Based partly on results from the Phase 3 PROPEL clinical trial, Amicus began a rolling submission seeking U.S. Food and Drug Administration approval of AT-GAA in December 2020, and announced plans to file approval requests with regulatory agencies elsewhere in 2021.
It was granted orphan drug status in 2017 by the U.S. Food and Drug Administration for this disorder.
What is Pompe disease?
Pompe disease is an inherited lysosomal storage disorder that’s caused by mutations in the GAA gene, which provides instructions to build the GAA enzyme. Many types of cells store sugar in the form of a complex carbohydrate molecule called glycogen. In order to use the energy stored in glycogen, cells need GAA to break it down. Without GAA, glycogen builds up within cells and interferes with their function, especially in the heart, lungs, and skeletal muscles, which causes the symptoms associated with Pompe disease.
The type of mutation determines age of disease onset and severity. The complete or near-complete loss of enzyme function is associated with the early childhood form of the condition.
How does AT-GAA work?
AT-GAA, a two-component therapy, consists of a man-made, optimized form of the GAA enzyme called cipaglucosidase alfa, which is administered with an oral small molecule called miglustat that works as a pharmacological chaperone.
Cipaglucosidase alfa compensates for the lack of natural GAA enzyme in patients and has been engineered (optimized) to more effectively enter cells. Miglustat stabilizes the active enzyme, so that cipaglucosidase alfa maintains greater activity over time. Chaperones are designed to enhance structural stability, or correct the misfolding of proteins.
Amicus presented lab research results showings that cipaglucosidase alfa maintained greater activity over time in the presence of miglustat, both in a buffer solution and in human blood, at the 2021 MDA virtual conference.
AT-GAA in clinical trials
AT-GAA was investigated in 20 Pompe patients in an open-label Phase 1/2 clinical trial (NCT02675465). The study’s objectives wereto evaluate the safety, tolerability, pharmacokinetics (movement in the body), pharmacodynamics (effects on the body), and efficacy of AT-GAA over 18 weeks of treatment followed by a long-term extension study.
Fifteen of its 20 patients had previously been treated with enzyme replacement therapy (ERT).
Trial results, released in 2019, showed that two years of treatment led to improvements in patients’ muscle strength and motor function, assessed by the 6-minute walk test (6MWT; it measures the distance an individual is able to walk on a hard, flat surface in six minutes). Lung function, measured by forced vital capacity (FVC) — the total volume of air that can be blown forcefully following a full inhalation — also remained stable or improved, and markers of muscle damage due to Pompe disease were lower.
Based on these results, Amicus opened the Phase 3 PROPEL trial (NCT03729362). This 52-week, randomized and double-blind 3 trial compared the safety and effectiveness of AT-GAA to that of the alglucosidase alfa, an ERT marketed as Lumizyme in the U.S. and the current standard treatment. PROPEL enrolled 123 adults with Pompe disease who were able to walk and breathe independently; of these people, 77% were using alglucosidase alfa prior to enrolling while the rest had never been treated with the ERT.
Patients were randomized to treatment with AT-GAA for one year (about two-thirds of participants) or to alglucosidase alpha.
Results, released in February 2021, showed improvements in 6MWT among all of the 117 patients who completed the trial, with mean 6MWT distances increasing by more in those given AT-GAA than those treated with alglucosidase alfa. This difference, however, did not reach statistical significance. Changes in FVC were significant, with AT-GAA-treated patients showing an FVC decrease of 0.9% over the study’s year, compared with a 4% decrease in those on alglucosidase alfa.
Other measures also generally favored AT-GAA, though not all differences were statistically significant. Those that did included assessments of strength, coordination and mobility, as well as biomarkers of muscle damage and glycogen clearance.
The side effects of AT-GAA observed in clinical trials have so far been mild and transitory, according to reports, and similar to those documented with alglucosidase alfa’s use. Injection-associated reactions were reported in about a quarter of participants for either treatment.
Alglucosidase alfa, however, can cause severe allergic and immune-mediated reactions in some patients, according to its U.S. label, and the FDA recommends that “appropriate medical support” be available when it is administered.
Last updated: March 17, 2021
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