Gene Therapy Shows Evidence of Dose-Dependent Effects on GM1 Gangliosidosis Biomarkers


At dose level 2, 3 of 4 participants had increases of β-Gal activity to normal levels for up to 12 months.

New interim data from the phase 1/2 Imagine-1 trial (NCT04713475)of PBGM01 (Passage Bio) gene therapy delivered via intracisternal magna injectionhas demonstrated dose-dependent improvements in key cerebrospinal fluid biomarkers in patients with early and late infantile GM1 gangliosidosis.

"We are highly encouraged by the compelling data emerging from our Imagine-1 study, with results underscoring the potential of PBGM01 to be a transformative therapy for GM1 patients,” William Chou, MD, president and chief executive officer, Passage Bio, said in a statement. “Updated data from the first eight treated patients show that PGBM01 continues to have a favorable safety profile, is well tolerated and shows initial evidence of improved survival relative to what is predicted by the natural history of the disease. Furthermore, Dose 2 of PBGM01 has shown the ability to achieve healthy control levels of β-Gal activity and GM1 gangliosides in CSF, with durability up to 12 months after treatment.”

Investigators in Imagine-1 study found that there were no treatment-related serious adverse events (AEs) during patient follow-up of 8 to 28 months and all were mild-to-moderate. There were no complications related to ICM administration, no clinically significant changes in liver function requiring intervention, and no evidence of dorsal root ganglion toxicity. PBGM01 had a favorable immunological profile with no clinically significant immune responses.

In assessing preliminary efficacy, investigators found initial evidence of improved survival compared to natural history data, with 100% of infantile patients (n = 3) surviving beyond 20 months as compared with natural history data (n = 154) that showed a mean survival of 18.9 months, although the cohort’s sample size is very small. Biomarker analyses showed robust and durable increases in CSF β-Galactosidase (β-Gal) with dose 2 of PBGM01. At this dose level, 3 of 4 participants had a 4.7-16.1x increase in CSF β-Gal activity at 30 days posttreatment, which exceeds average levels in healthy adults or natural history data of GM1. This increased activity was sustained for up to 12 months. Concurrently, participants in this dose cohort had decreased CSF GM1 ganglioside levels which reached normal adult levels at 1 year posttreatment and has continued to decline. These effects were stronger in dose 2 than 1, showing a dose-dependent effect.

READ MORE: Gene Therapy Shows Promise in Infantile GM1 Gangliosidosis

Imagine-1 is an open-label, dose-escalation study evaluating the AVhu68 gene therapy PBGM01 in six cohorts of pediatric participants with early and late infantile GM1. GM1 is a rare, fatal lysosomal storage disease in which patients have very low β-Gal activity due to mutations in the GLB1 gene. Imagine-1 is primarily assessing safety and tolerability of PBGM01 gene therapy as well as efficacy and ability to restore β-Gal activity. PBGM01 has been granted Fast Track, Orphan Drug (OD), and Rare Pediatric Disease designations from the FDA and OD designation from the European Commission.

Imagine-1 has finished enrollment at the first 2 dose levels and has treated the first participant at dose level 3. The trial is recruiting patients with late infantile and early infantile GM1 for cohorts evaluating dose level 3. Initial safety and biomarker data from dose level 3 are expected by mid-2024.

“Our momentum in the Imagine-1 study continues to be strong as the program progresses to evaluate its highest dose level, Dose 3, in patients with early and late infantile GM1,” Chou added. “We are excited to share that we have treated the first patient at Dose 3, and we are actively recruiting additional patients at clinical trial sites across multiple countries. We look forward to sharing initial data from Dose 3 patients by mid-2024 and want to express our deepest gratitude for the dedication and collaboration demonstrated by the families and investigators who have participated in our Imagine-1 trial.”

Passage Bio announces promising interim clinical data from first eight patients with GM1 Gangliosidosis in Imagine-1 study. News release. Passage Bio. August 7, 2023.
Related Videos
Jeffrey Chamberlain, PhD
Robert J. Hopkin, MD
Alan Beggs, PhD
Paul Harmatz, MD
Paul Harmatz, MD
Heather Lau, MD, MS, the executive director of global clinical development at Ultragenyx Pharmaceutical
Heather Lau, MD, MS, the executive director of global clinical development at Ultragenyx Pharmaceutical
Paul Harmatz, MD, on Challenges With Assessing Neurocognitive Outcomes
Paul Harmatz, MD, on Assessing D2S6 in Trials for MPS Type 2
© 2024 MJH Life Sciences

All rights reserved.