Prothena Corporation plc · NASDAQ:PRTA
Prothena — Investor Presentation (January 2025)
65 slides from Prothena's investor presentation, Jan 10, 2025
Slide 1: Corporate Overview
CORPORATE OVERVIEW January 2025
Slide 2: Forward-Looking Statements
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 mil
Slide 3: Our Mission Today
Our Mission Today We are Focused on Delivering Life-Saving Therapies… …for unmet medical needs caused by diseases of protein dysregulation 3
Slide 4: Addressing Devastating Proteinopathies Affecting Millions of Patients and Families Worldwide
We are Addressing Devastating Proteinopathies Affecting Millions of Patients and Families Worldwide NEURODEGENERATIVE DISEASES RARE PERIPHERAL AMYLOID DISEASES Amyloid Transthyretin Alzheimer’s Parkinson’s light chain amyloidosis disease (AD) disease (PD) amyloidosis (AL) (ATTR) >80 million >10 mill
Slide 5: Our Biology-Directed Engine Propels Prothena's Progress Across our Broad Pipeline
Our Biology-Directed Engine Propels Prothena’s Progress Across our Broad Pipeline Therapeutics engineered to optimally eliminate pathogenic proteins while preserving normal biology Multiple Clinical Programs Ongoing Disease- Wholly-owned Phase 3 program Driven Three partnered Phase 2 programs Antibo
Slide 6: Robust R&D Pipeline
Robust R&D Pipeline FOCUSED ON NEURODEGENERATIVE AND RARE PERIPHERAL AMYLOID DISEASES PROGRAM/ GLOBAL PROTEIN TARGET DISCOVERY PRE-CLINICAL PHASE 1 PHASE 2 PHASE 3 INDICATION PARTNER4 Birtamimab Kappa & Lambda SPA1 ODD2 Fast AFFIRM-AL (Phase 3) AL amyloidosis Track3 Light Chain Prasinezumab -Synucl
Slide 7: Alzheimer's Disease
Alzheimer’s Disease
Slide 8: Our Team has Pioneered Multiple Scientific Advances in Protein Dysregulation
Our Team has Pioneered Multiple Scientific Advances in Protein Dysregulation OUR LEGACY INCLUDES FOUNDATIONAL DISCOVERIES IN THE UNDERSTANDING OF ALZHEIMER’S DISEASE Pioneered fundamental discoveries elucidating the roles of beta amyloid (A), gamma secretase and beta secretase play in disease1 Firs
Slide 9: Our Legacy Drives Our Vision to Transform the Care of Alzheimer's Disease
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; designe
Slide 10: Targeting Alzheimer's Where it Matters
Targeting Alzheimer’s Where it Matters Aβ has been established as a disease modifying target Aβ plaque Vascular Aβ deposits (fibrils) in Alzheimer’s disease Microglia Reduction of Aβ plaque MTBR-Tau transmission associated with clinically Neurofibrillary meaningful slowing of tangles (NFT) disease p
Slide 11: Today's Clinical Science Validates the Mechanism Designed by Our Team
Today’s Clinical Science Validates the Mechanism Designed by Our Team Mean Difference from Placebo in Reduction of Amyloid Plaque1 and CDR-SB Progression Group Level Mean Difference Disease from Placebo on CDR Slowing of Progression Reduction of amyloid plaque Increase of amyloid plaque Group Level
Slide 12: Targeting Alzheimer's Where it Matters
