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Interim Safety and Biomarker Data from upliFT-D Trial of PBFT02 in FTD with GRN Mutation Forman MS, Vo s sT, Triglia P, Ni YG, Browne SE, Quadrini KJ, Chou W, Ducharme S, Irwin DJ, Santana I, Schulz PE, Takada L, Tartaglia C, de Souza LC ADPD 2025 #2589
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2 Disclosures • upliFT-D trial is also known as PBFT02-001, NCT04747431 • Sue Browne, PhD:
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3 Frontotemporal Dementia: A Devastating Disease Syndrome • FTD is a common cause of early-onset dementia accounting for 20% of cases, second only to AD • Signs and symptoms typically manifest in adulthood, and are often misdiagnosed initially: – Impaired social cognition and altered personality – Apathy, depression, irritability – Impaired expressive and receptive language • Pathologically, FTD is characterized by a rapidly progressive neurodegeneration, in particular affecting frontal and temporal cerebral cortex FTD-GRN • 5 to 10% of FTD is caused by mutations in granulin, GRN, gene –Haploinsufficiency reduces brain progranulin, PGRN, by 50-70% • Prevalence in EU + US is ~18,000 • No approved disease-modifying therapy
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4 Progranulin (PGRN) Deficiency is the Defining Characteristic of FTD-GRN, Leading to Neurodegeneration Progranulin is critical to maintaining CNS cell homeostasis Decreased PGRN Neuronal dysfunction, pathological changes and inflammation Neuronal vulnerability in affected regions Neurodegeneration Our approach: AAV gene therapy to deliver functional PGRN to the brain PBFT02 • Delivers functional GRN genes encoding PGRN to brain and spinal cord • Transduces multiple CNS cell types
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AA V1 Selected as Vector after Capsid Comparison in NHPs. Robust Vector Delivery to Brain Regions affected in FTD NHPs (n=2/group) ICM-delivered AAV.hGRN (3.3 x 1011 GC/g brain), day 0. Elevation curtailed by immune response to human PGRN. BL 0 7 14 21 28 35 0 10 20 30 40 50 60 70 80 Days hPGRN (ng/mL) AAV1.CB7.hGRN AAV5.CB7.hGRN AAVhu68.CB7.hGRN AAVhu68.UbC.hGRN Healthy adult range CBL, cerebellum; CSF, cerebrospinal fluid; CX, cortex (F-frontal, O-occipital, P-parietal, T, temporal); Hipp, hippocampus; ICM, intra-cisterna magna; hGRN, human granulin gene; NHP, non-human primate; PGRN, progranulin. Superior hPGRN levels in NHP CSF after ICM AAV1 compared to AAV5 and AAVhu68 (AAV9 variant) ICM PBFT02 administration to NHPs resulted in high gene distribution throughout the CNS • Proof of concept demonstrated in Grn-/- mice: PBFT02 improved lysosomal function and neuroinflammation 6
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6 upliFT-D: Global Phase 1/2 Trial with PBFT02 DURATION 2 years. Additional 3 years follow-up for safety and durability of effect PRIMARY ENDPOINTS Safety and tolerability SECONDARY ENDPOINTS Biomarkers • Progranulin(CSF,plasma) • NfL (CSF, plasma) • vMRI • Retinal nerve fiber layer and retinal lipofuscin deposits via OCT Clinical • CDR + NACC FTLD sum of boxes • Cathepsin D (CSF) • LAMP 1 (CSF) • Lyso-GL1 (CSF) • GFAP (CSF, plasma) TRIAL DESIGN COHORT 1 n=5 Dose 1 COHORT 2 n=5 Dose 1 / Dose 2 COHORT 3 n=3-5 COHORT 4 n=3-5 Dose 2 COHORT 5 n=3-5 IDMC review Multicenter Open-label Dose exploration 1/2 Phase Complete Dose 1: 4.5e13 GC Dose 2: 2.2e13 GC FTD-GRN FTD-C9orf72 EXPLORATORY BIOMARKERS GC, genome copies. Fluid biomarkers: GFAP, glial fibrillary acidic protein; LAMP-1, lysosomal-associated membrane protein 1; Lyso-GL1, glucosylsphingosine; NfL, neurofilament light chain.
