Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized, double-blind EDGE trial

Joel Charrow; Cristina Fraga; Xuefan Gu; Hiroyuki Ida; Nicola Longo; Elena Lukina; Alexandre Nonino; Sebastiaan J.M. Gaemers; Marie Helene Jouvin; Jing Li; Yaoshi Wu; Yong Xue; M. Judith Peterschmitt

doi:10.1016/j.ymgme.2017.12.001

Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized, double-blind EDGE trial

Joel Charrow^*, Cristina Fraga, Xuefan Gu, Hiroyuki Ida, Nicola Longo, Elena Lukina, Alexandre Nonino, Sebastiaan J.M. Gaemers, Marie Helene Jouvin, Jing Li, Yaoshi Wu, Yong Xue, M. Judith Peterschmitt

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (> 90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing. Of 170 enrolled patients, 156 completed the lead-in period and 131 met all requirements to enter the double-blind treatment period. To achieve the composite primary endpoint in the double-blind period, patients had to maintain clinical stability relative to baseline on all five endpoints (hemoglobin, platelet count, spleen and liver volumes, and bone symptoms) and meet pharmacokinetic and other tolerability requirements as determined by the investigator after 1 year of eliglustat treatment. After 1 year, 80.4% (95% CI: 67.6, 89.8) of once-daily patients were stable compared with 83.1% (95% CI: 71.0, 91.6) of twice-daily patients. The 95% CI for the mean difference of − 2.7% between groups was − 17.7, 11.9. Because the lower bound of the CI exceeded the pre-defined non-inferiority margin of − 15%, once-daily dosing could not be declared non-inferior to twice-daily dosing. Both once-daily and twice-daily patients maintained mean values for hematologic and visceral measures within established therapeutic goals during the double-blind treatment and long-term extension periods. Eliglustat was generally well-tolerated during this long-term trial (mean treatment duration: 3.3 years), with just four withdrawals (2%) for related adverse events (AE), and similar AE profiles for both dosing regimens. Patients on twice-daily eliglustat showed more stability overall, and this dose regimen was better tolerated, confirming the dosing regimen for most patients specified in the drug label.

Original language	English (US)
Pages (from-to)	347-356
Number of pages	10
Journal	Molecular Genetics and Metabolism
Volume	123
Issue number	3
DOIs	https://doi.org/10.1016/j.ymgme.2017.12.001
State	Published - Mar 2018

Funding

This study was sponsored by Sanofi Genzyme. The authors thank the patients and health-care professionals (Appendix B) who participated in the EDGE trial; Laurie LaRusso, Chestnut Medical Communications, for medical writing support funded by Sanofi Genzyme; Lisa Underhill, Medical Affairs, Sanofi Genzyme, for medical writing support and critical review of the manuscript; Meredith Foster (Sanofi Genzyme) and Riya Joshi (Sanofi Genzyme) and Regina Tayag (Prometrika, funded by Sanofi Genzyme) for biostatistical analyses and data review. This study was sponsored by Sanofi Genzyme. The authors thank the patients and health-care professionals (Appendix B) who participated in the EDGE trial; Laurie LaRusso, Chestnut Medical Communications, for medical writing support funded by Sanofi Genzyme; Lisa Underhill, Medical Affairs, Sanofi Genzyme, for medical writing support and critical review of the manuscript; Meredith Foster (Sanofi Genzyme) and Riya Joshi (Sanofi Genzyme) and Regina Tayag (Prometrika, funded by Sanofi Genzyme) for biostatistical analyses and data review.

Keywords

Clinical trial
Dosing study
Eliglustat
Gaucher disease type 1
Substrate reduction therapy

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Biochemistry
Molecular Biology
Genetics
Endocrinology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ymgme.2017.12.001

Cite this

Charrow, J., Fraga, C., Gu, X., Ida, H., Longo, N., Lukina, E., Nonino, A., Gaemers, S. J. M., Jouvin, M. H., Li, J., Wu, Y., Xue, Y., & Peterschmitt, M. J. (2018). Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized, double-blind EDGE trial. Molecular Genetics and Metabolism, 123(3), 347-356. https://doi.org/10.1016/j.ymgme.2017.12.001

@article{17037502a7a44798b87c2c353bfb5e72,

title = "Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized, double-blind EDGE trial",

abstract = "Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (> 90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing. Of 170 enrolled patients, 156 completed the lead-in period and 131 met all requirements to enter the double-blind treatment period. To achieve the composite primary endpoint in the double-blind period, patients had to maintain clinical stability relative to baseline on all five endpoints (hemoglobin, platelet count, spleen and liver volumes, and bone symptoms) and meet pharmacokinetic and other tolerability requirements as determined by the investigator after 1 year of eliglustat treatment. After 1 year, 80.4% (95% CI: 67.6, 89.8) of once-daily patients were stable compared with 83.1% (95% CI: 71.0, 91.6) of twice-daily patients. The 95% CI for the mean difference of − 2.7% between groups was − 17.7, 11.9. Because the lower bound of the CI exceeded the pre-defined non-inferiority margin of − 15%, once-daily dosing could not be declared non-inferior to twice-daily dosing. Both once-daily and twice-daily patients maintained mean values for hematologic and visceral measures within established therapeutic goals during the double-blind treatment and long-term extension periods. Eliglustat was generally well-tolerated during this long-term trial (mean treatment duration: 3.3 years), with just four withdrawals (2%) for related adverse events (AE), and similar AE profiles for both dosing regimens. Patients on twice-daily eliglustat showed more stability overall, and this dose regimen was better tolerated, confirming the dosing regimen for most patients specified in the drug label.",

