New blood-boosting drugs aim to staunch renal anemia
New blood-boosting drugs aim to staunch renal anemia
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新的补血药物旨在缓解肾性贫血
DOI：
10.1038/nm0312-332a
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
M. Moyer
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文献类型：
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作者：
M. Moyer
对于近90%患有贫血的严重慢性肾脏疾病的个体来说，护理标准可能是繁重的。每周两到三次，这些人必须去透析诊所接受埃洛普的注射，埃洛普是一种重组版的促红细胞生成素激素，可以刺激红细胞的形成。虽然有更持久的促红细胞生成素蛋白类似物，但美国唯一批准的一种-安进公司的Aranesp（达贝泊）-仍然需要每两周注射一次用于透析患者。不过，针对透析患者的长效药物可能即将问世。去年12月，美国食品和药物管理局（FDA）的一个咨询委员会以压倒性多数投票通过了pegineslavin，这是第一个每月一次的透析患者贫血药物。这种治疗需要更少的注射，而且还拥有独特的结构，有助于避免埃帕霉素药物罕见但严重的并发症。监管机构预计将在3月底前做出最终决定。尽管30亿美元的美国肾性贫血市场长期以来一直由总部位于加利福尼亚州千橡市的安进公司主导，该公司还生产了Epogen和Procrit，但新的药物pegineslavir是由总部位于加利福尼亚州帕洛阿尔托的Affymax公司开发的。去年，在美国和欧洲进行的两项3期临床试验表明，在维持透析患者的目标血红蛋白水平方面，pegineslavin与epoylavin一样有效。研究人员将未接受透析的个体排除在试验之外，因为早期的数据表明，该药物会增加死亡和心脏病的风险，原因尚不清楚。Affymax与日本武田公司共同开发的Pegineslavin，其作用与依泊苷很相似，因为它与骨髓中红细胞前体上的促红细胞生成素受体结合，以激活红细胞的产生。但由于这种分子含有稳定的聚乙二醇链，它不受降解酶的影响，半衰期较长，这意味着注射频率较低。此外，pegineslavin是一种小肽，其结构与天然蛋白质不同，这意味着它避免了与epoxin相关的罕见并发症：接受药物治疗的一小部分人产生了针对它的抗体，这些抗体中和了药物和身体的内源性促红细胞生成素，有效地阻止了血细胞的产生，使贫血恶化。位于巴尔的摩的约翰霍普金斯医学院（Johns Hopkins School of Medicine）的肾脏病学临床主任迈克尔·崔（Michael Choi）表示，peginesulfide避免了这种交叉反应，这提供了“一个巨大的优势”。如果欧洲药品管理局（European Medicines Agency）也批准，peginesulfide将成为欧洲第二种每月一次的肾性贫血药物，与瑞士罗氏（Roche）开发的持续促红细胞生成素受体激活剂Mircera并列。Mircera在2007年获得了欧洲和美国的批准，但随后因侵犯了安进的一项专利而被撤出美国市场。
For the nearly 90% of individuals with severe chronic kidney disease who suffer from anemia, the standard of care can be burdensome. Two or three times a week, these individuals must visit dialysis clinics to receive injections of epoetin, a recombinant version of the erythropoietin hormone that stimulates red blood cells to form. Although longer-lasting protein analogs of erythropoietin are available, the only one approved in the US—Amgen’s Aranesp (darbepoetin)—still requires biweekly injections for individuals on dialysis. Longer-acting agents for dialysis patients could be on the way, though. In December, a US Food and Drug Administration advisory committee voted overwhelmingly to approve peginesatide, the first once-monthly anemia drug for individuals on dialysis. The treatment requires fewer injections and also boasts a unique structure that helps it circumvent a rare yet serious complication of epoetin drugs. The regulatory agency expects to make a final decision before the end of March. Although the $3 billion US renal anemia market has long been dominated by Thousand Oaks, California–based Amgen, which also makes the epoetin drugs Epogen and Procrit, the newer agent, peginesatide, was developed by the Palo Alto, California–based firm Affymax. Last year, two phase 3 clinical trials in the US and Europe showed that peginesatide is as effective as epoetin at maintaining target hemoglobin levels in patients on dialysis. The researchers excluded individuals not on dialysis from the trials because earlier data suggested that the drug increases their risk of death and heart disease for as yet unknown reasons. Peginesatide, which Affymax is co-developing with Japan’s Takeda, works much like epoetin in that it binds the erythropoietin receptor on red blood cell precursors in bone marrow to activate red blood cell production. But because the molecule contains a stabilizing polyethylene glycol chain, it is shielded from degrading enzymes and has a longer half-life, which means less frequent injections. Plus, peginesatide is a small peptide with a different structure than the native protein, which means it avoids a rare complication associated with epoetin: a small percentage of people who receive the medication develop antibodies against it that neutralize both the drug and the body’s endogenous erythropoietin, effectively halting blood cell production and making their anemia worse. That peginesatide avoids this cross-reactivity provides “a huge advantage,” says Michael Choi, clinical director of nephrology at the Johns Hopkins School of Medicine in Baltimore.If also cleared by the European Medicines Agency, peginesatide will be the second oncemonthly renal anemia drug available in Europe, joining Mircera, a continuous erythropoietin receptor activator developed by Switzerland’s Roche. Mircera won European and US approval in 2007 but was subsequently pulled from the US market because it infringed on an Amgen patent.