A three way battle beckons in GM1 gangliosidosis

Early data could give clues about whether gene therapies from Sio, Passage Bio or Lysogene will come out on top in this rare inherited disease.

There is a boom in the number of gene therapies being developed for lysosomal storage disorders, though one of these diseases, GM1 gangliosidosis, has got little attention so far. It is now seeing a flurry of activity, with three projects already in or set to enter the clinic this year.

Two of these – Sio Gene Therapies’ AXO-AAV-GM1 and Passage Bio’s PBGM01 – are due to yield data in mid-2021, and Lysogene is not too far behind with LYS-GM101. Within the next year there will be a chance to see how the projects stack up against each other in the clinic. 

Sio, formerly known as Axovant, is in the lead for now. The group has already reported promising six-month data from the low-dose cohort of its phase I/II trial; notably, clinically meaningful increases have been seen in the enzyme beta-galactosidase, which is deficient in GM1 gangliosidosis.

This enzyme usually breaks down molecules called gangliosides; left unchecked, these build up to toxic levels in neurons and other cells, leading to neurodegeneration and other symptoms including liver and spleen enlargement and skeletal abnormalities.

There is a continuum of severity in GM1 gangliosidosis, with earlier-onset patients having more severe and rapidly progressing disease than juvenile or adult-onset patients. There are no approved therapies; early-onset patients die within a few years of diagnosis.

All three of these gene therapies aim to deliver a functioning copy of the GLB1 gene, which is mutated in GM1 gangliosidosis and encodes beta-galactosidase. But each is slightly different in the way it goes about this.

Upcoming readouts of GLB1 gene therapies in GM1 Gangliosidosis
Project Company Description Phase 1/2 trial Dose(s) Data due
AXO-AAV-GM1 Sio Gene Therapies AAV9 vector; IV delivery NCT03952637* 1.5x1013vg/kg & 4.5x1013vg/kg 6-mth data from low-dose cohort reported; 12-mth data due mid-2021 (5 pts)
PBGM01  Passage Bio AAVhu68 vector; ICM delivery Imagine-1, NCT04713475 3.3x1010vg/kg & 1.1x1011vg/kg First pt to be dosed Q1; 1-mth safety/biomarker data from low-dose cohort due mid-2021 (2 pts)
LYS-GM101 Lysogene AAVrh10 vector; ICM delivery NCT04273269 8x1012vg/kg First pt to be dosed H1; 3-mth safety/biomarker data due Q1 2022 (4 pts)
*Sponsored by National Human Genome Research Institute. ICM=intra-cisterna magna. Source: EvaluatePharma & clinicaltrials.gov.

AXO-AAV-GM1 is given intravenously, while PBGM01 and LYS-GM101 are both injected directly into the central nervous system, into the cisterna magna, a chamber at the base of the brain that contains cerebrospinal fluid.

Sio’s chief executive, Pavan Cheruvu, told Evaluate Vantage that going intravenous was a “deliberate choice”, as it could enable the therapy to address symptoms outside the brain.

“Many of these children don’t die from the neurological sequelae of the disease – often it’s because they have deposition of GM1 ganglioside in, for example, the rib cage, which impedes the normal motion of their lungs.”

Mr Cheruvu added that intravenously delivered AAV9 – the vector that Sio is using – has been shown to cross the blood-brain barrier, for example in the case of Novartis’s SMA gene therapy Zolgensma. This means that AXO-AAV-GM1 should also be able to address the symptoms in the brain and spinal cord, he said.

However, Lysogene has called the blood-brain barrier penetration of intravenous gene therapies poor, and a spokesperson for the company claimed several potential advantages of intra-cisterna magna (ICM) delivery, including the fact that it enables lower doses of vector and the treatment of patients with pre-existing immunity to the AAV capsid, who cannot receive intravenous AAV. 

The Lysogene spokesperson told Evaluate Vantage that gene therapy delivered via ICM should also be able to treat symptoms throughout the body, “as we and others have found distribution of ICM-delivered AAV vectors in the CNS and the periphery”.

Lysogene and Passage Bio both stressed the minimally invasive nature of ICM delivery, an image-guided procedure. “The intent is to avoid all [brain] structures and go straight into the cerebrospinal fluid,” Passage’s chief executive, Bruce Goldsmith, told Evaluate Vantage.


The safety of gene therapy is under the spotlight after several recent scares, and a couple of these have involved brain-directed projects: last year, Voyager and Lysogene itself saw abnormalities on MRI scans in patients who had received their therapies.

These issues were observed with Lysogene's separate Sarepta-partnered project, SAF302, which is delivered via intra-cerebral injection – something that Passage’s Mr Goldsmith believes should make all the difference.  

He noted that, unlike ICM delivery, intra-cerebral injection involves going through some brain tissue, and he added that the MRI abnormalities “could be an immune response to the local injection”.

The Lysogene spokesperson added: “There is no reason to believe that ICM administrations would cause similar effects.”

This should soon be put to the test, with Passage and Lysogene both due to start dosing in their phase I/II trials.

Passage will be the first to report data, in mid-2021, which could go some way to justifying the group’s $1bn market cap. The company raised $248m at its IPO last year despite having no projects in the clinic.

The initial readout for PBGM01 will concern 30-day safety and biomarker results from the first, low-dose cohort of the study, which will enrol two patients with late-infantile disease.

Mr Goldsmith said that Passage would be happy to see beta-gal enzyme levels of 10-20% of normal – which is around the level seen in adult-onset GM1 gangliosidosis patients. “Adult-onset patients live for 20-30 years, so even that may be transformational for these infants.”


If PBGM01 proves to be safe in this initial cohort, Passage plans to expand the trial to include both a higher dose and early-infantile patients. With the higher dose, Passage has ambitions of restoring patients to a normal phenotype, with Mr Goldsmith saying: “We’re shooting for 50% enzyme activity or even higher with upper dose.”

Sio is already not too far off this with its low dose of AXO-AAV-GM1: at six-months, beta-gal activity was restored to, on average, 38% of normal, in five patients with juvenile or late-infantile disease.

There were also promising signs on clinical assessments including those measuring mobility. Leerink analysts have cautioned that showing a benefit here over the natural history of disease will take longer than six months.

Sio also hopes to do better, and its trial is already testing a higher dose of the project; this cohort will also enrol early-infantile patients. “We think we’re already in the zipcode of a product that could be approved, but we think that the patient community deserves the very best shot possible, as it’s a one-time therapy,” Mr Cheruvu said.

He would not be drawn on a specific enzyme activity target that Sio has for the high dose. The next update with AXO-AAV-GM1, around mid-2021, will concern 12-month data from the low-dose arm.

Mr Cheruvu conceded that these results would be crucial given concerns about the durability of some other gene therapies, notably those for haemophilia A. “We’ve been very careful in the design of this vector, to try to avoid some of those common pitfalls – but I’m reluctant to talk about durability until we see those 12-month data.”

This story has been updated to correct the amount raised in Passage Bio's IPO.

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