Prothena Corporation plc · NASDAQ:PRTA
Prothena — Technical Presentation (December 2020)
38 slides from Prothena's technical presentation, Dec 9, 2020
Slide 1: PRX004, the First Investigational Anti-Amyloid Immunotherapy for ATTR Amyloidosis
PRX004, the First Investigational Anti-Amyloid Immunotherapy for the Treatment of ATTR Amyloidosis 9-month results from a Phase 1 long-term extension study December 9, 2020 CONFIDENTIAL
Slide 2: Agenda and Speakers
Agenda and Speakers • Introduction - Gene Kinney, PhD, President & Chief Executive Officer • ATTR Amyloidosis Overview - Wagner Zago, PhD, Chief Scientific Officer • PRX004 Phase 1 Study Results - Ole Suhr, MD, Senior Professor, Department of Public Health and Clinical Medicine, Umeå University • AT
Slide 3: Forward-looking Statements
Forward-looking Statements This overview contains forward-looking statements. These statements relate to, among other things: the design, proposed mechanism of action and possible clinical benefits of PRX004, and its potential as a treatment for ATTR amyloidosis; the potential of PRX004 to complemen
Slide 4: Introduction
Introduction Gene Kinney, PhD President & CEO
Slide 5: Protein Dysregulation and Amyloid Causes Multiple Fatal Diseases
Protein Dysregulation and Amyloid Causes Multiple Fatal Diseases Expertise in protein dysregulation applied to rare peripheral amyloid disease and neurodegeneration ü Understanding protein dysregulation in the context of disease ü Expertise in targeting toxic proteins to alleviate detrimental effect
Slide 6: PRX004: Depleter MOA for ATTR Amyloidosis
PRX004: Depleter MOA for ATTR Amyloidosis Differentiated MOA Phase 1 results of first-in-class amyloid depleter demonstrate: • Improvement in neuropathy Efficient High Unmet • Improvement in cardiac Development Need function PRX004 • Favorable safety & tolerability Focused Targeted Patient Physician
Slide 7: ATTR Amyloidosis Overview
ATTR Amyloidosis Overview Wagner Zago, PhD, Chief Scientific Officer
Slide 8: Amyloid Deposition Causes ATTR Amyloidosis
Amyloid Deposition Causes ATTR Amyloidosis Amyloid accumulates over time and is present in organs at diagnosis NON-PATHOGENIC PATHWAY PATHOGENIC PATHWAY NOT PATHOGENIC HEART Restrictive cardiomyopathy Heart failure PROTEIN MISFOLDING PERIPHERAL NERVES Loss of sensation LIVER FREE MONOMER, SOLUBLE AG
Slide 9: PRX004: Differentiated Depleter MOA
PRX004: Differentiated Depleter MOA Specifically targets non-native transthyretin (TTR) to clear amyloid NON-PATHOGENIC PATHWAY PATHOGENIC PATHWAY NOT PATHOGENIC HEART Restrictive cardiomyopathy Heart failure PROTEIN MISFOLDING PERIPHERAL NERVES Loss of sensation LIVER FREE MONOMER, SOLUBLE AGGREGAT
Slide 10: Prothena Developed PRX004 to Target an Epitope Exposed on Pathogenic Forms of TTR
Prothena Developed PRX004 to Target an Epitope Exposed on Pathogenic Forms of TTR1 • Epitope recognized by PRX004 is hidden in the TTR tetramer, but exposed in monomeric and aggregated forms of both hATTR and wtATTR2 TTR89-97 1-GPTGTGESKC PLMVKVLDAV RGSPAINVAV HVFRKAADDT WEPFASGKTS-50 51-ESGELHGLTT
Slide 11: PRX004: Designed to Deplete Amyloid
PRX004: Designed to Deplete Amyloid Summary of preclinical effects of mPRX004 mPRX004 (murine form of PRX004) preclinical results:1 ü Inhibits fibril formation ü Specifically binds to pathogenic TTR ü Reacts to amyloid deposits in multiple organs in both wtATTR and hATTR patients ü Promotes in vivo
Slide 12: mPRX004 Depletes Amyloid by Phagocytosis In Vitro
mPRX004* Depletes Amyloid by Phagocytosis In Vitro Control IgG mPRX004* In the presence of PRX004, phagocytes engulf amyloid, indicated by red fluorescence mPRX004 induces antibody-dependent phagocytosis of ATTR by phagocytes * Murine form of PRX004 12
Slide 13: Preclinical PK/PD Dose Selection Model, Confirmed in PRX004-101
