Date: 2015-02-10
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at WORLDSymposium™ 2015 in Orlando, Florida
Company: GSK (UK) Amicus Therapeutics (USA - NJ)
Product: migalastat
Action
mechanism: chaperone. Migalastat HCI is an orally-administered pharmacological chaperone in Phase III development for the treatment of 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 alpha-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. Migalastat HCl is designed to bind to and stabilize, or "chaperone" a patient's own alpha-galactosidase A (alpha-Gal A) enzyme in those patients with genetic mutations that are amenable to this chaperone in a cell-based assay
Disease: Fabry disease
Therapeutic area: Rare diseases - Genetic diseases
Country:
Trial
details: Study 012 (The ATTRACT, or FAB-AT1001-012 Study) is a randomised, open-label, 18-month Phase III study to compare the safety and efficacy of migalastat HCI (AT1001/GR181314A), and ERT in male and female patients with Fabry disease (Fabrazyme® and Replagal®). The primary outcome measure is renal function at 18 months. This open-label registration study enrolled 60 patients (26 males and 34 females) with Fabry disease with amenable mutations who had been treated with ERT for a minimum of 12 months prior to study entry. These patients were randomized 1.5:1 to switch to migalastat (36 patients) or remain on ERT (24 patients) for the primary 18-month treatment period, after which they were eligible to receive migalastat in a 12-month extension phase. Among the 60 patients enrolled, 56 (34 in the migalastat group and 22 in the ERT group) had amenable mutations in a GLP-validated human embryonic kidney (HEK) cell-based in vitro assay ("GLP HEK amenable").
Latest
news: * On February 10, 2015, Amicus Therapeutics, a biopharmaceutical company at the forefront of therapies for rare and orphan diseases, announced positive data on pre-specified patient reported outcomes from both of its Phase 3 studies of migalastat for Fabry disease at WORLDSymposium™ 2015 in Orlando, Florida. Amicus previously reported positive Phase 3 data in both treatment naïve (Study 011, or FACETS) and enzyme replacement therapy (ERT) switch patients (Study 012, or ATTRACT). Results from these studies have shown that treatment with migalastat has resulted in reductions in disease substrate, stability of kidney function and improvement in a key cardiac parameter (left ventricular mass index, or LVMi) in patients with amenable mutations. Pre-specified secondary and tertiary endpoints on patient-reported outcome measures from both Phase 3 studies are being reported for the first time at WORLDSymposium™ 2015. Stability in Measures of Pain and Quality of Life Observed in Phase 3 Study 012 (ATTRACT): Patient-reported outcome measures of pain and quality of life from the Phase 3 Study 012 (ATTRACT) in ERT switch patients were described as part of a poster and presentation at WORLDSymposium™ 2015. Measures of pain and quality of life from the Brief Pain Inventory (BPI) and Short Form 36 (SF36) remained stable when patients switched from ERT to migalastat. * On November 15, 2014, Amicus Therapeutics announced additional positive data on important secondary endpoints from its second Phase 3 study (Study 012) of migalastat for Fabry disease. In a poster at the American Society of Nephrology (ASN) Kidney Week 2014, results were presented from Fabry patients with amenable mutations in Study 012 who switched from standard of care enzyme replacement therapy (ERT) to migalastat as their only therapy for Fabry disease. Data from the Fabry Registry indicate that the leading cause of death in patients is from cardiac complications. In Study 012, patients who switched from ERT to migalastat showed a statistically significant decrease from baseline to month 18 in left ventricular mass index (LVMi). LVMi is a measure of cardiac hypertrophy, an increase in the size of the heart that has been associated with an increased risk of cardiac events in Fabry patients. Cardiac ECHO Parameters - Change from Baseline to Month 18* LVMI) (g/m2)** Migalastat Baseline Mean 95.3 (39%) (% abnormal) n=33 Migalastat Change -6.6 (-11.0, -2.1)*** (Mean, 95% CI) n=31 ERT Baseline Mean 92.9 (31%) (% abnormal) n=16 ERT Change -2.0 (-11.0, +7.0) (Mean, 95% CI) n=31 *Read in blinded manner in centralized lab every 6 months **Normal LVMI: 43-95 (female), 49-115 (male) ***Statistically significant (95% CI does not overlap zero) Migalastat also demonstrated a favorable outcome in a composite endpoint of Fabry-associated clinical events, which are a defined set of morbidities or worsening in a Fabry patient's renal, cardiac, or cerebrovascular status. Fabry-associated clinical events were observed in 29% (10/34) of patients who switched from ERT to migalastat and in 44% (8/18) of patients who remained on ERT. Dr. Kathy Nicholls, nephrologist from Royal Melbourne Hospital and University of Melbourne, and investigator with 7 years experience in treating Fabry patients in clinical studies of migalastat, said "Fabry patients randomized to switch from ERT to Migalastat showed stability in renal function at least comparable to those who continued on ERT. The new data on cardiac mass and clinical events are encouraging. An oral therapy for Fabry disease is very attractive to patients." "These data are profoundly important," said John F. Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics, Inc. "Migalastat is not oral ERT. It is a unique small molecule with a novel mechanism of action designed to restore enzyme activity in key cell types and organs of disease in Fabry patients with amenable mutations. Migalastat has previously shown a consistent and durable effect on substrate reduction and stabilization of kidney function. Now, for the first time, we are presenting data at ASN that demonstrate migalastat has a significant effect on a key cardiac manifestation of the disease. We intend to seek approval of migalastat in both the European Union and in the U.S. We are on track to hold our pre-submission meeting with European regulators this quarter, and expect to interact with the FDA in early 2015. Our goal is to make migalastat monotherapy available for all Fabry patients with amenable mutations as quickly as possible." * On August 20, 2014, Amicus Therapeutics announced positive 18-month data from its second Phase 3 study (Study 012) of the oral small molecule chaperone migalastat in Fabry patients with amenable mutations.Study 012 compared oral migalastat to standard-of-care enzyme replacement therapies (ERTs) for Fabry disease (Fabrazyme® and Replagal®). The co-primary outcome measures were the mean annualized changes in estimated glomerular filtration rate (eGFR) and measured (iohexol) GFR (mGFR) assessed by descriptive comparisons of migalastat and ERT over 18 months. Summary of Study 012 18-Month Results: Migalastat had a comparable effect to ERT on patients' kidney function as measured by the change in eGFR and mGFR. Levels of plasma lyso-Gb3, an important biomarker of disease, remained low and stable in patients with amenable mutations who switched from ERT to migalastat. Migalastat was generally safe and well-tolerated. Of 48 patients with GLP HEK-amenable mutations who completed Study 012, 46 (96%) elected to continue with the 12-month treatment extension and 45 remain on migalastat today as their only treatment for Fabry disease. As pre-specified in the final statistical analysis plan, the co-primary outcome measures of efficacy in Study 012 were the descriptive assessments of comparability of the mean annualized change in eGFR and mGFR for migalastat and ERT. Both eGFR and mGFR are considered important measures of renal function. Comparability on eGFR and mGFR was defined in two ways: * On June 30, 2014, Amicus Therapeutics provided updates and detailed the statistical analysis plan for its second Phase 3 study (Study 012) of migalastat monotherapy for Fabry patients with amenable mutations. The 18-month primary treatment period is now complete and top-line data from Study 012 are expected in the third quarter of 2014. If successful, Study 012 will trigger the process for European regulatory approval of migalastat as a monotherapy for Fabry patients with amenable mutations. Study 012 (The ATTRACT Study, or AT1001-012) Patient Disposition Highlights: Following randomization, 34 of 36 patients who switched to migalastat and 18 of 24 patients who continued with ERT completed the primary 18-month treatment period. Among patients completing the 18-month primary treatment period, 32 out of 34 in the migalastat group and 16 out of 18 in the ERT group had GLP HEK amenable mutations. 97% of patients with GLP HEK amenable mutations in the migalastat group (31 out of 32) elected to continue to receive migalastat in the 12-month treatment extension. 94% of patients with GLP HEK amenable mutations in the ERT group (15 out of 16) elected to switch from ERT to migalastat for the 12-month treatment extension. Study 012 Statistical Analysis Plan: Taking into account scientific advice from European regulatory authorities, the pre-specified co-primary outcome measures of efficacy in Study 012 are the descriptive assessments of comparability of the mean annualized change in measured (iohexol) glomerular filtration rate (mGFR) and estimated GFR (eGFR) for migalastat and ERT. Both mGFR and eGFR are considered important measures of renal function. Success on mGFR and eGFR will be measured in two ways: A 50% overlap in the confidence intervals between the migalastat and ERT treatment groups; and Study 012 (The ATTRACT, or FAB-AT1001-012 Study) has achieved final enrollment of 60 total patients in December 2012.
Whether the mean annualized changes for patients receiving migalastat are within 2.2 mL/min/1.73 m2/yr of patients receiving ERT.
Amicus has pre-specified that these renal function outcomes will be analyzed in patients with GLP HEK amenable mutations. Discussions with European regulators have centered on the entirety of the data to come from Study 012, considering the relatively low number of study participants due to the orphan nature of Fabry disease. In addition, in Europe the benefit/risk assessment is expected to be based on the overall data from this study and results from the entire clinical development program.
* On September 12, 2011, GSK and Amicus Therapeutics have announced the first patient has commenced dosing in a Phase III global registration study (Study 012) to compare the safety and efficacy of Amigal® , (migalastat HCl) and enzyme replacement therapy (ERT) for the treatment of Fabry disease.
The randomised, open-label, 18-month study will provide longer-term clinical data comparing migalastat HCl to ERT in patients with Fabry disease, a rare inherited lysosomal storage disorder.
GSK and Amicus are targeting up to 50 sites globally to enrol approximately 50 male and female Fabry patients who are currently receiving ERT treatment, and who have a genetic mutation that may be addressable with migalastat HCI. The primary outcome of efficacy will be renal function as measured by glomerular filtration rate (GFR).
Study 012 is the second of two Phase III studies intended to support the worldwide registration of migalastat HCl for Fabry disease. Amicus and GSK are also conducting a six-month, placebo-controlled Phase III study (Study 011) of migalastat HCI at 37 sites worldwide to support marketing applications for the U.S. Food and Drug Administration (FDA) and other regulatory agencies.
* On October 29, 2010, Amicus announced a definitive agreement with GSK to develop and commercialise migalastat HCl. Under the terms of the agreement, GSK received an exclusive worldwide license to develop, manufacture and commercialise migalastat HCl. In addition to the Phase III monotherapy studies (Study 011 and Study 012), Amicus and GSK are currently conducting a Phase II clinical study to evaluate migalastat HCI co-administered with ERT for the treatment of Fabry disease.
