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Chief Medical Officer 28 Intra-Cisterna Magna (ICM) Administration - Directly deliver vector into the CSF via a single injection to reach both CNS and peripheral tissues* Allows for broad CNS biodistribution Lower doses compared to IV systemic delivery Reduced impact of neutralizing antibodies - Administered under anesthesia using modern neuroimaging to allow for precise delivery - Currently being used in several clinical studies in both pediatric and adult populations Cisterna magna *Hinderer et. al, Human Gene Therapy. 2018 Jan; 29(1):15-24
Chairwoman Athena Countouriotis, M.D. Avenzo Therapeutics Derrell Porter, M.D. cTRL Therapeutics Dolan Sondhi, Ph.D. Weill Cornell Medicine Sandip Kapadia Harmony Biosciences Saqib Islam, J.D. SpringWorks William Chou, M.D. President & Chief Executive Officer William Chou, M.D. President & Chief Executive Officer Stuart Henderson SVP Corporate Development & Investor Relations Kathleen Borthwick SVP Finance & Interim CFO Mark Forman, M.D., Ph.D.
Potential best in class progranulin raising FTD-GRN gene therapy program Established manufacturing and process analytics capabilities Strong cash position with runway expected into 4Q 2025* Portfolio expansion into multiple adult neurodegenerative diseases * Based on cash, cash equivalents and marketable securities as of September 30, 2023 Thank You passagebio.com | NASDAQ: PASG 27 Demonstrated Leadership LEADERSHIP TEAM Deep experience in rare disease, CNS disorders and genetic medicines Chip Cale General Counsel & Corporate Secretary Eden Fucci SVP Technical Operations BOARD OF DIRECTORS Maxine Gowen, Ph.D.
Sources: 1Chen Y et al. J Neurol. 2015, 262:814-22; Takahashi H et al. Acta Neuropathol. 2017, 133:785-807. 2Fenoglio C et al. J Alzheimers Dis. 2009, 18:603-612. 3Hosokawa M et al. J Neuropath Exp Neurol. 2015, 74:158-65; Minami SS et al. Nat Med. 2014, 20:1157-64; Van Kampen JM & Kay DG. PLoS ONE 2017, 12:e0182896 Supporting Preclinical Evidence3 Prevalence - PGRN ablation exacerbates AD pathology in mice - PGRN overexpression reduces pathology burden in AD models - GRN SNP rs5848 is estimated to occur in 30% of general population, with a similar prevalence rate among AD patients2 24 TIMING MILESTONE FTD-GRN 1H 2024 Initiate dosing of Cohort 2 patients 2H 2024 6-month safety and biomarker data from Cohort 1 patients 1H 2025 12-month follow-up data from Cohort 1 patients 1H 2025 Initial safety and biomarker data from Cohort 2 patients PBFT02 Additional Indications 2H 2024 Obtain regulatory feedback on clinical pathway for treating FTD-C9orf72 and ALS patients Upcoming Milestones and Corporate Updates PIPELINE - Pursuing potential partnerships to advance pediatric clinical-stage programs (GM1, Krabbe & MLD) - Prioritizing advancement of Huntington's disease program through GTP partnership BALANCE SHEET - Cash balance of $133 million as of 9/30/23* - Cash as of 9/30/23 expected to fund operations into 4Q 2025* * Cash, cash equivalents and marketable securities 25 Our Vision To improve patient lives with neurodegenerative diseases by delivering genetic medicines that will permanently redefine the course of their conditions.
Trends Pharm Sci. 2022, 43:641-652; 2Beel S et al. Mol Neurodeg. 2018, 13:55. TDP-43 pathology is a hallmark of multiple neurodegenerative diseases1 - TDP-43 mislocalizes from nucleus to cytoplasm - Forms inclusion bodies associated with neurodegeneration 23 PBFT02 has Potential to Modulate Alzheimer's Disease - GRN SNP rs5848 carriers have reduced PGRN levels and increased risk for AD - AD patients with GRN SNP rs5848 show reduced PGRN levels and increased CSF tau Genetic risk1 SNP: single nucleotide polymorphism Third-party preclinical data.
SAFETY* PBFT02 Dose 1 generally well-tolerated to date in Patients 2 & 3, who received revised steroid regimen following protocol amendment - No serious AEs - All AEs mild to moderate in intensity - No evidence of clinically significant immune response, hepatotoxicity or venous sinus thrombosis - No evidence of DRG toxicity - No complications observed related to ICM injection BIOMARKERS Evidence of target engagement with 3.6-6.6-fold increase in CSF progranulin in all participants on Day 30 post treatment - Outperforming NHP data at this dose level No increase in plasma PGRN levels up to Day 180 Supraphysiologic CSF PGRN levels maintained at 6 months (n=1) ANTICIPATED NEXT STEPS -Initiate dosing of Cohort 2 patients in 1H 2024 - Additional 6-month data from Cohort 1 in 2H 2024 - 12-month follow-up data from Cohort 1 patients in 1H 2025 -Initial data from Cohort 2 in 1H 2025 Looking Ahead 22 PBFT02 has Potential to Correct Underlying Pathology in FTD-GRN, FTD-C9orf72, and ALS Elevating PGRN in TDP-43 models results in: - Normalized cytoplasmic TDP-43 accumulation - Improved survival2 Supraphysiologic PGRN ameliorates TDP-43 pathology in preclinical models 1Rhinn H et al.
