Passage Bio presented positive interim data from its Phase 1/2 upliFT-D clinical trial, evaluating PBFT02 for frontotemporal dementia (FTD) with granulin (GRN) mutations, at the 14th International Conference on Frontotemporal Dementias (ISFTD2024). The data demonstrated that Dose 1 of PBFT02 achieved robust and sustained increases in cerebrospinal fluid (CSF) progranulin levels in all treated patients in Cohort 1.
The upliFT-D trial (NCT04747431) is a global, multi-center, open-label, dose-escalation study assessing the safety and tolerability of PBFT02, administered via a single injection into the cisterna magna in patients aged 35 to 75 years with FTD-GRN. The trial sequentially enrolls two cohorts, with a possible third cohort based on the results of the first two. The primary endpoint is safety and tolerability, with secondary endpoints including disease biomarkers and clinical outcome measures. The study spans two years, with a three-year safety extension.
Safety and Tolerability
Dose 1 of PBFT02 was well-tolerated in all patients (n=4) who received an enhanced immunosuppression regimen following a protocol amendment. No serious adverse events (SAEs) were reported, and all treatment-emergent adverse events (AEs) were mild to moderate in severity. There was no evidence of clinically significant immune response, hepatotoxicity, or safety-related imaging abnormalities. One patient, who received a lower level of immunosuppression, experienced two asymptomatic SAEs consistent with an immune response, leading to the protocol amendment.
Biomarker Data
PBFT02 treatment resulted in a robust and durable increase in progranulin (PGRN) expression in the CSF of all patients. Relative to baseline, PBFT02 increased CSF PGRN expression up to 6-fold at one month (range: 10.7 to 17.3 ng/mL; n=5) and up to 10-fold at six months (range: 21.7 to 27.3 ng/mL; n=2). The effect was consistent across all patients, with CSF PGRN levels exceeding the range found in healthy adult controls (3.3 to 8.2 ng/mL; n=61). At 12 months (n=1), CSF PGRN remained elevated at 34.2 ng/mL, with the rate of increase slowing between six and 12 months (58% vs. 26%). Plasma PGRN expression remained below healthy reference levels across all patients.
Mechanism of Action
PBFT02 utilizes an adeno-associated virus (AAV1) viral vector to deliver a functional GRN gene, encoding for PGRN, via intra-cisterna magna (ICM) administration. This approach aims to elevate PGRN levels in the central nervous system to modify the course of neurodegenerative diseases. Preclinical studies support the potential clinical benefit of PBFT02, demonstrating broad vector distribution throughout the CNS and dose-dependent elevations in PGRN levels in CSF in non-human primates. Studies in murine FTD models have also shown improved lysosomal function and reduced neuroinflammation following PBFT02 administration.
"We are very encouraged by the positive Cohort 1 data from our upliFT-D trial demonstrating that intra-cisterna magna delivery of Dose 1 of PBFT02 resulted in robust and durable increases in CSF PRGN expression, with elevated levels maintained for up to one year after treatment,” said Will Chou, M.D., president and chief executive officer of Passage Bio.
