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Amicus advances chaperone-ERT combination platform in Pompe disease

Cranbury, New Jersey
Saturday, February 16, 2013, 15:00 Hrs  [IST]

Amicus Therapeutics, a biopharmaceutical company at the forefront of therapies for rare and orphan diseases, announced positive results from clinical and preclinical studies of the pharmacological chaperone AT2220 (duvoglustat HCl) in combination with chaperone-enzyme replacement therapy (ERT) for Pompe disease at the Lysosomal Disease Network WORLD Symposium (LDN WORLD).

Pompe disease is a lysosomal storage disease characterized by progressive skeletal muscle weakness and respiratory insufficiency. It is caused by a deficiency in GAA activity, which leads to accumulation of glycogen in tissues affected by the disease (primarily muscle).

John F Crowley, chairman and chief executive officer of Amicus stated, "The advancement of our core platform technology in Pompe and other lysosomal storage disorders is a continued great step forward for Amicus. Across these serious genetic diseases, we are leveraging this chaperone-ERT combination platform to work towards improving currently marketed ERTs and to develop our own proprietary next-generation ERTs that incorporate our small molecule chaperones. These chaperone stabilizers have the potential to enhance ERT activity and tissue uptake while also significantly reducing the immunogenicity of the ERTs. Through these programs we hope to offer new benefits and treatment options for patients with lysosomal storage diseases."

Positive results from a phase II study (Study 010) established human proof-of-concept that co-administration of AT2220 just prior to infusing ERT (Myozyme/Lumizyme, or rhGAA enzymes) increases GAA enzyme activity in muscle tissue compared to ERT alone. These results is be featured in an oral platform presentation at LDN WORLD on February 15.

Based on these results, Amicus plans to initiate a repeat-dose clinical study in the third quarter of 2013 to evaluate a novel intravenous formulation of AT2220 (AT2220-IV) co-administered with Myozyme/Lumizyme. AT2220-IV when co-administered with ERT is designed to have an improved pharmacokinetic (PK) profile compared to oral AT2220 for all Pompe patients, many of whom are unable to swallow an oral small molecule.

The upcoming clinical study will investigate multiple doses of AT2220-IV co-administered with Myozyme/Lumizyme every two weeks in Pompe patients. Objectives of the study are to characterize safety and PK for later evaluation of infants and special populations. Key parameters are expected to include GAA enzyme activity and AT2220 levels in plasma and muscle, as well as rhGAA antibody titers.

Preclinical studies of AT2220 co-formulated with rhGAA enzyme (Myozyme/Lumizyme) were presented for the first time at LDN WORLD. This chaperone-ERT co-formulation resulted in up to 2.5-fold greater enzyme uptake in multiple disease-relevant tissues and led to greater glycogen reduction compared to rhGAA alone in GAA knock-out mice. Collectively these data suggest that AT2220 directly binds to and stabilizes rhGAA, potentially leading to a larger amount of properly folded, active enzyme available for uptake into tissue. AT2220 co-formulated with ERT may also mitigate Pompe ERT-related immunogenicity since properly-folded proteins are less prone to aggregation and less immunogenic.

Following the completion of these preclinical studies, Amicus entered into a contract with Laureate Pharmaceuticals for the manufacture of a proprietary rhGAA enzyme. Amicus is developing AT2220 co-formulated with this proprietary enzyme as a next-generation ERT for Pompe disease. Through this approach Amicus believes it has the potential to improve the properties of the rhGAA enzyme itself while incorporating AT2220 as a small molecule stabilizer to increase exposure and tissue uptake, and reduce immunogenicity relative to currently marketed ERTs. Successful development of a more stable ERT may also enable novel routes of delivery such as subcutaneous administration.

AT2220 is an investigational, orally-administered pharmacological chaperone owned exclusively by Amicus. In published preclinical studies, AT2220-ERT co-administration resulted in significant increases in muscle rhGAA levels and decreases in glycogen levels in a mouse model of Pompe disease. Preclinical results to date also suggest that AT2220-ERT co-administration may mitigate ERT-induced immunogenicity by stabilizing the enzyme in its properly folded and active form. Initial ex vivo studies using T cells derived from blood from 50 healthy donors demonstrated that the addition of AT2220 may significantly reduce the immunogenicity of Myozyme and Lumizyme.

Amicus Therapeutics is developing orally-administered, small molecule drugs called pharmacological chaperones, a novel, first-in-class approach to treating a broad range of human genetic diseases.

 

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