Resolving with methylprednisolone at time of patient study withdrawal. 18 - Dose 1 resulted in supraphysiologic levels of CSF PGRN at Day 30 for all patients 3.6-6.6x increase in CSF PGRN at Day 30 relative to baseline (n=3) - Increase in CSF PGRN was sustained at 6- months (n=1) - Results exceeded what was observed in NHPs Shading: Reference range for healthy adult controls' PGRN levels in CSF (3.28 8.15 ng/mL, n = 61) (Passage Bio data) CSF= Cerebrospinal Fluid Initial Patients Treated with PBFT02 Have Seen a Substantial Increase in CSF PGRN 0 3 6 9 12 15 18 21 24 27 30 0 30 180 CSF PGRN, ng/mL Time (days) Dose 1 Progranulin, CSF Patient 1 Patient 2 Patient 3 At Dosing D30 D180 Patient 1 1.9 12.7 N/A Patient 2 2.8 17.3 27.3 Patient 3 2.9 10.7 N/A 6.3x 6.6x 3.6x Italics fold increase vs. baseline CSF Progranulin (ng/mL) 9.9x 19 Shading: Lower limit of normal of reference range for healthy adult controls' PGRN levels in plasma (91.6 372.4 ng/mL, n = 56) (Passage Bio data) - Plasma PGRN levels remained below normal levels at up to 6-months post-dose - PGRN increased only in the CSF where it has potential to correct deficit associated with neurodegeneration Plasma PGRN Levels Remained Below Normal Levels Post-Dose 0 10 20 30 40 50 60 70 80 90 100 0 7 14 30 90 180 Plasma PGRN, ng/mL Time (days) Dose 1 Progranulin, Plasma Patient 1 Patient 2 Patient 3 20 Summary AEs=adverse events; ICM=intra-cisterna magna * Patient follow-up ranged from 2 to 6 months post-dosing as of data cutoff of Jan 3, 2024.
Hepatotoxicity (resolved with methylprednisolone) 2. Venous sinus thrombosis - No SAEs - No hepatotoxicity or significant LFT changes from baseline - No venous sinus thrombosis or inflammation on MRIs - No clinically significant immune response requiring adjustment to immunosuppression regimen - All treatment emergent AEs mild to moderate in severity LFT: liver function test; SAE: serious adverse event 1 Day minus one refers to the day prior to dosing. 2 Day 14-21 LFT elevations were mild and self-resolved; Day 51-55 LFT elevations: ALT 16x upper limit of normal (ULN), AST 4x ULN, alkaline phosphatase 2x ULN, GGT 10x ULN; total bilirubin was normal.
CSF was sampled 14 days post-dose. Human PGRN Levels in CSF of NHPs 14 days post-ICM Dose 0 2 4 6 8 10 12 High Dose Medium Dose Low Dose Vehicle Human PGRN (ng/ml) Equivalent Clinical Dose Dose 1 Dose 2 Dose 3 (optional) - NHP immune response to hPGRN limits follow-up period to 14-days and may underestimate hPGRN levels achieved in CSF post-ICM administration 15 upliFT-D: Global Phase 1/2 Trial with PBFT02 OPTIONAL DOSE 3 DOSE 2 (1.1e11 GC/g)* DOSE 1 (3.3e10 GC/g)* COHORT 1 COHORT 2 OPTIONAL COHORT 3 Trial Design Phase 1/2, multicenter, open-label, dose escalation study; up to 15 patients across 3 cohorts Duration 2 years; with additional 3 years of follow-up for safety and durability of effect Primary Endpoints - Safety and tolerability Secondary Endpoints Biomarkers: - Progranulin (CSF, plasma) - NfL (CSF, plasma) - GFAP (CSF, plasma) - vMRI - Retinal nerve fiber layer and retinal lipofuscin deposits via OCT Clinical: - CDR + NACC FTLD sum of boxes Exploratory Biomarkers - Cathepsin D (CSF) - LAMP 1 (CSF) - Lys-GL1 (CSF) *Genome copies per gram of estimated brain weight IDMC review Recruiting 16 upliFT-D: Interim Data from First 3 Treated Patients - Patient 1 experienced two SAEs consistent with an immune response; study protocol was revised to increase steroid regimen - Patient 2 & Patient 3 received a higher level of steroid immunosuppression and did not experience SAEs; only mild-to-moderate treatment emergent AEs were reported - No evidence of DRG toxicity, as measured by nerve conduction studies - No complications related to ICM administration observed SAE: serious adverse event; AE: adverse event; DRG: dorsal root ganglion; ICM: intracisterna magna; NHP: non-human primate Patient follow-up ranged from 2 to 6 months post-dosing as of data cutoff of Jan 3, 2024 Safety Efficacy / Target Engagement - Interim data demonstrates PBFT02 potential for best-in-class efficacy at the low dose - In all patients, Dose 1 achieved supraphysiologic CSF PGRN levels at Day 30: 4-7x baseline - CSF PGRN levels exceeded levels observed in NHPs 17 Following Protocol Update to Increase Steroids, Patients 2 & 3 had no SAEs or Evidence of Significant Immune Response Patient 1 Patient 2 Patient 3 Immunosuppression1 Day -1-60: 60 mg oral prednisone Days 1-3: 1,000 mg IV methylprednisolone Days 4-60: 60 mg oral prednisone LFTs Day 14-21 and Day 51-55: elevated2 asymptomatic No significant change from baseline Imaging Findings Day 55: venous sinus thrombosis asymptomatic None None DRG Toxicity None None None ICM Complications None None None Length of Follow-up (as of Jan 3, 2024) 2 months (subject withdrew from study at week 10) 6 months 3 months Summary - 2 SAEs: both asymptomatic and consistent with immune response 1.
Thalamic atrophy is a key feature commonly found in FTD PBFT02 reduced lipofuscin at all doses, suggesting correction of underlying mechanism of disease - Lipofuscin: increased levels associated with lysosomal dysfunction - Correlated with underlying mechanism of FTD-GRN *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, one-way ANOVA followed by Tukey's multiple comparisons test Microgliosis reduction strongest at highest PBFT02 dose / PGRN level - Microgliosis: inflammatory response to pathogenic insults in the CNS - CD68: marker of activated microglia Murine FTD Model Murine FTD Model 14 Preclinical: PBFT02 Showed Dose-Related Increases in CSF Progranulin in NHPs Adult rhesus macaques received ICM PBFT02 (n = 3/dose) or vehicle (n =2) on study day 0.
Shading: Reference range for healthy adult controls' PGRN levels in CSF (n = 61) and plasma (n = 56) (Passage Bio data). Production of Human PGRN in Plasma AAV1 transgene delivery led to supraphysiologic hPGRN levels in CSF CSF PGRN (ng/mL) 0 10 20 30 40 CSF 0.1 1 10 100 LLOQ Normal Day RA2981 RA2982 RA3027 RA3153 RA3151 RA3170 RA3155 RA3160 AAVhu68 AAVhu68 (v2) AAV1 AAV5 RA2981 RA2982 RA3027 RA3153 RA3151 RA3170 RA3155 RA3160 AAVhu68 AAVhu68 (v2) AAV1 AAV5 RA2981 RA2982 RA3027 RA3153 RA3151 RA3170 RA3155 RA3160 AAVhu68 AAVhu68 (v2) AAV1 AAVhu68 AAV5 AAVhu68 (v2) AAV5 AAV1 Normal LLOQ Plasma Plasma PGRN (ng/mL) 0 10 20 30 40 0.1 1 10 100 Normal Day 1,000 12 Supraphysiologic PGRN Increases Potential for Improved Cellular Function - Progranulin is a secreted protein that binds to cell membrane receptors to affect multiple intracellular pathways Major role is regulating intracellular lysosomal activity Extracellular progranulin is endocytosed via multiple receptors - Driving supraphysiologic progranulin levels in the extracellular space increases the amount of progranulin available to enter target CNS cells Sources: Paushter et al., Acta Neuropathol. 2018;136(1):1-17., Rhinn et al., Trends in Pharmacological Sciences 2022; 43.8:641-652. 13 Preclinical: Higher CSF PGRN May Confer Reduction in Inflammatory Response Thalamus data shown above.
Trends Pharm Sci. 2022, 43:641-652 10 PBFT02 - Proprietary AAV1 construct delivering functional GRN gene encoding progranulin (PGRN) - Potential therapeutic benefit of a one-time approach - Delivered directly to the CSF via a single intra-cisterna magna (ICM) injection: Allows for broad CNS biodistribution Lower doses compared to IV systemic delivery Reduced impact of neutralizing antibodies - Able to achieve supraphysiologic levels of CSF progranulin, based on preclinical and initial clinical evidence - Received Orphan Drug and Fast Track designations by FDA and Orphan designation by EC Potential transformative therapy 11 Preclinical: PBFT02 Achieved Supraphysiologic Levels of CSF Progranulin in NHPs - AAV1 increased CSF PGRN levels ~5x more than AAV5 and AAVhu68 vectors, without further elevating peripheral levels Left, right: Two adult rhesus macaques per treatment received ICM AAV.hPGRN High dose, 3.0 x 1013 GC / 3.3 x 1011 GC/g brain) on study day 01 .