Targeting Alzheimer’s Where it Matters CHANGING THE TREATMENT PARADIGM THROUGH OUR BIOLOGY-DIRECTED ENGINE Dynamic biomarkers of the Alzheimer’s pathological cascade1 12 1 Jack, Clifford et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade, 2010 NIH Public Access
Slide 13: PRX012
PRX012 Alzheimer’s Disease
Slide 14: PRX012: Leading a Paradigm Shift in the Treatment of Alzheimer's Disease
PRX012: Leading a Paradigm Shift in the Treatment of Alzheimer’s Disease 300+ iterative antibody design and optimization campaigns led to… 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
Slide 15: Translating Patient Needs Into Antibody Engineering
Translating Patient Needs Into Antibody Engineering PATIENT-CENTRIC DESIGN STRATEGY FOR PRX012 TARGET PROFILE ANTIBODY DESIGN ATTRIBUTES OUR MISSION Maintain From First Effectively clear soluble and • N-terminal directed Generation insoluble aggregated amyloid Improve patient outcomes • Full effecto
Slide 16: PRX012: Promotes Comprehensive Clearance of Amyloid Plaques and Neutralization of Oligomers
PRX012: Promotes Comprehensive Clearance of Amyloid Plaques and Neutralization of Oligomers Designed to target and clear toxic aggregated forms of Aβ Free/ dispersed Aggregated Microglia PRX012 Aβ plaque Aβ Forms PRX012 elicits microglial-mediated phagocytosis Both unmodified Aβ fibrils and Phagocyt
Slide 17: PRX012 and Surrogate Demonstrate Equivalent Potent Binding Affinity for Aβ
PRX012 and Surrogate Demonstrate Equivalent Potent Binding Affinity for Aβ Surface Plasmon Resonance (SPR) Affinity for Aβ Species Aβ Fibrils Compound Fibril/Plaque N3pE-Aβ 60 Slow off-rate (PRX012 & PRX012s) PRX012 0.070a >67b Response (RU) 40 PRX012s 0.054a >67b Fast biphasic off-rate (aducanumab)
Slide 18: PRX012s Binds Aβ Protofibrils With Very High Affinity
PRX012s Binds Aβ Protofibrils With Very High Affinity Surface Plasmon Resonance Antibody Relative Affinity (KD1) Aβ Protofibrils Lecanemab1 1.97 nM (Tucker et al., 2015) Lecanemab2 1.91 nM dissociation Slower PRX012s 0.0975 nM SPR Binding Kinetics Antibody dissociation ka1 (1/Ms) kd1 (1/s) KD1 Lecan
Slide 19: PRX012s Induced Potent and Robust Clearance of Pyroglutamate-modified Aβ
PRX012s Induced Potent and Robust Clearance of Pyroglutamate-modified Aβ PRX012s PRX012s Abeta Aβ Donanemab Donanemab N3pE 40 Reduction %%Reduction N3pE ofof 20 Study Conditions Post-mortem AD brain tissue (same donor used for Tissue all conditions) Treatment PRX012s, donanemab, or IgG1 isotype cont
Slide 20: PRX012s Promotes Simultaneous Microglia-Mediated Phagocytosis of Aβ and N3pE-Aβ
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 Microglia Aβ N3pE-Aβ Merge hIgG1 PRX012s Microglia (Iba1: green) simultaneously phagocytose Aβ (red) and pyroglutamate-modified Aβ (AβpE3-42:
Slide 21: PRX012 Phase 1 SAD Design
PRX012 Phase 1 SAD Design Healthy Volunteer Cohorts Trial • Age 20 – 45 years Design 70 mg 200 mg • Phase 1, randomized 3:1, double-blind, placebo-controlled, n~8 n~8 single ascending dose trial (3:1) (3:1) • 1 subcutaneous dose of PRX012 or placebo • Evaluate the safety, tolerability, Early Alzheim
Slide 22: PRX012 Phase 1 Multiple Dose Design
