Study to Compare the Efficacy and Safety of Oral AT1001 and Enzyme Replacement Therapy in Patients With Fabry Disease

A Randomized, Open-Label Study to Compare the Efficacy and Safety of AT1001 and Enzyme Replacement Therapy (ERT) in Patients With Fabry Disease and AT1001-Responsive GLA Mutations, Who Were Previously Treated With ERT

Study to compare the efficacy and safety of migalastat and enzyme replacement therapy (ERT) in male and female participants with Fabry disease who are currently receiving ERT and who have an alpha galactosidase-A (α Gal-A) mutation that is amenable to migalastat, based on the clinical trial human embryonic kidney cell (HEK) assay.

Study Overview

• Status: Completed
• Conditions: Fabry Disease
• Intervention / Treatment: Drug: migalastat hydrochloride; Biological: agalsidase

Detailed Description

This was a Phase 3, randomized, open-label, active-controlled study to evaluate the efficacy and safety of 150 milligrams (mg) of migalastat hydrochloride (migalastat) (equivalent to 123 mg of migalastat) once every other day (QOD) and ERT in male and female participants with Fabry disease who were receiving ERT and who have an α Gal-A mutation that is amenable to migalastat, based on the clinical trial HEK assay. This was a 2-part study. Part 1, the 18-month randomized phase, evaluated participants who received either migalastat 150 mg QOD or ERT per prescribing physicians' instructions for efficacy and safety. Part 2, the optional 12-month open-label extension (OLE) phase in which all participants received migalastat, also explored efficacy and safety. For Part 2, all participants who received ERT in Part 1 were given migalastat. Data presented in this posting include efficacy data from the 18-month randomized period and safety data from the entire study (18-month randomized period and 12-month optional OLE [total of 30 months]).

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 03050
  • West Australia
    • Perth, West Australia, Australia, 6000
• Austria
  • Vienna, Austria, 1090
• Belgium
  • Edegem, Belgium, 2650
• Brazil
  • Sao Paulo, Brazil, 14048-900
• Denmark
  • Copenhagen, Denmark, 2100
• France
  • Garches, France, 92380
  • Lille, France, 59037
• Italy
  • Firenze, Italy, 50129
• Japan
  • Niigata, Japan, 951-8520
  • Osaka, Japan, 545-8586
  • Osaka, Japan, 565-0871
  • Tokyo, Japan, 105-8471
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
  • London, United Kingdom, WC1N 3BG
  • London, United Kingdom, NW3 2QG
  • Salford, United Kingdom, M6 8HD
• United States
  • California
    • Los Angeles, California, United States, 90048
  • Colorado
    • Aurora, Colorado, United States, 80045
  • Georgia
    • Decatur, Georgia, United States, 30033
  • Michigan
    • Grand Rapids, Michigan, United States, 49525
  • Oregon
    • Portland, Oregon, United States, 97239
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
  • Virginia
    • Fairfax, Virginia, United States, 22030
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 74 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female between the ages of 16 and 74 diagnosed with Fabry disease
• Confirmed α Gal-A mutation that is amenable to migalastat, based on the clinical trial HEK assay
• Participant has been on ERT for at least 12 months before screening/baseline
• Dose level and regimen of ERT have been stable for 3 months before screening/baseline and is at least 80% of the currently labeled dose and regimen for this time period
• Glomerular filtration rate (GFR) ≥ 30 milliliter (mL)/minute (min) /1.73 m^2
• Participants taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers must be on a stable dose for at least 4 weeks before screening/baseline
• Women who can become pregnant and all men agree to be sexually abstinent or use medically accepted methods of birth control throughout the duration of the study and for up to 30 days after last dose of study medication
• Participant is willing and able to provide written informed consent and assent if applicable

Exclusion Criteria:

