新的指导原则，安全性问题改变糖尿病治疗格局
New Guidelines, Safety Issues Reshape Diabetes SpaceBy Karen Pihl-Carey
Senior Staff Writer
The diabetes landscape is a tad riskier for drugs in development that have a safety glitch or two, and the bottom line could mean higher costs.
糖尿病治疗领域对于安全性有点问题的在研药物来说，风险稍微高了些，底线也意味着成本更高。
New FDA draft guidance calls for more patients and lengthier trials for companies with certain safety issues, but the rules are no different from what is expected in drug development for other chronic conditions, the agency has said.
FDA新的指导草案要求涉及安全性问题的公司加大病例数，延长试验时间，但FDA声称这些规定与其他慢性病治疗药物研发的要求是一致的。
In general, the FDA wants companies to exceed previous expectations considering the growing diabetes population and the increased complexity of treatments, but it will be an absolute stickler with those drugs exhibiting serious side effects. Specifically, it wants a Phase III trial to include at least 2,500 subjects, with 1,300 of them exposed to the drug for a year or more, and 300 exposed for 18 months or more. Certain diabetes drugs on the market, such as Januvia (sitagliptin; Merck & Co. Inc.) and Byetta (exenatide; Amylin Pharma-ceuticals Inc. and Eli Lilly and Co.) were approved based on trials that didn't go beyond a year.
总的来说，FDA是希望公司能考虑到日益增长的糖尿病人群和治疗的复杂程度，突破以前的设想。但对于出现严重副作用的药物来说，这绝对是个难题。比如说，要求三期临床病例数至少2500例，其中1300例要服用药物1年以上，300例服药1年半以上。而目前市售的一些药物如默克的Januvia和Amylin的Byetta试验不到一年就批准了。
Some companies with early stage diabetes products say the new rules are in line with what was already planned for development. Sirtris Pharmaceuticals Inc., for instance, is working on SRT501, an oral small molecule formulation of resveratrol that activates Sirt1. It is in five Phase Ib trials.
糖尿病产品处于早期研发的公司认为这一新给对于目前规划在研的产品没有冲突。如Sirtris制药公司正致力于可活化Sirt1的白藜芦醇的口服制剂SRT501，目前处于5个phase Ib测试。
\"The draft guidelines will not impact our timetables,\" said John Lacey, associate director of corporate communications at the Cambridge, Mass.-based company, who added that its programs were \"already meeting the draft guideline recommendations.\"
“指导草案不会影响我们的时间表，”位于剑桥的公司联络部的副主管John Lacey说，他补充说该项目符合指导草案的要求。
It is unclear, however, how the changes might affect later-stage compounds. Analyst Matthew Osborne of Lazard Capital Markets stated in a research note earlier this month his concern that they might delay a new drug application filing for Amylin's long-acting version of Byetta (exenatide LAR). The company is in the middle of enrolling Phase III trials for the compound and a regulatory submission is expected for the second quarter of 2009.
目前还不清楚这些变化对研发后期的药物影响如何。Lazard资本市场的分析师Matthew Osborne在本月早期的一个研究记录中表达了他的担忧，Amylin的长效型Byetta （exenatide LAR）可能会延迟新药申请。公司该产品正处于三期临床的中期，预计2009年第二季度提交审批。
But Osborne fears that date could shift as the result of the draft guidance. He downgraded the company's stock (NASDAQ:AMLN) to hold from buy.
但Osborne担心由于指导草案的变化日期可能变动。他调低了该公司的股票级别，从购买变为持有。
\"We are moving to the sidelines pending further evidence that safety does not appear to be a concern for exenatide LAR,\" he wrote.
“我们正处在界线上，需要更多证据证实exenatide LAR的安全性没有问题。”他写道。
The issue with Amylin's product is whether its nonstop activation of the GLP-1 receptor would cause a different physiologic response in a subset of patients. A serious safety concern - even if it affects a very small number of patients - could bump up the approval requirements.
Amylin产品的问题在于药物不停的刺激GLP-1受体是否会导致某类患者出现其他的生理反应。严重的安全性问题，即使只出现在很少的患者中，也会大大提高批准的要求。
But Amylin spokeswoman Alice Bahner Izzo said her company is confident the current development program for exenatide LAR is adequate for submission because the FDA has worked with the company all along \"and their thinking would have been reflected from the guideline update that they were clearly working on.
但是Amylin的发言人Alice Bahner Izzo说，公司相信当前exenatide LAR的研发项目能够提交，因为FDA与公司一直合作良好，“他们正在阐明从指导更新中反映出来的想法。”
\"The nice thing about the guidance,\" she added, \"is that it does recognize that diabetes is multi-faceted and it mentions the post-prandial glucose contribution to a once-a-week control,\" an important part for understanding Amylin's and other innovative diabetes therapies.
