Form 10-Q filed with the SEC. Prothena undertakes no obligation to update publicly any forward-looking statements contained in this presentation as a result of new information, future events or changes in Prothena's expectations. 3

4 Delivering Novel Protein Immunotherapies to Transform Patients Lives A catalyst-rich pipeline of first-in-class therapeutics based on a deep expertise in protein misfolding Integrated capabilities, disciplined decision-making and proven team Leveraging expertise to lead in Neuroscience and Orphan arenas Strong cash position of $460 million* at end of 3Q17 * Includes cash, cash equivalents and restricted cash. 4

5 A First-in-Class Pipeline Poised for Multiple Catalysts PROGRAM Preclinical Phase 1 Phase 2 Phase 3 COMMERCIALIZATION RIGHTS NEOD001 AL Amyloidosis Fast Track Designation The VITAL Amyloidosis Study (Phase 3) PRONTO (Phase 2b) PRX002/RG7935 Parkinson s Disease PASADENA (Phase 2) PRX004 ATTR Amyloidosis Preclinical 5

6 Advancing a Leading Neuroscience and Orphan Biotechnology Company Leverage core expertise to discover, develop and commercialize internal and external opportunities within the neuroscience and orphan arenas Neuroscience Orphan PRX002/RG7935 Parkinson s Disease PRX004 hattr-pn NEOD001 AL amyloidosis PRX004 hattr-cm wtattr Discovery & BD 6

7 Today s Agenda AL amyloidosis and NEOD001 Clinical perspectives Morie A. Gertz, MD, Mayo Clinic ATTR amyloidosis and PRX004 Parkinson s disease and PRX002/RG7935 Discovery Q&A 7

8 Today s Speakers Sarah Noonberg, M.D., Ph.D. Chief Medical Officer Prothena Morie A. Gertz, M.D. Roland Seidler Jr. Professor of Art and Medicine, Chair Emeritus, Department of Internal Medicine Mayo Clinic, Rochester, MN Wagner Zago, Ph.D. Chief Scientific Officer Prothena 8

9 Sarah Noonberg, MD, PhD Chief Medical Officer

10 NEOD001 for AL Amyloidosis

11 AL Amyloidosis is an Orphan Disease Unmet Need and Product Opportunity 1 1,2,3 1,2 1 Dispenzieri A, Merlini G. Plasma Cell Dyscrasias (Cancer Treatment and Research), 2016; 2 Duston MA, et. Al. Arch Intern Med., Merlini G et al. Blood,

12 AL Amyloidosis Patients Face a Long Journey Before Diagnosis *Lousada et al, ARC Online Survey, TIME and MULTIPLE DOCTORS* 37% of patients experienced a diagnosis > 12 months after initial symptoms 32% of patients were seen by 5 doctors before diagnosis; 8% of patients saw 1 doctor

13 Where AL Amyloidosis Patients Are Treated (US and EU) HIGHLY SPECIALIZED LESS SPECIALIZED AMYLOIDOSIS CENTERS OF EXCELLENCE AMYLOIDOSIS CENTERS MYELOMA/ CANCER CENTERS COMMUNITY HOSPITALS/ PRIVATE PRACTICE PATIENTS PER PHYSICIAN 13

14 Current Treatment Approaches Current goal of therapy is to reduce the number of abnormal plasma cells producing amyloidogenic light chain Do not address resident amyloid Often do not result in improved organ function or quality of life Established use of NT-proBNP in clinical care for staging, determining treatment outcome and predicting survival of patients with AL amyloidosis Safe and well tolerated therapies are needed to improve organ function (i.e. NT-proBNP, proteinuria, and NIS-LL) 14

15 Proposed NEOD001 MOA: Neutralize Soluble Amyloid and Clear Insoluble Amyloid 1. Plasma cells overproduce light chains that misfold, aggregate and become toxic amyloid 2. NEOD001 neutralizes circulating soluble amyloid 3. NEOD001 clears deposited insoluble amyloid by inducing macrophages to clear amyloid through phagocytosis 4. NEOD001 recycled to continue neutralizing circulating soluble amyloid and clearing deposited insoluble amyloid 15

