Imagine-01 Aiming to Evaluate Safety and Efficacy of GM1 Gangliosidosis Gene Therapy


The trial’s dose-escalation cohorts are assessing results from patients with type 2a and type 1 diseases separately.

Passage Bio’s PBGM01, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat infantile GM1 gangliosidosis, is currently being evaluated in the phase 1/2 Imagine-01 clinical trial (NCT04713475). The trial includes both patients with early onset infantile GM1 gangliosidosis (type 1) and late onset infantile GM1 gangliosidosis (type 2a). It was initiated in early 2021, with the company announcing the first patients’ dosing in April of that year.1

Led by study director Samiah Al-Zaidy, MD, vice president of clinical development and lead on the GM1 Program at Passage Bio, the trial is following a 2-part dose-escalation and dose-expansion design. The dose-escalation part includes 4 treatment cohorts: patients with type 2a disease treated at 3.3x1010 gene copies per gram of estimated brain weight (GC/g), patients with type 2a disease treated at 1.1 x1011 GC/g, patients with type 1 disease treated at 3.3x1010 GC/g, and patients with type 1 disease treated at 1.1 x1011 GC/g. Results will be assessed for patients with type 2a and type 1 diseases separately. The dose-expansion part will include 2 cohorts based on disease subtype, which will both receive treatment with a dose that will be selected based on a data review of the dose-escalation part. The trial has an estimated primary completion date of February 2026 and an estimated completion date of February 2029.

The study's primary outcome measures include the number of participants with treatment related adverse events (AEs) and serious AEs; the change in nerve conduction velocity and amplitude from baseline; the number of participants with clinically significant laboratory abnormalities as measured using hematology, chemistry, and coagulation tests; and assessments of humoral responses against the vector and the transgene in the serum and cerebrospinal fluid (CSF). Secondary outcome measures include changes from baseline in developmental milestones as assessed by the Vineland Adaptive Behavior Scale-II and the Bayley Scale of Infant and Toddler Development, Third Edition; changes in biomarkers of beta-galactosidase (β-Gal) activity in the blood and CSF; changes in biomarkers of β-Gal substrates in the blood and the CSF; changes in concentrations of biomarkers of disease progression in the plasma and CSF; changes in brain anatomy on MRI; changes in quality of life measured by Pediatric Quality of Life scales; and the change in ventilator-free survival compared with natural history data.

The trial includes patients aged 4 to 36 months (12 to 36 months for the first cohort) who have been diagnosed with GM1 gangliosidosis with 2 confirmed mutations in the GLB1 gene and a documented deficiency of β-Gal activity. The trial will exclude patients with any clinically significant neurocognitive deficit not attributable to GM1 gangliosidosis; a history of ventilation assisted respiratory support or tracheostomy being required as a result of their disease; intractable seizures or uncontrolled epilepsy; any contraindication to intra-cisterna magna injection, MRI, or lumbar puncture; prior treatment with gene therapy; or peripheral neuropathy. Additional exclusion criteria relate to concurrent treatments, treatment history, laboratory values, health status, and health history.

The trial originally received authorization to initiate from the United Kingdon’s Medicines Healthcare Products Regulatory Agency in December 2020, with FDA clearance of Passage Bio’s investigational new drug application coming soon after in January 2021.2,3 Interim results from the trial were presented in February of this year at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida. The findings included increases seen with the trial’s high-dose group in β-Gal activity.4 Stabilization in MRI severity scores was also observed in the treated patients. In a February 2023 interview with CGTLive™, Al-Zaidy spoke about potential future plans for the clinical trial based on the results presented at the WORLDSymposium.

“Future plans and future directions for the Imagine-01 study are really informed by the encouraging safety profile and the early assessment of the dose-dependent response that we're seeing in the biomarkers,” Al-Zaidy said. “As we shared previously, in December 2022, we are exploring the potential benefit of higher doses of PBGM01 in this dose-ascending phase. We look forward to sharing that in the near future.”

1. Passage Bio announces first patient dosed in imagine-1 study of PBGM01 gene therapy for infantile GM1 Gangliosidosis. News release. Passage Bio, Inc. April 1, 2021. Accessed April 7, 2023. 
2. Passage Bio receives MHRA clinical trial authorization for PBGM01 for treatment of GM1 gangliosidosis. News release. Passage Bio, Inc. December 10, 2020. Accessed April 7, 2023.
3. Passage Bio receives FDA clearance of IND application for lead gene therapy candidate PBGM01 for treatment of infantile GM1 gangliosidosis. News release. Passage Bio, Inc. January 4, 2021. Accessed April 7, 2023.
4. Jarnes JR, Hatings CA, Ficicioglu C, et al. Updated interim safety, biomarker, and efficacy data from Imagine-1: A phase 1/2 open-label, multicenter study to assess the safety, tolerability, and efficacy of a single dose, intra-cisterna magna (ICM) administration of PBGM01 in subjects with type I (early onset) and type IIA (late onset). Presented at WORLDSymposium 2023, held February 22-26, in Orlando, Florida. Abstract #186
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