RARE Daily

FDA Puts Hold on Passage Bio’s Experimental Gene Therapy Trial in GM1 Gangliosidosis

August 13, 2020

Rare Daily Staff

The U.S. Food and Drug Administration put a clinical hold on Passage Bio’s request for approval to start testing its experimental gene therapy PBGM01 in infants with GM1 gangliosidosis, a life threatening lysosomal storage disease.

Passage Bio reported the hold in its second quarter earnings report. The clinical hold is pending an additional review of Passage Bio’s proposed gene therapy delivery device.

GM1 gangliosidosis (GM1) is a rare and often life-threatening monogenic recessive disease caused by mutations in the GLB1 gene, which encodes lysosomal acid beta-galactosidase (β-gal). Reduced β-gal activity results in the accumulation of toxic levels of GM1 ganglioside in neurons throughout the brain, causing rapidly progressing neurodegeneration. GM1 manifests as a continuum of disease and is most severe in the infantile form, which is characterized by onset in the first six months of life by reduced muscle tone, progressive central nervous system (CNS) dysfunction, and rapid developmental regression. Life expectancy for infants with GM1 is two to four years, and infantile GM1 represents approximately 62.5 percent of cases. Currently, there are no approved disease-modifying therapies available.

Passage Bio’s PBGM01 is being developed in collaboration with the Gene Therapy Program at the University of Pennsylvania, headed by gene therapy pioneer James Wilson. It is an AAV-delivery gene therapy currently being developed for the treatment of infantile GM1that is designed to deliver a functional GLB1 gene encoding β-gal to the brain and peripheral tissues. By reducing the accumulation of GM1 gangliosides, PBGM01 has the potential to reverse neuronal toxicity, thereby restoring developmental potential. In preclinical models, PBGM01 has demonstrated broad brain distribution and wide uptake of the β-gal enzyme in both the CNS and critical peripheral organs, suggesting potential treatment for both the CNS and peripheral manifestations of GM1.

Passage Bio said the clinical hold on starting the first trial of PBGM01 was placed pending additional risk assessments of the biocompatibility of the proposed intra-cisterna magna injection (ICM) delivery device. The ICM route of administration delivers PBGM01 directly to the brain into the cisterna magna, a space within the lower portion of the brain, with techniques and delivery devices commonly used both in current medical practice and other clinical trials, including those for gene therapy.

Passage Bio said it is evaluating options for conducting additional risk assessments while it awaits official written feedback from the FDA. During the IND review, the company addressed specific clinical and protocol questions raised by the FDA, and the agency confirmed that there are no further clinical information requests. As a result of the clinical hold, Passage Bio said it now expects to initiate dosing of its phase 1/2 trial late in the fourth quarter of 2020 or early in the first quarter of 2021 and remains on track to report initial 30 day safety and biomarker data late in the first half of 2021.

“We are confident that we can efficiently and successfully address the FDA clinical hold questions related to biocompatibility of our proposed ICM delivery device so that we can begin to dose patients before the end of this year or early next year,” said Gary Romano,  chief medical officer of Passage Bio. “Importantly, we continue to believe that the initial clinical safety and biomarker data from this trial will be available late in the first half of 2021.”

The FDA granted Passage Bio both Orphan Drug and Rare Pediatric Disease Drug designations. Orphan Drug designation is intended to promote the development of safe and effective treatments for rare diseases through certain financial and market exclusivity incentives, and Rare Pediatric Disease designation is intended to encourage treatments for life-threatening disease affecting children of 18 years of age or younger by qualifying the sponsor for a priority review voucher upon approval that may be sold or transferred.

Photo: Gary Romano, chief medical officer of Passage Bio


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