16 Preclinical and Clinical Development Strategy Builds Confidence for Phase 3 Survival Cardiac Hospitalization Phase 1/2 Cardiac response: NT-proBNP Preclinical Target validation Demonstration of MOA Toxicology Safety, tolerability, immunogenicity, dose selection Organ response: cardiac, renal, peripheral nerve 16

17 NEOD001 Global Studies Phase 2b: Phase 3: Previously Treated with Plasma Cell Therapy Sample size and randomization: N=129; 1:1 Treatment regimen: NEOD mg/kg vs. placebo, IV q28 days Primary endpoint: NT-proBNP best response over 12 months Secondary endpoints: Includes Short Form-36, 6MWT, NT-proBNP change over time Newly Diagnosed, Treatment Naïve Sample size and randomization: N=260; 1:1 Treatment regimen: NEOD mg/kg vs. placebo, with concurrent standard of care in both arms, IV q28 days Primary endpoint: Composite endpoint of: All-cause mortality or cardiac hospitalizations Secondary endpoints: Includes Short Form-36, 6MWT 17 NCT# , EudraCT# NCT# , EudraCT#

18 PRONTO Population Very Similar to Phase 1/2 Study Population BASELINE VARIABLE PHASE 1/2 PRONTO* Male 61% 60% White 94% 90% Age (years), mean [SD] 62.2 [8.7] 62.5 [8.8] Age at Diagnosis (years), mean [SD] 58.9 [8.6] 59.1 [8.9] Duration since AL diagnosis (months), mean [SD] 45.4 [36.1] 47.4 [34.3] Response to First Line Therapy, n (%) Complete Response 35% 44% Very Good Partial Response 25% 40% Partial Response 16% 16% No Response 12% -- *Study ongoing, blinded data are preliminary as of October

19 PRONTO Population Very Similar to Phase 1/2 Study Population BASELINE VARIABLE PHASE 1/2 PRONTO* NT-proBNP (pg/ml), mean [SD] [1351.3] 2017 [1369.4] <1800 pg/ml 58% 57% 1800 pg/ml 42% 43% egfr (ml/min/1.73m 2 ), mean [SD] 65.6 [23.7] 60.5 [18.2] ALP (U/L), mean [SD] [84.0] [64.1] ECOG 0 41% 37% 1 52% 54% 2 7% 9% SF-36 PCS, mean [SD] Not Collected 40.1 [9.7] 6MWT distance (meters), mean [SD] Not Collected [87.9] *Study ongoing, blinded data are preliminary as of October cardiac evaluable patients n=36 19

20 VITAL Population Supports Evaluation of NEOD001 Effect on Morbidity and Mortality BASELINE VARIABLE VITAL Male 66% White 92% Age (years), mean [SD] 63 [9.6] Age at Diagnosis (years), mean [SD] 62.9 [9.6] Duration since AL diagnosis (months), mean [SD] 1.8 [2.9] Mayo Stage 1 8% 2 28% 3 38% 4 26% NT-proBNP (pg/ml), mean [SD] 3861 [2703.7] egfr (ml/min/1.73m 2 ), mean [SD] 70 [20.6] SF-36 PCS, mean [SD] 36.8 [9.9] 6MWT distance (meters), mean [SD] [95.0] Study ongoing, blinded data are preliminary as of October

21 VITAL Study Design Considerations Analysis of primary endpoint designed to maximize signal and minimize noise Central adjudication for primary endpoint events Cardiac hospitalization defined by disease progression Primary analysis excludes cardiac hospitalizations within first 90 days to account for PCD-related hospitalizaiton Entry criteria designed to capture appropriate level of morbidity and mortality Randomization stratified by Mayo stage for disease severity to ensure balance between treatment groups 21

