Passage Bio, Inc. · NASDAQ:PASG
Passage Bio — ESGCT 2024
19 slides from Passage Bio's conference presentation, Oct 24, 2024
Slide 1: Non-clinical and early clinical development of PBFT02, an AAV gene therapy for FTD-GRN
Non-clinical and early clinical development of PBFT02, an AAV gene therapy for FTD with GRN mutations (FTD-GRN) SE Browne, YG Ni, KJ Quadrini, T Voss, MS Forman, J Chavez, N Miller, C Hinderer, JM Wilson ESGCT OR070, 24 October 2024
Slide 2: Disclosures
Disclosures • Sue Browne, Ph.D, Yan Yi, Ph.D and Juan Chavez, MD, Ph.D are employees of Passage Bio, Inc. (the “Company”) and have certain equity interests in the Company • James Wilson, MD, Ph.D is a paid advisor to the Company and has certain equity interests in the Company. • James Wilson, MD, Ph
Slide 3: FTD-GRN: A Devastating Adult Disease
FTD-GRN: A Devastating Adult Disease Frontotemporal Degeneration, FTD FTD-GRN • Rapidly progressive, fatal, • 5 to 10% of FTD is caused by neurodegenerative disease affecting mutations in the granulin (GRN) gene the frontal and temporal lobes of the – Haploinsufficiency reduces brain brain progranul
Slide 4: Progranulin Deficiency is the Defining Characteristic of FTD-GRN
Progranulin (PGRN) Deficiency is the Defining Characteristic of FTD-GRN, Leading to Neurodegeneration Progranulin is critical to maintaining CNS cell homeostasis Our approach: AAV gene therapy to deliver functional PGRN to the brain 4 Rhinn H et al. Trends Pharm Sci. 2022, 43:641-652.
Slide 5: PBFT02 Development Pathway
PBFT02 Development Pathway • Transgene cassette design • Dose ranging in granulin-deficient mice • Vector selection in NHPs Discovery Pre-clinical IND • Clinical lead biodistribution, safety, toxicology in NHPs • Ph 1/2 clinical study in FTD-GRN Phase 1/2 Pivotal Filing/Comm 5 Abbreviations: NHP, no
Slide 6: hGRN Transgene Cassette Optimized
Discovery & Lead ID hGRN Transgene Cassette Optimized • Codon-optimized sequence of the human GRN gene under the control of the ubiquitous CB7 promoter • Designed to deliver functional GRN genes encoding PGRN to brain and spinal cord • Ability to transduce multiple CNS cell types 6
Slide 7: Proof of Concept: hGRN Transgene Delivery Improved Lysosomal Function in PGRN-Deficient Mice
Proof of Concept: hGRN Transgene Delivery Improved Lysosomal Function in PGRN-Deficient Mice Efficacy in Grn knockout mice after tool AAVhu68.hGRN vector ICV administration to CSF Grn-/- (AAV9 variant) 2 mo hPGRN Expressed in Brain of Grn-/- mice Reduced Lipofuscin Fluorescence in Thalamus Reduced B
Slide 8: AAV1 Selected as Vector Serotype after a Capsid Comparison Study in NHPs
AAV1 Selected as Vector Serotype after a Capsid Comparison Study in NHPs • Superior hPGRN levels in CSF Human PGRN in NHP CSF after AAV1 compared to AAV5 Vector Comparison AAV1.CB7.hGRN and AAVhu68 (AAV9 variant) 80 AAV5.CB7.hGRN AAVhu68.CB7.hGRN ‒ Clinical delivery route, ICM 70 AAVhu68.UbC.hGRN •
Slide 9: PBFT02 Dose Selection: Efficacy in Grn-/- Mice
Non-clinical PBFT02 Dose Selection: Efficacy in Grn-/- Mice Retinal Grn-/- mice Lipofuscinosis degeneration Focal Lysosomal enzyme Microglial Phagocytic neuronal Phenotype dysregulation activation Astrogliosis microglia loss Normal lifespan Age / 0 1 2 3 4 5 6 7 8 9 10 11 12 23 months ICV AAV1 / PBF
Slide 10: PBFT02 Improved Lysosomal Function in the Brain
