Interim Safety and Biomarker Data From upliFT‐D Trial of PBFT02 in FTD with GRN Mutations

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BACKGROUND: Approximately 25-30% of frontotemporal dementia (FTD) is caused by autosomal dominant mutations, usually in one of three genes, C9orf72, GRN, or MAPT. There are currently no disease-modifying treatments approved for FTD, including FTD-GRN. PBFT02 is being developed as a disease-modifying therapy for patients with FTD-GRN and FTD-C9orf72. METHODS: PBFT02 is an AAV1 vector that delivers a copy of the human GRN gene directly to the CSF via a single intra-cisterna magna (ICM) administration. PBFT02 is being studied in a first-in-human clinical trial, upliFT-D (NCT04747431 [ClinicalTrials.gov]), which will sequentially enroll three FTD-GRN cohorts and two FTD-C9orf72 cohorts. The primary objective is safety and tolerability; secondary objectives include biomarkers of target engagement (e.g., progranulin; PGRN), biological activity, and disease progression. The 2-year trial will be followed by a 3-year extension for safety and durability of effect. RESULTS: As of December 2024, 7 participants received PBFT02 Dose 1 (3.3 E+10 genome copies/g brain weight, or 4.50 E+13 total genome copies), with an immunosuppressive regimen of oral prednisone 60mg for 30 days (N=1) or 1g IV methylprednisolone on study days 1-3, followed by 60mg oral prednisone on days 4-60 (N=6). PBFT02 increased CSF PGRN in all participants, from below 3 ng/mL at baseline to 13 - 27 ng/mL at six months (n=4) and 22 - 34 ng/mL at 12 months (n=2). Responses were stable and durable at 12 (N=2) and 18 months (N=1). In contrast, plasma PGRN remained below the mean healthy reference values in all participants to date. Plasma NfL levels were stable at 12 months (N=2) and demonstrated a reduced rate of change when compared to published natural history data. Two of 7 participants experienced a total of 3 SAEs, with 1 episode of hepatotoxicity and 2 episodes of asymptomatic venous sinus thrombosis. All remaining patients in cohort 2 will be treated with Dose 2, a 50% lower dose than Dose 1. Updated data will be included at the time of the presentation. CONCLUSIONS: Interim safety and biomarker data from the upliFT-D trial provides early evidence that PBFT02 has potential as a one-time therapy for FTD-GRN, thus supporting further clinical development.

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