PRX012 Phase 1 Multiple Dose Design Trial Overview1 Key Inclusion Dose Escalation: “A” and “B” Cohorts2,3 Dose Expansion Key Objectives Criteria • Evaluate the safety, 45 mg A Cohort (n~32) • Patients with tolerability, and SC 6X Q4W early AD immunogenicity 70 mg A Cohort (n~32) • Effect on brain •
Slide 23: BMS-986446
BMS-986446 (formerly PRX005) Alzheimer’s Disease Global Neuroscience Collaboration with Bristol Myers Squibb
Slide 24: BMS-986446: Potential Best-in-Class anti-Tau antibody for Alzheimer's Disease
BMS-986446: Potential Best-in-Class anti-Tau antibody for Alzheimer’s Disease Phase 2 Trial (NCT06268886): Ongoing BMS-986446 Alzheimer’s disease • Global, double-blind, placebo-controlled Current Status: Phase 2 • 475 participants with early AD • Randomized, 3 arms (two doses and placebo) Anti-Tau
Slide 25: BMS-986446: MTBR-Specific Anti-Tau Antibody
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 thou
Slide 26: BMS-986446 (PRX005): Superior in Blocking Cellular Internalization of Tau
BMS-986446 (PRX005): Superior in Blocking Cellular Internalization of Tau and Downstream Neurotoxicity Compared to Other Anti-Tau Antibodies PRX005 blocks internalization of tau Repeats 1 and 2 defined as the strongest inhibitory regions in screening with cellular 100 internalization and neurotoxici
Slide 27: (m)PRX005 Treatment Reduces Pathological Tau and Ameliorates Behavioral Deficit
(m)PRX005 Treatment Reduces Pathological Tau and Ameliorates Behavioral Deficit in Transgenic Tau Mouse Model All values are mean ± SE (n=15-20) Reduction of tau pathological markers Delay of behavioral deficit *p<0.05 *p<0.05 pTau-199/202 in brainstem (% area) * * Chronic dosing start pTau-212 in b
Slide 28: BMS-986446: TargetTau-1 Phase 2 Trial Design
BMS-986446: TargetTau-1 Phase 2 Trial Design TargetTau-1 Trial Overview (NCT06268886)1 Key Inclusion Criteria Primary Endpoint • Ages 50 – 80 years Placebo • Mean change from baseline in CDR-SB score • MCI due to AD or vs. placebo at 76 weeks mild AD dementia Randomized BMS-986446 Secondary Endpoint
Slide 29: PRX123
PRX123 Alzheimer’s Disease
Slide 30: Potential Best-in-class Dual Aβ/Tau Vaccine for Treatment & Prevention of AD
Vaccine Constructs: Potential Best-in-class Dual Aβ/Tau Vaccine for the Treatment & Prevention of AD PROTHENA IS PIONEERING THE DEVELOPMENT OF DUAL Aβ/TAU VACCINE CANDIDATE PRX123 • Synergistic mechanism designed for increased efficacy over single-target vaccines Cleavage Site A MTBR of tau – Stron
Slide 31: Desirable Attributes of Aβ/Tau Vaccines and Prothena's Design Strategies
Desirable Attributes of Aβ/Tau Vaccines and Prothena’s Design Strategies Design Strategy Desirable Output • Linear peptides, proprietary ✓ Optimal antigen presentation RESPONSE cleavable linkers with persistent immune response 1 Antibody levels, balanced • Optimal carriers, immunization ✓ Overcomes
Slide 32: Dual Aβ/Tau Vaccines Demonstrate Desirable Quantity, Quality and Safety
Prothena’s Dual Aβ/Tau Vaccines Demonstrate Desirable Quantity, Quality and Safety Quantity Quality Safety Unable to induce measurable cytotoxic T-cell activity against Aβ and tau in Non-human primates (ELISpot) Prothena’s Dual Vaccine Positive Control Aβ Tau ✓ Epitope, affinity, Aβ clearance, ✓ Avo