22 Additional Activities Supporting NEOD001 RAIN Study Investigator Sponsored Study evaluating effect of NEOD001 vs. placebo on renal amyloidosis Anticipated to enroll at 9 US sites Enrollment ongoing, 12 month treatment period Clinicaltrials.gov #NCT Understanding the pharmacoeconomic impact of AL amyloidosis Continued research on health care resource utilization, healthrelated quality of life, loss of productivity Continued research on NT-proBNP Growing the body of evidence to support predictive value of this biomarker Activities to enhance disease awareness TM 22

23 Morie A. Gertz, MD Chair Emeritus, Department of Internal Medicine Mayo Clinic

24 Morie Gertz, MD Chair Emeritus, Internal Medicine, Mayo Clinic Treating physician specializing in amyloidosis and multiple myeloma Served as President of the Mayo Rochester Officers & Councilors and was awarded the Mayo Distinguished Clinician Award for his contributions to patient care Author of more than 450 publications and book chapters and 500 abstracts, letters and editorials Serves on three journal editorial boards including the Journal of Clinical Oncology Medical advisor for the Amyloidosis Support Groups 24

25 Morie A. Gertz MD Chair Emeritus, Internal Medicine Mayo Clinic 25

26 What is NT-proBNP? N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) A hormone secreted by cardiomyocytes in response to mechanical cardiac stress NT-proBNP and BNP are produced from the same precursor protein (probnp) in ~1x1 ratio NT-proBNP is a more stable marker and has better analytic properties NT-proBNP is used as a clinical marker for detecting and monitoring heart failure Cardiomyocyte preprobnp probnp Cleavage NT-proBNP BNP Blood 26

27 Multiple Differences Between AL Cardiac Amyloidosis and Heart Failure Parameter AL Cardiac Amyloid Heart Failure Incidence 1, ,000 Prevalence 6,000 5,700,000 Median Survival <1-6 years (Stage dependent) 5 years LV function - EF HFpEF HFpEF/HFrEF Average Age (years) NT-proBNP response to diuretics Not sustained without lowering of light chains Decrease ACE/Beta Blockers Harmful Life Prolonging Pathophysiology Light Chain Toxicity Multiple NT-proBNP consistently shown to predict survival Circulation. 2015;132, Lancet. 2016;387(10038): Yes No

28 NT-proBNP Clinical Use in AL Amyloidosis NT-proBNP is widely established as a cardiac biomarker in clinical care for AL amyloidosis patients Multiple uses, including: - Staging and prognosis (Mayo criteria) - As a surrogate measure to evaluate cardiac response to treatment - Monitoring for cardiac disease progression 28

29 Current Treatment Approaches No approved therapies Preventing organ progression is treatment goal 1 Current treatments focus on plasma cell clone A shift since 2010 from alkylating agents to proteasome inhibitors has resulted in better hematologic response, but two-year survival largely unchanged 2 Significant number of patients have ongoing organ dysfunction 1 Kaufman, et al, Muchtar,et al,

30 Staging and Prognosis in AL Amyloidosis: Revised Mayo Staging System Prognostic model developed from 810 newly diagnosed AL amyloidosis patients; tested on validation sets Evaluates organ functions and plasma cell markers for determinants of survival In multivariate analysis, only NT-proBNP, FLC differential and troponin measured at diagnosis were independently prognostic for survival Score is 0-4 based on presence of these prognostic factors Prognostic Factors NT-proBNP Troponin dflc Score 1 Point Each For: 1800 pg/ml ng/ml 18 mg/dl Kumar et al,

31 Overall Survival (proportion) Mayo Stage and Overall Survival in Newly Diagnosed AL Amyloidosis patients (N=583) Stage 1 (22%, n=125) Stage 2 (25%, n=144) Stage 3 (27%, n=160) Stage 4 (26%, n=154) Follow-Up From Diagnosis (months) No. at risk % 54% 36% 35% 17% 9% Stage Median OS (months) Kumar et al,

