AAN 2023: AT-GAA motor function gains now seen for 4 years in Pompe

US, UK approval decisions on 2-part therapy expected later this year

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Treatment with AT-GAA, Amicus Therapeutics’ experimental two-part therapy for Pompe disease, has now been shown to improve motor function, and to stabilize or improve lung function, for up to four years in adults.

That’s according to new analyses from the ongoing Amicus-sponsored Phase 1/2 ATB200-02 trial (NCT02675465), which also found the therapy to be safe and able to stabilize or slightly improve muscle strength.

In a study abstract, researchers noted participants who had previously received Pompe treatment “had durable mean improvements [from the study’s start] in motor function that were sustained up to 48 months of follow-up; respiratory function was stable and maintained over the same period.”

Meanwhile, patients receiving treatment for the first time also showed “improvements [from the study’s start] in motor and respiratory function” that also continued for the four years, the team noted.

These findings were shared last week at the American Academy of Neurology (AAN) 2023 annual meeting by Tahseen Mozaffar, MD, of the University of California Irvine. His oral presentation was titled “Long-term Follow-up of Cipaglucosidase Alfa/Miglustat in Ambulatory Patients with Pompe Disease: An Open-label Phase I/II Study.”

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Decisions on AT-GAA Pompe disease treatment are likely this year

Most patients in trial had previously used ERT

Both components of the treatment duo are under regulatory review in the U.S. and the U.K. for late-onset Pompe disease. Decisions by regulatory authorities in both countries are expected later this year.

In the European Union, one part of the treatment already has been approved, and a committee last month adopted a positive opinion on the therapy’s second part, known as miglustat. A decision on whether to approve miglustat in the EU is expected in the third quarter of this year.

The first component of AT-GAA is cipaglucosidase alfa, a lab-made version of the GAA enzyme that’s lacking or deficient in Pompe patients. That’s the part that’s been approved in Europe, under the brand name Pombiliti. The second component helps stabilize the enzyme.

The first in-human study of AT-GAA to launch was ATB200-02, which enrolled 29 adults, ages 18-75, with Pompe disease. Six of the participants were not ambulatory, but the other 23 were able to walk.

Most of the patients — 23 people in all — had previously used enzyme replacement therapy (ERT), which works to reduce muscle wasting and heart problems in Pompe. Among those who could walk, 11 had been on ERT for two to six years, and six had received such treatment for at least seven years.

Two trial stages identified the optimal doses of cipaglucosidase alfa and miglustat. Then, the long-term safety and efficacy of AT-GAA at these optimized doses was monitored for a period of two years.

Participants will continue to receive the experimental therapy until the study discontinues or AT-GAA is approved and becomes commercially available.

Cipaglusoidase alfa is given as an into-the-vein (intravenous) infusion at a dose of 20 mg/kg alongside oral miglustat, administered at a dose of 260 mg once every two weeks.

Data presented at a scientific conference last year indicated that up to three years of treatment with AT-GAA was associated with improvements in walking ability for ambulatory patients, as assessed by the six-minute walk distance (6MWD), regardless of patients’ prior ERT use.

Lung function, measured with forced vital capacity (FVC), was stable among ERT-experienced patients and steadily improved for those who had not previously used ERT.

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In the AAN presentation, Mozaffar provided an update on ambulatory patients continuing in the ATB200-02 trial who had now received up to 48 months, or four years, of treatment.

The findings were generally consistent with those from the three-year analysis, with patients continuing to see improvements in walking ability after four years.

[The new findings show] an improvement relative to the expected decline in many patients receiving long-term ERT.

Specifically, 6MWD scores were improved by a mean of about 26 meters (approximately 85 feet) for the nine ERT-experienced patients who remained in the trial after four years relative to the study’s start.

Gains in the ERT-naive group were similar, with 6MWD scores rising from 67.8 meters (222.4 feet) at the study’s start to 82.8 meters (271.7 feet) after four years.

Among patients on prior ERT, FVC scores remained generally stable throughout treatment. Those who had never used ERT continued to see progressive improvements, as has since been seen in Phase 3 testing, Mozaffar noted.

That finding is “an improvement relative to the expected decline in many patients receiving long-term ERT,” according to Mozaffar.

Additional tests indicated small improvements in muscle strength after four years, “suggesting more of a stabilization than a massive increase,” Mozaffar said.

Disease-associated biomarkers were generally reduced up to four years, with the most notable reductions among those who were ERT-naive before the trial.

AT-GAA’s safety profile was consistent with the known side effects associated with ERT.

The most common side effects were falls, cold-like symptoms, joint pain, diarrhea, and headache, most of which were mild or moderate and did not lead to study withdrawal.

Benefits of AT-GAA for adults with Pompe also have been shown in the Phase 3 PROPEL trial (NCT03729362), which supported Amicus’ regulatory applications.

As authorities review AT-GAA’s potential as a treatment for adults with Pompe, the Phase 3 ROSSELLA trial (NCT04808505) is evaluating its safety and effectiveness in children with infantile-onset Pompe disease.

ROSSELLA is recruiting up to 36 patients younger than 18 at a single center in Florida. All participants will receive AT-GAA over a 104-week treatment period.