Linaclotide: promising IBS-C efficacy in an era of provisional study endpoints.
Linaclotide: promising IBS-C efficacy in an era of provisional study endpoints.
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利那洛肽：在临时研究终点时代，有望实现 IBS-C 疗效。
DOI：
10.1038/ajg.2012.325
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Sayuk,GregoryS
中科院分区：
文献类型：
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作者：
Sayuk,GregoryS
最近在肠易激综合征(IBS)药物治疗方面的令人失望的进展并没有挫伤人们对利纳克洛德的热情，利纳氯肽是一种新型鸟苷环化酶-C激动剂，用于治疗便秘为主的肠易激综合征(IBS-C)。这一期的《美国胃肠病学杂志》报道了两项关于单剂量每日服用利纳氯肽的近期3期研究。重要的是，这些研究首次检验了食品和药物管理局(FDA)对IBS-C的临时联合反应终点，该终点要求改善腹痛和排便症状。FDA的这一终点的潜在局限性涉及缺乏其他潜在的重要IBS症状的纳入，以及无法与最近的其他IBS-C试验直接比较。这两项研究都成功地在大约三分之一的研究对象中达到了这一终点，导致需要治疗(NNT)的人数为5到8人，才能达到FDA的应答者。在近50%的受试者中观察到对利纳氯肽的个别症状反应，并对这些差异提供了与FDA终点相比的潜在解释。适当的缓解措施也被评估，NNTs为3.4-6.8，与其他当代IBS-C研究相比是有利的。总体而言，两项利那克定试验都发现，就严重不良事件而言，该药物是安全的，尽管促分泌剂的作用机制导致大约五分之一的受试者腹泻。总而言之，这些研究启发了其他几个关于利纳氯肽的重要问题，包括它在管理IBS-C方面相对于现有治疗方案(如卢比前列酮)的作用。更广泛的临床应用将揭示用FDA临时终点测量的观察到的反应是否会转化为IBS患者的实际改善经验。
Recent disappointing developments in the pharmacotherapy of irritable bowel syndrome (IBS) have not dampened the enthusiasm surrounding linaclotide, a novel guanylate cyclase-C agonist for the management of constipation-predominant IBS (IBS-C). Two recent phase 3 studies reporting on a single, daily dose of linaclotide are presented in this issue of theAmerican Journal of Gastroenterology. Importantly, these studies are the first to examine a provisional Food and Drug Administration (FDA) combined response endpoint for IBS-C, which mandates improvements of both abdominal pain and defecatory symptoms. Potential limitations of this FDA endpoint relate to a lack of inclusion of other potentially important IBS symptoms and an inability to directly compare findings with other recent IBS-C trials. Both studies successfully reached this endpoint in approximately one-third of study subjects, resulting in numbers needed to treat (NNT) of five to eight, to achieve an FDA responder. Individual symptom responses to linaclotide were seen in nearly 50% of participants, and potential explanations for these discrepancies when compared with the FDA endpoint are offered. Adequate relief measures also were assessed and, with NNTs of 3.4–6.8, compared favorably with other contemporary IBS-C studies. Overall, both linaclotide trials found the medication to be safe in terms of serious adverse events, though the secretagogue mechanism of action led to diarrhea in approximately one in five subjects. Together, these studies inspire several other important questions regarding linaclotide, including its role in the management of IBS-C relative to existing treatment options, such as lubiprostone. Greater clinical use of linaclotide will reveal whether the observed responses measured with the FDA provisional endpoint will translate into real-world experiences of improvement in IBS patients.