32 NT-proBNP Response and Survival in AL Amyloidosis NT-proBNP is the only cardiac biomarker consistently shown to predict survival based on response after interventional treatment 1 Other cardiac biomarkers including troponin or echocardiographic parameters are not similarly predictive NT-proBNP response, regardless of interventional treatment approach, is predictive of patient outcome Unique clinical impact due to direct regulation of NT-proBNP by pathologic processes downstream of cardiac LC toxicity 1 Merlini et al,

33 Proportion surviving NT-proBNP Response Shown to Predict Survival of AL Amyloidosis Patients Goal of Therapy is Preventing Organ Progression p<0.001 p<0.001 NT-proBNP response (at least 300 ng/l and 30% decrease), 100 people NT-proBNP stable, 108 patients NT-proBNP progression (at least 300 ng/l and 30% increase), 169 patients Time* (Months) *survival 6 months following initial treatment Comenzo, et. al.,

34 Summary Significant need to improve cardiac function; major source of morbidity and mortality in AL amyloidosis NT-proBNP reflects cardiac damage and recovery Cardiac involvement is the primary determinant of survival and preventing organ progression is the aim of therapy NT-proBNP is the only clinically qualified cardiac biomarker shown to predict survival following intervention in AL amyloidosis NT-proBNP is directly related to pathophysiologic pathway in AL amyloidosis 34

35 Future Directions: Amyloidosis Research Consortium Rationale, application, and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is universally accepted by the AL amyloidosis specialists, as a surrogate end point for survival. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type, and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. Merlini et al,

36 Wagner Zago, PhD Chief Scientific Officer

37 LCs Directly Modulate NT-proBNP Release by Cardiomyocytes via Pathways of Toxicity NT-proBNP is clinically qualified as a surrogate endpoint for survival in patients with AL amyloidosis NT-proBNP is directly related to pathophysiologic pathways induced by toxic LC Differences between AL amyloidosis and other forms of heart failure Anatomic restrictions (stretching) Direct oxidative damage and myocardial toxicity Are cytoxicity and NT-proBNP pathways inter-related? In vitro assessment of LC-induced toxicity and BNP production NT-proBNP Rat Neonatal Heart Cardiomyocyte Aggregated LC Pathway Analysis Hmox-1, heme oxygenase-1; LC, light chain 37

38 Agg-LC bound to Cells (relative units) Hmox-1 Levels Hmox-1 Relative (relative Quantity, units) AU Secreted NT-proBNP Levels (pg/ml) Aggregated LCs Bind to Cardiomyocytes and Induce Oxidative Stress and NT-proBNP Secretion Binding to Cardiomyocytes Hmox-1 Levels (response to oxidative stress) 8 P< NT-proBNP Levels Log [Agg-LC] (mg/ml) 0 ROS, Hmox-1 Cardiomyocyte Hmox-1 inhibitor: 30 µm tin protoporphyrin IX BNP, brain natriuretic peptide; LC, light chain 38

39 Aggregated LC Mediated Induction of Cellular Oxidative Stress Directly Upregulates BNP Expression NT-proBNP levels are a direct measure of cardiotoxicity induced by aggregated LC, which may not be present in other forms of heart failure AL AMYLOIDOSIS INSOLUBLE AGGREGATED LIGHT CHAIN MECHANICAL STRAIN SOLUBLE TOXICITY ROS Hmox-1 MAPK OTHER FORMS OF HEART FAILURE HEMODYNAMIC CHANGES MECHANICAL STRAIN INCREASED NT-PROBNP PRODUCTION Hmox-1, heme oxygenase-1; MAPK, mitogen-activated protein kinase; NT-proBNP, N-terminal probrain natriuretic peptide. 39

40 PRX004 for ATTR Amyloidosis

41 Advancing a Leading Neuroscience and Orphan Biotechnology Company Leverage core expertise to discover, develop and commercialize internal and external opportunities within the neuroscience and orphan arenas Neuroscience Orphan PRX002/RG7935 Parkinson s Disease PRX004 hattr-pn Discovery & BD NEOD001 AL amyloidosis PRX004 hattr-cm wtattr 41

