GM1 Treatment PBGM91 Shows Positive Interim Data in Phase 1/2, Additional Cohorts Planned


Two patients with late infantile GM1 gangliosidosis in Cohort 1 received a low dose of the treatment, reporting no serious adverse events. Passage Bio noted it plans to move forward with 2 additional cohorts.

Bruce Goldsmith, PhD, president and CEO, Passage Bio

Bruce Goldsmith, PhD

The phase 1/2 Imagine-1 trial (NCT04713475) of PBGM01, an AAVhu68 gene therapy for treatment of early and late infantile GM1 gangliosidosis (GM1), will proceed with 2 additional planned patient cohorts, Passage Bio recently announced. The recommendation to proceed was made by the Independent Data Monitoring Committee following positive interim and safety biomarker data from the first cohort of patients with late infantile GM1. 

The Imagine-1 trial is a global, open-label study of PBGM01, planned to be evaluated in 4 cohorts of 2 pediatric subjects each, with different dose-escalation cohorts for late infantile GM1 and early infantile GM1. Patients are now being recruited in parallel for the high-dose cohort of patients with late infantile GM1 (Cohort 2) and a low-dose cohort of patients with early infantile GM1 (Cohort 3). 

Cohort 1 enrolled 2 patients with late infantile GM1, who received a low dose of PBGM01, delivered by intra-cisterna magna (ICM) injection. In the first cohort, no serious adverse events (AEs) reported, complications with ICM injection, or evidence of dorsal root ganglion toxicity were reported. All AEs were mild to moderate, and moderate AEs resolved without intervention and were not related to treatment. 

READ MORE: Patient Death Reported in Phase 1b Mini-Dystrophin Gene Therapy Trial in DMD

“We are extremely encouraged by the interim data in this first low dose cohort of patients with late infantile GM1. The favorable safety profile of PBGM01 as well as the increase in beta-galactosidase activity in both CSF and serum with the lowest dose at this early timepoint supports moving forward in 2 additional cohorts.” Bruce Goldsmith, PhD, president and CEO, Passage Bio, said in a statement. 

“We are most grateful to the children with GM1, their families and caregivers, as well as the clinical trial investigators who have chosen to participate in Imagine-1. We also could not have progressed to this point without our strong collaboration with University of Pennsylvania’s Gene Therapy Program, whose experience in developing optimal AAV technologies is unmatched. The results from the first cohort reinforce our confidence in our selected AAV technology as well as the ICM route of administration for our GM1 program and our additional clinical programs,” Goldsmith added. 

Data from Cohort 1 was compared with initial data from an ongoing natural history study that is being run in collaboration with the Orphan Disease Center at the University of Pennsylvania, which measured both cerebrospinal fluid (CSF) and serum levels of beta-galactosidase in this patient population. Mean values of enzyme activity in CSF and serum were comparable to both patients in Cohort 1. 

For both patients in Cohort 1, beta-galactosidase activity in the CSF and serum increased following PBGM01 administration. At the 30-day mark, patient 1 had a 1.5-fold increase in enzyme activity in the CSF from baseline, with the increase maintained at 6 months. Patient 2 had a 4.8-fold increase in enzyme activity in the CSSF at 30 days from baseline. 

Looking at serum levels, patient 1 had enzyme activity that was slightly above baseline at 30 days and 1.7-fold over baseline at 3 months, with the increase again maintained at 6 months. Patient 2 had enzyme activity at 30 days that was 1.2-fold over baseline. Patient 2 also showed baseline GM1 ganglioside in CSF values that were 4 times higher than patient 1 at baseline. Levels increased by 85% at 30 days in patient 1, remaining stable at that level at 6 months, and for patient 2, levels increased by 46% at 40 days, consistent with high increases in CSF enzyme activity. 

The treatment has previously received fast track, orphan drug, and rare pediatric disease designations from the FDA, also having received orphan designation form the European Commission. Detailed findings and additional clinical data are anticipated to be presented at the 18th Annual WORLDSymposium, February 7-11, 2022.

“Children with infantile GM1 experience a rapid decline in neurologic function and unfortunately there are no disease-modifying treatments available to them,” principal investigator for the Imagine-1 study,” Roberto Giugliani, MD, PhD, MSc, professor, department of genetics, University of Rio Grande do Sul, and chief, Medical Genetics Services, Hospital de Clinicas de Porto Algere, Brazil, said in a statement. “The disease is devastating to patients and their families, so I am encouraged by the early data with PBGM0—that it was not only well-tolerated but also showed an increase in activity of the beta-galactosidase enzyme in both serum and CSF. I look forward to the continued clinical advancement of PBGM01 and learning its potential for GM1 patients.”

Passage Bio announces positive interim safety and biomarker data and advances phase ½ trial of PBGM01 in GM1 Gangliosidosis. News release. Passage Bio. December 17, 2021. Accessed December 21, 2021.
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