Samiah Al-Zaidy, MD, Vice President of Clinical Development and Lead on the Passage Bio GM1 Gangliosidosis (GM1) Program, discusses the updated data from Imagine-1 evaluating PBGM01 in GM1, which was presented at WORLDSymposium 2023.
Background of GM1
GM1 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: infantile; juvenile; and adult onset or chronic. 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 so management is primarily supportive.
Study Update
Imagine-1 is a phase 1/2 study of PBGM01, a gene therapy for GM1. Patients with early onset and late onset infantile GM1 (type 1 and 2a, respectively) have been enrolled in a dose escalation phase testing low- and high-dose PBGM01. Primary outcomes include the number of subjects with safety events, nerve conduction study changes, and immune response to PBGM01. Secondary outcomes include longitudinal neurodevelopmental assessments (e.g., Vineland-II & Bayley-III), change in key biomarkers (CSF & serum β-gal; CSF GM1-gangliosides), neuroimaging, and QoL assessments. Dosing of Cohorts 1 (low-dose, late-onset), 2 (high-dose, late-onset), and 3 (low-dose, early-onset) is now complete; Cohort 4 (high-dose, early-onset) is currently enrolling.
PBGM01 is a gene therapy that utilizes an 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 the accumulation of toxic GM1 gangliosides and reverse neuronal toxicity, thus restoring developmental potential.
In December 2022, interim data were presented on the first 6 patients treated from Cohorts 1–3. Data presented at this time indicated positive safety and tolerability for PBGM01 as no treatment-related serious adverse events (SAEs) were reported, nor clinically significant changes in liver function requiring intervention. There was also no evidence of dorsal root ganglion toxicity, nor complications related to ICM administration. This data also suggested a favorable immune profile for PBGM01, with no antibodies to the transgene product. The data reported also demonstrated that PBGM01 administration led to dose-dependent increases in CSF β-Gal activity and dose-dependent decreases in CSF GM1 ganglioside levels.
At WORLDSymposium 2023, data presented included MRI severity score findings and updated biomarker data.
The MRI severity score measures cerebral and cerebellar atrophy, abnormalities in white matter, and signal abnormalities in the basal ganglia and hippocampi to determine levels of structural damage. Natural history data from late infantile GM1 patients showed MRI severity scores increased in the majority of children during a follow-up period of 6 months to 4 years. Preliminary data over a follow-up period of 6-12 months showed PBGM01 administration was associated with stabilization of MRI severity scores in all treated patients.
Updated biomarker data demonstrated that PBGM01 administration resulted in decreases in β-Gal substrate Dp5 levels in urine, suggesting ICM delivery of PBGM01 results in peripheral β-Gal activity. Both patients who received the high dose exhibited prominent decreases in urine Dp5 levels. Patients with high baseline levels treated with the low dose of PBGM01 exhibited decreases in urine Dp5 levels.
To learn more about GM1 gangliosidosis and other rare lysosomal storage disorders, visit checkrare.com/diseases/lysosomal-storage-disorders/