42 42 ATTR Amyloidosis: Misfolded TTR Protein Drives Organ Dysfunction and Failure

43 Transthyretin Protein (TTR) FREE TETRAMER MISFOLDED MONOMER SOLUBLE AGGREGATE AMYLOID FIBRILS ORGAN DISFUNCTION Protein Misfolding Functional TTR Structures TTR Structures Associated with Pathology Naturally occurs in tetrameric form Responsible for transporting thyroxine and retinol (vitamin A) Tetramer implicated in neuroprotection (trophic factor, Aβ clearance) Mutant forms dissociate, misfold and aggregate Amyloid fibrils deposit in the organs and nerves, causing progressive damage 43

44 Epitope Unique to Pathogenic Forms of TTR TTR89-97 Epitope is buried in the tetramer but exposed in the monomer 2ROX 1-GPTGTGESKC PLMVKVLDAV RGSPAINVAV HVFRKAADDT WEPFASGKTS ESGELHGLTT EEEFVEGIYK VEIDTKSYWK ALGISPFHEH AEVVFTANDS GPRRYTIAAL LSPYSYSTTA VVTNPKE-127 In collaboration with Avi Chakravartty (University of Toronto) Higaki et al. (2016) Amyloid 23,

45 ATTR Formation (ThT fluorescence) mprx004* Specifically Binds to Misfolded Agg-TTR Species and Inhibits ATTR Formation Specificity to Mis-TTR Inhibition of Amyloid Formation kda Total TTR Antibody TTR mprx TTR Agg- TTR Agg- TTR 146- Tetramer 66- Dimer 20- (TTR-V122I) mprx004 (mg/ml) Higaki et al. (2016) Amyloid 23, *Murine form of PRX004 45

46 mprx004* Specifically Binds to ATTR Deposits in Multiple Organs and Genetic Variations ATTR Heart Sciatic Nerve GI Tract Wt-ATTR V122I V30M V30M Brown = mprx004-positive amyloid deposits Normal Heart Sciatic Nerve GI Tract Higaki et al. (2016) Amyloid 23, *Murine form of PRX004 46

47 % Macrophages with Intracell. ATTR In Vitro Amyloid Clearance mprx004* Promotes Phagocytosis of Aggregated TTR Uptake of Aggregated phrodo-ttr by THP-1 Cells Control IgG mprx004* mprx004 mab Higaki et al. (2016) Amyloid 23, Red = phagocytosed aggregated TTR *Murine form of PRX mprx004 induces antibody-dependent phagocytosis of ATTR aggregates by macrophages

48 % Phrodo-ATTR+ Phagocytes with Phagocytes Intracell. ATTR (%) In Vivo Amyloid Clearance mprx004* Promotes Phagocytosis of Aggregated TTR mprx004 (10mg/kg) ATTR Fibrils (Phrodo) 60 Phagocytosis of ATTR p< MINUTES Peritoneal phagocytes (flow cytometry) 0 control 27/1 mprx004 14G8 48 Systemically-administered mprx004 induces antibody-dependent phagocytosis of ATTR aggregates in vivo *Murine form of PRX004

49 Prothena s Proprietary Misfolded TTR Assay: Tested Across Multiple TTR Mutations Misfolded Monomer mis-ttr mab Amyloid Fibrils Prothena s high-sensitivity immunoassay detects circulating mis-ttr in patient and asymptomatic hattr plasma 49

50 PRX004: Targeted Approach to ATTR Amyloidosis Normal TTR Toxic Misfolded TTR FREE TETRAMER MISFOLDED MONOMER SOLUBLE AGGREGATE AMYLOID FIBRILS ORGAN DISFUNCTION Macrophage Other approaches aim Stabilize TTR tetramers Reduce production PRX004 Designed to target all genetic (hattr and wtattr) forms of misfolded TTR that cause the disease, sparing normal TTR Expect to initiate P1 by mid

