Passage Bio presented interim data from its Phase 1/2 upliFT-D clinical trial, showcasing positive results for PBFT02 in patients with frontotemporal dementia (FTD) with granulin (GRN) mutations. The data, presented at the 14th International Conference on Frontotemporal Dementias (ISFTD2024), highlighted the safety and biomarker responses observed in the first cohort of treated patients.
The upliFT-D trial is evaluating PBFT02, an adeno-associated virus (AAV)-delivery gene therapy designed to increase progranulin (PGRN) levels in the central nervous system. The interim results from Cohort 1 (n=5) indicated that a single injection of Dose 1 of PBFT02 into the cisterna magna led to substantial and sustained increases in CSF PGRN expression.
Safety and Tolerability
Following a protocol amendment to enhance immunosuppression, Dose 1 of PBFT02 was well-tolerated in all subsequent patients. No serious adverse events (SAEs) were reported in patients who received the revised immunosuppression regimen. All treatment-emergent adverse events (AEs) were mild to moderate in severity, and there was no evidence of clinically significant immune responses, hepatotoxicity, or safety-related imaging abnormalities. Nerve conduction studies also showed no evidence of dorsal root ganglion (DRG) toxicity, and no complications occurred during ICM administration.
Biomarker Response
PBFT02 treatment resulted in a notable increase in PGRN expression in all patients. Relative to baseline, CSF PGRN expression increased up to six-fold at one month (range of 10.7 to 17.3 ng/mL; n=5) and up to 10-fold at six months (range of 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, though the rate of increase slowed between six and 12 months (58% vs. 26%). Plasma PGRN expression remained below healthy reference levels across all patients.
Company Commentary
"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. "Furthermore, PBFT02 continued to be well-tolerated among all Cohort 1 patients who received enhanced immunosuppression, with no serious adverse events or evidence of clinically significant immune responses observed in these patients."
About the upliFT-D Trial
upliFT-D (NCT04747431) is a Phase 1/2 global, multi-center, open-label, dose-escalation clinical trial of PBFT02 administered by single injection into the cisterna magna in patients aged 35 to 75 years with FTD-GRN. The primary endpoint of the clinical trial is to evaluate the safety and tolerability of PBFT02. Secondary endpoints include disease biomarkers and clinical outcome measures. The trial includes a two-year clinical trial period with a three-year safety extension.
