Hematology Research Center, Russian Academy of Medical Sciences, Moscow, Russia.
Blood. 2010 Aug 12;116(6):893-9. doi: 10.1182/blood-2010-03-273151. Epub 2010 May 3.
Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia. The composite primary efficacy end point required improvement after 52 weeks in at least 2 of these 3 disease manifestations and was met by 77% (95% confidence interval [CI] = 58%-89%) of all patients and 91% (95% CI = 72%-98%) of the 22 patients completing 52 weeks. Statistically significant improvements occurred in mean hemoglobin level (1.62 g/dL; 95% CI =1.05-2.18 g/dL), platelet count (40.3%; 95% CI = 23.7-57.0 g/dL), spleen volume (-38.5%; 95% CI = -43.5%--33.5%), liver volume (-17.0%; 95% CI = -21.6%-12.3%), and lumbar spine bone mineral density (0.31 Z-score; 95% CI = 0.09-0.53). Elevated biomarkers (chitotriosidase; chemokine CCL18; angiotensin-converting enzyme; tartrate-resistant acid phosphatase) decreased by 35% to 50%. Plasma glucosylceramide and ganglioside GM3 normalized. Eliglustat tartrate was well tolerated: 7 mild, transient adverse events in 6 patients were considered treatment-related. Individual pharmacokinetics varied; mean time to maximal observed concentration was 2.3 hours and mean half-life was 6.8 hours. Eliglustat tartrate appears to be a promising oral treatment for GD1.
依利格鲁司他酒石酸盐（Genz-112638）是一种葡萄糖神经酰胺合酶的特异性抑制剂，目前正在开发成为一种用于治疗 1 型戈谢病（Gaucher disease type 1，GD1）的口服底物还原治疗药物。一项针对 26 名 GD1 患者（16 名女性，10 名男性；平均年龄 34 岁）的多中心、开放性、单臂 2 期研究评估了依利格鲁司他酒石酸盐的疗效、安全性和药代动力学，该药物以基于血浆药物浓度的 50 或 100mg 剂量每日口服 2 次。入选标准要求存在脾肿大伴血小板减少和/或贫血。主要复合疗效终点要求在 52 周时至少有 3 种疾病表现中的 2 种得到改善，所有患者中有 77%（95%置信区间[CI]为 58%-89%）和 22 名完成 52 周的患者中有 91%（95%CI为 72%-98%）符合这一要求。血红蛋白水平（1.62g/dL；95%CI=1.05-2.18g/dL）、血小板计数（40.3%；95%CI=23.7-57.0g/dL）、脾脏体积（-38.5%；95%CI=-43.5%--33.5%）、肝脏体积（-17.0%；95%CI=-21.6%-12.3%）和腰椎骨密度（0.31Z 评分；95%CI=0.09-0.53）均出现显著改善。升高的生物标志物（几丁质酶；趋化因子 CCL18；血管紧张素转换酶；耐酒石酸酸性磷酸酶）下降了 35%至 50%。血浆葡萄糖神经酰胺和神经节苷脂 GM3 恢复正常。依利格鲁司他酒石酸盐耐受性良好：6 名患者中有 7 名出现轻度、短暂的不良事件，认为与治疗相关。个体药代动力学存在差异；最大观察浓度的中位达峰时间为 2.3 小时，中位半衰期为 6.8 小时。依利格鲁司他酒石酸盐似乎是一种很有前途的 GD1 口服治疗药物。