51 PRX002/RG7935 for Parkinson s Disease and Other Related Synucleinopathies (Worldwide Collaboration with Roche)

52 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 motor 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 52

53 Strong Scientific Evidence Supports Anti-alphasynuclein Therapeutic Approaches for Parkinson s and Other Alpha-synucleinopathies Alpha-synuclein pathology is strongly implicated in Parkinson s disease Lewy pathology follows the topological progression of disease Genetically validated target (missense mutations, gene dose) Alpha-synuclein as an extracellular target during pathogenesis Caudal-rostral staging, host-to-graft transfer, various propagation models Possible common mechanism among misfolded proteins in CNS (e.g., amyloid-beta, tau, TDP-43, SOD1) Passive anti-αlpha-synuclein immunization is a potential disease-modifying therapy for PD αlpha-synuclein is not deposited extracellularly in brain vessels and parenchyma in PD Strong preclinical efficacy in various in vivo αlpha-synucleinopathy models 53

54 Caudal-rostral (Braak) Staging of Alphasynuclein Pathology Pathology Inclusions present in olfactory bulb and dorsal motor nucleus of the vagal and glossopharyngeal nerves Pathology spreads through the pons to midbrain and basal forebrain Pathology spreads to neocortex Clinical Manifestations Loss of Smell GI Dysfunction Sleep Disturbances Motor Symptoms Cognitive Impairment Depression Modified from Goedert, Science

55 Preclinical Evidence of Cell-to-Cell Transmission in a Mouse Model 1 MONTH 3 MONTHS 6 MONTHS 12 MONTHS Injection site 1 synapse away Modified from Rey et al., NJM synapses away 55

56 56 Synuclein Immunotherapy May Reduce Neuronal Toxicity and Prevent Cell-to-Cell Transfer

57 9E4* Blocks Cell-to-Cell Transmission and Cleavage of Alpha-synuclein In Vitro Cell-to-cell Transmission asyn GFP* asyn Games D et al. J Neurosci GFP, green flourescent protein *Murine form of PRX002/RG After 24h

58 9E4* Demonstrated to Reduce Alpha-synuclein Pathology and Ameliorate Behavioral Deficits in Various Animal Models *Murine form of PRX002/RG

59 Summary of Findings with 9E4* Anti-αlpha-synuclein immunotherapy with 9E4 was demonstrated in various animal and in vitro models of αlpha-synucleinopathy to promote: Reduction of αlpha-synuclein pathology Blockade of cell-to-cell transmission Blockade of cleavage by calpain Reduction of gliosis Preservation of synaptic integrity Amelioration of motor, cognitive, and sensorimotor behavioral deficits High affinity/avidity to alpha-synuclein aggregates (0.048nM) versus monomers (20nM) Targeting specific epitopes of alpha-synuclein with antibodies is suitable to test the alphasynuclein hypothesis in Parkinson s disease *Murine form of PRX002/RG

60 Sarah Noonberg, MD, PhD Chief Medical Officer PRX002/RG7935 Phase 2 Clinical Development

61 PRX002/RG7935 Clinical Development Phase 1 SAD Study in Healthy Volunteers 1 Acceptable safety, immunogenicity and PK data reported in 2015 at Movement Disorder Society Phase 1b MAD Study in Patients with Parkinson s Disease 2 Presented at AD/PD April 2017 Acceptable safety and tolerability across all dose levels Robust CNS penetration: Dose-dependent increase in PRX002/RG7935 levels in CSF with mean concentration of PRX002/RG7935 in CSF of 0.3% relative to serum across all dose levels Rapid, dose-and time-dependent reduction in levels of free serum alpha-synuclein: Significant mean reduction of up to 97% (p < ) Selected two dose-levels for Phase 2 program Initiated Phase 2 PASADENA Study in patients with early Parkinson s disease in 2Q17 1 Further study details available at ClinicalTrials.gov ID # NCT Further study details available at ClinicalTrials.gov ID # NCT

