Department of Medicine, Sickle Cell Center, Medical College of Georgia, Augusta, GA, USA.
Am J Hematol. 2012 Nov;87(11):1017-21. doi: 10.1002/ajh.23306. Epub 2012 Aug 7.
Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly noncytotoxic therapeutics. Fetal hemoglobin (HbF, α(2) γ(2) ) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK-1001), an orally-bioavailable, promoter-targeted fetal globin gene-inducing agent, was evaluated in a randomized, blinded, dose-ranging Phase I/II trial in 24 adult patients with HbSS or S/β thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6-week cycles, with a two-week interim dose holiday. Twenty-one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK-1001 was well-tolerated with no unexpected drug-related adverse events; a dose-limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hr. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo-treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF, and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK-1001 in sickle cell disease.
需要治疗镰状细胞综合征的药物，特别是非细胞毒性的治疗药物。胎儿血红蛋白（HbF，α(2)γ(2)）已被确定为疾病严重程度的主要调节因子；HbF 水平升高与临床症状较轻和生存改善相关。因此，口服生物利用度的、靶向启动子的胎儿珠蛋白基因诱导剂——丁酸钠二甲酯（HQK-1001），在 24 名 HbSS 或 S/β 地中海贫血的成年患者中进行了随机、双盲、剂量递增的 I/II 期试验，以确定三种递增剂量水平的安全性和耐受性。该研究治疗药物每日一次给药，持续两个 6 周周期，中间有两周的停药期。21 名患者完成了研究。5 名患者接受了 10 或 20mg/kg 剂量的研究药物，7 名患者接受了 30mg/kg/d 剂量的研究药物，4 名患者接受了安慰剂。HQK-1001 耐受性良好，无意外的药物相关不良事件；未确定剂量限制性毒性。血浆药物水平持续维持在 24 小时以上的目标水平。与基线相比，观察到 HbF 升高，特别是在 30mg/kg/天的剂量下；在 7 名治疗患者中，有 5 名患者的 HbF 平均绝对增加了 0.2g/dl，总血红蛋白（Hgb）平均增加了 0.83g/dl，而安慰剂对照组没有增加。这些有利的 PK 特征、耐受性、早期 HbF 升高和总 Hgb 表明，需要进行更长时间的试验来更明确地评估 HQK-1001 在镰状细胞病中的治疗潜力。
