加州大学旧金山分校贝尼奥夫儿童医院Elliott Vichinsky研究组取得一项新成果，他们的研究提出voxelotor可攻克镰状细胞病。 这一研究成果于2019年8月8日发表在国际顶尖学术期刊《新英格兰医学杂志》上。

Voxelotor是一种HBS聚合抑制剂。 在一项多中心、3期、双盲、随机、安慰剂的对照试验中，研究团队比较了镰状细胞病患者分别服用1500毫克voxelotor、900毫克voxelotor和安慰剂的疗效和安全性。主要观察指标为有血红蛋白反应的参与者的百分比，在该意向治疗分析中，血红蛋白反应定义为治疗24周后血红蛋白水平比基线增加1.0 g/dl以上。共有274名参与者按照1：1：1的比例随机分为三组，每日一次分别口服1500毫克voxelotor、900毫克voxelotor或安慰剂。大多数参与者患有镰状细胞性贫血（纯合血红蛋白S或血红蛋白Sβ0-地中海贫血），大约三分之二的患者参与前就接受羟基脲治疗。在意向治疗分析中，1500毫克voxelotor组受试者的血红蛋白反应率明显高于安慰剂组。

在治疗开始后的24周内，voxelotor不同剂量组中贫血恶化的受试者数目显著少于安慰剂组。在第24周，1500毫克voxelotor组受试者的间接胆红素水平和网织红细胞百分比显著低于安慰剂组。治疗期间各组发生不良反应或病情恶化的百分比相差不大。1500毫克voxelotor组中不低于3级不良事件的发生率为26%，900毫克voxelotor组为23%，安慰剂组为26%。大多数不良事件与试验药物或安慰剂无关。综上所述，voxelotor可显著提高血红蛋白水平，降低溶血标志物，该发现与抑制HBS聚合一致，表明了治疗镰状细胞病的潜力。

据介绍，脱氧镰状血红蛋白(HBS)容易聚合在一起导致镰状细胞病。因此，直接抑制HBS聚合可有助改善疾病预后。
 

附：英文原文

Title: A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease

Author:Elliott Vichinsky, M.D., Carolyn C. Hoppe, M.D., Kenneth I. Ataga, M.D., Russell E. Ware, M.D., Ph.D., Videlis Nduba, M.B., Ch.B., M.P.H., Amal El-Beshlawy, M.D., Hoda Hassab, M.D., Maureen M. Achebe, M.D., M.P.H., Salam Alkindi, M.B., B.Ch., R. Clark Brown, M.D., Ph.D., David L. Diuguid, M.D., Paul Telfer, M.D., Dimitris A. Tsitsikas, M.D., Ashraf Elghandour, M.D., Victor R. Gordeuk, M.D., Julie Kanter, M.D., Miguel R. Abboud, M.D., Joshua Lehrer-Graiwer, M.D., Margaret Tonda, Pharm.D., Allison Intondi, Ph.D., Barbara Tong, Ph.D., Jo Howard, M.D. for the HOPE Trial Investigators*

Issue&Volume: Vol.381, No.6

Abstract:

BACKGROUND

Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor.

METHODS

In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis.

RESULTS

A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sβ0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators.

CONCLUSIONS

In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential.

DOI: 10.1056/NEJMoa1903212

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1903212