Slide 33: Birtamimab
Birtamimab AL Amyloidosis
Slide 34: Birtamimab: Differentiated Approach to AL Amyloidosis
Birtamimab: Differentiated Approach to AL Amyloidosis Phase 3 AFFIRM-AL (NCT04973137): Ongoing5 Birtamimab • Trial designed per FDA Special Protocol AL amyloidosis Assessment (SPA) with unprecedented P ≤ 0.10 Current Status: Phase 3 • Primary Endpoint: Time to all-cause mortality Anti-Amyloid Mechan
Slide 35: Abnormal Light Chains Deposit As Amyloid in Vital Organs, Most Commonly the Heart
Abnormal Light Chains Deposit As Amyloid in Vital Organs, Most Commonly the Heart1 AL AMYLOIDOSIS PATHOGENIC PATHWAY CARDIAC DYSFUNCTION & EARLY MORTALITY2,3 SOLUBLE TOXIC INSOLUBLE PLASMA CELL DYSCRASIA1,2 LIGHT CHAIN AGGREGATES2,3 AMYLOID DEPOSITS2 Continuous accumulation of toxic amyloid in Light
Slide 36: Birtamimab's Anti-Amyloid Mechanism Designed to Address the Unmet Need
Birtamimab’s Anti-Amyloid Mechanism Designed to Address the Unmet Need for Patients AL AMYLOIDOSIS PATHOGENIC PATHWAY2-4 CARDIAC DYSFUNCTION & EARLY MORTALITY SOLUBLE TOXIC INSOLUBLE PLASMA CELL DYSCRASIA LIGHT CHAIN AGGREGATES AMYLOID DEPOSITS Current plasma cell directed Birtamimab’s transformativ
Slide 37: Birtamimab Designed to Address Unmet Need
Birtamimab Designed to Address Unmet Need Birtamimab1,2 CAEL-1013-5 Daratumumab1,6,7 (Prothena) (AZ/Alexion) (Janssen) Anti-Fibril mAb Demonstrated Early Survival Benefit in a Randomized Clinical Triala MOA: Clears Insoluble Deposits MOA: Neutralizes Soluble Aggregates Monthly Dosing Humanized Addit
Slide 38: Birtamimab Demonstrated Significant Amyloid Clearance and Prolonged Survival in Preclinical Model
Birtamimab1 Demonstrated Significant Amyloid Clearance and Prolonged Survival in Preclinical Model Birtamimab1 Removes Amyloid In Vivo Birtamimab1 Prolongs Survival in Transgenic Mouse Model 100% survival with birtamimab1 p < 0.0025 100 80 Percent survival 60 40 Control mAB 20 Birtamimab1 0 0 10 20
Slide 39: Phase 3 VITAL Trial Overview
Phase 3 VITAL Trial Overview1 Global, randomized, double-blinded, placebo-controlled clinical trial − Sample size and randomization ▪ N=260 ▪ 1:1 30% of patients enrolled in VITAL − Key eligibility criteria (N=77) were characterized as ▪ Confirmed diagnosis of AL amyloidosis Mayo Stage IV at baselin
Slide 40: Previous Phase 3 VITAL Trial Demonstrated Significant Survival Benefit in Mayo Stage IV
Previous Phase 3 VITAL Trial Demonstrated Significant Survival Benefit in Mayo Stage IVa,1 Time to All-Cause Mortality (ACM) in Mayo Stage IV Patientsb Post Hoc Analyses of Initial Phase 3 Randomized Trial (VITAL) 1.0 in Mayo Stage IV Patients Birtamimab + SoC (n=38) Efficacy Reduced 0.8 Risk of • U
Slide 41: Birtamimab Survival Benefit Persists When Adjusted for Key Baseline Variables
Birtamimab Survival Benefit Persists When Adjusted for Key Baseline Variables (Mayo Stage IV)a,1 a Adapted from Gertz et al. Blood. 2023. 41 1 Gertz MA, et al. Blood. 2023;142(14):1208-1218.
