Passage Bio’s Gene Therapy for GM1 Gangliosidosis Hit with Clinical Hold

 

Passage Bio’s first attempt to develop a GM1 gangliosidosis gene therapy treatment has run into a roadblock in the form of a clinical hold.

Philadelphia-based Passage Bio disclosed in its quarterly report that the FDA placed a clinical hold pending risk assessments for its experimental treatment PBGM01, which the company is developing in collaboration with the University of Pennsylvania’s Gene Therapy Program. Passage Bio said its first Investigational New Drug Application for PBGM01 was placed on clinical hold pending additional risk assessments of the biocompatibility of the proposed 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.

In its announcement, Passage Bio said it is evaluating options for conducting additional risk assessments while it awaits official written feedback from the FDA. As a result of the clinical hold, the company now expects to initiate dosing of its Phase I/II 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. 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,” Gary Romano, Passage Bio’s chief medical officer said in a statement.

Passage Bio’s PBGM01 is an AAV-delivery gene therapy being developed for the treatment of infantile GM1, in which patients have mutations in the GLB1 gene causing little or no residual β-gal enzyme activity and subsequent neurodegeneration. PBGM01 utilizes a next-generation AAVhu68 capsid administered through intra-cisterna magna (ICM) 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 May, the FDA granted Rare Pediatric Disease designation to PBGM01 broadly for the treatment of GM1 gangliosidosis. It had previously been awarded Orphan Drug designation from the FDA for the same indication.

GM1 gangliosidosis (GM1) is a rare and often life-threatening monogenic recessive lysosomal storage 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. Life expectancy for infants with GM1 is two to four years.