Enhancing Delivery of Acid Alpha-Glucosidase (GAA) to Skeletal Muscle in Pompe Disease (PD): Key Challenges and Attributes of AT-GAA

Pre-Clinical Research
Nithiya Selvan , Suresh Venkateswaran , Jessier Feng , Finn Hung , Matthew Madrid , Nickita Mehta , Matthew Graziano , Nastry Brignol , Yuliya McAnany , Richie Khanna , Su Xu , Steven Tuske , Jon Brudvig , Hung Do
1. Amicus Therapeutics, Inc., 2. Amicus Therapeutics, Inc., 3. Amicus Therapeutics, Inc., 4. Amicus Therapeutics, Inc., 5. Amicus Therapeutics, Inc., 6. Amicus Therapeutics, Inc., 7. Amicus Therapeutics, Inc., 8. Amicus Therapeutics, Inc., 9. Amicus Therapeutics, Inc., 10. Amicus Therapeutics, Inc., 11. Amicus Therapeutics, Inc., 12. Amicus Therapeutics, Inc., 13. Sanford Research, 14. Amicus Therapeutics, Inc.

Background: PD is a rare neuromuscular disorder caused by deficiency of GAA, a lysosomal glycogen-catabolizing enzyme. Despite availability of a recombinant human GAA enzyme replacement therapy (rhGAA ERT), clinical unmet needs remain, including suboptimal response in skeletal muscles caused in part by several key challenges (eg, instability of ERT in circulation, inefficient uptake via the CI-MPR at low interstitial concentrations). GAA requires processing to attain maximal activity for glycogen degradation; however, the relative contributions of proteolytic and N-glycan processing are poorly understood. AT-GAA—an investigational 2-component therapy comprising cipaglucosidase alfa (a next-generation rhGAA enriched with bis-phosphorylated N-glycans for improved uptake) administered with miglustat (a small molecule stabilizer of cipaglucosidase alfa)—has been demonstrated to significantly improve the PD pathogenic cascade (eg, glycogen reduction, reversal of autophagic dysfunction, and muscle pathology) compared to alglucosidase alfa in Gaa knockout (KO) mice. We demonstrate that N-glycan processing is required for enzyme activation and further describe the relative impact of the 2 components of AT-GAA on observed efficacy in Gaa KO mice.

Objectives: To evaluate cipaglucosidase alfa and GAA variants resistant to N-glycan trimming for processing and enzyme activation. The relative effect of each of the individual components of AT-GAA (cipaglucosidase alfa and miglustat) on observed efficacy are further characterized in Gaa KO mice.

Results: Cipaglucosidase alfa was fully processed, activated, and indistinguishable from mature, endogenous human GAA; GAA variants resistant to N-glycan trimming demonstrated lower activity. In Gaa KO mice, miglustat stabilized cipaglucosidase alfa and preserved its activity in the unfavorable physiological pH of blood following infusion.

Conclusion: Results highlight the importance of improving both rhGAA ERT uptake and preserving intracellular processing to maximize glycogen degradation. In Gaa KO mice, the impact of miglustat on cipaglucosidase alfa stability and activity is demonstrated, which has relevance toward developing an effective treatment for PD.