Discussing Interim Data on AT845 in Adults With Late-Onset Pompe Disease

Tahseen Mozaffar, MD, FAAN, spoke on recently reported positive interim safety data from the phase 1/2 FORTIS study, noting that the treatment was thus far safe and well-tolerated in patients.

Pompe disease is a rare, inherited lysosomal disease, for which only 1 treatment approach, enzyme replacement therapy (ERT), is approved by the FDA. Sanofi announced that FDA had granted approval to avalglucosidase alfa-ngpt (Nexviazyme) for the treatment of late-onset Pompe disease (LOPD) in patients aged 1 year and older in August 2021, but the therapy also poses risk of infusion-related reaction and requires biweekly administration.1

AT845 (Astellas Pharma), an investigational adeno-associated gene replacement therapy offers another approach, delivers a functional GAA gene to express acid alpha glucosidase directly into muscle cells. The treatment is being evaluated in the ongoing, multicenter, open-label, ascending dose phase1/2 FORTIS study (NCT04174105) in adults with LOPD, with investigators recently announcing positive interim safety data from 4 enrolled patients.2

Tahseen Mozaffar, MD, FAAN, director, UC Irvine-MDA ALS and Neuromuscular Center, director, Division of Neuromuscular Diseases, Neurology School of Medicine, and professor of neurology, pathology, and orthopaedic surgery, University of California, Irvine, spoke with NeurologyLive® on the first-in-human study, noting that the treatment was “very safe” and well-tolerated to date. Enrollment in the study is ongoing, he said, further calling for physicians to refer patients in order to expedite the trial’s timeframe.

NeurologyLive®: Can you provide some background on the FORTIS study?

Tahseen Mozaffar, MD, FAAN: The reason gene therapies are being tried, even though we have now 2 approved enzyme replacement therapies, is the challenge with enzyme replacement therapy is that you have biweekly injections that result in fairly high levels of the enzyme in the circulation, but then they taper off over the next 2 weeks, and effectively, the body has no enzyme replacement during that period. The primary goal of the gene therapy is to have stable trough levels of the enzyme, which is produced internally. So, rather than being dependent on exogenously delivered enzyme, your body is producing the enzyme itself, and depending on the technique, it's being produced in the liver, versus being produced in the muscle, where it's needed the most. FORTIS is a muscle-directed approach, where the enzyme is going to be produced locally in the muscle, it will have steady levels, and hopefully, it will do a better job of clearing out glycogen and stabilizing the disease.

What were the key findings? Were any surprising in any way?

This presentation was primarily about the initial experience with this study. So far, to date, we have dosed 4 patients with the gene therapy, 2 in the lower dose, and 2 in the higher dose—and when I say lower dose or higher dose, they're still therapeutically meaningful doses, except that for safety purposes, we wanted to start with a lower dose and go to a higher dose. We have demonstrated that the vector, which is the virus that we deliver, gets engrafted into the muscle, which is data from the muscle biopsy. We don't have data on enzyme production yet. Two out of the 4 patients have chosen—and this was an option for the patients, to go off their exogenously delivered enzyme replacement—that usually happens 16 weeks after the gene therapy. So, 2 out of the 4 have [opted to do this], 1 declined to do it, and the other patient hasn't reached 16 weeks yet, so we don't know what that patient will do.

The treatment has been incredibly safe. The infusions were very well tolerated. There were no major treatment-related adverse events or treatment emergent adverse events. There was 1 patient that did develop abnormally high liver function tests, especially the transaminases, which responded to steroid therapy and came down. But the other 3 patients to date have not experienced any treatment emergent adverse events.

When is a full data readout from the FORTIS study expected? Are there current plans for additional phases of study?

The study is planning to enroll anywhere from 8 to 12 patients. Again, we haven't reached a full complement of patients yet. And then there are a whole bunch of studies that we need to do to determine the efficacy end points—so whether there is enzyme in an adequate amount, whether there is glycogen clearance, etc. I think a lot of that data is still missing. The way the study is designed, it is meant to be a slower process because you [administer treatment to] 1 patient, you wait for 8 weeks for the safety signal, then you go on to the next patient, then you wait, then the data safety board decides whether we can go to a higher a higher gene dosage cohort or not. This design is a very deliberately designed study to ensure safety, so it's going to be a number of months before we can get to a position where we can have some of these data available for full disclosure.

What are the benefits AT845 could offer adults with late-onset Pompe disease, if successful?

As I emphasized before, the biggest advantage here would be that, rather than being dependent on an exogenously delivered enzyme that has to be given every 2 weeks with a significant amount of infusion-related reaction, plus a time commitment—because the infusion takes about 4 hours—you would be in a situation where your body is producing its own enzyme, either in the liver or in the muscle. One of the advantages with the liver approach is, you have immunological tolerance, so you don't create immunity to it. With the muscle, it's much less, as well. But the other advantage, especially with the FORTIS trial, is that the enzyme is produced where it's needed the most. So, you don't have to depend on the enzymes being secreted by the liver, and then hoping that it'll get to the muscle. Here, the enzyme is directly being produced in the muscle in the heart, where it's needed the most. We anticipate that the efficacy is going to be higher.

What further research is still needed?

I think gene therapy is one [area that needs more research]. Right now, they are using AV genes, which are nonintegrating genes, which means that at some point, there's a potential that we may need to redose, although, surprisingly, the hepatocytes or the liver cells, and even muscle cells, have not lost their transduction efficiency in some of the other trials. We don't think it's going to be imminently required. The other approaches would be to use the mRNA approach, which is what Pfizer and Moderna did for vaccine delivery, and there are other gene therapy trials and other glycogen storage diseases that are using the mRNA technique, rather than a DNA technique. I think we need to be able to figure out how to redose these patients if they ever require treatment again, because the moment they see the viral vector, they develop antibodies to it, which are long-lasting antibodies. The other challenge is, right now, roughly about half of our patients with Pompe are not eligible for the trial because they already have circulating antibodies to the virus. We need to be able to figure out a way to suppress them so these patients who require the gene therapy, who are very deserving of [it], would be able to get the gene therapy.

Is there anything else you would like to add?

I think it's important to mention that [FORTIS] has been a very safe study to date. It's very well tolerated. We are still looking for patients, so if some of these physicians have patients who are eligible, I would highly encourage them to refer them for these sites. There are sites in California, there are sites in Utah, there are sites in other states as well, but I think it's an important study, and if we can get more referrals, we should be able to do it in a faster timeframe.

Transcript edited for clarity.

1. FDA approves Nexviazyme® (avalglucosidase alfa-ngpt), an important new treatment option for late-onset Pompe disease. News release. Sanofi Genzyme. August 6, 2021. Accessed February 18, 2022. https://www.sanofi.com/en/media-room/press-releases/2021/2021-08-06-17-42-21-2276588 
2. Astellas announces positive safety data from the FORTIS study of AT845 in adults with late-onset Pompe disease. News release. February 7, 2022. Accessed February 18, 2022. https://www.biospace.com/article/releases/astellas-announces-positive-safety-data-from-the-fortis-study-of-at845-in-adults-with-late-onset-pompe-disease/