“关于指导好的一面是承认糖尿病的多面性，也提到了餐后血糖也助于一周一次的控制，”这是了解Amylin及其他创新的糖尿病疗法的重要一面。
In November, the FDA added to an existing black box warning of the diabetes drug Avandia (rosiglitazone, GlaxoSmithKline plc) that Type II diabetes patients, particularly those with underlying heart disease, are at an increased risk for heart attack. The FDA has denied that its new draft guidance is in response to Avandia's potential side effects, but it does suggest trials even longer than 18 months in some circumstances.
去年11月，FDA把葛兰素史克的降糖药文迪雅加到现有的黑匣警告中，II型糖尿病患者，尤其是有心脏病的患者，有增加心脏病发作的风险。FDA否认新草案是针对文迪雅的潜在副作用，但建议某些情况下临床试验要做1年半以上。
Companies developing peroxisome proliferator-activated receptor (PPAR) agonists, like Avandia, are urged to conduct two-year carinogenicity evaluations. The agency also may require data of up to two years to describe immunogenic potential in products with certain safety signals \"cardiovascular or otherwise.\"
研发过氧物酶增殖子活化的受体（PPAR）激动剂，类似文迪雅的公司，要求做两年的基因评价。FDA也需要两年的数据来描述涉及“心血管或其他方面”安全信息的产品潜在的免疫原性。
Longer trials could be a huge burden on a young company like InteKrin Therapeutics Inc., which licensed in January an oral PPAR gamma-selective modulator and partial agonist, INT131, from Amgen Inc. But the company has stressed that INT131 does not agonize the full receptor and therefore does not turn on the genes associated with weight gain and edema, as seen with Avandia and Actos. Other companies working on PPAR agonists include Metabolex Inc. and Plexxikon Inc. InteKrin raised $23 million in its first round in January to fund Phase IIb trials of INT131.
更长的临床试验对于InteKrin治疗公司这样的新公司来说，是个巨大的负担。他们1月份刚从安进公司获得口服PPARγ-选择性调节子和部分激动剂INT131的许可。但公司强调，INT131不会激发所有的受体，因此不会启动增重或水肿相关的基因，不同于文迪雅和Actos。其他研发PPAR激动剂的公司包括Metabolex和 Plexxikon。InteKrin已筹集了2300万美元用于ITNT131的phase IIb试验。
Jim Reddoch, an analyst with Friedman, Billings, Ramsey, reiterated his outperform rating for Amylin, prompting the stock to climb mid-month, based on projected peak annual sales of $2 billion for Byetta and its long-acting version. He didn't believe the draft guidance would adversely effect exenatide LAR's timeline because it seems to focus more on heart safety.
基于预计的byetta及其长效型20亿美元的年销售额，分析师Jim Reddoch 反复强调Amylin的优秀评级，推动股票在月中旬的上涨。他认为指导草案对exenatide LAR的进展没有不良影响，因为外界关注的是心脏安全性。
Some followers of the diabetes market breathed a sigh of relief when the new guidance emerged, since it appeared that the FDA stood by the age-old surrogate endpoint of improvement in HbA1c. Many had feared the agency might require costlier outcome trials with an emphasis on cardiovascular events or mortality. And it still might. Earlier this month, Sen. Chuck Grassley (R-Iowa) announced an investigation into the use of surrogate endpoints to approve drugs such as Avandia.
新的指导出来时，糖尿病市场的后来者可以松口气了，因为FDA似乎支持使用较早的HbA1c改善的中间指标。很多人害怕FDA会要求成本更高的针对心血管或死亡率的测试指标的试验。也许还会吧。本月早些时候，Sen Chuck Grassley就宣布要调查批准文迪雅时使用的中间指标。
Safety Is Not The Only Challenge
安全性并不是唯一的挑战
For the time being, it appears that companies with solid safety profiles of their drugs have nothing to worry about. And some analysts, like Aileen Salares of Leerink Swann & Co., stand by long-acting Byetta. She issued her own note a few weeks ago saying that the drug's small pivotal trial \"is not viewed as an impediment to a timely approval.\" She believes Amylin can use extensive post-market data on the twice-daily version of Byetta to prove the long-acting version's safety. Byetta was approved for Type II diabetes in 2005.
目前来说，药物安全性无忧的公司似乎没什么好担心。像leerink swann的分析师Aileen Salares也支持长效的byetta. 她数周前发表了自己的看法，认为该药物小规模的关键试验不妨碍药物的适时批准。她认为Amylin可以运用市售的一天两次的Byetta的广泛数据来验证长效型的安全性。Byetta已在2005年批准用于II型糖尿病。
In any case, she said, \"reduced GI discomfort such as nausea may be a sufficient signal to alleviate safety concerns with the LAR formulation.\"
无论如何，她说，“降低了胃肠道不适如恶心，足以看作是减少了LAR制剂安全性顾虑的信号。”
Likewise, Salares didn't think the new guidance would affect other companies she covers, such as Biodel Inc., which is in Phase III trials with 800 patients to test its injectable rapid acting insulin VIAject, or MannKind Corp., which is developing the inhaled Technosphere Insulin, a product that could show an advantage over the currently marketed inhaled product, Exubera, because of its reduced antigenicity and a lower hypoglycemia risk.
