Passage Bio’s PBFT02, an investigational adeno-associated virus (AAV) vector-based gene therapy that is intended to deliver a functional copy of the granulin (GRN) gene, has demonstrated the ability to raise levels of cerebrospinal fluid (CSF) progranulin (PGRN) in patients with frontotemporal dementia (FTD) with GRN mutations treated in the phase 1/2 upliFT-D clinical trial (NCT04747431).1
Among 3 patients in the study’s first cohort, a 3.6 to 6.6-fold increase in CSF PGRN over baseline was observed at 30 days posttreatment. Furthermore, at 30 days posttreatment, CSF PGRN had reached 10.7 to 17.3 ng/mL in these patients, which was greater than the levels seen in a population of 61 healthy adults used as a control, whose CSF PRGN was measured at 3.3 to 8.2 ng/mL. At 6 months posttreatment, supraphysiologic levels of CSF PGRN were maintained, with one patient showing 27.3 ng/mL. Although, it was noted that levels of PRGN in the plasma in the 3 treated patients remained lower than those of the healthy control group up through the data cutoff.
In terms of safety, the first patient treated (referred to as Patient 1) experienced 2 asymptomatic serious adverse events (SAEs) that were deemed in line with an immune response to the gene therapy. Patient 1 had been administered 60 mg oral prednisone for 60 days as per trial protocol. Prior to the treatment of Patient 2 and Patient 3, the immunosuppression regimen in the study protocol was modified to include 1,000 mg IV methylprednisolone on days 1-3 posttreatment followed by 60 mg oral prednisone through day 60 posttreatment. Patients 2 and 3 did not experience any SAEs nor was any indication of a clinically significant immune response, hepatotoxicity, or safety-related imaging abnormalities observed in these 2 patients. Furthermore, treatment-emergent AEs experienced by Patients 2 and 3 were all deemed mild to moderate with regard to severity. Among all 3 treated patients, there was no dorsal root ganglion toxicity detected and there were no complications reported in relation to the administration of the gene therapy via intra-cisterna magna injection.
"We are proud to announce initial clinical data from our upliFT-D clinical trial, which showcases the ability of PBFT02 to elevate CSF progranulin to supraphysiologic levels at the lowest tested dose, Dose 1, up to 6 months post-treatment,” Mark Forman, MD, PhD, the chief medical officer at Passage Bio, said in a statement.1 “We believe these data, surpassing our expectations based on preclinical nonhuman primate models, validate the compelling potential of PBFT02 to address progranulin deficiency—a key driver of disease progression in individuals with FTD-GRN.”
- Passage Bio's PBFT02, an investigational gene therapy for frontotemporal dementia (FTD) with GRN mutations, demonstrated the ability to raise cerebrospinal fluid (CSF) progranulin (PGRN) levels in the phase 1/2 upliFT-D clinical trial.
- In the study, three treated patients showed a 3.6 to 6.6-fold increase in CSF PGRN at 30 days posttreatment, reaching supraphysiologic levels at 6 months. Safety results indicated mild to moderate treatment-emergent adverse events, with modifications to the immunosuppression regimen after the first patient experienced asymptomatic serious adverse events.
- Passage Bio plans to begin dosing patients in upliFT-D's second cohort in the first half of 2024, with expectations to report safety and biomarker data in 2025, and is exploring PBFT02's therapeutic potential in multiple diseases, including FTD-C9orf72, amyotrophic lateral sclerosis, and Alzheimer's disease.
Passage Bio noted that it expects to begin dosing patients in upliFT-D's second cohort within the first half of 2024 and to report initial safety and biomarker data from these patients in the first half of 2025. Meanwhile, the company anticipates announcing the full 6-month safety and biomarker data from the patients in cohort 1 in the second half of 2024 and the 12-month follow-up data from the cohort 1 patients in the first half of 2025.
"Driven by promising initial data for PBFT02 in FTD-GRN and evidence supporting progranulin’s role in neurodegeneration, we are refining our strategic priorities to explore the therapeutic potential of PBFT02 in multiple diseases, including FTD-C9orf72, amyotrophic lateral sclerosis, and Alzheimer disease,” William Chou, MD, the president and chief executive officer at Passage Bio, added to the statement.1 “As we pursue this strategy, we are actively exploring potential partnerships to advance our GM1 gangliosidosis program as well as our other clinical-stage pediatric programs. This shift in strategy aims to optimize focus and resources and provides each of our gene therapy candidates the best chance to get to patients in need.”
PBFT02, which uses an AAV1 vector, is not the only AAV gene therapy currently in development for the treatment of FTD-GRN. Prevail Therapeutics is developing PR006, an AAV9 vector-based gene therapy that is also intended to deliver a healthy copy of GRN for the treatment of FTD-GRN.2 PR006 is being evaluated in the phase 1/2 PROCLAIM trial (NCT04408625), which dosed its first patient in 2020. The trial is primarily investigating the safety and tolerability of PR006 via incidence of AEs or SAEs, and GRN and AAV9 immunogenicity levels in blood and CSF.
1. Passage Bio announces promising initial data from phase 1/2 clinical trial of PBFT02 in FTD-GRN and updated strategic priorities. News release. Passage Bio, Inc. December 20, 2023. Accessed January 15, 2024. https://www.passagebio.com/investors-and-news/press-releases-and-statements/news-details/2023/Passage-Bio-Announces-Promising-Initial-Data-From-Phase-12-Clinical-Trial-of-PBFT02-in-FTD-GRN-and-Updated-Strategic-Priorities/default.aspx
2. Prevail Therapeutics announces first patient dosed in phase 1/2 PROCLAIM clinical trial evaluating PR006 for the treatment of frontotemporal dementia patients with GRN mutations. News release. Prevail Therapeutics. December 11, 2020. Accessed July 18, 2023. https://www.prevailtherapeutics.com/prevail-therapeutics-announces-first-patient-dosed-in-phase-1-2-proclaim-clinical-trial-evaluating-pr006-for-the-treatment-of-frontotemporal-dementia-patients-with-grn-mutations/