62 Trial Design Randomize 1:1:1 N=300 PRX002/RG7935 Phase 2 PASADENA Study Design Part 1 52-week double-blind treatment Part 2 52-week extension PRX002/RG mg IV q4w Placebo IV q4w PRX002/RG mg IV q4w PRX002/RG7935 z IV q4w 4500 mg (BW 65 kg) or 3500 mg (< 65 kg) PRX002/RG7935 IV q4w 4500 mg (BW 8 65 kg) or 3500 mg (< 65 kg) : 4 PRX002/RG mg IV q4w zzzzzzz PRX002/RG mg (BW 65 kg) or 3500 mg (< 65 kg) Primary objective Secondary objectives Evaluate the efficacy of PRX002/RG7935 using the MDS-UPDRS Evaluate the effects of PRX002/RG7935 on DaT-SPECT signal and symptoms Safety and tolerability of PRX002/RG7935 for up to 104 weeks Evaluate the pharmacokinetics of PRX002/RG Exploratory objectives Multiple clinical, radiographic and biochemical endpoints IV, intravenous NCT #

63 The Movement Disorders Society Unified Parkinson s Disease Rating Scale (MDS-UPDRS) Scale measures Parkinson s disease progression in four parts: Non-motor experiences of daily living Motor experiences of daily living Motor examination Motor complications from therapies Parts 1-3 primary endpoint for PASADENA Designed to capture both the presence and severity of both motor and non-motor symptoms Regulatory precedent for approved PD therapies 63 65

64 DaT-SPECT TM A Key Secondary Endpoint to Assess Disease Progression FDA-approved imaging technique Detects loss of functional dopaminergic neuron terminals in patients Provides assessment of disease severity and progression Progression not impacted by concomitant use of L-dopa gehealthcare.com 64 55

65 Discovery Wagner Zago, PhD Chief Scientific Officer

66 Discovery Pipeline Leverage core expertise to discover, develop and commercialize internal and external opportunities within the neuroscience and orphan arenas Neuroscience Orphan Tau Ab Neuroinflammation Receptors/Channels TDP-43 Sortilin Notch3 ALECT2 Collagen 66

67 Cell-to-cell transmission of misfolded proteins causes spread of pathology

68 Evidence of Sequential Spreading and Protein Propagation in Human Brain Alpha-syn Pathology (PD) Ab plaques (AD) Tau Inclusions (AD) TDP-43 Pathology (bvftd) Modified from Goedert, Science 2015; Brettschneider et al,

69 CNS Misfolding Protein Targets for Immunotherapy Pathogenic forms of misfolded proteins (tau, synuclein, TDP-43, HTT, SOD1) may be released in the extracellular environment and propagate pathological responses Antibodies to particular epitopes bind to pathogenic forms of proteins, potentially: Stopping seeding and propagation by blocking of uptake into healthy cells and promoting clearance (perivascular, microglia) Neutralizing cytotoxic forms Disaggregating to non-pathogenic species Blocking post-translational modifications (cleavage, phosphorylation) Fundamental attributes for efficacy: Epitope Binding strength to pathogenic forms 69

70 Internalized Tau (fluorescence) Potential Tau Indications: AD, PSP, FTD and CTE Prothena surveyed sites along the entire protein (45-65 kda) and identified novel epitopes with apparent superior efficacy Blockade of tau binding to cells, cell-to-cell transmission, and downstream functional effects (e.g. neurotoxicity) In vivo efficacy in tau transgenic mice and fibril tau propagation models. Tau Epitope N-terminal Programs in Development Biogen (BMS and Neurimmune), Abbvie, Prothena mabs Tested 9 Aggregated tau internalization in vitro model Mid region Eli Lilly, Axon-Neuro 21 C-terminal (total or posttranslational) Janssen/AC Immune, Genentech/AC Immune, Roche, Merck/Teijin 20 Monoclonal antibodies Novel and efficacious 5 70