同样，Salares认为新的指导不会影响她关注的其他公司如Biodel公司，在三期临床试验的800名患者中测试了他们的速效胰岛素VIAject，或Mannkind公司，正研发吸入型胰岛素，因为降低了抗原性和血糖过低的风险，可能优于市售的同类产品Exubera。
But an inhaled product making it to market does not necessarily mean a windfall for MannKind, as Exubera's developer Nektar Therapeutics Inc. discovered. Analysts originally expected the product to reach $2 billion in sales five years after launch, eventually cannibalizing injectable insulin, but patient adoption of the new technology has been slow and sales were about $274 million in 2007, with 69 percent going to Nektar, leaving partner Pfizer Inc. with little to show for its efforts. The pharmaceutical company backed out of its deal last fall.
但吸入型产品推向市场并不意味着Mannkind像Exubera的研发者Nektar那样会大发横财。分析师最初希望该产品上市5年内销售额能达到20亿美元，最终替代注射型胰岛素，但该新技术在患者中的应用迟缓，2007年年销售额仅2.74亿美元，其中69%归Nektar所有，留给搭档辉瑞的寥寥，不足以体现其付出。去年秋天制药公司退出合约。
Indicating a trend by pharma to step away from non-injectable therapies, two other pharmaceutical companies, Eli Lilly & Co. and Novo Nordisk A/S dropped support of inhaled diabetes therapies AIR, from Alkermes Inc., and AERx iDMS, from Aradigm Corp. As a result, Generex Biotechnology Corp. has watched its stock decline by more than 30 percent to under $1.
另两家制药公司礼来和诺和诺德也放弃了他们的吸入剂产品，Alkermes的AIR技术和Aradigm的AERx iDMS技术，暗示了制药业放弃了非注射给药的疗法。结果，Generes生物技术公司看到自己的股票跌了30%多，低于1美元。
That company issued a press release in mid-March reiterating its belief that pharma's rejection of inhaled diabetes therapies only gives Generex a competitive edge with its own oral insulin flagship product, Generex Oral-Lyn, which is in Phase III studies and was approved in India last October.
该公司3月中旬发布了一项声明，重申他们相信制药公司放弃糖尿病吸入疗法只会造就该公司口服胰岛素旗舰产品，Generex Oral-Lyn的竞争优势，该药处于三期临床试验，并于去年十月在印度获得批准。
Navdeep Jaikaria, an analyst with Rodman & Renshaw, said in a research report, which seemed to boost the company's stock (NASDAQ:GNBT) slightly, that negative news of companies developing inhalable insulin has placed \"unwarranted pressure on the shares of Generex.\" If anything, he said, their loss is Generex's gain, as safety issues with inhalable insulin only pave the way for an oral therapy as a viable alternative to injectables.
Rodman& Renshaw的分析师Navdeep Jaikaria在一个研究报告中说，吸入型胰岛素的研发公司的负面消息给Generex的股价带来了不可预测的压力，该报告似乎推动该公司的股票略有上扬。如果有什么影响的话，他说，他们的损失正是Generex的收获，因为吸入型胰岛素的安全性顾虑正为口服治疗成为注射剂唯一替代品铺平了道路。
It is unclear whether any of the inhalable insulin companies would face costlier trials to get their products approved because the FDA's draft guidance is vague in referring to \"safety issues.\" There are observations, however, that inhaled insulins lead to a decline in lung function, and there are formulation problems, Jaikaria said, with converting insulin into an inhalable powder. Oral-Lyn delivers insulin through the oral cavity and leaves no deposit in the lungs, the company has said.
还不清楚吸入型胰岛素的研发公司为求产品获批是否会面对成本更高的试验，因为FDA的指导草案中提及“安全性问题”时还含混不清。
Another diabetes therapy in limbo is Novartis AG's drug Galvus (vildagliptin), a DPP-4 inhibitor, which is on hold in the U.S. It was approved in Europe in February with a revised label due to an imbalance in liver enzyme levels seen in patients taking the higher dose. Januvia (Merck & Co. Inc.) is the only DPP-4 inhibitor on the market, but several companies, such as AstraZeneca plc, Bristol-Myers Squibb & Co. and Takeda Pharmaceuticals, are working in the space.
另一个深陷困境的糖尿病治疗药物是诺华的Galvus，DPP-4抑制剂，目前在美国被驳回。在欧洲今年1月诺华修改了标签后得到批准，因为该药在服用高剂量的患者中引起了肝药酶的紊乱。默克的Januvia是目前唯一市售的DPP-4抑制剂药物，但其他公司如阿斯利康、百时美施贵宝和Takeda也涉足该领域。
Published March 31, 2008
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