GM1 Gangliosidosis Gene Therapy Shows Promise in Phase 1/2 Trial


No treatment-related serious adverse events were reported.

Passage Bio’s PBGM01, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat GM1 gangliosidosis being evaluated in the phase 1/2 Imagine-01 clinical trial (NCT04713475), was well-tolerated and demonstrated signs of efficacy in interim data from the first 6 patients treated.1

PBGM01 is intended to provide a functional copy of GLB1, the disease-targeted gene, via AAVhu68, and is administered with an intra-cisterna magna (ICM) injection. The announced data includes 2 patients with late onset infantile GM1 gangliosidosis (type 2a) treated with the trial’s low dose of 3.3x1010 gene copy per gram of estimated brain weight (GC/g) (cohort 1), 2 patients with late onset infantile GM1 gangliosidosis treated with the trial’s high dose of 1.1x1011 GC/g (cohort 2), and 2 patients with early onset infantile GM1 gangliosidosis (type 1) treated at the low dose (cohort 3). The first patient treated at the low dose showed a 4.7-fold increase from baseline in activity of beta-galactosidase (β-Gal), the enzyme encoded by GLB1, at 30 days post-treatment, and a 3.6-fold increase from baseline at 6 months. The second patent showed a 5.2-fold increase in β-Gal activity from baseline at the 30-day mark. For the patients treated at the low dose, β-Gal activity at 6 months showed a 1.2 to 2.8-fold increase from baseline.

In addition, the first patient in cohort 2 showed a decrease in levels of GM1 ganglioside, the substrate of β-Gal, in the cerebrospinal fluid (CSF) of 30% from baseline at the 30-day mark and 75% from baseline at the 6-month mark. The second patient in cohort 2 showed a 21% decrease in CSF GM1 ganglioside at 30 days. Results for the patients in cohorts 1 and 3 were variable. An assessment of changes in overall developmental age indicated that patients with milder developmental delay at baseline showed improvement, with 2 of the patients treated at the low dose who had modest developmental delay at baseline showing improvement in overall developmental age.

In terms of safety, which was based on follow-up ranging from 3 to 20 months, PBGM01 was well-tolerated. The severity of treatment-related AEs ranged from mild to moderate.

“The new interim data from cohorts 1-3 continue to strengthen the favorable safety profile of PBGM01, with no treatment-related serious adverse events, no complications related to ICM administration and no evidence of dorsal root ganglion toxicity,” Mark Forman, MD, PhD, chief medical officer, Passage Bio, said in a statement regarding the news.1 “We are also seeing dose-dependent increases in CSF β-Gal enzyme activity, decreases in CSF GM1 ganglioside levels, and meaningful improvement across developmental areas on both the Vineland and Bayley scales in a subset of patients with more modest developmental delay at baseline. We look forward to presenting additional data from cohorts 1-3 at the 19th Annual WORLDSymposium in February 2023.”

The chronological age of the 6 patients ranged from 6 months to 31 months (median, 16) at baseline and included 4 male patients and 2 female patients.2 The time of symptom onset for the patients ranged from birth to 14 months old. DBS β-Gal activity levels at baseline ranged from 0.0 to 0.2 nmol/ml/hr. The developmental age (Bayley) of the patients at baseline ranged from 0.5 months to 12 months (median, 3.75) and their development delay (Bayley) ranged from 2 months to 24 months (median, 13.25).

Two patients with early onset Infantile GM1 gangliosidosis were also treated at the trial’s high dose (cohort 4).1 These 2 patients had baseline chronological ages of 7 months and 5.5 months, developmental ages of 5 months and 1.5 months, and developmental delays of 2 months and 4 months, respectively.2 Passage Bio expects to announce treatment data from these patients in the middle of next year.1

Based on the safety data reported thus far, the company also expects that it will evaluate additional patients at the current high dose or a new, higher dose.2 Passage Bio additionally announced intention to pursue continued communications with regulatory agencies for the purpose of planning a confirmatory study.

“We are excited to share interim data from this first 6 patients in our Imagine-1 study, which further reinforce our confidence in PBGM01 as a promising treatment option for GM1 gangliosidosis,” William Chou, MD, chief executive officer, Passage Bio, added to the statement.1 “The goals of this phase 1/2 study are to establish the safety profile for PBGM01, determine the optimal dose for therapeutic effect, and gain understanding of how PBGM01 can benefit patients across infantile GM1 populations. We are encouraged by emerging trends in the data and look forward to receiving results from cohort 4 to further inform our program and support interactions with regulatory authorities. We couldn’t be more thankful for the conviction and perseverance of the families and investigators participating in our Imagine-1 trial.”

1. Passage Bio announces positive interim clinical data from first six patients with GM1 gangliosidosis in Imagine-1 study. News release. Passage Bio, Inc. December 14, 2022. 
2. Chou M, Jarnes J, Forman M. PBGM01 Study in Infantile GM1 Gangliosidosis. December 14, 2022. 

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