71 Deposition of misfolded proteins in periphery causes organ dysfunction and failure

72 ALECT2* Implicated in Renal and Hepatic Amyloidosis Recently described renal amyloid composed of LECT2, with extensive congophilic deposits in the glomeruli, interstitium and vessels ALECT2 replicates characteristics of amyloidogenic proteins such as AL and ATTR LECT2 IHC Leads to renal failure ALECT2 (Congo-Red) Growing diagnosis with increased awareness and availability of diagnostic tools Prothena identified potential novel misfolding epitopes and antibodies specific to pathogenic forms being generated *Leukocyte cell-derived chemotaxin 2 (LECT2) Source: Said et al., 2013, Larsen et al.,

73 Prothena Discovery Engine

74 Expertise Driving Novel Programs in Neuroscience and Orphan Diseases Discovery approach based on a deep understanding of novel biology Optimally target the protein Develop proprietary screening assay platforms and animal models Develop proprietary biomarkers and target engagement assays Unique ability to generate antibodies that influence the biology appropriately Establish and leverage strong collaborations with academia Proven track record of translating science into clinical development within neuroscience and orphan arenas α4 integrin (natalizumab), Ab (bapineuzumab), PRX002/RG7935, NEOD001 74

75 Gene Kinney, PhD President & Chief Executive Officer

76 Development Prothena R&D Pipeline PROGRAM Discovery Preclinical Phase 1 Phase 2 Phase 3 Discovery Development NEOD001 AL Amyloidosis PRX002 Parkinson s Disease PRX004 ATTR Amyloidosis Tau AD, PSP, FTD, CTE ALECT2 ALECT2 Amyloidosis Aβ AD TDP-43 ALS, FTD Sortilin FTD, Neuroinflammation Other The VITAL Amyloidosis Study (Phase 3) PRONTO (Phase 2b) PASADENA (Phase 2) Preclinical Discovery Discovery Discovery Discovery Discovery Discovery AD, Alzheimer s disease; PSP, progressive supranuclear palsy; FTD, frontotemporal dementia; ALS, amyotrophic lateral sclerosis 76

77 Advancing a Leading Neuroscience and Orphan Biotechnology Company Leverage core expertise to discover, develop and commercialize internal and external opportunities within the neuroscience and orphan arenas Neuroscience PRX002/RG7935 Parkinson s Disease Tau Ab PRX004 hattr-pn TDP-43 Sortilin Notch3 Discovery & BD Orphan NEOD001 AL amyloidosis PRX004 hattr-cm wtattr ALECT2 Collagen 77

78 R&D Milestones NEOD001 for the potential treatment of AL amyloidosis Complete enrollment in the P3 VITAL Amyloidosis Study expected by mid-may 2017 (N=260) Topline results from the P2b PRONTO study expected in 2Q18 (N=129) Final event from the P3 VITAL study expected in 2H19 PRX002/RG7935 for the potential treatment of Parkinson s disease and other related synucleinopathies (worldwide collaboration with Roche) Present P1b MAD results at AD/PD on April 2, 2017 P2 clinical study expected to begin in 2Q17 (N~300) PRX003 for the potential treatment of inflammatory diseases, including psoriasis Topline results from the P1b MAD study expected in October 2017 (N=33) PRX004 for the potential treatment of ATTR amyloidosis P1 clinical study expected to begin by mid

79 Advancing a Leading Neuroscience and Orphan Biotechnology Company Leverage core expertise to discover, develop and commercialize internal and external opportunities within the neuroscience and orphan arenas Neuroscience PRX002/RG7935 Parkinson s Disease Tau Ab PRX004 hattr-pn TDP-43 Sortilin Notch3 Discovery & BD Orphan NEOD001 AL amyloidosis PRX004 hattr-cm wtattr ALECT2 Collagen 79

80 Thank You