Passage Bio Presents New Data for Patients with GM1 Gangliosidosis in Imagine-1 Study

Passage Bio presented updated clinical data from Imagine-1, a phase 1/2 study of PBGM01, a gene therapy for GM1 gangliosidosis, at the 18th Annual WORLDSymposium.

Photo: Bruce Goldsmith, president and CEO of Passage Bio

GM1 gangliosidosis (GM1) is a rare monogenic lysosomal storage disease 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 toxic levels of GM1 gangliosides in neurons throughout the brain, causing rapidly progressive neurodegeneration. GM1 accumulation also results in progressive damage to other tissues including the heart, liver, and bones and manifests with hypotonia (reduced muscle tone), progressive CNS dysfunction, seizures, and rapid developmental regression. Life expectancy for infants with GM1 ranges from 2-10 years, and infantile GM1 represents approximately 60 percent of the global GM1 incidence of 0.5 to 1 in 100,000 live births. Currently there are no approved disease-modifying treatments for the disorder.

PBGM01 is an AAV-delivery gene therapy in development to treat infantile GM1, in which patients have mutations in the GLB1 gene that cause little or no residual beta-galactosidase enzyme activity and subsequent neurodegeneration. PBGM01 utilizes a next-generation AAVhu68 capsid administered through the cisterna magna 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, thereby restoring developmental potential. In preclinical models, PBGM01 has demonstrated broad brain distribution and high levels of expression of the beta-galactosidase enzyme in both the CNS and critical peripheral organs, suggesting potential treatment for both the CNS and peripheral manifestations of GM1.

The data presented included clinical assessments of development milestones for Cohort 1 (two patients with late infantile GM1 who were administered a low dose of PBGM01), which showed meaningful improvement in development milestones and no reported serious adverse events or complications related to 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 interim biomarker and safety data reported in December for these first two patients were positive indicators that PBGM01 is exerting a biological effect, and it is also important to see improvement in developmental milestones for these children,” said Eliseo Salinas, chief research and development officer of Passage Bio. “We are very encouraged by the initial reports of clinical improvement. We look forward to further follow up and continuing with additional cohorts in the Imagine-1 study.”

The Bayley III is an extensive formal tool for the assessment of developmental delays in early childhood comprising physical, cognitive, social-emotional, linguistic, and behavioral milestones. Improvement in all developmental areas through the six-month assessments was observed for patient 1. Through the six months following administration of low dose PBGM01, overall development age tracked closely to chronologic age progressing from 12 months at baseline to 17 months at the six-month study visit. The nine-month Bayley III assessment by the study investigator was not conducted due to potential COVID-19 exposure.

At the three-month assessments for patient 2, improvement was observed for motor, receptive language, and cognitive domains. Despite a severe developmental delay at study start, the overall development age progressed during the three months following administration of PBGM01 from 7 months at baseline to 9 months. Also, at month four, following the three-month Vineland and Bayley assessments, patient 2 was clinically observed to have regained previously lost developmental milestones, such as the ability to walk and use expressive language.

The Vineland II scale is a standardized tool for caregivers to assess four broad areas of development: communication, daily living skills, socialization, and motor skills. Through the nine-month assessments following PBGM01 administration, improvement in all developmental areas was documented for patient 1, with notable progress in the domains of fine motor skills, receptive language, and interpersonal relationships. 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 observed through the three-month assessments for patient 2, 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 three-month assessments.

“After initially gaining early milestones, children with late onset GM1 typically plateau at 12-13 months of age developmentally before regressing. Seeing a child continuing to achieve new developmental milestones at 2 years of age is highly encouraging and atypical of this condition,” said Roberto Giugliani, Department of Genetics UFRGS and Medical Genetics Service HCPA, Porto Alegre, Brazil, and Imagine-1 principal investigator. “In 35 years of seeing GM1 patients, I have also never seen a child regain the ability to walk after losing this skill. While still relatively early, these results are exciting.”

“Our focus for each of our clinical programs is selecting in partnership with Penn’s Gene Therapy Program an optimal AAV capsid, expression cassette, and ICM delivery method for our gene therapies,” said Bruce Goldsmith, president and CEO of Passage Bio.” The effectiveness of this approach is being validated with our Imagine-1 trial and it reinforces our confidence as we advance our other two global clinical trials for Krabbe disease and frontotemporal dementia with granulin mutations.”

Following positive interim safety and biomarker data for Cohort 1, the Imagine-1 study has progressed to enroll additional cohorts: Cohort 2 with children with late infantile GM1 receiving a high dose of PBGM01; and Cohort 3 with children with early infantile GM1 receiving the same low dose of PBGM01 as Cohort 1. Thus far, one patient in each of the cohorts has been dosed. Interim data from these two cohorts is anticipated in the second quarter of 2022.

The U.S. Food and Drug Administration has granted PBGM01 Fast Track, Orphan Drug, and Rare Pediatric Disease designations. PBGM01 has also received an Orphan designation from the European Commission.

Author: Rare Daily Staff