Alzheimers Dement 2023;19, [9] Crowell et al. Neuroepi. 2021; 55:361-368 5 - One time therapy - Durable, supraphysiologic CSF PGRN levels - Administration directly to CSF with nonsurgical injection Lead Clinical Program: PBFT02 Has Demonstrated Best in Class Potential in FTD-GRN Differentiated, Potential Best in Class Product Profile Initial Data from First 3 Treated Patients - Supraphysiologic CSF PGRN levels 4x-7x above baseline in all patients at 30 days following treatment (n=3) - Supraphysiologic CSF PGRN levels maintained at up to 6 months following treatment (n=1) Global Dose-Escalation Study of PBFT02 in FTD-GRN 6 Discovery UPenn GTP Research Analytics and Vector Engineering Process/Analytic Development Passage CMC R&D Lab Proven Analytical Capabilities Integrated Process Development GMP QC Capabilities Strong Regulatory CMC Scientific Expertise Scale-up Capability GMP Manufacturing Longstanding Partnership with Catalent End-to-End Clinical Supply Chain Leading CMC Capabilities Via a Hybrid Approach External Manufacturing Partnerships and End-to-End Supply Chain Key Strategic Partnerships Internal State-of-the-Art CMC Capabilities Partnerships In House Critical analytical and development capabilities maintained in-house PBFT02 Frontotemporal Dementia GRN 8 FTD-GRN: A Devastating Adult Disease 10pt Calibri footer OVERVIEW - Devastating form of dementia caused by a GRN gene mutation resulting in progranulin (PGRN) deficiency and haploinsufficiency - No disease-modifying therapies are currently approved EPIDEMIOLOGY - Approximately 5 10% of all FTD is caused by a GRN mutation, with an estimated prevalence in the U.S. and E.U. of ~18,000 patients CLINICAL SYMPTOMS - Disease progression is rapid and degenerative including loss of speech, loss of expression, severe behavioral changes and immobility 9 Progranulin Deficiency is the Defining Characteristic of FTD-GRN and Leads to Neurodegeneration Progranulin is critical to maintaining CNS cell homeostasis Source: Rhinn H et al.
J Neurol 2019; 266:2075-2086, [2] Galvin JE, et al. Neurology 2017; 89:2049-2056, [3] Onyike CU, et al. Int Rev Psychiatry 2013; 25:130-137, [4] Moore KM, et al. Lancet Neurol 2020; 19: 145 156, [5] Brown et al. Neuroepi 2021; 55:342-353, [6] CDC ALS Registry Dashboard, [7] Sheng J, et al. Gene 2014; 141-145, [8] Alz Assoc. 2023 Alzheimer's Disease Facts and Figures.
Potential best in class progranulin raising FTD-GRN gene therapy program Established manufacturing and process analytics capabilities Strong cash position with runway expected into 4Q 2025* Portfolio expansion into additional adult neurodegenerative diseases * Based on cash, cash equivalents and marketable securities as of September 30, 2023 4 Pipeline with Potential to Address Multiple Neurodegenerative Diseases Program Indication US/EU prevalence Discovery Pre-clinical Phase 1/2 Pivotal PBFT02 Frontotemporal dementia - GRN 18,0001-3 Frontotemporal dementia - C9orf72 21,0002-4 Amyotrophic lateral sclerosis 72,6005-6 Alzheimer's disease with rs5848 SNP 3.9M7-8 Unnamed Huntington's disease 60,0009 PBGM01 GM1 gangliosidosis PBKR03 Krabbe disease PBML04 Metachromatic leukodystrophy Pursuing potential partnerships Sources: [1] Greaves CV, et al.
Passage Bio undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise. 3 Our Vision To improve patient lives with neurodegenerative diseases by delivering genetic medicines that will permanently redefine the course of their conditions.
These forward-looking statements may be accompanied by such words as aim, anticipate, believe, could, estimate, expect, forecast, goal, intend, may, might, plan, potential, possible, will, would, and other words and terms of similar meaning. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop and obtain regulatory approval for our product candidates; the timing and results of preclinical studies and clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; the risk that positive results in a preclinical study or clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; failure to protect and enforce our intellectual property, and other proprietary rights; our dependence on collaborators and other third parties for the development and manufacture of product candidates and other aspects of our business, which are outside of our full control; risks associated with current and potential delays, work stoppages, or supply chain disruptions; and the other risks and uncertainties that are described in the Risk Factors section in documents the company files from time to time with the Securities and Exchange Commission (SEC), and other reports as filed with the SEC.