MDA 2023: Data support AT-GAA’s long-term benefits for LOPD patients
Treatment's effects on walking and lung function were sustained after 2 years
After two years being treated with AT-GAA (cipaglucosidase alfa/miglustat), adults with late-onset Pompe disease (LOPD) maintained their improvements in walking ability and had stabilized breathing function, as well as a reduction in the levels of disease biomarkers, according to data from a Phase 3 extension study
Findings were presented at the Muscular Dystrophy Association’s MDA Clinical & Scientific conference, in a talk, titled “Long-term efficacy and safety of cipaglucosidase alfa/miglustat in patients with Pompe disease: a Phase III open-label extension study (ATB200-07).” The work was funded by AT-GAA’s developer, Amicus Therapeutics.
In Pompe disease, mutations lead to impaired function or absence of the GAA enzyme that is needed to break down glycogen, leading to a toxic buildup of this sugar molecule in cells.
US and UK to decide whether to approve AT-GAA for LOPD later this year
AT-GAA is an experimental treatment for Pompe disease that includes a version of the GAA enzyme, called cipaglucosidase alfa, given alongside a molecule that helps to stabilize it. The European Commission recently approved cipaglucosidase alfa, brand name Pombiliti, to treat adults with LOPD. A recommendation on the treatment’s other component, called miglustat, is expected by the end of June. Authorities in the U.S. and U.K. are expected to decide whether or not to approve AT-GAA for LOPD later this year.
Regulatory applications for AT-GAA are supported by data from the Phase 3 clinical trial PROPEL (NCT03729362). The study enrolled 123 ambulatory (able to walk) adults with LOPD.
Participants in PROPEL were randomly assigned to AT-GAA or Lumizyme (alglucosidase alfa), the first enzyme replacement therapy (ERT) approved for Pompe, for about a year. Results showed AT-GAA outperformed Lumizyme on measures of walking ability and lung function among patients who had previously been on ERT.
After the initial portion of the study, participants had the option to enter an open-label extension study (NCT04138277) in which all participants are being treated with AT-GAA and monitored for long-term safety and efficacy outcomes.
The extension study included 119 patients, 91 of whom had been on ERT before PROPEL. Among the patients, 82 were on AT-GAA in the original PROPEL trial (AT-GAA group), while the other 37 switched from Lumizyme to AT-GAA upon entering the extension study (switch group).
Over 90% of patients who entered the extension study remained in it for at least a year — a total of 104 weeks (two years) on AT-GAA for patients in the AT-GAA group. Of note, a participant in the AT-GAA group was never dosed.
Data demonstrate treatment with [AT-GAA] up to 104 weeks was associated with a durable effect and was well tolerated, supporting long-term benefits of treatment for patients with LOPD.
No new safety issues reported in extension study
No new safety issues have been reported so far in the extension study. Three patients chose to drop out of the study due to infusion-related reactions, including hives, low blood pressure, and anaphylaxis (severe allergic reaction).
“There were no major safety concerns identified,” Tahseen Mozaffar, MD, of the University of California Irvine, said at the MDA conference.
Efficacy outcomes in the study include six-minute walk distance (6MWD, a common measure of walking ability and exercise capacity), as well as forced vital capacity (FVC), a measure of lung function based on how much air a person can forcibly exhale.
In the PROPEL trial, average 6MWD increased markedly for ERT-experienced patients given AT-GAA. Results from the extension study suggest that average 6MWD scores generally remained stable after an additional year on AT-GAA. Scores were also stable in the extension study for patients who switched to AT-GAA after being on Lumizyme in the original study.
For patients who had been on prior ERT, FVC was generally stable in the original study and remained stable after an additional year in the extension study — after two years on AT-GAA, the average decline in FVC was 0.6% in this group.
ERT-experienced patients who were treated with AT-GAA in both studies showed improvement in terms of six-minute walk test and continued to show stability in FVC, Mozaffar said.
“All of these outcomes remained stable throughout the open-label study,” he added.
ERT-experienced patients given Lumizyme in the original study experienced a decrease in FVC during the original study, but FVC values stabilized in the extension study after patients had switched to AT-GAA.
Treatment improved 6MWD scores for patients in both groups
For patients who had not been on prior ERT, average 6MWD scores improved markedly in both the AT-GAA and Lumizyme groups in the original study, and the improvements remained stable after a year on AT-GAA in the extension study.
Among patients who hadn’t been on ERT before, FVC values tended to decrease somewhat in the original study, both for patients on AT-GAA and those on Lumizyme. These values then stabilized in the extension study.
“We really don’t have a good explanation for that, of why patients who were [ERT-]naïve did not respond as well,” Mozaffar said, though he noted that the number of ERT-naïve patients was quite low, and that the overall decline in FVC “in the scheme of things, is really not that large.”
Data from the extension study suggested that, in all groups, AT-GAA treatment led to a sustained reduction in the levels of creatine kinase, a marker of muscle damage, and hexose tetrasaccharide, a marker of toxic glycogen buildup.
“Data demonstrate treatment with [AT-GAA] up to 104 weeks was associated with a durable effect and was well tolerated, supporting long-term benefits of treatment for patients with LOPD,” the scientists concluded in their abstract.
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