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

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.