Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
HDES Hospital, Ponta Delgada, Açores, Portugal.
Mol Genet Metab. 2018 Mar;123(3):347-356. doi: 10.1016/j.ymgme.2017.12.001. Epub 2018 Jan 4.
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 1year of eliglustat treatment. After 1year, 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: 3.3years), 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.
依鲁替尼是一种用于治疗 1 型戈谢病（GD1）的一线口服药物，适用于具有相容 CYP2D6 代谢表型的成人（>90%的患者）。这项随机、双盲 EDGE 试验（NCT01074944，赛诺菲）评估了依鲁替尼的每日一次剂量与批准的每日两次剂量在相同的总日剂量下在 GD1 成人中的疗效。受试者在 6-18 个月的导入期内接受每日两次的治疗。仅在导入期内达到血红蛋白、血小板计数、脾脏和肝脏体积以及骨骼症状的预定治疗目标的受试者才被随机分配到每日一次或两次剂量组。在 170 名入组的患者中，156 名完成了导入期，131 名满足所有要求进入双盲治疗期。为了在双盲期达到复合主要终点，患者必须在所有五个终点（血红蛋白、血小板计数、脾脏和肝脏体积以及骨骼症状）上相对于基线保持临床稳定，并在接受依鲁替尼治疗 1 年后满足药代动力学和其他可耐受的要求。治疗 1 年后，每日一次组的 80.4%（95%CI：67.6，89.8）患者稳定，每日两次组的 83.1%（95%CI：71.0，91.6）患者稳定。两组间 -2.7%的平均差异的 95%CI 为-17.7，11.9。由于置信区间的下限超过了预先设定的非劣效性边界-15%，因此不能宣布每日一次的剂量方案不劣于每日两次的剂量方案。在双盲治疗和长期扩展期间，每日一次和每日两次的患者都保持了血液学和内脏测量值的平均值在既定的治疗目标内。依鲁替尼在这项长期试验中总体上耐受性良好（平均治疗持续时间：3.3 年），只有 4 例（2%）因相关不良事件（AE）停药，两种剂量方案的 AE 谱相似。每日两次的依鲁替尼总体上更稳定，且这种剂量方案更耐受，这证实了药物标签中规定的大多数患者的剂量方案。
