Amicus Therapeutics Presents Additional Results From Phase 2 Chaperone-Enzyme Replacement Therapy (ERT) Study for Fabry Disease at LDN World Symposium
Dr.
Amicus, in collaboration with GlaxoSmithKline (GSK), is developing the investigational pharmacological chaperone migalastat HCl as a monotherapy and in combination with ERT for the treatment of Fabry disease. When co-administered with ERT, migalastat HCl binds to and stabilizes infused enzyme in the circulation.
Migalastat HCl (150 mg and 450 mg) Co-Administered with ERT (Fabrazyme and Replagal)
Each patient in Study 013 received their current dose and regimen of ERT (Fabrazyme® or Replagal®, infused alpha-Gal A enzymes) at one infusion. A single oral dose of migalastat HCl (150 mg or 450 mg) was co-administered 2 hours prior to the next infusion of the same ERT at the same dose and regimen. Among 20 total males who enrolled, 3 opted to participate in the migalastat 150 mg and then again in the 450 mg treatment arms.
- Safety: finalized safety data are expected in 2Q13. As currently evaluated, 2 serious adverse events (SAEs) occurred in one patient (transient ischemic attack and hospitalization for acute pain and acroparesthesia due to Fabry disease) and were considered by the investigator to be unrelated to migalastat HCl when co-administered with ERT. Of the remaining treatment emergent adverse events the majority were unrelated to study drug.
- Active enzyme in plasma: active alpha-Gal A enzyme levels were measured in plasma (total area under the curve, or AUC) during and after each infusion. Following co-administration, active enzyme levels in plasma increased in 22 out of 23 instances and were unchanged in 1 instance compared to ERT alone. These PK results demonstrated a drug-drug interaction between both doses of migalastat HCl and both ERTs.
- Enzyme uptake into skin: alpha-Gal A enzyme levels were also measured in skin following each infusion. Increased levels of alpha-Gal A enzyme measured in skin biopsy samples on day 2 and, to a lesser extent, on day 7, showed increased enzyme uptake into tissue compared to ERT alone. This exploratory assessment showed that the greatest increases in active alpha-Gal A enzyme levels were observed following migalastat HCl 450 mg co-administered with ERT.
| Alpha-Gal A Levels of Active Enzyme | |||
|
Mean-Fold Increase in Plasma Area Under Curve (AUC) vs. ERT Alone (Range) |
Mean-Fold Increase in Skin at Day 2 vs. ERT Alone (Range) |
Mean-Fold Increase in Skin at Day 7 vs. ERT Alone (Range) |
|
| Migalastat HCl 150 mg + Replagal 0.2 mg/kg (n = 4) | 4.3 (3.2 to 5.0) | 1.8 (1.4 to 2.3) | 1.4 (1.1 to 1.8) |
| Migalastat HCl 150 mg + Fabrazyme 0.5 mg/kg (n = 5)* | 3.0 (2.0 to 4.2) | 2.6 (1.1 to 3.9) | 1.4 (0.7 to 2.8) |
| Migalastat HCl 150 mg + Fabrazyme 1.0 mg/kg (n = 3) | 2.0 (1.6 to 2.2) | 1.9 (1.6 to 2.1) | 1.4 (1.2 to 1.7) |
| Migalastat HCl 450 mg + Replagal 0.2 mg/kg (n = 4) | 3.1 (2.3 to 5.0) | 2.3 (1.6 to 3.7) | 2.1 (1.0 to 2.8) |
| Migalastat HCl 450 mg + Fabrazyme 0.5 mg/kg (n = 1)* | 2.4 | 3.7 | 1.9 |
| Migalastat HCl 450 mg + Fabrazyme 1.0 mg/kg (n = 6) | 2.0 (1.0 to 3.2) | 1.8 (1.0 to 2.5) | 1.5 (0.6 to 3.3) |
* Due to Fabrazyme supply difficulties during enrollment, subjects had been receiving 0.5 mg/kg Fabrazyme infused every two weeks
In addition to chaperone-ERT co-administration in Fabry disease, Amicus and GSK are developing migalastat HCl co-formulated with
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About
About Migalastat HCl
Amicus in collaboration with GlaxoSmithKline (GSK) is developing the investigational pharmacological chaperone migalastat HCl for the treatment of Fabry disease. Amicus has commercial rights to all Fabry products in
As a monotherapy, migalastat HCl is designed to bind to and stabilize, or "chaperone" a patient's own alpha-galactosidase A (alpha-Gal A) enzyme in patients with genetic mutations that are amenable to this chaperone in a cell-based assay. Migalastat HCl monotherapy is in Phase 3 development (Study 011 and Study 012) for Fabry patients with genetic mutations that are amenable to this chaperone monotherapy in a cell-based assay. Study 011 is a placebo-controlled study intended primarily to support U.S. registration, and Study 012 compares migalastat HCl to ERT to primarily support global registration.
For patients currently receiving ERT for Fabry disease, migalastat HCl in combination with ERT may improve ERT outcomes by keeping the infused alpha-Gal A enzyme in its properly folded and active form thereby allowing more active enzyme to reach tissues.2 Migalastat HCl co-administered with ERT is in Phase 2 (Study 013) and migalastat HCl co-formulated with
About Fabry Disease
Fabry disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A). The role of alpha-Gal A within the body is to break down specific lipids in lysosomes, including globotriaosylceramide (GL-3, also known as Gb3). Lipids that can be degraded by the action of α-Gal are called "substrates" of the enzyme. Reduced or absent levels of alpha-Gal A activity leads to the accumulation of GL-3 in the affected tissues, including the kidneys, heart, central nervous system, and skin. This accumulation of GL-3 is believed to cause the various symptoms of Fabry disease, including pain, kidney failure, and increased risk of heart attack and stroke.
It is currently estimated that Fabry disease affects approximately 5,000 to 10,000 people worldwide. However, several literature reports suggest that Fabry disease may be significantly under diagnosed, and the prevalence of the disease may be much higher.
2. Benjamin, et al., Molecular Therapy:
Forward-Looking Statements
This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 relating to clinical development of Amicus' candidate drug products and the timing and reporting of results from clinical trials evaluating Amicus' candidate drug products. Words such as, but not limited to, "look forward to," "believe," "expect," "anticipate," "estimate," "intend," "plan," "targets," "likely," "will," "may," "would," "should" and "could," and similar expressions or words identify forward-looking statements. Such forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties. The inclusion of forward-looking statements should not be regarded as a representation by Amicus that any of its plans will be achieved. Any or all of the forward-looking statements in this
press release may turn out to be wrong. They can be affected by inaccurate assumptions Amicus might make or by known or unknown risks and uncertainties. For example, with respect to statements regarding the goals, progress, timing and outcomes of discussions with regulatory authorities and the potential goals, progress, timing and results of clinical trials, actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in the business of Amicus, including, without limitation: the potential that results of clinical or pre-clinical studies indicate that the product candidates are unsafe or ineffective; the potential that it may be difficult to enroll patients in our clinical trials; the potential that regulatory authorities may not grant or may delay approval for our product candidates; the potential that preclinical and clinical
studies could be delayed because we identify serious side effects or other safety issues; the potential that we will need additional funding to complete all of our studies and, our dependence on third parties in the conduct of our clinical studies. Further, the results of earlier preclinical studies and/or clinical trials may not be predictive of future results. In addition, all forward looking statements are subject to other risks detailed in our Quarterly Report on Form 10-Q for the quarter ended
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