Race to Treat GM1 Gangliosidosis With Gene Therapy Continues


The first US-based patient has been dosed in Lysogene’s clinical trial of LYS-GM101, following 2 other competing trials.

Lysogene, a clinical-stage gene therapy company, recently announced that it has dosed its first US-based patient in its phase 1/2 clinical trial (NCT04273269) assessing LYS-GM101 gene therapy for the treatment of GM1 gangliosidosis.1 

The fatal, autosomal-recessive disease caused by mutations in the GLB1 gene causes progressive neurodegeneration and currently has no approved treatments. In addition to Lysogene, Passage Bio and Sio Gene Therapies are also currently evaluating gene therapies for this indication.

Lysogene is currently evaluating a recombinant adeno-associated virus vector serotype rb.10 that carries the human GBL1 gene. Delivered intracisternaly, the trial will evaluate safety and efficacy in patients with early or late infantile GM1 gangliosidosis.

"We are pleased with the rapid progress we are making with our teams in our effort to bring a new therapeutic solution to patients and families affected by GM1 gangliosidosis" said Karen Aiach, founder, chairman, and chief executive officer of Lysogene, in a statement.1 "By promptly opening a new site in the US and dosing the second patient we demonstrate our quality and timely execution despite a challenging and persistent COVID-19 environment."

LYS-GM101 previously received both orphan drug designation and rare pediatric disease designation by the FDA in 2017 and 2016, respectively, and orphan drug designation in the European Union in 2017.

The phase 1/2 clinical trial is a multi-center, single-arm, 2-stage adaptive-design study with a goal enrollment of 16 patients. In the initial safety and proof-of-concept stage, 4 participants will receive a single dose of 8x10^12 vg/Kg LYS-GM101. The second stage of the study, which will assess efficacy, will include additional participants.

Participants with early infantile GM1 gangliosidosis who are less than 1 year old and have the ability to swallow, and those with late infantile GM1 gangliosidosis who are aged 3 or younger with the ability to sit are eligible for inclusion. Those with uncontrolled seizure disorders, more than 40% brain atrophy, and those who are currently or have prior participation in another investigational clinical trial, including for gene therapy, are excluded. Current clinical trial sites are the Children’s Hospital of Orange County in the US, Hôpital Armand-Trousseau, Centre de Référence des Maladies Lysosomales in France, and Manchester University NHS Foundation Trust in the UK. Initial 3-month safety and biomarker data are expected to be reported in Q1 2022. 

In addition to the clinical trial, Lysogene is also supporting a natural history study of patients with GM1 glangliosidosis to collect footage affected children performing everyday tasks and behaviors in an effort to better understand and assess functional decline and improvements in this population. 

Lysogene is just steps behind its competitors in the space, as Passage Bio dosed its first patient in its IMAGINE-1 study (NCT04713475) in April of this year following a brief clinical hold placed by the FDA.2 Their gene therapy candidate, PBGM01, is similar to Lysogene’s in that it is injected directly into the cisterna magna. Alternately, Sio’s candidate, AXO-AAV-GM1 is delivered intravenously for systemic administration and is being evaluated in both GM1 (NCT03952637) and GM2 gangliosidosis, also known as Tay-Sachs and Sandhoff disease. Sio reported promising cerebrospinal fluid data in May at the ASGCT 2021 Annual Meeting, including 18% to 49% reductions from baseline in accumulated GM1 ganglioside observed in CSF of 4 out of 5 children in the low-dose cohort at 6 months, with signs of clinical stabilization observed in all 5 patients.3 Passage is expected to report initial safety and 30-day biomarker data in mid-2021. 

1. Lysogene announces first patient in the United States dosed with LYS-GM101 investigational gene therapy for the treatment of GM1 gangliosidosis. News release. Lysogene. August 30, 2021. https://www.biospace.com/article/releases/-lysogene-announces-first-patient-in-the-united-states-dosed-with-lys-gm101-investigational-gene-therapy-for-the-treatment-of-gm1-gangliosidosis-/
2. Passage bio announces first patient dosed in IMAGINE-1 study of PBGM01 gene therapy for infantile GM1 gangliosidosis. News release. Passage Bio. April 1, 2021. https://www.passagebio.com/investors-and-news/press-releases-and-statements/news-details/2021/Passage-Bio-Announces-First-Patient-Dosed-in-Imagine-1-Study-of-PBGM01-Gene-Therapy-for-Infantile-GM1-Gangliosidosis/default.aspx
3. Sio Gene Therapies announces CSF reductions in GM1 ganglioside from clinical trial of AXO-AAV-GM1 gene therapy. News release. Sio Gene Therapies. May 13, 2021. https://investors.siogtx.com/news-releases/news-release-details/sio-gene-therapies-announces-csf-reductions-gm1-ganglioside
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