Preclinical PK/PD Dose Selection Model, Confirmed in PRX004–101 Preclinical PK/PD Model Clinical Confirmation of Preclinical PK/PD Model 3 10 30 mg/kg 3 10 30mg/kg Variables 3 10 30mg/kg Variables Max) Max) (% Max) Modeled Amyloid Binding (% Max) 100 • Binding kinetics and 100 100 • Reduction in fre
Slide 14: PRX004 Phase 1 Study Results
PRX004 Phase 1 Study Results Ole Suhr, MD Senior Professor, Department of Public Health and Clinical Medicine, Umeå University
Slide 15: PRX004 Phase 1 Study Design
PRX004 Phase 1 Study Design NCT03336580 Escalation Phase Long Term Extension Phase* • 3+3 study design • Up to 15 additional doses • 6 Dose levels: 0.1, 0.3, 1, 3, 10, & 30 mg/kg IV q28d for IV q28d 3 months Primary Objectives: • Evaluate safety, tolerability, PK and target engagement (misTTR assay)
Slide 16: PRX004: Summary of Baseline Demographic Data
PRX004: Summary of Baseline Demographic Data PRX004 PRX004 PRX004 PRX004 PRX004 PRX004 Overall 0.1 mg/kg 0.3 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg 30 mg/kg (n=21) (n=3) (n=3) (n=3) (n=3) (n=3) (n=6) Age Range (years) 68-72 65-68 66-75 58-78 42-75 44-70 42-78 Sex: Male/ (%) 66.7 33.3 66.7 66.7 33.3 83.3 61.
Slide 17: No Serious Treatment Related AEs
No Serious Treatment Related AEs PRX004 exposure and summary of TEAEs Dose Escalation Phase, Cohorts 1-6, completed (all subjects received at least 3 doses of PRX004) During the study (end of Long-Term Extension): • 223 infusions were given over 21 patients • Patients received between 3-17 infusions
Slide 18: PRX004 Safe and Well Tolerated Through LTE
PRX004 Safe and Well Tolerated Through LTE • For subjects administered PRX004 at all dose levels and time points: – Multiple IV infusions of PRX004 were generally safe and well-tolerated – No dose-limiting toxicities, no serious, related TEAEs and no life-threatening or fatal events have been report
Slide 19: PRX004 Exposure Increases in a Dose Proportional Manner
PRX004 Exposure Increases in a Dose Proportional Manner Month 1 - First Dose Month 3 - Third Dose 1000 1000 Concentration (µg/mL) Concentration (µg/mL) 100 100 10 10 1 1 0.1 0.1 0 8 16 24 168 336 504 672 0 8 16 24 168 336 504 672 Time (hr) Time (hr) C1 (0.1 mg/kg) C4 (3 mg/kg) C2 (0.3 mg/kg) C5 (10
Slide 20: Neuropathy Impairment Assessments in Clinical Studies
Neuropathy Impairment Assessments in Clinical Studies BP: Blood Pressure HRdb: Heart Rate Response to Deep Breathing NCS: Nerve Conduction Studies QST: Quantitative Sensory Testing Adapted from Adams D et al., Neurology. 2015 20
Slide 21: Observed Improvement in Neuropathy with PRX004
Observed Improvement in Neuropathy with PRX004 • NIS for each of the 7 evaluable patients was more favorable than 12 published historical data Natural history1 • 3 of these 7 patients demonstrated improvement in neuropathy with a 8 ΔNIS from baseline mean change in NIS of –3.33 points 4 PRX004 Phase
Slide 22: Observed Improvement in Cardiac Systolic Function with PRX004
Observed Improvement in Cardiac Systolic Function with PRX004 • Improvement in GLS in all 7 evaluable patients 3 • In the 3 patients who improved on NIS, GLS improvement was more pronounced, with a mean change of –1.51% ΔGLS from baseline 2 1 PRX004 Phase 1 Placebo- Patisiran1 All PRX004 Alone treat
Slide 23: NYHA Classification Remained Stable with PRX004
NYHA Classification Remained Stable with PRX004 • Classification at baseline: – NYHA I (n=6) NYHA Patient Symptoms – NYHA II (n=1) Class • All patients (n=7) were stable at their last No limitation of physical activity. Ordinary assessed timepoint I physical activity does not cause undue fatigue, pa
Slide 24: Summary of Phase 1 Study Results
Summary of Phase 1 Study Results PRX004 in ATTR amyloidosis • First clinical results from a depleter mechanism of action in ATTR amyloidosis – 223 total doses administered through the end of the study – Patient received between 3 – 17 doses • All six dose levels of PRX004 found to be generally safe
Slide 25: ATTR Amyloidosis Patient Journey – Diagnosis, Treatment Options, and Unmet Need
