Passage Bio, Inc. announced initial safety and biomarker data from three Cohort 1 patients in the ongoing global Phase 1/2 upliFT-D clinical trial evaluating PBFT02, an adeno-associated virus (AAV)-delivery gene therapy for the treatment of patients with frontotemporal dementia (FTD) with granulin (GRN) mutations. These strategic priorities and clinical milestones underscore Passage Bio's dedication to advancing cutting-edge, one-time genetic medicines and protecting patients and families against loss in neurodegenerative conditions. FTD is one of the more common causes of early-onset dementia.

In approximately 5% to 10% of individuals with FTD?approximately 18,000 individuals in the United States and Europe?the disease occurs because of mutations in the GRN gene, causing a deficiency of progranulin (PGRN). PGRN is a complex and highly conserved protein thought to have multiple roles in cell biology, development and inflammation. Emerging evidence suggests that PGRN deficiency may contribute to lysosomal dysfunction.

The upliFT-D clinical trial evaluates PBFT02 as a single dose delivered via intra-cisterna magna (ICM) injection. PBFT02 uses an AAV1 viral vector to deliver a functional copy of the GRN gene encoding PGRN to a patient's cells. Topline interim results from first three patients in the uplift-D clinical trial, Safety (patient follow-up up to six months): Dose 1 of PBFT02 was generally well-tolerated in patients 2 and 3, who received an enhanced steroid regimen following protocol amendment.

No serious adverse events (SAEs). All treatment emergent adverse events (AEs) were mild to moderate in severity. No evidence of clinically significant immune response, hepatotoxicity or safety related imaging abnormalities.

Patient 1 received a low level of immunosuppression (60 mg oral prednisone for 60 days) and experienced two SAEs that were both asymptomatic and consistent with an immune response. Following patient 1, the protocol was amended to increase the steroid regimen (1,000 mg IV methylprednisolone on days 1-3 followed by 60 mg oral prednisone through day 60) for patients 2 and 3. No evidence of dorsal root ganglion (DRG) toxicity, as measured by nerve conduction studies, and no complications were observed related to ICM administration across any of the three patients. Biomarkers: Dose 1 of PBFT02 treatment resulted in a 3.6 to 6.6-fold increase in CSF PGRN at day 30 (n=3) relative to baseline.

CSF PGRN increased to supraphysiologic levels of 10.7 to 17.3 ng/mL at day 30, exceeding the range found in healthy adult controls of 3.3 to 8.2 ng/mL (n=61). CSF PGRN remained at supraphysiologic levels at six months with a concentration of 27.3 ng/mL (n=1). Plasma PGRN levels remained below levels found in healthy adult controls through the available follow-up period across all patients.