Slide 42: Birtamimab: Confirmatory Phase 3 AFFIRM-AL Trial Design
Birtamimab: Confirmatory Phase 3 AFFIRM-AL Trial Design Trial Overview (NCT04973137)1 Key Eligibility Criteria Primary Endpoint • Confirmed diagnosis Birtamimab of AL amyloidosis • Time to all-cause mortality (IV Q4W) • Patients with + Standard of Carea Secondary Endpoints significant cardiac Random
Slide 43: AL Amyloidosis Patients Require Urgent Treatment Upon Diagnosis
AL Amyloidosis Patients Require Urgent Treatment Upon Diagnosis1,2 PRESENTATION2-3 DIAGNOSIS JOURNEY2,4 TREATMENT5 PCP CARDIOLOGIST NEPHROLOGIST HEMATOLOGIST/ONCOLOGIST SYMPTOMS/SIGNS INCLUDE: • Stiff heart Normal Hearta,6 Amyloidosis Heartb,7 • Shortness of breath • Blood pressure changes NEUROLOGI
Slide 44: Unmet Need: Early Mortality
Unmet Need: Early Mortality Phase 3 ANDROMEDA Study: Daratumumab (D) + Bortezomib, Cyclophosphamide, and Dexamethasone (VCd) in AL Amyloidosis Patients1 Highlights urgent need to increase early survival for patients with cardiac involvement 44 1 Adapted from presentation by E Kastritis at the 66 th
Slide 45: Established Market: Significant opportunity of currently treated patients with high unmet need
Established Market: Significant opportunity of currently treated patients with high unmet need1-6 Total Treated AL Amyloidosis Patients: ~16K in the U.S. Cardiac Involvement: ~13K patients Significant Cardiac Involvement: ~7K patients Mayo Stage IV: ~30% • Studied in AFFIRM-AL trial • High risk of e
Slide 46: Established Patient Population and Consolidated Prescriber Base Enable Focused Launch
Established Patient Population and Consolidated Prescriber Base Enable Birtamimab Market Penetration with Focused Launch Established Consolidated Regulatory and IP Patient Population1-6 Prescriber Base6 Positioning Treated AL amyloidosis patients with • ~75% US + EU patients primarily cardiac involv
Slide 47: Birtamimab: Global Commercial Opportunity
Birtamimab: Global Commercial Opportunity Birtamimab has the potential to be the first anti-amyloid MOA to address significant unmet needs in AL amyloidosis, positioning it as 1L and critical component of SOC $ Multi-Billion Only treatment to demonstrate early survival Market Potential benefit in a
Slide 48: Prasinezumab
Prasinezumab Parkinson’s Disease Worldwide Collaboration with Roche
Slide 49: Prasinezumab: Potential First-in-Class Treatment for Parkinson's Disease
Prasinezumab: Potential First-in-Class Treatment for Parkinson’s Disease Phase 2 Clinical Development Program: Prasinezumab Parkinson’s Disease • First anti-a-synuclein antibody to slow progression on measures of PD Current Status: Phase 2b Complete • Consistent positive trends across multiple endpo
Slide 50: α-Synuclein Pathology is Strongly Implicated in Parkinson's Disease
-Synuclein Pathology is Strongly Implicated in Parkinson’s Disease Accumulation of -Synuclein Neuronal -Synuclein Dopaminergic neurodegeneration is a predominant Symptoms neuropathological feature and Biological or Clinical Measures Functional impairment follows the topological progression of dis
Slide 51: Prasinezumab: α-Synuclein Immunotherapy
Prasinezumab: -Synuclein Immunotherapy REDUCE NEURONAL TOXICITY AND PREVENT CELL-TO-CELL TRANSMISSION1 Diseased Neuron Protected Neuron -Synuclein as an extracellular target during pathogenesis Aggregated • Caudal-rostral staging, extracellular host-to-graft transfer, -Synuclein various propagati
Slide 52: Prasinezumab: Clinical Development Program for Early Parkinson's Disease