ATTR Amyloidosis Patient Journey – Diagnosis, Treatment Options, and Unmet Need Daniel Lenihan, MD Director, Cardio-Oncology Center of Excellence Cardiovascular Division, Washington University in St. Louis
Slide 26: ATTR Amyloidosis is Caused by Amyloid Deposition
ATTR Amyloidosis is Caused by Amyloid Deposition • ATTR amyloidosis is a rare, progressive, and fatal disease caused by amyloid deposition leading to organ dysfunction and failure • In amyloidosis, proteins misfold, form toxic aggregates and deposit as amyloid in vital organs – Most commonly the hea
Slide 27: Patients Often Present with Advanced Cardiac Disease
Patients Often Present with Advanced Cardiac Disease 1• Patients may present with symptoms attributed to Patient with other cardiovascular conditions ATTR Amyloidosis • ATTR suggested as significant underlying cause of heart failure with preserved ejection fraction (HFpEF) • ~35% of ATTR patients mi
Slide 28: Confirming ATTR Amyloidosis Diagnosis Requires Piecing Together Clinical Assessments
Confirming ATTR Amyloidosis Diagnosis Requires Piecing Together a Patchwork of Clinical Assessments ATTR Amyloidosis ATTR Amyloidosis Diagnostic Dynamics Clinical Assessments Exclude AL amyloidosis • Most patients are admitted to the hospital with a Echocardiogram clinical event that sparks suspicio
Slide 29: Tafamidis Showed Little/No Benefit in NYHA Class III ATTR Patients
Tafamidis Showed Little/No Benefit in NYHA Class III ATTR Amyloidosis Patients; NYHA Class IV Not Studied Source: Maurer M et al. 2018; ATTR-ACT Phase 3 Study 29
Slide 30: Next Steps and Summary
Next Steps and Summary Radhika Tripuraneni, MD, MPH Chief Development Officer
Slide 31: NYHA Class III and IV Patients Lack Effective Treatment Options
NYHA Class III and IV Patients Lack Effective Treatment Options Representing 130k-490k Patients Globally HFpEF Patients ATTR-CM Patients NYHA Class III-IV 4-13%2,3 32-34%4,5,6 11m patients1 400k-1.4m patients 130-490k patients Urgent need in significant patient population for amyloid targeting thera
Slide 32: Phase 3 Study of Birtamimab in AL Amyloidosis: All-Cause Mortality
Phase 3 Study of Birtamimab in AL Amyloidosis: All-Cause Mortality, Mayo Stage IV (n=77) Amyloidosis AL ATTR Birtamimab + SOC Type Amyloid deposition in Amyloid deposition in All-Cause Mortality Cause vital organs vital organs Probability Involved Light chain Transthyretin protein Placebo + SOC (hem
Slide 33: Planning Moderate-to-Advanced ATTR-CM Study with PRX004
Planning Moderate-to-Advanced ATTR-CM Study with PRX004 • Planning underway for next study, to initiate in 2021 - Depleter MOA designed to clear amyloid deposition responsible for early mortality - Expanding patient population due to increased awareness - Significant need for therapies that improve
Slide 34: Concluding Remarks
Concluding Remarks Gene Kinney, PhD President & CEO
Slide 35: PRX004: Uniquely Positioned to Change the Treatment Paradigm in ATTR-Cardiomyopathy
PRX004: Uniquely Positioned to Change the Treatment Paradigm in ATTR-Cardiomyopathy Differentiated MOA First-in-class amyloid depleter • PRX004 demonstrated clinical benefit - Improvement in neuropathy and cardiac function Efficient High Unmet - Safe and well-tolerated Development Need • Further stu
Slide 36: Robust R&D Pipeline
Robust R&D Pipeline Focused on neurodegenerative and rare peripheral amyloid diseases Biomarker Commercial Program / Target Discovery Preclinical Phase 1 Phase 2 Phase 3 Enabled Rights Prasinezumab / a-synuclein PASADENA (Phase 2) ü MRI-ASL Parkinson’s Disease PRX004 / TTR ü Non-native TTR* Phase 1
Slide 37: Upcoming R&D Milestones
Upcoming R&D Milestones • Prasinezumab for the potential treatment of PD (worldwide collaboration with Roche) ü Part 1 of the Phase 2 PASADENA study in patients with early PD (N=316) showed signals of efficacy. Results presented as an oral Top Abstract presentation at virtual MDS Congress 2020. Part
Slide 38: Q&A
Q&A