AT2220-Enzyme Replacement Therapy (ERT) Co-Administration Increases Pompe Enzyme (rhGAA) Activity in First 3 Dose Cohorts in Phase 2 Study
AT2220 Mitigates ERT-Related Immunogenicity in ex vivo Studies
For people with Pompe disease, deficient GAA enzyme leads to the accumulation of glycogen in tissues affected by disease (primarily muscle). Myozyme and Lumizyme (alglucosidase alfa, or recombinant human GAA enzyme, rhGAA) are the first and only approved treatments for Pompe disease. The clinical benefit of Myozyme and Lumizyme may be limited by low stability of the recombinant enzyme at neutral pH and body temperature, modest tissue uptake, and immune responses that affect tolerability and efficacy. Published preclinical data2 suggest that AT2220 in combination with this ERT may improve rhGAA enzyme activity, reduce glycogen accumulation, and potentially mitigate ERT-related immunogenicity in patients with Pompe disease.
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
The ex vivo studies are utilizing
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.
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.
Study 010 Design
Study 010 is a Phase 2 open-label, multi-center study to evaluate the safety and PK effects of four increasing oral doses of AT2220 (50 mg, 100 mg, 250 mg, or 600 mg) co-administered with ERT (Myozyme®/Lumizyme®) versus ERT alone in individuals with Pompe disease. The study has completed enrollment of male and female patients who have been on a stable dose and regimen of ERT for at least three months.
All patients are given a regularly scheduled ERT infusion. One hour prior to the initiation of the next ERT infusion, subjects receive a single oral dose of AT2220. Plasma rhGAA activity and protein levels are evaluated during each infusion. Each patient undergoes muscle biopsies three or seven days after each infusion to measure tissue GAA enzyme activity with and without the chaperone, as well as to measure the level of AT2220 in the muscle. More information about Study 010 can be obtained by visiting www.clinicaltrials.gov: NCT1380743 or www.pompestudy.com.
About AT2220 for Pompe Disease
AT2220 is an investigational, orally-administered pharmacological chaperone owned exclusively by Amicus. The Company is currently investigating AT2220 (duvoglustat HCl) co-administered with the ERT alglucosidase alfa (Myozyme/Lumizyme) in a Phase 2 study (Study 010) in individuals with Pompe disease. 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.
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). Pompe disease affects an estimated 5,000 to 10,000 individuals worldwide and is clinically heterogeneous in the age of onset, the extent of organ involvement, and the rate of progression.
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Sara Pellegrinospellegrino@amicustherapeutics.com (609) 662-5044
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