A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE) (ENCORE)

A Phase 3, Randomized, Multi-Center, Multi-National, Open-Label, Active Comparator Study to Evaluate the Efficacy and Safety of Genz-112638 in Patients With Gaucher Disease Type 1 Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE)

This Phase 3 study was designed to confirm the efficacy and safety of eliglustat tartrate (Genz-112638) in participants with Gaucher disease type 1 who had reached therapeutic goals with enzyme replacement therapy (ERT).

Study Overview

• Status: Completed
• Conditions: Gaucher Disease, Type 1
• Intervention / Treatment: Drug: Eliglustat tartrate; Drug: Imiglucerase

Detailed Description

Gaucher disease is characterized by lysosomal accumulation of glucosylceramide due to impaired glucosylceramide hydrolysis. Gaucher disease type 1, which is the most common form, accounts for greater than (>) 90% of cases and does not involve the central nervous system (CNS). Typical manifestations of Gaucher disease type 1 include splenomegaly, hepatomegaly, thrombocytopenia, anemia, bone disease, and decreased quality of life. The disease manifestations are caused by the accumulation of glucosylceramide (storage material) in macrophages (called Gaucher cells) which have infiltrated the spleen and liver as well as other tissues.

Eliglustat tartrate is a small molecule drug developed as an oral therapy which acts to specifically inhibit production of this storage material in Gaucher cells.

This study was designed to determine the efficacy, safety, and PK of eliglustat tartrate in adult participants with Gaucher disease type 1 who had been stabilized on ERT.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital General de Agudos J.M Ramos Mejia
  • Buenos Aires, Argentina
    • Hospital General de Ninos Dr. Ricardo Gutierrez
• Australia
  • Perth, WA, Australia
    • Royal Perth Hospital
• Brazil
  • Curitiba, Brazil
    • Hospital de Clínicas da Universidade Federal do Paraná
  • Rio de Janeiro, Brazil
    • Instituto de Estadual de Hematologia Arthur de Siqueria Cavalcanti
  • São Paulo, Brazil
    • IGEIM
• Canada
  • Toronto Ontario, Canada
    • Mount Sinai Hospital and the Samuel Lunenfeld Research Institute
• Egypt
  • Cairo, Egypt
    • Abou El Reesh Children's University Hospital (El Mounira), Faculty of Medicine (Kasr Al-Aini), Cairo University Hospitals, El Mounira, Cairo, Egypt
• France
  • Clichy, France
    • Hôpital Beaujon
• Germany
  • Berlin, Germany
    • Charité Universitätsmedizin Berlin
  • Hamburg, Germany
    • Asklepios Klinik St. Georg
  • Oberhausen, Germany
    • Katholische Kliniken Oberhausen gem. GmbH
• Italy
  • Firenze, Italy
    • Azienda Ospedaliero Universitaria Careggi
  • Udine, Italy
    • Azienda Ospedialiero-Universitaria S. Maria Della Misericordia
• Russian Federation
  • Moscow, Russian Federation
    • Hematology Research Center of Ministry of Healthcare of the Russian Federation
• Spain
  • Zaragoza, Spain
    • Hospital University Miguel Servet
• United Kingdom
  • Cambridge, United Kingdom
    • Cambridge University Hosptials, Addenbrookes Hospital
• United States
  • California
    • Beverly Hills, California, United States
      • Tower Hematology Oncology Medical Group
    • San Francisco, California, United States
      • UCSF MS Center
  • Colorado
    • Aurora, Colorado, United States
      • University of Colorado Health Science Center - Aurora
  • Connecticut
    • New Haven, Connecticut, United States
      • Yale University School of Medicine
  • Florida
    • Coral Springs, Florida, United States
      • Northwest Oncology Hematology Associates PA
  • Georgia
    • Decatur, Georgia, United States
      • Emory University Medical Genetics
  • Illinois
    • Chicago, Illinois, United States
      • Children's Memorial Hospital
  • Iowa
    • Iowa City, Iowa, United States
      • University of Iowa Hospitals and Clinics
  • New York
    • Albany, New York, United States
      • Albany Medical Center
    • Manhasset, New York, United States, 11030
      • North Shore University Medical Center
    • New York, New York, United States
      • Mount Sinai School of Medicine
    • New York, New York, United States
      • New York University School of Medicine
  • North Carolina
    • Durham, North Carolina, United States
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States
      • University of Pittsburgh Medical Center
  • Virginia
    • Springfield, Virginia, United States
      • O and O Alpan LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The participant (and/or their parent/legal guardian) was willing and able to provide signed informed consent prior to any study-related procedures to be performed
• The participant was at least 18 years old at the time of randomization
• The participant had a confirmed diagnosis of Gaucher disease type 1
• The participant had received treatment with ERT for at least 3 years. Within the 9 months prior to randomization, the participant had received a total monthly dose of 30 to 130 Units/kilogram for at least 6 months
• The participant had reached Gaucher disease therapeutic goals prior to randomization
• Female participants of childbearing potential must have had a documented negative pregnancy test prior to dosing. In addition, all female participants of childbearing potential must use a medically accepted form of contraception throughout the study

