Miglustat — a component of AT-GAA, an investigational therapy for late-onset Pompe disease (PD) — enhances the activity of the other component in AT-GAA, cipaglucosidase alfa, researchers report.
These findings were presented at the 2021 MDA Virtual Clinical & Scientific Conference, in the poster “Enhancing Delivery of Acid Alpha-glucosidase (GAA) to Skeletal Muscle in Pompe Disease (PD): Key Challenges and Attributes of AT-GAA.”
Pompe disease is caused by mutations that lead to the deficiency of an enzyme called acid alpha-glucosidase (GAA), which is important for breaking down the sugar molecule glycogen. In this disease, glycogen builds in tissues — particularly muscles — to toxic affect.
AT-GAA is a two-component therapy that is being developed by Amicus Therapeutics. One of its components is cipaglucosidase alfa, a lab-made form of GAA that has been engineered to more effectively get into cells. The other is miglustat, which is given to stabilize the active enzyme. Miglustat is sold under the brand name Zavesca as a treatment for Gaucher disease.
Researchers from Amicus presented data showing the stabilizing effects of miglustat. They demonstrated that cipaglucosidase alfa maintained greater activity over time in the presence of miglustat, both in a buffer solution and in human blood.
For example, when the enzyme was alone, its activity in human blood decreased by more than 50% after four hours. However, when miglustat was added (at a concentration of 170 micromolar), the enzyme’s activity was over 80% after four hours.
In mice engineered to lack GAA, treatment with cipaglucosidase alfa alone reduced glycogen levels in various muscles significantly. In fact, cipaglucosidase alfa alone was more effective in this regard than treatment with alglucosidase alfa, an enzyme replacement treatment for Pompe marketed as Lumizyme in the U.S.
The addition of miglustat to cipaglucosidase alfa led to a greater decrease in muscle glycogen levels in the mouse triceps (equivalent to the upper arm in people). Glycogen levels in the heart and quadracepts (thigh) were not significantly altered by the addition of miglustat to cipaglucosidase alfa.
Notably, treatment with miglustat alone had no effect on glycogen levels. Treatment with both cipaglucosidase alfa and miglustat in combination normalized cellular abnormalities in GAA-deficient mice, whereas treatment with miglustat alone did not.
From these findings, the researchers concluded that “cipaglucosidase alfa is the primary contributor of AT-GAA efficacy. While co-administration of miglustat with cipaglucosidase alfa improves treatment, outcomes compared to administration of cipaglucosidase alone, miglustat alone is not sufficient to ameliorate cellular [changes] associated with PD [Pompe disease] in [GAA-deficient] mice.”
Other experiments aimed to better understand how the GAA enzyme is processed within cells. The researchers found that two types of modifications, called proteolytic cleavage and glycan trimming, are necessary for optimal function of the GAA protein. Proteolytic cleavage essentially means breaking down the enzyme into a smaller form, whereas glycans (added to the therapeutic molecule to improve its uptake by cells) are sugar molecules.
The researchers said that cipaglucosidase alfa undergoes the same processing within cells as does the naturally occurring protein.
This research was funded by Amicus.
Recent data from the Phase 3 PROPEL clinical trial (NCT03729362) showed that AT-GAA treatment led to improvements in measures of physical and lung function in adults with Pompe disease. Amicus has begun a rolling submission seeking approval of AT-GAA in the U.S.; the filing of applications to regulatory agencies elsewhere is expected to begin this year.
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