Passage Bio Presents PBFT02 Data at ESGCT Conference

Passage Bio, Inc., a clinical stage company specializing in genetic medicines for neurodegenerative diseases, presented its latest findings at the European Society of Gene & Cell Therapy (ESGCT) 31st Annual Congress. Held in Rome, Italy, from October 22-25, 2024, the focus of their presentation was the preclinical and interim clinical data of their gene therapy candidate, PBFT02, designed to treat frontotemporal dementia with GRN mutations (FTD-GRN).

The preclinical studies demonstrated that an AAV1 vector significantly increased human progranulin levels in the cerebrospinal fluid (CSF) compared to AAV5 and AAVhu68 vectors. In nonclinical models, PBFT02 showed considerable progress in improving lysosomal histopathology and reducing neuroinflammation in Grn knockout mice, as well as achieving widespread vector distribution in the nervous system of non-human primates.

During her oral presentation, Sue Browne, Ph.D., Chief Scientific Officer of Passage Bio, shared the robust preclinical data that informed their vector and dose selection strategy. The interim clinical data presented from the upliFT-D trial confirmed the preclinical findings, demonstrating that PBFT02 could be a leading therapy for raising progranulin levels.

Will Chou, M.D., President and CEO of Passage Bio, emphasized the importance of these findings, explaining that the positive preclinical outcomes gave the company confidence in selecting the AAV1 vector and intra-cisterna magna (ICM) administration approach for their ongoing clinical study. Chou highlighted that translating these results into the clinic was encouraging, with interim data indicating that PBFT02 had a favorable safety profile and provided durable increases in CSF progranulin levels.

Key data from the research included a capsid comparison study in non-human primates, revealing that the AAV1 vector achieved higher human progranulin levels in the CSF post-ICM administration compared to AAV5 and AAVhu68. Additionally, a dose escalation study in Grn knockout mice demonstrated that PBFT02 improved lysosomal histopathology and reduced neuroinflammation following intra-CSF delivery. Moreover, the biodistribution study in non-human primates showed that ICM administration of PBFT02 led to widespread gene distribution across the nervous system, including critical brain regions and the spinal cord. The treatment was well-tolerated and resulted in dose-dependent increases in progranulin levels in the CSF. Interim data from the upliFT-D clinical trial further supported these findings, showing that the first dose of PBFT02 was generally well-tolerated and led to consistent, long-lasting increases in CSF progranulin levels among patients, sustained up to 12 months post-administration.

PBFT02 uses an AAV1 viral vector administered through ICM to deliver a functional GRN gene, which encodes for progranulin. This approach aims to elevate progranulin levels in the central nervous system to alter the progression of neurodegenerative diseases. Interim clinical data from the ongoing upliFT-D Phase 1/2 study in FTD-GRN participants demonstrated significant rises in CSF progranulin levels following ICM administration of PBFT02.

Extensive preclinical studies support the potential clinical benefits of PBFT02. In non-human primates, a single ICM administration of PBFT02 resulted in broad vector distribution throughout the central nervous system with robust, dose-dependent increases in CSF progranulin levels. Additionally, PBFT02 proved effective at transducing ependymal cells in non-human primates. In a murine model of FTD, PBFT02 administration improved lysosomal function and reduced neuroinflammation.

Passage Bio remains dedicated to advancing PBFT02 and exploring its therapeutic potential for additional neurodegenerative diseases that could benefit from increased progranulin levels.