David Weinstein, MD, Senior Vice President of Clinical Development at Passage Bio, discusses new interim clinical data from the Imagine-1 study of PBGM01, a gene therapy for GM1 gangliosidosis. This data was recently presented at WORLDSymposium 2022.
GM1 gangliosidosis is an inherited lysosomal storage disorder caused by mutations in the GLB1 gene, which encodes the lysosomal enzyme beta-galactosidase (β-gal). Reduced β-gal activity results in the accumulation of GM1 gangliosides in neurons, causing rapidly progressive neurodegeneration. Progressive damage is also seen in the heart, liver, and bones. The condition may be classified into three major types: classic infantile (type 1); juvenile (type 2); and adult onset or chronic (type 3). Common signs and symptoms among all three subtypes include hypotonia, progressive CNS dysfunction, seizures, and rapid developmental regression. Currently, there is no targeted treatment approved for GM1 gangliosidosis so management is primarily supportive.
Imagine-1 is a phase 1/2 study of PBGM01, a gene therapy for GM1 gangliosidosis. PBGM01 is a gene therapy that utilizes a AAVhu68 capsid administered via intra cisterna magna (ICM) to deliver a functional GLB1 gene encoding beta-galactosidase to the brain and peripheral tissues. By increasing beta-galactosidase activity, PBGM01 has the potential to reduce accumulation of toxic GM1 gangliosides and reverse neuronal toxicity, thus restoring developmental potential.
As Dr. Weinstein explains, Cohort 1 of the study includes two patients with late infantile GM1 administered a low dose of PBGM01. Safety and efficacy data from this cohort was evaluated by an independent data monitoring committee in December and Passage Bio was given permission to begin dosing Cohorts 2 and 3. Overall, the interim data presented showed meaningful improvement in development milestones. Additionally, there were no reported serious adverse events or complications related to the intra cisterna magna delivery. Development milestones were evaluated using two standardized, norm-referenced scales – the Bayley III, a formal assessment tool used by trained healthcare providers, and the Vineland II, a scale for parent or caregiver assessment.
The Bayley III data showed improvement in all developmental areas through the 6-month assessments for patient 1. Overall development age tracked closely to chronological age, progressing from 12 months at baseline to 17 months at the 6-month study visit. (The 9-month assessment was not conducted due to potential COVID-19 exposure.) At the 3-month assessments for patient 2, improvement was observed for motor, receptive language, and cognitive domains. Later, patient 2 was clinically observed to have regained previously lost developmental milestones, such as the ability to walk and use of expressive language.
Similar patterns were also observed with the Vineland II assessments. For example, patient 1 went from a baseline of taking a few steps to running without falling. He also achieved meaningful gains with expressive language never used before, now able to use 10 to 20 other words with specific meaning. Overall development age progressed from 12 months at study start to 23 months at the nine-month interim assessments, approaching the patient’s chronologic age of 24 months. Meaningful improvements were also observed through the 3-month assessments for patient 2, most notably in expressive language and interpersonal relationships. Caregiver/family reports of overall development age progressed through the period following administration of PBGM01, from 13 months at baseline to 16 months at the 3-month assessment.
Overall, these data give a lot of hope for the future of these patients and others with GM1 gangliosidosis
To learn more about GM1 gangliosidosis and other rare lysosomal storage disorders, visit checkrare.com/diseases/lysosomal-storage-disorders/