• Participant has undergone, or is scheduled to undergo, kidney transplantation or any other solid organ transplantation
• Participant is on regular dialysis that is specifically for the treatment of chronic kidney disease
• Participant has had a documented transient ischemic attack, stroke, unstable angina, or myocardial infarction within the 3 months before screening/baseline
• Participant has clinically significant unstable cardiac disease in the opinion of the investigator (for example, cardiac disease requiring active management, such as symptomatic arrhythmia, unstable angina, or New York Heart Association (NYHA) class III or IV congestive heart failure)
• Pregnant or breast-feeding
• History of allergy or sensitivity to study medication (including excipients) or other iminosugars (for example, miglustat, miglitol)
• Participant has absolute contraindication to iohexol and/or inability to undergo iohexol GFR testing
• Participant requires treatment with Glyset® (miglitol), or Zavesca® (miglustat)
• Participant received any investigational/experimental drug, biologic or device within 30 days of screening/baseline
• Any intercurrent illness or condition that may preclude the participant from fulfilling the study requirements or suggests to the investigator that the participant may have an unacceptable risk by participating in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Migalastat; Participants received 150 mg migalastat orally QOD during the 18-month randomized treatment period and the optional 12-month OLE period. Participants received an inactive reminder capsule on alternate days during both treatment periods.	Drug: migalastat hydrochloride; 150-mg capsule administered orally QOD; Other Names: AT1001; Galafold; Migalastat
Active Comparator: ERT; Participants received ERT (either agalsidase alfa or agalsidase beta) as prescribed by the participant's treating physician and administered in accordance with the approved prescribing information during the 18-month randomized treatment period. Participants were required to be given >80% of the currently labeled dose and regimen during the 18-month randomized treatment period. During the optional 12-month OLE period, participants received 150 mg migalastat orally QOD. Participants received an inactive reminder capsule on alternate days during the OLE.	Biological: agalsidase; Agalsidase via intravenous infusion as prescribed by the participant's treating physician and in accordance with the approved prescribing information; Other Names: agalsidase beta; Fabrazyme; agalsidase alfa; Replagal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Rate Of Change From Baseline To Month 18 In Measured Glomerular Filtration Rate	To assess renal function, measured glomerular filtration rate (GFR) was measured by the plasma clearance of unlabeled iohexol (mGFR-iohexol), a non-ionic contrast agent. The annualized rate of change in mGFR-iohexol from Baseline to Month 18 was analyzed using an analysis of covariance (ANCOVA) model with the following factors as covariates: treatment group, sex, age, Baseline GFR (mGFR-iohexol), and Baseline 24-hour (hr) urine protein. A threshold of <2.2 milliliter (mL)/minute (min)/1.73 meter squared (m^2)/year was established to compare migalastat to ERT. This difference of 2.2 mL/min/1.73 m2/year is based on the smallest expected rate of decline in estimated glomerular filtration rate (eGFR) for participants treated with agalsidase alfa for 18 months.	Baseline to Month 18
Annualized Rate Of Change From Baseline To Month 18 In eGFR	The eGFR assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was calculated using the following: eGFR-CKD-EPI = 141 x min (Serum Creatinine/κ,1)^(α) x max(Serum Creatinine/κ,1)^(-1.209) x 0.993^(Age) x 1.1018 (if female) x 1.159 (if African American or black) where: κ is 0.7 for females and 0.9 for males; α is -0.329 for females and -0.411 for males; min indicates the minimum of Serum Creatinine/κ or 1; max indicates the maximum of Serum Creatinine/κ or 1. The annualized rate of change in eGFR-CKD-EPI from Baseline to Month 18 was analyzed using an ANCOVA model with the following factors as covariates: treatment group, sex, age, Baseline GFR (eGFR-CKD-EPI), and Baseline 24-hr urine protein. A threshold of <2.2 mL/min/1.73m^2/year was established to compare migalastat to ERT. This difference of 2.2 mL/min/1.73 m2/year is based on the smallest expected rate of decline in eGFR for participants treated with agalsidase alfa for 18 months.	Baseline to Month 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Rate Of Change From Baseline To Month 18 In eGFR By The Modification Of Diet In Renal Disease Equation	The GFR estimated by the Modification Of Diet In Renal Disease equation (eGFR-MDRD) was calculated using the following equation: eGFR-MDRD = 175 x (Serum Creatinine)^(-1.154) x (Age)^(-0.203) x 1.212 (if participant's race is black or African American) x 0.742 (if participant is female). The eGFR-MDRD from Baseline to Month 18 was analyzed using an ANCOVA model with the following factors as covariates: treatment group, sex, age, Baseline GFR (eGFR-CKD-EPI), and Baseline 24-hr urine protein.	Baseline to Month 18

