Discontinued GM1 Gangliosidosis Gene Therapy Shows no Evidence of Clinical Benefit


Data from defunct company Lysogene’s discontinued trial of LYS-GM101 were presented at WORLDSymposium.

Treatment with LYS-GM101 gene therapy was generally well-tolerated but showed little evidence of a biochemical or clinical benefit in participants with infantile GM1 gangliosidosis treated in a phase 1/2 clinical trial (NCT04273269).1

Data from the trial, which was discontinued by its sponsor Lysogene, were presented at the 2024 WORLDSymposium, held February 4-9, in San Diego, California, by Arunabha Ghosh, MB BChir, PhD, clinical research fellow – pediatric inherited metabolic diseases, Central Manchester University Hospitals NHS Foundation Trust.The trial had treated5 patients, 2 with late infantile GM1 and 3 with early infantile GM1.

“Infantile GM1 gangliosidosis is a fatal, autosomal recessive disease caused by biallelic mutations in GLB1, leading to deficiency of β-galactosidase, neuronal accumulation of GM1 ganglioside, and progressive neurodegeneration,” Ghosh and colleagues wrote.1

LYS-GM101 had a manageable safety profile, although there were 2 cases of post-anesthesia stridor related to the study and 1 case of eosinophilic esophagitis likely related to tacrolimus. Most adverse events (AEs) related to the study were mild-to-moderate. Serious AEs included seizures, dystonia, and stridor (requiring tracheostomy in 1 participant). The trial also demonstrated feasibility of the intracisternal route of administration.

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

The investigators found that all participants developed antibodies against the AAVrh.10 vector, none developed antibodies against β-galactosidase, and no T-cell responses against β-galactosidase were identified. Three participants died, 2 due to progression of neurologic disease and 1 after a respiratory illness in the content of progressive neurological decline. These participants were aged 18 to 45 months and were between 14 and 29 months post infusion. Another was lost to follow-up.

“While the safety profile of LYS-GM101 appeared acceptable, and the intracisternal route of administration proved feasible, there was little evidence for potential efficacy of the therapy, with limited biochemical correction, and clear clinical decline in all participants,” Ghosh and colleagues wrote.1

The gene therapy did not show much preliminary biochemical or clinical efficacy, with all participants experiencing evident progression of neurological disease on Hammersmith and Bayley-III scales. Investigators observed only a modest effect on β-galactosidase cerebrospinal fluid (CSF) levels (peak level 20-75 nmol/L/hr) well below average control levels of 300 nmol/L/hr. Similarly, CSF GM1 ganglioside levels fell in all participants, with a maximum change of –34% to –64% but did not normalize. CSF neurofilament light concentrations increased in all participants. Furthermore, MRI imaging revealed cerebral atrophy, ex-vacuo dilatation of ventricles, and cerebellar atrophy.1

“Were there to be future development of this gene therapy product, potential improvements could include further optimization of dosing, recruitment of younger participants (not possible without a newborn screening strategy), or alternations to the vector/transgene product itself,” Ghosh and colleagues concluded.1

Lysogene discontinued the trial due to financial reasons shortly before the company was delisted and liquidated. The company sought offers after opening reorganization proceedings in January 2023 but later converted these proceedings into liquidation proceedings later that year. As a result, all ofthe company’s programs have ceased development.2

1. Ghosh A, Héron B, Donald A, et al. Safety and preliminary efficacy of LYS-GM101 gene therapy in patients with GM1 gangliosidosis: Results of a phase I/II open-label clinical trial. Presented at: 2024 WORLDSymposium; February 4-9; San Diego, California.
2. Lysogene announces the conversion of the reorganization proceedings into judicial liquidation and its delisting. News release. Lysogene. May 26, 2023. https://finance.yahoo.com/news/lysogene-announces-conversion-reorganization-proceedings-153200586.html
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