FDA终于批准阿格列汀治疗2型糖尿病

经过数年来的反复审查和驳回，美国食品药品管理局(FDA)最终批准二肽基肽酶Ⅳ(DPP-4)抑制剂阿格列汀上市。

FDA批准了该药品的3种版本：单剂(Nesina)、含二甲双胍的复方制剂(Kazano)，以及含吡格列酮的复方制剂(Oseni)。这3种版本的阿格列汀的适应证均为，结合饮食与运动干预治疗2型糖尿病。

阿格列汀生产商武田制药表示，该药的作用机制是减缓肠促胰岛素GLP-1(胰高血糖素样肽-1)和GIP(葡萄糖依赖性促胰岛素多肽)的失活。Oseni是首个在美国获准上市的包含DPP-4抑制剂和噻唑烷二酮的复方制剂。

阿格列汀是第4种获得FDA批准的DPP-4抑制剂。默克的西格列汀(捷诺维)是首个获得批准的DPP-4抑制剂，之后依次为沙格列汀(安立泽，由阿斯利康和百时美-施贵宝销售)和利拉利汀(Tradjenta，由勃林格-殷格翰和礼来销售)。

武田制药早在2008年就提出了上市申请，但获准之路并不平坦。首先，2007年罗格列酮(文迪雅)与心肌梗死风险增加之间的关联引起了公众的担忧，FDA随即于2008年开始要求所有糖尿病治疗都必须具有心血管安全性。武田制药只好重新开展临床试验，以便纳入心血管终点指标。出于安全性考虑，该公司随后接到了2项提供更多信息的要求——其中一项针对阿格列汀单药治疗，另一项针对阿格列汀/吡格列酮联合治疗。

结果，FDA对每种药品的批准令都带有诸多附加条件，包括不同的警告和要求。

作为单剂，Nesina在至少14项试验中显示出了在26周内使糖化血红蛋白(HbA1c)水平降低0.4%~0.6%(与安慰剂相比)的效能。该药品将有6.25 mg、12.5 mg和25 mg三种片剂可供选用。但FDA要求针对阿格列汀单药治疗开展5项上市后研究：1项监测肝脏异常、严重胰腺炎和严重超敏反应的增强药物警戒计划；3项按照儿科研究公平法案(PREA)开展的儿科研究，包括1项剂量探索研究和2项安全性、有效性研究(分别采用Nesina单药治疗和Nesina+二甲双胍联合治疗)。

在4项临床试验中，与Nesina相比，包含二甲双胍的复方制剂Kazano可使HbA1c多降低1.1%，与二甲双胍单药治疗相比可使HbA1c多降低0.5%。Kazano有12.5 mg阿格列汀/500 mg二甲双胍和12.5 mg阿格列汀/1,000 mg二甲双胍两种规格可供选择。FDA要求针对Kazano开展2项上市后研究：1项监测肝脏异常、严重胰腺炎和严重超敏反应的计划；1项儿科安全性与有效性研究。Kazano将附带一则有关乳酸酸中毒的加框警告。

阿格列汀/吡格列酮复方制剂Oseni有6种规格可供选用：5 mg/15 mg、25 mg/30 mg、25 mg/45 mg、12.5 mg/15 mg、12.5 mg/30 mg和12.5 mg/45 mg。与阿格列汀单药治疗相比，该药可使HbA1c额外降低0.4%~0.9%，与吡格列酮单药治疗相比可额外降低0.4%~0.6%。武田制药将开展1项有关Oseni与肝脏异常、胰腺炎和超敏反应的上市后研究。该药将附带一则有关心力衰竭的加框警告。

Oseni和Nesina均已在日本获准上市，但除了美国和日本之外尚无其他国家批准这些药品。

尽管人们对所有糖尿病治疗的心血管安全性仍有担忧，但近期一项Meta分析显示，DPP-4抑制剂可能大幅降低主要心血管事件的风险。这项研究由百时美-施贵宝和阿斯利康资助，已在2012年11月底的美国心脏协会(AHA)年会上发表。

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By: ALICIA AULT, Cardiology News Digital Network

After several years of reviews and rejections, the dipeptidyl peptidase IV inhibitor alogliptin has finally been approved by the Food and Drug Administration.

The FDA approved three versions of the product: as a single agent (Nesina); in combination with metformin (Kazano); and, in combination with pioglitazone (Oseni). All are indicated for treatment of type 2 diabetes in combination with diet and exercise.

Alogliptin is designed to slow the inactivation of incretin hormones GLP-1 (glucagonlike peptide–1) and GIP (glucose-dependent insulinotropic peptide), according to the drug’s maker, Takeda Pharmaceutical Company Ltd. Oseni is the first product approved in the United States that includes a DPP-4 inhibitor and a thiazolidinedione in a single tablet, the company said.

Alogliptin is the fourth DPP-4 inhibitor to win FDA approval. Merck’s sitagliptin (Januvia) is the market leader; the others in the class are saxagliptin (Onglyza, marketed by AstraZeneca and Bristol-Myers Squibb) and linagliptin (Tradjenta, marketed by Boehringer Ingelheim and Lilly).

These approvals are 5 years in the making. Takeda submitted an application for the drug in 2008, but was tripped up by several developments. First, shortly after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction, the FDA in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety. Takeda had to restart its clinical development to incorporate trials with cardiovascular endpoints. The company subsequently received two requests – one for alogliptin as a single agent and another for the combination with pioglitazone – for more information, because of safety concerns.

As a result, the agency’s approval for each product is a mixed bag, with each carrying different warnings and requirements.

The single agent, Nesina, showed in more than 14 trials that it reduced hemoglobin A1c by 0.4-0.6 percentage points compared with placebo over 26 weeks. It will be available in 6.25-mg, 12.5-mg, and 25-mg tablets. But the agency is requiring five postmarketing studies for alogliptin as a single agent: an enhanced pharmacovigilance program to monitor for liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions; and three pediatric studies under the Pediatric Research Equity Act (PREA), including a dose-finding study and two safety and efficacy studies, one with Nesina as a monotherapy and one with Nesina and metformin.

The metformin combination, Kazano, reduced HbA1c by 1.1 percentage points more than Nesina, and 0.5 percentage points more than metformin alone in four clinical trials. The two dosages are 12.5 mg alogliptin/500 mg metformin and 12.5 mg/1,000 mg. The FDA is requiring two postmarketing studies for Kazano: a program to monitor for liver abnormalities, serious pancreatitis, and severe hypersensitivity reactions; and a pediatric safety and efficacy study. Kazano will carry a boxed warning for lactic acidosis.

Oseni, the alogliptin/pioglitazone combination, in six fixed-dose formulations (5 mg/15 mg, 25 mg/30 mg, 25 mg/45 mg, 12.5 mg/15 mg, 12.5 mg/30 mg, and 12.5 mg/45 mg), reduced HbA1c by 0.4-0.9 percentage points more than alogliptin alone, and 0.4-0.6 percentage points better than pioglitazone alone in studies. Takeda will have to conduct a postmarketing study on liver abnormalities, pancreatitis, and hypersensitivity reactions for Oseni, as well. The drug will have a boxed warning for heart failure.

Both Oseni and Nesina are approved in Japan, but those are the only other global approvals for the products.

Although there has been some concern with all diabetes therapeutics and cardiovascular safety, a recent meta-analysis showed that DPP-4 inhibitors may substantially reduce the risk of major cardiovascular events. The study, funded by Bristol-Myers Squibb and AstraZeneca, was reported at the annual scientific sessions of the American Heart Association in late November.