PBFT02 Improved Lysosomal Function in the Brain Dose ranging in Grn-/- mice after intra-CSF delivery Lipofuscin deposition in brain Thalamus Lipofuscin was reduced by ICV PBFT02 Baseline Day 90 1500 ### ### * • Partially reversed existing *** PBFT02 Dose 1 pathology *** *** Lipofuscin Count 1000 Dos
Slide 11: Neuroinflammation Reduced in the Brain after PBFT02
Neuroinflammation Reduced in the Brain after PBFT02 Dose ranging in Grn-/- mice after intra-CSF delivery Activated microglia reduced Thalamus CD68 Immunohistochemistry in both cortical and sub- Baseline Day 90 8000 ## cortical brain regions after ### * PBFT02 ICV PBFT02 Dose 1 CD68 Area (μm2) 6000 D
Slide 12: Intra-Cisterna Magna Administration of PBFT02 Enables PGRN Delivery Throughout CNS
Intra-Cisterna Magna (ICM) Administration of PBFT02 Enables PGRN Delivery Throughout CNS • Directly delivers vector into the CSF via a single infusion, to reach CNS, PNS, and peripheral tissues1 – Allows for broad CNS biodistribution – Lower doses compared to IV systemic delivery – Reduced impact of
Slide 13: ICM Administration to NHPs Achieved High Levels of Gene Distribution Throughout the Nervous System
ICM Administration to NHPs Achieved High Levels of Gene Distribution Throughout the Nervous System Vector Biodistribution 90 days post-PBFT02 to NHPs • Robust vector delivery to cortical and sub- Brain Spinal Cord DRG, TRG cortical brain regions affected in FTD • NHP PBFT02 dose 1 (equivalent to upl
Slide 14: PBFT02 Dose-Dependently Increased PGRN in NHP CSF
Human PGRN in CSF PBFT02 Dose-Dependently 15 Veh Dose 1 Increased PGRN in NHP CSF hPGRN (ng/mL) Dose 2 10 Dose 3 • Human PGRN was detected in NHP CSF shortly after ICM PBFT02 administration 5 • Dose-dependent increases in PGRN seen 0 up to day 14 0 7 14 30 28 60 90 Days • Thereafter, an immune respo
Slide 15: PBFT02 was Well Tolerated in NHPs
PBFT02 was Well Tolerated in NHPs Followed for 90 days after a single ICM delivery of one of 3 doses Assessments Observations in NHPs Abnormal clinical, neurological, or None behavioral signs Blood and CSF clinical pathology Mild and transient increases in CSF leukocytes only DRG, TRG, sensory nerve
Slide 16: upliFT-D: Global Phase 1/2 Trial with PBFT02
upliFT-D: Global Phase 1/2 Trial with PBFT02 •Phase 1/2 multi-center, open label Safety Observations dose-escalation study • All four Cohort 1 participants who •Primary endpoints: Safety and tolerability received a revised immunosuppression regimen* had no SAEs or significant COHORT 1 COHORT 2 OPTIO
Slide 17: Cohort Interim Data: PBFT02 Administration Leads to Robust and Sustained Increases in CSF PGRN
Cohort 1 Interim Data: PBFT02 Administration Leads to Robust and Sustained Increases in CSF PGRN CSF Progranulin 36 33 Dose 1 • Continued elevation of CSF PGRN 30 at 6 M (n=2) and 12 M (n=1) 27 ‒Rate of increase slowing over CSF PGRN, ng/mL 24 21 time • Consistent response across all 18 15 12 five t
Slide 18: PBFT02 Preclinical and Clinical Development Summary
PBFT02 Preclinical and Clinical Development Summary Strong preclinical profile of PBFT02, a gene therapy to elevate PGRN in FTD-GRN • PBFT02 improved lysosomal histopathology and neuroinflammation in Grn-/- mice • Broad transduction across the brain and spinal cord in NHPs after ICM administration i
Slide 19: We would like to thank the patients, families, caregivers
We would like to thank the patients, families, caregivers, investigators, and our collaborators at Penn’s GTP