Exclusion Criteria:

• The participant had a partial or total splenectomy within 3 years prior to randomization
• The participant had received substrate reduction therapies for Gaucher disease within 6 months prior to randomization
• The participant had Gaucher disease type 2 or 3 or was suspected of having Gaucher disease type 3
• The participant had any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal (GI), pulmonary, neurologic, endocrine, metabolic (e.g. hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may confound the study results or, in the opinion of the Investigator, may preclude participation in the study
• The participant had tested positive for the human immunodeficiency virus (HIV) antibody, Hepatitis C antibody, or Hepatitis B surface antigen
• The participant had received an investigational product within 30 days prior to randomization
• The participant was pregnant or lactating

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Investigational; Eliglustat tartrate	Drug: Eliglustat tartrate; Primary analysis period (PAP): Eliglustat tartrate capsule 50 milligram (mg) twice daily (BID) orally from Day 1 to Week 4 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 8, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 52. Dose adjustments after Week 4 and Week 8 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. If Genz-99067 trough plasma concentration was less than (<) 5 nanogram per milliliter [ng/mL] next higher dose was administered whereas if Genz-99067 trough plasma concentration was greater than or equal to (>=) 5 ng/mL same dose was continued. Pharmacokinetic (PK) assessment at Week 2 and 6 were used for dose adjustment after Week 4 and Week 8, respectively. Long-term treatment period (LTTP): Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6.; Other Names: Genz-112638
ACTIVE_COMPARATOR: Imiglucerase	Drug: Imiglucerase; PAP: Imiglucerase intravenous infusion every other week (q2w) up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change. LTTP: Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. If Genz-99067 trough plasma concentration was <5 ng/mL the next higher dose was administered whereas if the Genz-99067 trough plasma concentration was >=5 ng/mL the same dose was continued. The PK assessment at Week 54 and Week 58 were used for dose adjustment after Week 56 and Week 60, respectively.; Other Names: Cerezyme®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Remained Stable for 52 Weeks During the Primary Analysis Period	For a participant to be classified as stable, the participant must have remained stable in hematological parameters (hemoglobin levels and platelet counts) and organ volumes (spleen, when applicable, and liver volumes in multiples of normal [MN]). Stable hematological parameters were defined as hemoglobin level did not decrease more than (>) 1.5 gram per deciliter (g/dL) from baseline and platelet count did not decrease >25% from baseline. Stable organ volumes were defined as spleen volume (in MN) did not increase >25% from baseline, if applicable, and liver volume (in MN) did not increase >20% from baseline.	Baseline up to Week 52
Percentage of Participants Who Remained Stable Annually for 4 Years During the LTTP	For a participant to be classified as stable, the participant must have remained stable in hematological parameters (hemoglobin levels and platelet counts) and organ volumes (spleen, when applicable, and liver volumes in MN). Stable hematological parameters were defined as hemoglobin level did not decrease >1.5 g/dL from baseline and platelet count did not decrease >25% from baseline. Stable organ volumes were defined as spleen volume (in MN) did not increase >25% from baseline, if applicable, and liver volume did not increase >20% from baseline.	Week 52 up to week 208

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total T-Scores for Bone Mineral Density	Images of the spine and bilateral femur were obtained by dual energy X-Ray absorptiometry (DXA) to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score greater than [>]-1), osteopenia (score -2.5 to less than or equal to [<=] -1), and osteoporosis (score <= -2.5).	Baseline
Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 52	Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 52 minus T-score at baseline.	Baseline, Week 52
Total Z-Scores for Bone Mineral Density	Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2).	Baseline
Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 52	Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Absolute change = Z-score at Week 52 minus Z-score at baseline.	Baseline, Week 52
Hemoglobin Level		Baseline
Absolute Change From Baseline in Hemoglobin Levels at Week 52	Absolute change = hemoglobin level at Week 52 minus hemoglobin level at baseline.	Baseline, Week 52
Percent Change From Baseline in Platelet Counts at Week 52	Percent change in platelet counts = ([platelet count at Week 52 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.	Baseline, Week 52
Percent Change From Baseline in Spleen Volume (MN) at Week 52	Percent change in spleen volume = ([spleen volume at Week 52 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN.	Baseline, Week 52
Percent Change From Baseline in Liver Volume (in MN) at Week 52	Percent change in liver volume = ([liver volume at Week 52 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.	Baseline, Week 52
Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 208	Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 208 minus T-score at baseline.	Baseline, Week 208
Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 208	Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Absolute change = Z-score at Week 208 minus Z-score at baseline.	Baseline, Week 208
Absolute Change From Baseline in Hemoglobin Levels at Week 208	Absolute change = hemoglobin level at Week 208 minus hemoglobin level at baseline.	Baseline, Week 208
Percent Change From Baseline in Platelet Counts at Week 208	Percent change in platelet counts = ([platelet count at Week 208 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.	Baseline, Week 208
Percent Change From Baseline in Spleen Volume (in MN) at Week 208	Percent change in spleen volume = ([spleen volume at Week 208 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN.	Baseline, Week 208
Percent Change From Baseline in Liver Volume (in MN) at Week 208	Percent change in liver volume = ([liver volume at Week 208 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.	Baseline, Week 208

