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Amicus Therapeutics Announces Positive Pompe Program Updates

Study 010 Preliminary Results – 3 Cohorts of AT2220 Co-Administered with ERT (n=16)

Study 010 is investigating single ascending oral doses of AT2220 (50 mg, 100 mg, 250 mg, and 600 mg) co-administered with Myozyme or Lumizyme in patients with Pompe disease. Each patient receives one infusion of ERT alone, and then a single dose of AT2220 just prior to the next ERT infusion. Highlights from the first three dose cohorts of AT2220 were as follows:

Safety: To date, single doses of AT2220 co-administered with ERT have been generally well-tolerated, with no drug-related adverse events reported. In addition, AT2220 was cleared from muscle to negligible levels by Day 7 in all three cohorts. Per the study protocol, an independent data safety monitoring board reviewed safety data from the first 3 cohorts and determined that the study should continue into the fourth and highest dose group (Cohort 4). Amicus has fully enrolled Cohort 4 and continues to anticipate results during the fourth quarter 2012.

rhGAA Enzyme Activity in Plasma: 24-hour plasma PK was measured at each infusion. Dose-related increases in rhGAA activity in plasma samples in 16 out of 16 patients following co-administration suggest an increase in properly folded, active rhGAA enzyme available for uptake into tissue.  
rhGAA Enzyme Activity in Plasma Area Under the Curve (AUC)
ERT + AT2220 vs. ERT Alone
Cohort AT222 Dose with ERT Mean Fold-Increase vs. ERT Alone (Range)
1 (n=4) 50 mg 1.5 (1.2 to 1.6)
2 (n=6) 100 mg 1.7 (1.5 to 1.9)
3 (n=6) 250 mg 2.0 (1.6 to 2.6)

rhGAA Enzyme Activity in Muscle: Muscle biopsies were taken to measure rhGAA enzyme uptake into muscle tissue, with and without AT2220. In Cohort 1, all 4 patients received muscle biopsies on Day 7. In Cohorts 2 and 3, muscle biopsies were taken on Day 3 for half the patients, and on Day 7 for the other half of patients. In Cohort 1, no consistent change in rhGAA enzyme activity was observed. In Cohorts 2 and 3, the results suggest that more enzyme may be taken up into muscle tissue following AT2220 co-administration compared to ERT alone. Generally, Day 3 biopsies showed significantly greater levels of rhGAA activity, with or without AT2220, than Day 7. 
rhGAA Enzyme Activity in Muscle
ERT + AT2220 vs. ERT Alone
Study 010 Cohorts 1-3 (n=16) Fold-Increase vs. ERT alone
Cohort 1: ERT + AT2220 50 mg (n=4)  
Muscle Biopsy Day 7 (n=4) 0.7, 0.9, 1.0, 1.4
Cohort 2: ERT + AT2220 100 mg (n=6)  
Muscle Biopsy Day 3 (n=3) 0.8, 1.4, 1.6
Muscle Biopsy Day 7 (n=3) 1.0, 1.1, 1.6
Cohort 3: ERT + AT2220 250 mg (n=6)  
Muscle Biopsy Day 3 (n=3) 0.8, 1.0, 1.4
Muscle Biopsy Day 7 (n=3)* 1.0, 1.9
*1 ERT sample insufficient for determining fold-increase with ERT+AT2220

Effect of AT2220 on ex vivo ERT-Related Immunogenicity

In parallel with Study 010, Amicus is conducting ex vivo studies supported by a grant from the Muscular Dystrophy Association to evaluate the immunogenicity of Myozyme and Lumizyme, with and without AT2220. Immune responses in the form of antibodies to rhGAA occur in a majority of Pompe patients receiving Myozyme/Lumizyme infusions 3 and may limit treatment outcomes with ERT. By stabilizing the folded and active form of the rhGAA enzyme, AT2220 may mitigate ERT-induced immunogenicity since unfolded and aggregated proteins are generally more antigenic than properly folded proteins.

The ex vivo studies are utilizing Antitope Ltd.'s EpiScreen™ assay to measure T-cell responses in human blood samples. These studies have been completed in blood samples from healthy volunteers and will be repeated in blood samples from Pompe patients in Study 010. Results may help to determine if particular human leukocyte antigen (HLA) types are predictive of an antibody response to Myozyme and Lumizyme, and whether the addition of AT2220 can decrease immunological responses induced by Myozyme and Lumizyme.

Initial studies completed using T cells from 50 healthy donor blood samples demonstrated that the addition of AT2220 may significantly reduce the immunogenicity of Myozyme and Lumizyme. Highlights were as follows.
  • Myozyme alone elicited a T-cell response in 36% of samples, which decreased to 14% in the presence of AT2220.
  • Lumizyme alone elicited a T-cell response in 28% of samples, which decreased to 10% in the presence of AT2220.

David J. Lockhart, PhD, Chief Scientific Officer of Amicus Therapeutics, stated, "Myozyme and Lumizyme elicit a strong T-cell response in the ex vivo EpiScreen assay, and they are both known to elicit an antibody response in most Pompe patients treated with ERT. The addition of our small molecule chaperone AT2220 reduced the observed T-cell response to both Myozyme and Lumizyme in the EpiScreen assays. We are currently conducting additional studies using blood samples from the Pompe patients in Study 010 and expect to have results by the end of the year."

EpiScreen has been used to characterize the immunogenicity of several well-known human therapeutic proteins, including Avastin and Herceptin. The assay results have correlated well with clinical immunogenicity as measured by the antibody response in patients reported in published literature.

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