Collaborators and Investigators

• Sponsor: Amicus Therapeutics

Publications and helpful links

General Publications

• Benjamin ER, Della Valle MC, Wu X, Katz E, Pruthi F, Bond S, Bronfin B, Williams H, Yu J, Bichet DG, Germain DP, Giugliani R, Hughes D, Schiffmann R, Wilcox WR, Desnick RJ, Kirk J, Barth J, Barlow C, Valenzano KJ, Castelli J, Lockhart DJ. The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat. Genet Med. 2017 Apr;19(4):430-438. doi: 10.1038/gim.2016.122. Epub 2016 Sep 22.
• Feldt-Rasmussen U, Hughes D, Sunder-Plassmann G, Shankar S, Nedd K, Olivotto I, Ortiz D, Ohashi T, Hamazaki T, Skuban N, Yu J, Barth JA, Nicholls K. Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study. Mol Genet Metab. 2020 Sep-Oct;131(1-2):219-228. doi: 10.1016/j.ymgme.2020.07.007. Epub 2020 Aug 15.
• Bichet DG, Aerts JM, Auray-Blais C, Maruyama H, Mehta AB, Skuban N, Krusinska E, Schiffmann R. Assessment of plasma lyso-Gb3 for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease. Genet Med. 2021 Jan;23(1):192-201. doi: 10.1038/s41436-020-00968-z. Epub 2020 Sep 30. Erratum In: Genet Med. 2020 Nov 20;:
• Haninger-Vacariu N, El-Hadi S, Pauler U, Foretnik M, Kain R, Prohaszka Z, Schmidt A, Skuban N, Barth JA, Sunder-Plassmann G. Pregnancy Outcome after Exposure to Migalastat for Fabry Disease: A Clinical Report. Case Rep Obstet Gynecol. 2019 Dec 21;2019:1030259. doi: 10.1155/2019/1030259. eCollection 2019.
• Narita I, Ohashi T, Sakai N, Hamazaki T, Skuban N, Castelli JP, Lagast H, Barth JA. Efficacy and safety of migalastat in a Japanese population: a subgroup analysis of the ATTRACT study. Clin Exp Nephrol. 2020 Feb;24(2):157-166. doi: 10.1007/s10157-019-01810-w. Epub 2019 Dec 30.
• Hughes DA, Nicholls K, Shankar SP, Sunder-Plassmann G, Koeller D, Nedd K, Vockley G, Hamazaki T, Lachmann R, Ohashi T, Olivotto I, Sakai N, Deegan P, Dimmock D, Eyskens F, Germain DP, Goker-Alpan O, Hachulla E, Jovanovic A, Lourenco CM, Narita I, Thomas M, Wilcox WR, Bichet DG, Schiffmann R, Ludington E, Viereck C, Kirk J, Yu J, Johnson F, Boudes P, Benjamin ER, Lockhart DJ, Barlow C, Skuban N, Castelli JP, Barth J, Feldt-Rasmussen U. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J Med Genet. 2017 Apr;54(4):288-296. doi: 10.1136/jmedgenet-2016-104178. Epub 2016 Nov 10. Erratum In: J Med Genet. 2018 Apr 16;:

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2011
• Primary Completion (Actual): May 27, 2014
• Study Completion (Actual): May 28, 2015

Study Registration Dates

• First Submitted: October 6, 2010
• First Submitted That Met QC Criteria: October 8, 2010
• First Posted (Estimate): October 11, 2010

Study Record Updates

• Last Update Posted (Actual): November 1, 2018
• Last Update Submitted That Met QC Criteria: October 1, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: Amicus Therapeutics; AT1001; Galafold; Migalastat
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Fabry Disease
• Other Study ID Numbers: AT1001-012; ATTRACT (Other Identifier: Amicus Therapeutics); 2010-022636-37 (EudraCT Number)