keywords = "Clinical trial, Dosing study, Eliglustat, Gaucher disease type 1, Substrate reduction therapy",

author = "Joel Charrow and Cristina Fraga and Xuefan Gu and Hiroyuki Ida and Nicola Longo and Elena Lukina and Alexandre Nonino and Gaemers, {Sebastiaan J.M.} and Jouvin, {Marie Helene} and Jing Li and Yaoshi Wu and Yong Xue and Peterschmitt, {M. Judith}",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2018",

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doi = "10.1016/j.ymgme.2017.12.001",

language = "English (US)",

volume = "123",

pages = "347--356",

journal = "Molecular Genetics and Metabolism",

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Charrow, J, Fraga, C, Gu, X, Ida, H, Longo, N, Lukina, E, Nonino, A, Gaemers, SJM, Jouvin, MH, Li, J, Wu, Y, Xue, Y & Peterschmitt, MJ 2018, 'Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized, double-blind EDGE trial', Molecular Genetics and Metabolism, vol. 123, no. 3, pp. 347-356. https://doi.org/10.1016/j.ymgme.2017.12.001

TY - JOUR

T1 - Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1

T2 - The Phase 3, randomized, double-blind EDGE trial

AU - Charrow, Joel

AU - Fraga, Cristina

AU - Gu, Xuefan

AU - Ida, Hiroyuki

AU - Longo, Nicola

AU - Lukina, Elena

AU - Nonino, Alexandre

AU - Gaemers, Sebastiaan J.M.

AU - Jouvin, Marie Helene

AU - Li, Jing

AU - Wu, Yaoshi

AU - Xue, Yong

AU - Peterschmitt, M. Judith

PY - 2018/3

Y1 - 2018/3

N2 - Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (> 90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing. Of 170 enrolled patients, 156 completed the lead-in period and 131 met all requirements to enter the double-blind treatment period. To achieve the composite primary endpoint in the double-blind period, patients had to maintain clinical stability relative to baseline on all five endpoints (hemoglobin, platelet count, spleen and liver volumes, and bone symptoms) and meet pharmacokinetic and other tolerability requirements as determined by the investigator after 1 year of eliglustat treatment. After 1 year, 80.4% (95% CI: 67.6, 89.8) of once-daily patients were stable compared with 83.1% (95% CI: 71.0, 91.6) of twice-daily patients. The 95% CI for the mean difference of − 2.7% between groups was − 17.7, 11.9. Because the lower bound of the CI exceeded the pre-defined non-inferiority margin of − 15%, once-daily dosing could not be declared non-inferior to twice-daily dosing. Both once-daily and twice-daily patients maintained mean values for hematologic and visceral measures within established therapeutic goals during the double-blind treatment and long-term extension periods. Eliglustat was generally well-tolerated during this long-term trial (mean treatment duration: 3.3 years), with just four withdrawals (2%) for related adverse events (AE), and similar AE profiles for both dosing regimens. Patients on twice-daily eliglustat showed more stability overall, and this dose regimen was better tolerated, confirming the dosing regimen for most patients specified in the drug label.

AB - Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (> 90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing. Of 170 enrolled patients, 156 completed the lead-in period and 131 met all requirements to enter the double-blind treatment period. To achieve the composite primary endpoint in the double-blind period, patients had to maintain clinical stability relative to baseline on all five endpoints (hemoglobin, platelet count, spleen and liver volumes, and bone symptoms) and meet pharmacokinetic and other tolerability requirements as determined by the investigator after 1 year of eliglustat treatment. After 1 year, 80.4% (95% CI: 67.6, 89.8) of once-daily patients were stable compared with 83.1% (95% CI: 71.0, 91.6) of twice-daily patients. The 95% CI for the mean difference of − 2.7% between groups was − 17.7, 11.9. Because the lower bound of the CI exceeded the pre-defined non-inferiority margin of − 15%, once-daily dosing could not be declared non-inferior to twice-daily dosing. Both once-daily and twice-daily patients maintained mean values for hematologic and visceral measures within established therapeutic goals during the double-blind treatment and long-term extension periods. Eliglustat was generally well-tolerated during this long-term trial (mean treatment duration: 3.3 years), with just four withdrawals (2%) for related adverse events (AE), and similar AE profiles for both dosing regimens. Patients on twice-daily eliglustat showed more stability overall, and this dose regimen was better tolerated, confirming the dosing regimen for most patients specified in the drug label.

KW - Clinical trial

KW - Dosing study

KW - Eliglustat

KW - Gaucher disease type 1

KW - Substrate reduction therapy

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ER -

Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized, double-blind EDGE trial

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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