Passage Bio (PASG) Receives FDA Clearance of IND Application for PBFT02 Gene Therapy Candidate for Treatment of Patients with Frontotemporal Dementia with Granulin Mutations

January 28, 2021 7:18 AM EST

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Passage Bio, Inc. (Nasdaq: PASG), a genetic medicines company focused on developing transformative therapies for rare, monogenic central nervous system (CNS) disorders, today announced that the U.S. Food and Drug Administration (FDA) has cleared an investigational new drug (IND) application for PBFT02, an adeno-associated virus (AAV)-delivery gene therapy that is being studied for the treatment of patients with Frontotemporal Dementia (FTD) with granulin (GRN) mutations. FTD is a debilitating form of early onset dementia that currently has no approved disease-modifying therapies.

“We are pleased to be advancing our second therapy into clinical development in our quest to bring transformative medicines to patients who need them,” said Bruce Goldsmith, Ph.D., chief executive officer of Passage Bio. “FTD can have a devastating impact on a person’s quality of life and create a substantial caregiving and economic burden for families. We are excited to investigate the potential of PBFT02 as a treatment for FTD-GRN as we initiate our clinical development program in the coming months.”

FTD is one of the more common causes of early-onset (midlife) dementia, causing impairment in behavior, language and executive function, and occurs at similar frequency to Alzheimer’s disease in patients younger than 65 years. In approximately 5 to 10 percent of individuals with FTD – 3,000 to 6,000 in the United States – the disease occurs because of mutations in the GRN gene, causing a deficiency of progranulin (PGRN). PGRN is a complex and highly conserved protein. The mechanism by which PGRN deficiency results in FTD is uncertain, but increasing evidence points to PGRN’s role in lysosomal function. The rapid progression of FTD results in an average survival of eight years after onset of symptoms.

Passage Bio is developing PBFT02 to treat FTD-GRN as a single dose delivered via intra-cisterna magna (ICM) injection. The gene therapy utilizes an AAV1 viral vector to deliver a modified DNA encoding the GRN gene to a patient's cells. The goal of this vector and delivery approach is to provide higher than normal levels of PGRN to the central nervous system to overcome the progranulin deficiency in GRN mutation carriers, who have been observed to have reduced cerebrospinal fluid PGRN levels ranging from 30% to 50% of the PGRN levels observed in normal, mutation non-carriers.

Clinical Development of PBFT02 Supported by University of Pennsylvania’s Gene Therapy Program (GTP) Pre-Clinical Data

Passage Bio is advancing PBFT02 into the clinic supported by preclinical data generated by its collaborator, University of Pennsylvania’s Gene Therapy Program (GTP). The data, published in the peer-reviewed scientific journal Annals of Clinical and Translational Neurology, showed that a single administration of an optimized AAV containing the GRN gene resulted in elevated levels of PGRN in the brain and cerebral spinal fluid (CSF), reduced lysosomal storage lesions, normalized lysosomal enzyme expression and corrected microgliosis in a mouse model of progranulin deficiency. A single administration of PBFT02 via the optimized AAV1-GRN vector demonstrated transduction broadly across the brain, including a very high transduction of ependymal cells that line the ventricles of the brain and are involved with CSF production, resulting in CSF progranulin levels of more than 50-fold normal.

The FDA has granted an Orphan Drug designation for PBFT02 for the treatment of FTD-GRN.

Phase 1/2 Study Initiation Anticipated for 1H21

Passage Bio expects to initiate a Phase1/2 clinical trial for PBFT02 in the first half of 2021. The trial is designed as a dose-escalation study of a single ICM dose of PBFT02 in subjects with FTD and heterozygous mutations in the GRN gene. The primary endpoint of the Phase 1/2 study is safety and tolerability; secondary endpoints include CSF progranulin levels, disease biomarkers, and clinical outcome measure. Initial data from the trial is anticipated to potentially readout in late 2021 or early 2022, depending on the timing of when the first patient is treated in the study.

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