Frontotemporal Dementia Gene Therapy Trial Initiates Dosing


PBFT02, developed by Passage Bio, is delivered via intra cisterna magna administration to the brain.

Passage Bio has dosed the first patient with frontotemporal dementia with granulin mutations (FTD-GRN) with their gene therapy PBFT02 in the phase 1/2 upliFT-D study (NCT04747431).

“Dosing the first patient in our upliFT-D trial is an important milestone for the Passage Bio team and for the PBFT02 program, our first program in the clinic for adults,” Edgar (Chip) Cale, interim chief executive officer, Passage Bio, said in a statement. “We look forward to continuing our important work to develop PBFT02 as a potential treatment option for the thousands of people living with FTD-GRN. We are grateful for the support from the families and clinical trial investigators who have chosen to participate in our studies.”

PBFT02 uses an adeno-associated virus vector (AAV1) to deliver a functional copy of the GRN gene to patients with FT. GRN encodes progranulin, a deficiency of which is thought to contribute to lysosomal dysfunction. The therapy has shown preclinical efficacy in studies conducted by University of Pennsylvania’s Gene Therapy Program, Passage Bio’s collaborator on the program. Preclinical studies demonstrated broad transduction across the brain and increases in cerebrospinal fluid PGRN concentrations to more than 50-fold normal human concentrations.

READ MORE: Gene Therapy for Frontotemporal Dementia Granted Orphan Drug Status

“FTD-GRN is a devastating disease with no approved disease-modifying therapies, and we are hopeful this trial will provide evidence that PBFT02 could become a meaningful treatment option for adults living with FTD-GRN,” said Mark Forman, MD, PhD, chief medical officer of Passage Bio. “Our approach, which employs the AAV1 vector and intra cisterna magna (ICM) administration, provides a potential opportunity to achieve higher than normal levels of PGRN in the central nervous system, thereby overcoming the PGRN deficiency in GRN mutation carriers with a diagnosis of early symptomatic FTD-GRN. We look forward to building on our preclinical data with this Phase 1/2 trial.”

The upliFT-D study is a 2-year study with a 3-year safety extension that is evaluating PBFT02 delivered via ICM injection. The trial is currently enrolling patients with early symptomatic FTD-GRN between the ages of 35 to 75 years. The study will evaluate 2 dose levels of PBFT02 in 2 cohorts, with an optional third dose cohort.

The primary end point is safety and tolerability as measured by adverse events (AEs) and serious AEs. Other primary outcome measures include nerve conduction velocity, nerve conduction amplitude, and humoral response. Secondary outcome measures will assess clinical dementia rating, neurocognitive assessments, biomarkers of disease progression, brain anatomy, activities of daily living, and survival.

CGTLive previously spoke with David Weinstein, MD, senior vice president, clinical development, Passage Bio, about ICM administration of gene therapies to the brain, a technique the company is employing in other programs such as their GM1 gangliosidosis gene therapy program, PBGM01.

“The brain has been a hard target because of the blood brain barrier. In order to get gene therapy into the brain, higher doses had to be used, and there was higher risk of toxicity using traditional approaches. I think the ICM approach shows us an alternative way. We’re able to use a dose of the vector much lower than has been used in prior trials and because we're injecting directly into the CSF, we're able to treat people who have preexisting antibodies,” Weinstein told CGTLive.

Passage Bio doses first patient in global clinical trial of PBFT02 gene therapy for frontotemporal dementia with granulin mutations. News release. Passage Bio. August 11, 2022.
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