Interim Safety and Biomarker Data From upliFT‐D Trial of PBFT02 in FTD with GRN Mutations
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.007 | 0.006 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.003 | 0.004 |
| Insufficient payload (model declined to judge) | 0.012 | 0.004 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".