PHILADELPHIA, PA — Passage Bio, Inc. (NASDAQ: PASG) has announced encouraging updates from the ongoing Phase 1/2 upliFT-D clinical trial for PBFT02, a one-time gene therapy for frontotemporal dementia (FTD) caused by granulin (GRN) mutations. The data reflect robust biomarker improvements and durable effects, supporting the promise of PBFT02 as a groundbreaking treatment for this devastating neurodegenerative disease.
PBFT02, using a gene replacement approach, demonstrated significant increases in cerebrospinal fluid (CSF) progranulin (PGRN) levels across treated patients. At the highest dosage, a mean increase to 25.9 ng/mL was observed at 12 months, compared to baseline levels under 3 ng/mL. Early results from a reduced second dose group also showed notable increases, with patient levels reaching a healthy adult reference range. Furthermore, patients exhibited a slower rate of plasma neurofilament light chain (NfL) accrual, a key marker of disease progression.
“We are pleased to share updated data highlighting the promise of PBFT02 for the frontotemporal dementia community,” said Will Chou, M.D., Passage Bio’s president and chief executive officer. “These data continue to demonstrate the ability of our investigational, one-time gene therapy to elevate progranulin in a robust and durable manner while also reducing the rate of increase of plasma neurofilament levels compared to rates observed in natural history studies.”
The therapy’s safety profile also showed improvement, with no new safety concerns emerging during the trial. While 5 of 8 patients reported mild-to-moderate adverse events, 3 patients experienced serious adverse events, including asymptomatic venous sinus thrombosis and hepatotoxicity. One case of pulmonary embolism, deemed possibly related to PBFT02, was managed successfully with anticoagulants.
To further enhance safety and efficacy, Passage Bio plans to amend the trial protocol. Changes will include a prophylactic low-dose anticoagulation regimen and adjusted inclusion criteria to target patients in earlier stages of FTD progression. The company anticipates regulatory submission of the revised protocol by July 2025, with next-stage cohorts expected to enroll by year-end.
Passage Bio remains on track to seek regulatory feedback on potential registrational trial design in 2026. Additional interim data from low-dose cohorts will be reported in the first half of the same year.
PBFT02 uses an AAV1 vector system to deliver a functional GRN gene directly to the central nervous system via cisterna magna injection. Preclinical models have shown strong PGRN elevation, improved lysosomal function, and reduced neuroinflammation, supporting the therapy’s potential to alter the course of FTD.
With the updates reinforcing promise for FTD-GRN patients, Passage Bio continues its mission to address critical unmet medical needs in neurodegenerative diseases through cutting-edge gene therapies.
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