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company

Publications and helpful links

General Publications

• McEachern KA, Fung J, Komarnitsky S, Siegel CS, Chuang WL, Hutto E, Shayman JA, Grabowski GA, Aerts JM, Cheng SH, Copeland DP, Marshall J. A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease. Mol Genet Metab. 2007 Jul;91(3):259-67. doi: 10.1016/j.ymgme.2007.04.001. Epub 2007 May 16.
• Lukina E, Watman N, Arreguin EA, Banikazemi M, Dragosky M, Iastrebner M, Rosenbaum H, Phillips M, Pastores GM, Rosenthal DI, Kaper M, Singh T, Puga AC, Bonate PL, Peterschmitt MJ. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood. 2010 Aug 12;116(6):893-9. doi: 10.1182/blood-2010-03-273151. Epub 2010 May 3.
• Lukina E, Watman N, Arreguin EA, Dragosky M, Iastrebner M, Rosenbaum H, Phillips M, Pastores GM, Kamath RS, Rosenthal DI, Kaper M, Singh T, Puga AC, Peterschmitt MJ. Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study. Blood. 2010 Nov 18;116(20):4095-8. doi: 10.1182/blood-2010-06-293902. Epub 2010 Aug 16. Erratum In: Blood. 2011 May 19;117(20):5551.
• Kamath RS, Lukina E, Watman N, Dragosky M, Pastores GM, Arreguin EA, Rosenbaum H, Zimran A, Aguzzi R, Puga AC, Norfleet AM, Peterschmitt MJ, Rosenthal DI. Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat. Skeletal Radiol. 2014 Oct;43(10):1353-60. doi: 10.1007/s00256-014-1891-9. Epub 2014 May 10.
• Lukina E, Watman N, Dragosky M, Pastores GM, Arreguin EA, Rosenbaum H, Zimran A, Angell J, Ross L, Puga AC, Peterschmitt JM. Eliglustat, an investigational oral therapy for Gaucher disease type 1: Phase 2 trial results after 4 years of treatment. Blood Cells Mol Dis. 2014 Dec;53(4):274-6. doi: 10.1016/j.bcmd.2014.04.002. Epub 2014 May 15.
• Cox TM, Drelichman G, Cravo R, Balwani M, Burrow TA, Martins AM, Lukina E, Rosenbloom B, Goker-Alpan O, Watman N, El-Beshlawy A, Kishnani PS, Pedroso ML, Gaemers SJM, Tayag R, Peterschmitt MJ. Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy. Blood. 2017 Apr 27;129(17):2375-2383. doi: 10.1182/blood-2016-12-758409. Epub 2017 Feb 6.
• Cox TM, Drelichman G, Cravo R, Balwani M, Burrow TA, Martins AM, Lukina E, Rosenbloom B, Ross L, Angell J, Puga AC. Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial. Lancet. 2015 Jun 13;385(9985):2355-62. doi: 10.1016/S0140-6736(14)61841-9. Epub 2015 Mar 26. Erratum In: Lancet. 2015 Jun 13;385(9985):2354.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (ACTUAL): November 1, 2012
• Study Completion (ACTUAL): June 1, 2015

Study Registration Dates

• First Submitted: July 20, 2009
• First Submitted That Met QC Criteria: July 21, 2009
• First Posted (ESTIMATE): July 22, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): November 25, 2016
• Last Update Submitted That Met QC Criteria: October 11, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: substrate reduction therapy; Gaucher disease,; Genz-112638,; beta-glucosidase,; acid ß-glucosidase,; glucocerebrosidase,; glucosylceramide,; D-glucosyl-N-acylsphingosine glucohydrolase,
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Gaucher Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Eliglustat
• Other Study ID Numbers: GZGD02607; 2008-005223-28 (EUDRACT_NUMBER); EFC12812 (OTHER: Sanofi)