Gene Therapy Shows Promise in Infantile GM1 Gangliosidosis

Samiah Al-Zaidy, MD

The most recent data from the phase 1/2 Imagine-01 clinical trial (NCT04713475) evaluating PBGM01, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat infantile GM1 gangliosidosis, have continued to show encouraging safety and efficacy. The data were presented at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida.

Shortly before the presentation, CGTLive spoke with Samiah Al-Zaidy, MD, vice president of clinical development and lead on the GM1 Program at Passage Bio, about the results, as well as future plans for further study of the therapy, which may focus on the evaluation of higher doses.

CGTLive: Can you tell us a bit about the current unmet needs for patients with infantile GM1 gangliosidosis?

Samiah Al-Zaidy, MD: There’s a tremendous unmet need in GM1 gangliosidosis. This is a devastating disease that is on a continuum of a spectrum. On one end of the spectrum, you have the very severe "early infantile", or also as described in the literature as "infantile". Unfortunately, these children are born with neurological symptoms and continue to progress fairly rapidly, and eventually succumb to their disease within the first few years of their life. On the other end of the spectrum, you do have the adult onset, which robs patients of their quality of life and their ability to function on a daily basis. So it's quite a devastating neurological disease, where patients regress, and there are no approved options for treatment, so supportive care is the only option for these patients.

Can you give a topline overview of the interim data from Imagine-01 being presented at WORLDSymposium and the key takeaways?

We're very excited and encouraged by the data from the PBGM01 treatment demonstrated in the Imagine-01 study. Recently, we shared data on our first 6 patients treated in December 2022 through a webinar, so we are building on those data. Given this is a phase 1/2 study, first and foremost safety is what we want to be able to share. We're very encouraged by how well-tolerated PBGM01 has been in our study participants. We have not seen any serious adverse events related to PBGM01, we have not seen antibodies developed to the transgene, we have no dorsal root ganglia toxicity or evidence of that, based on our data, and most importantly, we are very encouraged by how well-tolerated the administration through the intra cisterna magna has been in these young infants. So overall, we are very encouraged by our safety profile for PBGM01.

And moving on to the efficacy data, we're building on what we had shared back in December 2022. We are excited to share that we continue to see a dose-dependent response in the cerebrospinal fluid (CSF) beta-galactosidase (β-Gal) activity across our cohorts. So we're seeing trends towards a significant increase in β-Gal activity in the CSF at the high dose. Along those lines, we shared some of our substrate data in December, where we were seeing clearance at a high dose in a dose-dependent manner. And we're very encouraged by additional new substrate data that we are sharing this year at the WORLDSymposium, where we're sharing our urine Dp5 substrate data. These are O-glycans, they are toxic to the nerve cells, and as they build up, they cause neurological manifestations. Evidence for clearance of these suggests β-Gal enzyme activity. So we're very encouraged to see that we are seeing prominent decreases in the Dp5 in the urine, which supports that there is peripheral β-Gal enzyme activity in these patients.

And additionally, at WORLDSymposium, we are sharing new data on our MRI severity scores for these patients. The MRI severity score is a score that is applied in patients with GM1 gangliosidosis. It's based on cerebral and cerebellar atrophy, white matter abnormalities, abnormalities of the basal ganglia, and the hippocampi. The higher the score, the more structural damage in the brain. And we're really encouraged by what we're seeing—we're seeing stabilization of these scores in our patients, in contrast to what we would expect to see in natural history for untreated patients, where the score would continue to rise over time as the disease progresses. So while it is a preliminary readout for these data, we're really encouraged by what we're seeing. And finally, we continue to see that across our developmental outcome assessments, we are seeing transfer stabilization in our patients. So we're very encouraged by that data, and we are excited to share it.

What do you see as the potential advantages of PBGM01 over the current standard of care?

If we go back to earlier, we discussed how devastating this disease is, and how there's a tremendous unmet need. Currently, the only option for these families is supportive care. Supportive care consists of offering support to patients and their families with the aim to prevent serious complications and provide comfort care. There is no reversal of the loss of function with supportive care. The hope is that with PBGM01, what we're seeing through our encouraging data, the goal ultimately is to see that translate into clinical improvements through halting the progression of the disease and/or hopefully restoring some of the function while prolonging survival. So that is the hope and the ultimate goal with this gene therapy.

Were there any limitations in the study and or any unexpected results that you'd like to see explored further?

At this point of our assessment of our data, we don't see any potential limitations. We're actually very encouraged by the safety profile. And this allows us to explore additional higher doses in the future and the therapeutic potential of these higher doses.

Are there any future plans for this research that you can share with us at the moment?

Future plans and future directions for the Imagine-01 study are really informed by the encouraging safety profile and the early assessment of the dose-dependent response that we're seeing in the biomarkers. As we shared previously, in December 2022, we are exploring the potential benefit of higher doses of PBGM01 in this dose-ascending phase. We look forward to sharing that in the near future.

Is there anything else that you want to add, either about these data or just anything in general that you want to share?

I'd like to share with the audience that there is a great potential for PBGM01 in patients with GM1 gangliosidosis and that we continue to build on our momentum. I'd also invite the audience to follow Passage Bio. We are uniquely positioned, following our partnership with the Gene Therapy Program at the University of Pennsylvania, and most certainly with the tremendous talent that we have at Passage Bio.

Transcript edited for clarity.