Ongoing Trial for PBFT02 Shows Improvement of Frontotemporal Dementia With Granulin Mutations

Updated phase 1/2 clinical trial data on PBFT02, a cerebrospinal fluid injection, shows slowed neurodegeneration in patients with frontotemporal dementia with granulin mutations.¹ A recent type C meeting with developers, Passage Bio, and the US Food and Drug Administration (FDA) recommended a randomized controlled trial of the medication as a next step, which the company has not confirmed due to ethical and logistical questions.

The phase 1/2 upliFT-D clinical trial is evaluating PBFT02 for treatment of frontotemporal dementia with granulin mutations, measuring medication safety along with brain atrophy, plasma neurofilament levels, and cerebrospinal fluid (CSF) progranulin.² Differing doses are being evaluated: dose 1 contains 4.5e13 total genome copies, and the lower dose 2 contains 2.2e13 total genome copies. As of January 2026, 9 patients (5 female, 4 male) are enrolled in the trial, with 7 receiving dose 1 and 2 receiving dose 2. Average disease duration at baseline was 2.9 years for the dose 1 group and 2 years for the dose 2 group. Clinical Dementia Rating Scale (CDR) score, brain atrophy (measured by volumetric magnetic resonance imaging (MRI)), plasma neurofilament levels, and CSF progranulin expression were measured at baseline and 12 months. Patients with CDR scores of 0.5 and 1 are the target population, and patients with scores above 2 have been excluded from future enrollment as the upliFT-D study continues.

Will Chou, MD, president and chief executive officer of Passage Bio, commented, “the data shared today suggest that PBFT02 may slow neurodegeneration in patients with [frontotemporal dementia with granulin mutations], with improvements observed in both brain atrophy and plasma neurofilament levels, 2 well-established biomarkers of disease progression.”¹ Looking forward, he added, “we continue to observe durable and robust elevations in progranulin, the target protein, and are encouraged by the emerging data from dose 2 patients, which indicate that this lower dose level can achieve similar progranulin expression as observed with dose 1, our higher dose.”

Latest data showed robust increases in CSF progranulin at both dose 1 and dose 2, as well as reduced brain atrophy in patients at earlier stages of disease progression. Using volumetric MRI, patients with a baseline CDR score of 1 showed an average 64% reduction in whole brain atrophy at 12 months, compared with natural disease progression data. Patients also showed stabilization of plasma neurofilament levels at 12 months, with an average reduction of 1 pg/ml compared with baseline. In dose 1, CSF progranulin levels increased from under 3 ng/ml at baseline to average 22.8 ng/ml at 12 months and 24.2 ng/ml at 18 months. Dose 2 showed a progranulin mean of 8.6 ng/ml at 1 month and achieved comparable progranulin levels to dose 1 at 6 months. PFBT02 was generally well-tolerated with no new treatment-related serious adverse events reported. There was no evidence of dorsal root ganglion toxicity or complications from intracisterna magna administration.

PBFT02 is given in the form of intracisterna magna administration, meaning it is injected directly into cerebrospinal fluid.³ This form allows for broader distribution throughout the central nervous system and can utilize lower doses than an intravenous delivery, as well as reduce impact of neutralizing antibodies.⁴ Intracisterna magna administration is a nonsurgical, computed tomography-guided procedure which takes less than 60 minutes and does not penetrate brain tissue.³ The medication is an adenoassisted virus delivery of the functional granulin gene, assisting in expression of progranulin both intra and extracellularly. PBFT02 is intended to increase progranulin levels, and has potential as a one-time therapy, Passage Bio noted.²

After completing a recent type C meeting with the FDA, developers of PBFT02 received recommendation of a randomized controlled study design for a future registrational trial. Chou highlighted that “despite the rare, underserved nature of this devastating disease and the availability of robust natural history data, FDA did not support a single-arm trial design for this indication and instead indicated that a randomized controlled trial would be required for registrational purposes. In light of this outcome and the associated ethical, logistical, and financial challenges, we are currently evaluating potential next steps for the PBFT02 clinical development program and for the company.”¹ Passage Bio is currently enrolling patients for cohort 3 and 4 of the phase 1/2 upliFT-D trial.²

References

1. Passage Bio reports updated interim data from upliFT-D trial and provides regulatory and corporate updates. Press release. April 20, 2026. Accessed April 20, 2026. https://www.globenewswire.com/news-release/2026/04/20/3276853/0/en/passage-bio-reports-updated-interim-data-from-uplift-d-trial-and-provides-regulatory-and-corporate-updates.html

2. Investor presentation: redefining the course of neurodegenerative conditions. Passage Bio. April 2026. Accessed April 20, 2026. https://www.passagebio.com/investors-and-news/events-and-presentations/default.aspx

3. Kim V, Roychowdhury S. Abstract 314: intracisterna magna (ICM) injection. Stroke: Vasc Intervent Neuro. 2025;4(S1).

4. Hinderer C, Bell P, Katz N, et al. Evaluation of intrathecal routes of administration for adeno-associated viral vectors in large animals. Hum Gene Ther. 2018;29(1):15-24.