Passage Bio, a clinical-stage genetic medicines company focused on neurodegenerative diseases, has shared encouraging updated interim data from its ongoing Phase 1/2 upliFT-D clinical trial, which is evaluating PBFT02, a one-time gene therapy for frontotemporal dementia (FTD) caused by granulin (GRN) mutations. The data indicates that PBFT02 effectively and durably increases levels of cerebrospinal fluid (CSF) progranulin (PGRN), the protein deficient in FTD-GRN, with Dose 1 achieving a mean of 23.8 ng/mL at 18 months post-treatment. This robust elevation in PGRN is crucial as it directly addresses the underlying pathology of the disease. Furthermore, patients treated with Dose 1 PBFT02 showed a significantly reduced annual rate of increase in plasma neurofilament light chain (NfL) levels—a biomarker for neuronal damage—rising only 4% on average at 12 months, in stark contrast to the 28-29% expected increase observed in untreated FTD-GRN patients from natural history studies. This suggests that PBFT02 may be effectively slowing the progression of neurodegeneration.

While generally well-tolerated, the study did note serious adverse events in three of eight patients, including venous sinus thrombosis, hepatotoxicity, and a pulmonary embolism, although no evidence of dorsal root ganglion (DRG) toxicity or complications during the intra cisterna magna (ICM) administration were observed. In response to these findings, Passage Bio plans to amend the upliFT-D protocol to introduce a short course of low-dose prophylactic anticoagulation and to enroll patients with earlier-stage disease (prodromal or mild cognitive impairment) in future cohorts, a decision supported by both study investigators and the Independent Data Monitoring Committee (IDMC). The company is on track to submit this amended protocol to health authorities in early July 2025 and anticipates engaging with regulatory authorities on the design of a future registrational trial in the first half of 2026, aiming to bring this potentially transformative one-time gene therapy closer to patients.