Fabry Disease | Amicus Therapeutics

Fabry Disease

We are developing an oral pharmacological chaperone, migalastat, for the treatment of Fabry disease.

  • Fabry disease is an X-linked disease caused by mutations in the GLA gene, which encodes the alpha-Gal A enzyme. These mutations can cause alpha-Gal A, to be either absent or deficient.
  • When alpha-Gal A is absent or deficient the substrate, GL-3 and lyso-Gb 3 accumulate, leading to damage of cells within affected parts of the individual’s body and causing the various pathologies seen in Fabry disease.
  • Fabry disease leads to progressive, irreversible organ damage, typically involving the nervous, cardiac, and renal systems, as well as multiple other tissues.
  • The symptoms can be severe, differ from patient to patient, and begin at an early age, resulting in significant clinical, humanistic, and healthcare costs.
  • Fabry disease requires lifelong medical intervention to manage the complications of this devastating disease across multiple organ systems.

Enzyme replacement therapy (ERT) with recombinant human alpha-Gal A (agalsidase beta) or gene-activated alpha-Gal A (agalsidase alfa) is the current standard of care for Fabry disease.

To learn more about Fabry disease and its symptoms, inheritance, and multisystemic impact, please visit FabryFacts.com, an online resource developed by Amicus Therapeutics.

Migalastat Monotherapy

We are developing oral migalastat as a monotherapy for Fabry disease patients with genetic mutations that are amenable to this chaperone therapy. Many individuals with Fabry disease make some alpha-Gal A enzyme that is capable of degrading substrate. However, because of a genetic mutation, the endogenously produced alpha-Gal A is not effectively delivered to lysosomes to reduce GL-3. As a monotherapy, migalastat is an investigational oral, small molecule drug designed to bind to and stabilize the endogenous alpha-Gal A that is made in the patient’s own cells, with the intention of enabling its trafficking to lysosomes (designed to act as a “pharmacological chaperone”). Once delivered to lysosomes, the alpha-Gal A enzyme can degrade the accumulated GL-3. This approach is designed for patients with amenable mutations that could be capable of responding to oral migalastat as a monotherapy treatment on the basis of their genotype.

If approved, we estimate that approximately 30-50% of the Fabry disease population is 16 and older and have amenable mutations and may be eligible to receive migalastat monotherapy.

Development Status

Migalastat, is a small molecule pharmacological chaperone for the treatment of Fabry disease that has been approved for use in the European Union (EU) under the brand name Galafold™ (migalastat) for adult and adolescent patients over the age of 16 with Fabry disease with an amenable mutation. Regulatory submissions and commercialization is ongoing in some countries outside the EU.

We conducted two Phase 3 global registration studies (the FACETS Study, Study 011, and the ATTRACT Study, Study 012) of migalastat monotherapy. Both studies included males and females with Fabry disease who had alpha-Gal A mutations that were amenable to migalastat chaperone monotherapy.

Study 011 was a 6-month, randomized, double-blind, placebo-controlled study that investigated the efficacy and safety of oral migalastat (150 mg every other day) compared to placebo in patients with Fabry disease who were naïve to ERT (or had stopped ERT for at least 6 months) followed by an 18-month open-label period during which all patients received oral migalastat. The primary analysis in Study 011 measured a ≥50% reduction of the disease substrate GL-3 in the interstitial capillaries of the kidneys following 6 months treatment with migalastat. Secondary endpoints in Study 011 included renal function, cardiac parameters (e.g. left ventricular mass index, LVMi), gastrointestinal symptoms, and safety.

Study 012 was an 18-month, randomized, open-label, active comparator study that investigated the efficacy and safety of oral migalastat (150 mg every other day) compared to standard of care infused ERTs (agalsidase beta or agalsidase alfa) in patients with Fabry disease, who have amenable mutations and who were receiving ERT prior to study entry, followed by a 12-month open-label extension during which all patients received oral migalastat. The co-primary endpoints in Study 012 measured comparability of migalastat and ERT on renal function (mean annualized change in measured (iohexol) glomerular filtration rate (mGFR) and estimated GFR (eGFR) for migalastat and ERT from baseline to 18 months). Secondary endpoints for Study 012 included renal function, cardiac parameters (e.g., LVMi), composite clinical outcome, and safety.