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7 Key Eligibility and Baseline Demographics for UpliFT-D FTD-GRN Dose 1 Participants Eligibility • Ages 35 to 75, inclusive • Pathogenic GRN mutation carrier • Symptomatic FTD-GRN • Able to live in the community 1CDR +NACC FTLD sum of boxes. bvFTD, behavioral variant; IvPPA, Logopenic variant primary progressive aphasia , svPPA, semantic variant PPA. DOSE 1 (n=7) Mean / % / n Range Age (yrs) 63.3 51-71 Sex M: 57% F: 43% FTD-GRN phenotype (n) bvFTD: 5 lvPPA: 1 svPPA: 1 Disease duration at baseline (yrs) 2.9 1 - 5 PGRN, CSF (ng/mL) 2.3 1.5 - 2.9 PGRN, plasma (ng/mL) 38.5 22.4 - 89.0 NfL, plasma (pg/mL) 43.4 12.4 - 105 Clinical Dementia Rating Scale, Global (%) 1: 57% 2: 43% Clinical Dementia Rating Scale, Sum of Boxes1 9.6 5 - 17 Learn more about upliFT-D here:
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8 upliFT-D: Interim Safety Profile Interim Safety Highlights* - Dose 1 PBFT02 in FTD-GRN Patients (n=7) • In 5 of 7 participants, all treatment emergent AEs were mild to moderate • 2 of 7 participants experienced a total of 3 SAEs – Participant 1: asymptomatic venous sinus thrombosis (VST) and hepatotoxicity,leading to a revised immunosuppression regimen in all subsequent patients** – Participant 7: asymptomatic VST, on treatment with anticoagulants. No evidence of hepatotoxicity,atypical immune response, or other laboratory abnormalities • No evidence of a clinically significant immune response following introduction of new immunosuppression regimen • No evidence of DRG toxicity • No complications during ICM administration *Participant safety follow-up ranged from 1 to 18 months post-dosing as of data cutoff of January 24, 2025. **Participant 1 received oral prednisone 60 mg daily through day 60; subsequent patients received a revised immunosuppressiveregimen of 1g methylprednisoloneIV daily to day 3, followed by oral prednisone 60 mg to day 60, then taper. AE, adverse event; DRG, dorsal root ganglion;ICM, intra-cisterna magna; SAE, serious adverse event; VST, venous sinus thrombosis. Remaining participants in Cohort 2 to receive Dose 2: 50% of Dose 1
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9 PBFT02 Dose 1 Associated with Expected Immune Responses to Capsid. No Response to hPGRN Detected • No Dose 1 participant had anti-AAV1 neutralizing antibodies at baseline • As expected, most participants developed anti-AAV1 antibodies in CSF and serum at 30 days post-PBFT02 treatment • Four participants developed T-cell response against AAV1 post-PBFT02 treatment, with no clinical significance • No T- or B-cell immune response against hPGRN was detected Anti-AAV1 Neutralizing Antibody Responses in CSF T-cell responses against AAV1 in 4 participants Time (Months) P7: CSF Nab data pending
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10 PBFT02 Generated Robust, Durable Increases in CSF PGRN Shading: Healthy adult sample range for CSF PGRN (range: 3.28 – 8.15 ng/mL, mean: 4.76 ng/mL, n = 61) (Passage Bio data). P7: Data pending. CSF, cerebrospinal fluid. 0 10 20 30 40 0 1 6 12 18 PGRN, ng/mL Time (months) Progranulin in CSF is elevated after Dose 1 PBFT02 Promising PGRN profile: • Consistent elevation from baseline • Durable to 18 months • Levels overall plateauing by 6-12 months Baseline M1 M6 M12 M18 N 6 6 4 2 1 Min 1.5 8.0 13.2 22.3 35.9 Max 2.9 17.3 27.3 34.0 35.9 Mean 2.3 12.4 20.0 28.2 - CSF Progranulin (ng/mL) in FTD-GRN Participants Healthy adult range
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11 Shading: Lower limit of healthy adult sample range for plasma PGRN (91.6 – 372.4 ng/mL, n = 56) (Passage Bio data). P7: Data pending • Plasma PGRN levels remained below normal levels up to 12 months post-dose in FTD-GRN patients • PGRN increased only in the CNS, where it has potential to reduce neurodegeneration PGRN Elevation Localized to CNS Following ICM PBFT02 Administration 0 50 100 150 0 1 3 12 PGRN, ng/mL 6 Time (months) Plasma PGRN below healthy adult levels after Dose 1 PBFT02 Healthy adult range
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12 -50 -30 -10 10 30 50 0 1 6 12 % Change from Baseline Pt 2 Pt3 Pt4 Pt5 Linear (Natural history) • Plasma NfL is the only FTD-GRN disease progression biomarker with published natural history data1,2 • Both participants 12 M post-PBFT02 had a reduced annual rate of change in plasma NfL compared to published natural history data1 Baseline plasma NfL (neurofilament light chain) range: 39.6 to 45.6 pg/mL, n=4. 1Natural history: 15 symptomatic FTD-GRN patients, mean years since diagnosis 2.9 (Saracino et al, J Neurol Neurosurg Psych 2021; 92:1278-1288); 2 van der Ende et al, Lancet Neurol 2019; 18:1103-11. Plasma NfL Showed Early Evidence of Improvement in a Disease Progression Biomarker vs Natural History Months Plasma NfL % Change from Baseline (> 6 M data) Plasma NfL Annual Rate of Change Natural history (linear extrapolation)
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13 Conclusions: PBFT02 Dose 1 in FTD-GRN 1Patient safety follow-up ranged from 1 to 18 months post-dosing as of data cutoff of January 24, 2025. CSF, cerebrospinal fluid; NfL, neurofilament light chain; SAE, serious adverse event. • Dose 1 PBFT02 demonstrated robust, consistent elevation of CSF PGRN and was durable up to 18 months post-treatment • Early evidence of improvement in disease progression vs. natural history as measured by plasma NfL • PBFT02 was well tolerated in 5 of 7 Dose 1 recipients with modified immunosuppression regimen 1 • 2 of 7 Dose 1 participants had SAEs, which were asymptomatic • Currently enrolling FTD-GRN and FTD-C9orf72 participants to receive Dose 2 PBFT02 (50% of Dose 1)
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We would like to thank the patients, families, caregivers, investigators, and our collaborators