Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes.
Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes.
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DOI：
10.1016/j.steroids.2018.02.010
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发表时间：
2018-06
期刊：
影响因子：
2.7
通讯作者：
McCall JM
中科院分区：
文献类型：
--
作者：
Hoffman EP;Riddle V;Siegler MA;Dickerson D;Backonja M;Kramer WG;Nagaraju K;Gordish-Dressman H;Damsker JM;McCall JM
糖皮质激素药物是高效的抗炎药，但长期使用伴随着广泛的药效学安全性问题，对患者的生活质量有相当大的负面影响。Vamorolone(VBP15)是一种一流的类固醇多功能药物，通过与糖皮质激素受体的高亲和力结合、对盐皮质激素受体的高亲和力拮抗以及膜稳定特性，显示出有效的抑制促炎NFkB通路的作用。在多种小鼠炎症模型的临床前数据显示，抗炎效果保留，但大部分或全部副作用消失。我们报告了首次人类第一阶段临床试验(86名健康成年男性)，单次递增剂量(0.1-20.0 mg/kg)和多个递增剂量(1.0-20 mg/kg/天；14天疗程)。Vamorolone在所有剂量水平下耐受性良好。Vamorolone的药代动力学和代谢特征与强的松相似。生物标记物研究显示，传统糖皮质激素药物的副作用(骨骼脆性、代谢障碍、免疫抑制)消失。肾上腺轴的抑制程度比强的松小10倍。解析了其晶体结构，并与泼尼松、地塞米松进行了比较。在结构上有重叠，但在糖皮质激素与糖皮质激素受体Asn564相互作用的C环处构象不同。预测的Asn564与黄曲霉毒素结合的丧失可能是基因转录活性丧失的原因。Vamorolone是一种游离型类固醇，它保留了糖皮质激素(激动剂)和盐皮质激素(拮抗剂)受体的高亲和力结合和核移位，但不显示现有糖皮质激素药物的药效学安全性问题，最高可达20 mg/kg/天。
Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties. Pre-clinical data in multiple mouse models of inflammation showed retention of anti-inflammatory efficacy, but loss of most or all side effects. We report first-in-human Phase 1 clinical trials (86 healthy adult males), with single ascending doses (0.1–20.0 mg/kg), and multiple ascending doses (1.0–20 mg/kg/day; 14 days treatment). Vamorolone was well-tolerated at all dose levels. Vamorolone showed pharmacokinetic and metabolism profiles similar to prednisone. Biomarker studies showed loss of side effects of traditional glucocorticoid drugs (bone fragility, metabolic disturbance, immune suppression). Suppression of the adrenal axis was 10-fold less than prednisone. The crystallographic structure of vamorolone was solved, and compared to prednisone and dexamethasone. There was overlap in structure, but differences in conformation at the C-ring where glucocorticoids interact with Asn564 of the glucocorticoid receptor. The predicted loss of Asn564 binding to vamorolone may underlie the loss of gene transcriptional activity. Vamorolone is a dissociative steroid that retains high affinity binding and nuclear translocation of both glucocorticoid (agonist) and mineralocorticoid (antagonist) receptors, but does not show pharmacodynamic safety concerns of existing glucocorticoid drugs at up to 20 mg/kg/day.
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影响因子：
5.8
作者：
Kauh, Eunkyung;Mixson, Lori;Ruddy, Marcella
通讯作者：
Ruddy, Marcella
影响因子：
4.1
作者：
Graeff, Christian;Marin, Fernando;Glueer, Claus-Christian
通讯作者：
Glueer, Claus-Christian
DOI：
10.1165/rcmb.2013-0396oc
发表时间：
2014-09-01
影响因子：
6.4
作者：
Alcala, Sarah E.;Benton, Angela S.;Freishtat, Robert J.
通讯作者：
Freishtat, Robert J.
DOI：
10.1016/s1474-4422(14)70318-7
发表时间：
2015-02
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Raman SV;Hor KN;Mazur W;Halnon NJ;Kissel JT;He X;Tran T;Smart S;McCarthy B;Taylor MD;Jefferies JL;Rafael-Fortney JA;Lowe J;Roble SL;Cripe LH
通讯作者：
Cripe LH
影响因子：
4.6
作者：
Hathout, Yetrib;Conklin, Laurie S.;Hoffman, Eric P.
通讯作者：
Hoffman, Eric P.