Regulatory authorities in the U.S., EU, Australia, and Switzerland have granted orphan drug designation for migalastat.

Intravenous Migalastat Co-Formulated with Novel Enzyme Replacement Therapy

For Fabry disease patients who do not have amenable mutations, we are leveraging our CHART™ (Chaperone-Advanced Replacement Therapy) platform to investigate a novel Fabry ERT (enzyme replacement therapy) to be formulated with intravenous migalastat. When formulated with ERT, migalastat is designed to bind to infused alpha-Gal A in circulation with the intention of stabilizing the active form of the enzyme.

Development Status

Our own proprietary cell line is being used to develop a novel ERT for the treatment of Fabry disease, to be formulated with investigational intravenous migalastat.

Migalastat Monotherapy: Phase 3 Long-Term Safety Study 041 (AT1001-041 Study, formerly MGM116041)

Long-Term, Open-Label Study of Migalastat (AT1001) in Subjects with Fabry Disease Who Completed Treatment in a Previous Monotherapy Trial with Migalastat

Completed. Patients are eligible to roll over into Study 041 upon completion of the primary treatment and open-label extension periods in the FACETS (Study 011), ATTRACT (Study 012), or Phase 2 Extension Study 205.

Open-label extension study to evaluate long-term safety and efficacy of migalastat.

More information: www.clinicaltrials.gov: NCT01458119

Migalastat Monotherapy: Phase 3 Long-Term Safety Study 042 (AT1001-042 Study)

Open-Label Extension Study of the Long-Term Effects of Migalastat in Patients with Fabry Disease

Recruiting. Intended to provide continued treatment with migalastat for subjects with Fabry disease who completed treatment of a previous migalastat monotherapy study.

Open-label extension study to assess the long-term safety and effectiveness of migalastat in subjects with Fabry disease who completed migalastat treatment in a previous study.

More information: www.clinicaltrials.gov: NCT02194985

Migalastat Monotherapy: Physician Initiated Request (MGM116188)

Program Allows Physicians to Request Permission from Amicus Therapeutics for Treatment Access to Migalastat for Specific Adult Patients with Fabry Disease

Ongoing, currently recruiting. Physicians may request permission to treat specific patients with migalastat. Patients have amenable GLA mutations, do not meet eligibility criteria for existing migalastat clinical studies, and are unsuitable for or unable to access ERT.

Open-label treatment in up to 20 patients for 6 months with renewal every 6 months.

More information: www.clinicaltrials.gov: NCT01476163

Fabry Disease
Completed Studies

Migalastat Monotherapy: Phase 3 Study 011 (The FACETS, or AT1001-011 Study)

Study of the Effects of Oral Migalastat (AT1001) in Patients with Fabry Disease

Completed. In December 2011, the study completed enrollment of 67 patients, who were identified as having amenable GLA mutations and met additional entry criteria.

Placebo-controlled, double-blind Phase 3 study of migalastat.

More information: www.clinicaltrials.gov: NCT00925301

Migalastat Monotherapy: Phase 3 Study 012 (The ATTRACT or AT1001-012 Study)

Study to Compare the Efficacy and Safety of Oral Migalastat (AT1001) and Enzyme Replacement Therapy in Patients with Fabry Disease

Completed. Enrolled more than 50 patients, who were identified as having amenable GLA mutations and had been receiving enzyme replacement therapy (ERT) for at least 12 months.

Randomized, open-label, 18-month Phase 3 study investigating the safety and efficacy of migalastat compared to current standard of care ERTs Fabrazyme® (agalsidase beta) or Replagal® (agalsidase alfa) for Fabry disease.

More information: www.clinicaltrials.gov: NCT01218659.