GM1 Gangliosidosis Gene Therapy Trial Safe to Continue


Lysogene’s MPS IIIA gene therapy program recently failed its primary endpoint in the phase 2/3 AAVANCE trial.

The independent Data Safety Monitoring Board (DSMB) on the P1-GM-101 clinical trial (NCT04273269) assessing LYS-GM101 (Lysogene) gene therapy in patients with GM1 gangliosidosis has recommended the trial to continue after reviewing safety data.1

"We are very encouraged with the positive DSMB review, which confirms that our gene therapy and the route of administration have been well tolerated by the patients. In addition, we are pleased to see significant changes in beta-galactosidase (β-gal) and GM1 ganglioside levels in the cerebrospinal fluid. The biomarker data provide evidence for sustained expression and biological activity of the transgene product delivered by LYS-GM101,” Marie Trad, MD, chief medical officer, Lysogene, said in a statement.1 “These results mark an important milestone for the development of LYS-GM101 and pave the way for the initiation of the confirmatory efficacy phase of our trial".

The DSMB reviewed data from the first phase of the study, comprised of the first 2 patients with late infantile (LI) GM1 gangliosidosis as well as 3 patients with early infantile (EI) GM1 gangliosidosis enrolled earlier this year. Investigators found that there were no adverse events linked to the intracisternal administration or the LYS0GM101 therapy itself at a minimum of 3 months follow-up post-treatment for up to over a year of follow-up in the 2 earliest patients treated.

Lysogene also announced updated biomarker data in these 4 patients from the trial that demonstrated increases in β-gal enzyme activity in cerebrospinal fluid (CSF) from baseline. β-gal activity increased by 11 pmol/ml/h at 6 months (1.5-fold increase from baseline) in 1 patient with LI GM1 gangliosidosis. In the second patient with LI GM1 gangliosidosis, β-gal activity increased by 44 and 33 pmol/ml/h at 6 and 12 months after dosing, (2.5- and 2.1-fold increases from baseline). In the 2 patients with EI GM1 gangliosidosis, β-gal activity increased by 14 at 3 months and 13 pmol/ml/h at 6 months post-treatment (2.1- and 2.8-fold increases from baseline).

WATCH NOW: Gene Therapy for GM1 Gangliosidosis: Latest Updates

Investigators also observed decreases in GM1 ganglioside in CSF, with decreases of 62% at 6 months post-treatment in 1 participant with LI GM1 gangliosidosisand 28% at 6 months and 64% at 12 months in the other participant with LI GM1 gangliosidosis. The 2 patients with EI GM1 gangliosidosis had GM1 ganglioside reductions of 34% at 3 months and 42% at 6 months post-treatment compared to baseline.

LYS-GM101 uses an adeno-associated virus rh10 vector to deliver the human β-gal gene. The second phase of the P1-GM-101 trial will seek to confirm efficacy of the therapy in 12 participants to be enrolled after interim analysis of the first portion has been completed. Lysogene noted in its announcement that the company will need to pursue a licensing collaboration for 1 or more of its programs to secure an adequate cash runway to continue development of LYS-GM101. Lysogene’s current cash runway only extends until February 2023. A collaboration may be difficult, as the company’s phase 2/3 AAVance clinical trial (NCT03612869) its LYS-SAF302 gene therapy intended for the treatment of mucopolysaccharidosis type IIIA just this month failed its primary endpoint of cognitive development compared to natural history.2

“While we are disappointed with the results in the main cohort of the patients enrolled at 30 months or older, these can likely be explained by the rapid progression of the disease and the recent learning from other clinical studies that gene therapy treatment of neurodegenerative diseases should be initiated at the earliest possible age in order to provide a therapeutic benefit before the onset of irreversible neuronal damage,” Karen Aiach, founder, chairman, and chief executive officer, Lysogene, said in a statement at that time.2 “The positive signs of efficacy observed in very young children enrolled before the age of 30 months indicate that early dosing of LYS-SAF302 gene therapy in children with MPS IIIA might have a real beneficial effect on these patients and transform their lives. The trial results clearly delineate the patient population that would benefit from treatment with LYS-SAF302. We are very much encouraged by these results and are eager to continue our discussions with the regulatory agencies to take LYS-SAF302 to the next level in younger patients.”

1. Lysogene : Announces favorable DSMB review recommending study continuation and positive biomarker data in stage 1 of adaptative clinical trial with LYS-GM101 gene therapy in GM1 gangliosidosis. News release. Lysogene. November 29, 2022.
2. Lysogene provides updates and topline results from phase 2/3 AAVance gene therapy clinical study. News release. Lysogene. November 18, 2022.
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