PBFT02 Development and Preclinical Results - PBFT02 is an AAV gene therapy designed to deliver functional PGRN to the brain for the treatment of FTD-GRN [13] - In Grn-/- mice, AAV.hGRN vector ICV administration improved lysosomal function, reduced lipofuscin fluorescence in the thalamus, and reduced brain hexosaminidase activity [21, 23] - AAV1 was selected as the vector serotype due to superior hPGRN levels in CSF compared to AAV5 and AAVhu68 in NHPs [28, 29] - In Grn-/- mice, PBFT02 reduced lipofuscin deposition and neuroinflammation in the brain after intra-CSF delivery [34, 37] - ICM administration of PBFT02 enables PGRN delivery throughout the CNS [40] - In NHPs, PBFT02 dose-dependently increased PGRN in CSF up to day 14 [46, 48] - In NHPs, PBFT02 at Dose 1 resulted in approximately 10e4 GC/ug DNA throughout the brain [43] Clinical Trial (upliFT-D) and Safety - The upliFT-D trial is a global Phase 1/2 multi-center, open-label, dose-escalation study with PBFT02 [52, 55] - FTD-GRN Cohort 1 (n = 5) dosing is complete [56] - All four Cohort 1 participants who received a revised immunosuppression regimen had no SAEs or significant immune responses [57] - Cohort 1 interim data shows PBFT02 administration leads to robust and sustained increases in CSF PGRN [58]

PBFT02 continued to demonstrate robust, durable elevation in CSF PGRN levels and improvement in plasma NfL, a disease progression biomarker, compared to natural history Dose 2, 50% lower than Dose 1, substantially increased CSF PGRN levels at 30-days, reaching the upper limit of a healthy adult reference range Plan to amend upliFT-D protocol to include a prophylactic course of low dose anticoagulation and modify inclusion criteria to study patients earlier in disease progression Remain on track to seek regu ...

Core Insights - Passage Bio, Inc. reported strong performance in 2024, advancing its PBFT02 program with promising data in FTD-GRN patients, showing robust and durable progranulin expression and early evidence of improvement in a disease progression biomarker [3][6] - The company has extended its cash runway into Q1 2027 by implementing cost-reduction measures and moving to an outsourced analytical testing model [6][15] - Upcoming milestones include reporting 12-month data from Dose 1 and interim safety and biomarker data from Dose 2 in 2H 2025, and seeking regulatory feedback on the registrational trial design in 1H 2026 [6][5] Clinical Trial Updates - Interim data from the upliFT-D clinical trial demonstrated that Dose 1 PBFT02 increased cerebrospinal fluid (CSF) progranulin (PGRN) levels significantly, from below 3 ng/mL at baseline to 13-27 ng/mL at six months and 22-34 ng/mL at 12 months [6] - Plasma neurofilament light chain (NfL) levels were found to be 13% lower than baseline on average at 12 months post-treatment, contrasting with an expected increase of 29% per year based on natural history data [6] - The first FTD-GRN patient has been enrolled to receive Dose 2 PBFT02, which is 50% lower than Dose 1, to facilitate discussions with health authorities regarding a registrational study design [6][3] Financial Performance - As of December 31, 2024, the company reported cash, cash equivalents, and marketable securities totaling $76.8 million, down from $114.3 million as of December 31, 2023 [15] - Research and Development (R&D) expenses for Q4 2024 were $9.6 million, and for the full year, they totaled $40.2 million, compared to $12.1 million and $61.4 million for the same periods in 2023 [15] - The net loss for Q4 2024 was $12.7 million, or $0.20 per share, and for the full year, it was $64.8 million, or $1.07 per share, showing a decrease in losses compared to the previous year [15][21]