FDA Grants Fast Track Designations to 3 Gene Therapies for Rare CNS Diseases

Bruce Goldsmith, PhD

The FDA has granted a fast track designation to PBFT02, PBKR03, and PBGM01, according to a statement from Passage Bio, the company developing the 3 gene therapies, which are all intended as treatments for patients with various rare central nervous system (CNS) disorders.

The fast track designation is meant to expedite the development and review of promising therapies for life-threatening diseases. Through the fast track program, Passage will have the ability to meet more frequently with the FDA and, if an application is submitted, the 3 therapies will be eligible for priority review.

PBFT02 is being examined for frontotemporal dementia and progranulin mutations (FTD-GRN), PBKR03 is under exploration for Krabbe disease, and PBGM01 is being examined for GM1 gangliosidosis (GM1). All 3 agents are currently being examined in separate phase 1/2 studies, although recruitment is only open currently for PBGM01. Passage anticipates recruitment opening for the remaining 2 studies within the next few months.

“At Passage Bio, we are working to address some of the world’s rarest and most devastating neurological diseases that affect infants and adults,” Bruce Goldsmith, PhD, president and chief executive officer of Passage Bio, said in a statement. “The FDA’s decision to grant fast track designation to each of our lead gene therapy candidates highlights the urgent need for new treatments in these diseases and represents an important step towards achieving our objective of getting potentially transformative therapies to patients as quickly as possible.”

The first study (NCT04747431), known as upliFT-D, is exploring PBFT02 as a therapy for patients with FTD-GRN. The AAV1-based gene therapy is designed to deliver a copy of the GRN gene, which encodes human progranulin. The therapy is delivered directly to the cisterna magna via a one-time administration.

The study is planning to enroll an initial 6 patients to explore doses of the medication ranging from 3.3 x 10¹⁰ gene copies per gram of estimated brain weight (GC/g) to 2.2 x 10¹¹ GC/g. The primary outcome measures will focus on safety, nerve conduction, neurological examination, and response. Several neurocognition parameters, changes in brain anatomy, survival, biomarkers, and change in activities of daily living will be assessed as secondary endpoints.

The second study (NCT04771416), which is known as GALax-C, is investigating PBKR03 for patients with infantile Krabbe disease, also known as globoid cell leukodystrophy. For this study, an AAVhu68-based gene therapy is administered via a single-dose to the cisterna magna. This AAVhu68 gene therapy is designed to deliver a copy of the GALC gene, which encodes human galactosylceramidase.

This dose finding study has an estimated enrollment goal of 24 patients. In the first portion of the study, patients aged >4 but <9 will receive 1 of 4 doses ranging from 1.5 x 10¹¹ GC/g to 5 x 10¹¹ GC/g. Once a superior dose is identified, it will be examined separately in an expansion cohort. The primary outcome measures will focus on safety, nerve conduction, and response to the viral vector. Secondary end points include changes in developmental milestones, biomarkers, brain anatomy changes, quality of life, ventilator-free survival, and incidence of feeding tube placement at or before month 24.

The third agent under investigation, PBGM01, is being explored for patients with GM1 gangliosidosis in the Imagine-1 study (NCT04713475). This agent is also an AAVhu68-based gene therapy and is administered via a single-dose to the cisterna magna. PBGM01 is designed to deliver a copy of the GLB1 gene, which encodes human beta-galactosidase.

This 2-stage, dose-finding study plans to enroll 20 patients with either early onset infantile (type 1) or late onset infantile (type 2a) GM1 gangliosidosis. Two doses will be examined in the first stage of the study: 3.3 x 10¹⁰ GC/g and 1.1 x 10¹¹ GC/g across each type of GM1 gangliosidosis individually. The optimal dose from this stage of the study will be further examined in expansion cohorts for type 1 and type 2 disease. The primary end points focus on safety, nerve conduction, and humoral response to the viral vector. Secondary end points are looking at changes in developmental milestones, biomarkers, brain anatomy changes, quality of life, and ventilator-free survival.

“In the last year, we have laid the groundwork for Passage Bio to boldly execute on our strategy,” said Goldsmith. “These regulatory designations are intended to accelerate the timelines in our efforts to make a meaningful difference in patients’ lives.”

The company anticipates reporting initial 30-day safety and biomarker data for PBGM01 by mid-year 2021. Additionally, preliminary data for PBKR03 and PBFT02 are anticipated in late 2021 or early 2022. In addition to these 3 therapies, the company is also examining a number of other gene therapies in preclinical studies, including therapies for metachromatic leukodystrophy, amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease type 2A.