Programs

Fabry Disease

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, to enable its trafficking (i.e., as a “pharmacological chaperone”) to lysosomes.

  • 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.

For more information, view our mechanism of disease video and download our Fabry disease awareness brochure and Fabry disease infographic.

Migalastat

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

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

Study 011 was a 24-month study that investigated the safety and efficacy of oral migalastat, (150 mg every other day) compared to placebo in Fabry disease patients naïve to or not receiving ERT. The study began with a 6-month, double-blind, placebo-controlled treatment period, after which all patients were treated with migalastat for a 6-month, open-label follow-up period, and a subsequent 12-month, open-label extension phase. The primary analysis in Study 011 measured the reduction of the disease substrate GL-3 in the interstitial capillaries of the kidneys following treatment with migalastat. Secondary endpoints in Study 011 included renal function, cardiac parameters (e.g. left ventricular mass index, LVMi), gastrointestinal symptoms, and clinical events.

Study 012 was a 30-month study that investigated the safety and efficacy of oral migalastat (150 mg, every other day) compared to standard of care infused ERTs (agalsidase alfa and agalsidase beta). Patients on a stable dose and regimen of ERT were randomized to switch to migalastat or remain on ERT for an 18-month, open-label primary treatment period, after which all patients were treated with migalastat for a 12-month, open-label extension phase. 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).

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

Migalastat in Combination with ERT

For Fabry disease patients who do not have amenable mutations, we are leveraging our CHART™ platform to investigate migalastat in combination with a novel ERT. In combination 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

We are in preclinical development with our own proprietary cell line to produce a novel ERT for the treatment of Fabry disease, to be formulated with migalastat.