Prasinezumab: Clinical Development Program for Early Parkinson’s Disease Phase 2 PASADENA (NCT03100149) Phase 2b PADOVA (NCT04777331) • N=316, randomized 1:1:1 (1500 mg, 4500 mg, placebo), Q4W • N=586, randomized 1:1 (1500 mg, placebo), Q4W IV dosing for IV dosing for 52 weeks (Part 1), followed by
Slide 53: Phase 2b PADOVA Trial Summary of Results
Phase 2b PADOVA Trial Summary of Results 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
Slide 54: Phase 2 PASADENA Trial Summary of Results
Phase 2 PASADENA Trial Summary of Results 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 individu
Slide 55: PASADENA Open-Label Extension
PASADENA Open-Label Extension PRASINEZUMAB CONTINUED TO SLOW PROGRESSION OF MOTOR DEFICITS IN EARLY-STAGE PD 4-year change from baseline on MDS UPDRS Part III OFF score1 PASADENA: Open-Label Extension Compared prasinezumab population with a propensity score-balanced cohort of real-world data (RWD) P
Slide 56: PASADENA Open-Label Extension
PASADENA Open-Label Extension PRASINEZUMAB CONTINUED TO SLOW PROGRESSION OF MOTOR DEFICITS IN EARLY-STAGE PD 4-year change from baseline on MDS UPDRS Part III ON score1 PASADENA: Open-Label Extension The data suggests that prasinezumab slowed the progression of motor deficits (MDS-UPDRS Part III ON
Slide 57: Coramitug
Coramitug (formerly PRX004) ATTR Amyloidosis with Cardiomyopathy ATTR Business Acquired by Novo Nordisk
Slide 58: Coramitug: Potential First-in-Class Treatment for ATTR-CM
Coramitug (formerly PRX004): Potential First-in-Class Treatment for ATTR-CM Phase 2 Signal Detection Trial (NCT05442047): Coramitug Ongoing ATTR amyloidosis with • N = ~99 ATTR-CM patients, 3 arms cardiomyopathy (ATTR-CM) • Participants receive IV infusion Q4W of 10 mg/kg or Current Status: Phase 2
Slide 59: Differentiated Mechanism for ATTR-CM
Differentiated Mechanism for ATTR-CM NON-PATHOGENIC PATHWAY PATHOGENIC PATHWAY HEART Protein Misfolding Restrictive cardiomyopathy Heart failure PERIPHERAL NERVES Loss of sensation LIVER FREE MONOMER, SOLUBLE Loss of reflex TETRAMER AGGREGATE Muscle weakness AMYLOID FIBRILS Coramitug: Current Treatm
Slide 60: Designed to Deplete Amyloid
Designed to Deplete Amyloid SUMMARY OF PRECLINICAL EFFECTS OF mPRX004 mPRX004 (murine ✓ Inhibits fibril formation form of PRX004) ✓ Specifically binds to pathogenic TTR preclinical results:1 ✓ Reacts to amyloid deposits in multiple organs in both wtATTR and ATTRv patients ✓ Promotes in vivo ATTR amy
Slide 61: Upcoming Milestones
Upcoming Milestones
Slide 62: Clinical Milestones
Clinical Milestones TRANSFORMATIONAL PERIOD AHEAD Wholly-owned Programs Birtamimab for potential treatment of AL amyloidosis 1H25 Confirmatory Phase 3 AFFIRM-AL topline data (NCT04973137) PRX012 for potential treatment of Alzheimer’s disease 2024 Ongoing Phase 1 ASCENT clinical trials update Mid
Slide 63: Appendix: Partnership and Collaboration Details
APPENDIX: Partnership and Collaboration Details
Slide 64: Bristol Myers Squibb Collaboration: Advancing Two Clinical Stage Programs
Bristol Myers Squibb Collaboration: Advancing Two Clinical Stage Programs 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-98644
Slide 65: Worldwide Collaboration with Roche
Worldwide Collaboration with Roche Total Milestones $755 million $-- ✓ Upfront, P1, P2 and P2b milestones $135 million1 -- Clinical, regulatory & first sale $290 million -- U.S. sales milestones $155 million -- Ex-U.S. sales milestones $175 million – • Up to double digit • Leads clinical • U.S