Passage Bio, Inc. (Nasdaq: PASG) has announced encouraging interim results from its Phase 1/2 upliFT-D clinical trial, evaluating PBFT02 as a potential gene therapy for frontotemporal dementia (FTD) caused by granulin (GRN) mutations. The data indicate that PBFT02 is capable of elevating cerebrospinal fluid (CSF) progranulin (PGRN) levels and reducing plasma neurofilament light chain (NfL), a biomarker associated with disease progression. The company anticipates reporting further data in the second half of 2025 and is planning regulatory discussions for a pivotal trial design in early 2026.
The upliFT-D trial is a global, multi-center, open-label study assessing the safety and efficacy of PBFT02 in adults aged 35 to 75 with either FTD-GRN or FTD-C9orf72. The trial involves sequential enrollment into cohorts, with ongoing enrollment. The primary endpoint focuses on safety and tolerability, while secondary endpoints include disease biomarkers and clinical outcome measures over a two-year period, followed by a three-year safety extension.
Durable PGRN Elevation and NfL Reduction
Interim data from FTD-GRN patients treated with Dose 1 of PBFT02 showed a consistent increase in CSF PGRN expression. Baseline levels below 3 ng/mL rose to 13-27 ng/mL at six months (n=4) and 22-34 ng/mL at 12 months (n=2). According to Passage Bio, CSF PGRN levels generally plateaued by month 6 and remained durable through 18 months (n=1).
Furthermore, plasma NfL levels were 13% lower than baseline on average at 12 months (n=2) post-treatment. This is a notable finding, as published natural history data indicates that plasma NfL levels in untreated symptomatic FTD-GRN patients typically increase by 29% per year.
Will Chou, M.D., president and chief executive officer of Passage Bio, stated, "We are pleased to report updated interim data from our ongoing upliFT-D clinical trial in FTD-GRN patients showing that Dose 1 PBFT02 consistently increased CSF PGRN expression and that this elevation translated to early signals of improvement in a disease progression biomarker when compared to published natural history data."
Safety and Tolerability
In terms of safety, most treatment-emergent adverse events (AEs) were mild to moderate in severity in 5 out of 7 patients. Two patients experienced serious adverse events (SAEs), including venous sinus thrombosis (VST) and hepatotoxicity in one patient, which led to a revised immunosuppression regimen (1,000 mg IV methylprednisolone on days 1-3 followed by 60 mg oral prednisone through day 60). Another patient experienced VST, which resolved with anticoagulants. No clinically significant immune responses were observed in patients receiving the revised immunosuppression regimen, and no dorsal root ganglion (DRG) toxicity was detected.
Dose Optimization and Manufacturing Advancements
Passage Bio is now evaluating a lower dose level, Dose 2 (50% lower than Dose 1), to optimize dosing for future regulatory discussions. The company has also completed process development and scale-up of a high-productivity, suspension-based manufacturing process for PBFT02, which is expected to reduce production costs and support late-stage trials.
Financial Runway and Upcoming Milestones
To extend its financial runway into the first quarter of 2027, Passage Bio will transition to an outsourced analytical testing model and reduce operating expenses. The company is also on track to initiate dosing of FTD-C9orf72 patients in the first half of 2025. The company anticipates reporting 12-month data from Dose 1 and interim safety and biomarker data from Dose 2 in the second half of 2025 and plans to seek regulatory feedback on the FTD-GRN pivotal trial design in the first half of 2026.
About PBFT02
PBFT02 is a gene replacement therapy that uses an AAV1 viral vector to deliver a functional GRN gene, encoding PGRN, via intracisternal magna (ICM) administration. The approach aims to elevate PGRN levels in the central nervous system to modify the course of neurodegenerative diseases. Preclinical studies have demonstrated broad vector distribution throughout the CNS and dose-dependent elevations in PGRN levels in CSF following ICM administration of PBFT02 in non-human primates. In murine FTD models, PBFT02 improved lysosomal function and reduced neuroinflammation.
