SAINT II 结果显示新药对缺血性中风没有效果


  October 27, 2006 -- 在第三期试验显示治疗组没有显著降低中风相关的失能后,AstraZeneca宣布将不会继续进行研发中新药NXY-059,Cerovive的后续研发 。
  
  该公司在声明中指出「急性缺血性中风NXY-059试验(SAINT II)」的完整结果,即将在2007年于旧金山举行的国际中风研讨会中报告。
  
  SAINT II 是一个随机双盲安慰剂控制试验,试验对象来自31个国家的350家医学中心共计3,200位的缺血性中风病患,主要研究者是Alberta大学的Ashfaq Shuaib,一级结果是以Rankin量表评估降低中风相关失能的效果。
  
  不过,该公司发布的新闻指出,试验中NXY-059与安慰剂的比较并没有达到统计上的显著差异,胜算比是0.94 (P = .33)。
  
  【阻止自由基】
  NXY-059是一种自由基阻止剂,在动物中风模式中显示有神经保护效果;SAINT II的结果是令人失望的,不像发表在新英格兰医学期刊(2006;354:588-600)的SAINT I报告般有正面结果,当时的结果显示,在缺血性中风六小时内以NXY-059治疗,在90天时可以显著改善、减少失能,但是在其它方面,如神经功能,并无显著效果,神经功能系以「国家健康研究中心中风量表(National Institutes of Health Stroke Scale/ NIHSS)」进行。
  
  SAINT I 的事后分析有一项有趣的发现,病患使用 tPA后以NXY-059治疗,转变成出血性脑中风的发生率低 (P = .001), 有症状之颅内出血发生率也低(P = .036)。
  
  SAINT I 试验是首次在神经保护策略方面有正面效果的大型临床试验,以往此类制剂的杰出结果仅只是动物中风模式;在 SAINT I之后,SAINT II的研究对象从1,700人增至3,200人以提升统计的强度。
  
  该产品的全球副总裁Tomas Odergren在公司的声明稿中指出,AstraZeneca不会继续NXY-059在急性缺血性中风的研发,不过,计画对SAINT I 和SAINT II的资料进行综合分析,看看是否有遗漏某些信息。
  
  【强调需要确认】
  杜克大学医学中心的杜克脑血管疾病中心主任、美国心脏学会中风委员会现任主席Larry B. Goldstein医师向Medscape表示,SAINT II的结果显然令人失望,但也并非完全无法预期;本研究也指出次组事后分析 — 例如,降低tPA相关的出血 — 可能使人误解,也知道新治疗的单一试验得到的发现还需要第二个试验来做确认。
  
  哥伦比亚大学的Ralph L. Sacco医师也认为这一新闻不论是对于急性中风治疗和神经保护方面,都令人失望,他向Medscape表示,我们在SAINT I之后是审慎乐观的,知道需要有大型试验来验证,我仍对正确的药物用在适当的中风病患、得到有反应的结果感到乐观,我们在神经保护方面的试验有帮助,但是风险仍高。
  
  道琼新闻网讯昨天报告AstraZeneca's股价因此新闻下挫,在最近抗凝血剂Exanta (ximelagatran)、肺癌药物Iressa和糖尿病药物Galida在试验末期受到重挫后,AstraZeneca现在仅剩下一线之天。
  
  新闻也指出,德意志银行先前预测NXY-059的销售额约为七亿五千万美金,引述德意志银行分析师对投资者所述:此挫败可能促使投资者对末期试验的广度和风险提出质疑。
  
  同样是由AstraZeneca在昨天发布的第三季结果,显示销售上升11% 且每股盈余达34%。

SAINT II Results Show No Benef

By Susan Jeffrey
Medscape Medical News

October 27, 2006 — AstraZeneca has announced that it will not pursue further development of an investigational drug, NXY-059, known as Cerovive, after results of a phase 3 trial showed no significant reduction in stroke-related disability with treatment vs placebo.

In a statement, the company notes that full results from the Stroke Acute Ischemic NXY-059 Trial (SAINT II) will be reported at the upcoming International Stroke Conference in February 2007 in San Francisco.

SAINT II was a randomized, double-blind, placebo-controlled trial of the drug in 3200 patients with ischemic stroke, enrolled from 350 participating centers in 31 countries. Principal investigator was Ashfaq Shuaib, MBBS, from the University of Alberta, Edmonton. The primary outcome was reduction in stroke-related disability assessed by the modified Rankin scale.

However, the trial ultimately fell short of achieving statistical significance with NXY-059 compared with placebo on this primary end point, with an odds ratio of 0.94 (P = .33), the company release said.

Trapping Free Radicals

NXY-059 is a free-radical trapping agent that had been shown to be neuroprotective in animal models of stroke. The results of SAINT II are disappointing in light of positive results seen with the agent in SAINT I, published earlier this year in the New England Journal of Medicine (2006;354:588-600), showing that treatment with NXY-059 within 6 hours of ischemic stroke significantly improved the primary outcome of reduced disability at 90 days, although treatment did not have a significant effect on other outcomes, including neurologic function on the National Institutes of Health Stroke Scale (NIHSS).

An intriguing finding from a post hoc analysis of SAINT I was that, in patients who received tPA, treatment with NXY-059 was associated with a lower incidence of hemorrhagic transformation (P = .001) and of symptomatic intracranial hemorrhage (P = .036).

The SAINT I trial marked the first time that a neuroprotective strategy had shown benefit in a large clinical trial, despite excellent results with many such agents in animal models of stroke. After SAINT I, the enrollment in SAINT II was increased to 3200 from 1700 to increase its statistical power.

"AstraZeneca plans no further development of NXY-059 in acute ischemic stroke," Tomas Odergren, vice president and global product director for the agent, said in the company statement. However, it does plan a pooled analysis of SAINT I and SAINT II data to see what further information might be gleaned, the release notes.

Underlines Need for Confirmation

The result from SAINT II "is obviously disappointing but not entirely unexpected," Larry B. Goldstein, MD, director of the Duke Center for Cerebrovascular Disease at Duke University Medical Center, in Durham, North Carolina, and current chair of the American Heart Association Stroke Council, told Medscape. "It also points out that post hoc subgroup analyses — ie, reduction of tPA-related hemorrhages in the prior study — can be misleading, and findings from a single trial of a putative new therapy need to be confirmed in a second trial."

Ralph L. Sacco, MD, from Columbia University, in New York, also characterized the news as disappointing, both for the field of acute stroke therapy and in particular the concept of neuroprotection. "We were cautiously optimistic after SAINT I but knew that a larger trial was required to substantiate the findings," he told Medscape. "I still remain optimistic that the right drug, in the right stroke patient, using a sensitive outcome, will show benefits in a neuroprotection trial, but the stakes remain high."

Dow Jones Newswires reported yesterday that AstraZeneca's share price dipped on the news. "AstraZeneca is now left with a very thin pipeline after the recent expensive failures in late-stage testing of drugs such as blood-thinner Exanta (ximelagatran), lung cancer drug Iressa, and Galida for diabetes," the newswire report notes.

It adds that analysts at Deutsche Bank AG had previously forecast sales of around $750 million for NXY-059 and quotes Deutsche Bank analysts as saying in a note to investors that "the setback is likely to prompt investors to question the breadth and risk profile of the late-stage pipeline" at the company.

Third-quarter results, though, also released yesterday by AstraZeneca, showed sales up 11% and earnings per share up 34%.

    
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