2014-11-18国际、国内临床信息汇总

诺华心衰药物LCZ696临床三期数据积极

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发布日期：2014-11-18  来源：生物谷  

心脏病一直以来都是人类健康的心腹大患。这类疾病最为恐怖的一点就是其发病的突然性往往会令患者及其家人措手不及。最近诺华公司宣布公司开发的治疗心衰药物LCZ696临床三期数据却着实令诺华高层实实在在的心跳加速了一把。

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根据临床三期研究显示，这一药物能够明显降低患者对紧急救助的需求。研究人员介绍，相对于对照组依那普利（一种ACE拮抗剂），LCZ696将患者因心脏病发所的死亡风险降低了约20%。而这一点也是分析人士和厂商衡量一种心脏病药物年销售额时的重要参考标准。此外，实验组患者的急诊室救助率降低了30%，总住院率降低了16%。同时患者在家进行几种治疗的比例也有明显降低。尽管LCZ696治疗的患者和接受依那普利治疗的患者疗程时间基本相同，但是在这一治疗过程中实验组患者接受集中治疗和接受静脉注射增进心跳药物的比例更低。这一点无疑对患者和医院来说都是个好消息。

LCZ696的有效成分主要是缬沙坦和AHU-377，这两种成分都能够直接阻断一种名为脑啡肽酶的血管紧张肽受体。这也是诺华公司心脏病研发部门继serelaxin研发失败后的又一力作。可以说公司上下都对其寄予厚望。公司将这一药物的研发分为两个部分，其一是在美国心脏学会进行的关于促进心衰患者心脏正常收缩和舒张的研究；其二是研究这一药物对心肌的紧张和松弛的研究。

市场普遍认为这一药物一旦能够上市将使诺华公司在心衰患者群体中建立明显优势，公司预计LCZ696的年销售额峰值可能达到50亿美元之多。

详细英文报道：

Novartis execs all the way up to CEO Joe Jimenez have already expressed just how delighted they are in the Phase III efficacy data that's been emerging about the heart failure drug LCZ696. This afternoon, their enthusiasm in the would-be "multiblockbuster" was supported by the addition of some promising pharmacoeconomic data--particularly in cutting the need for acute care.

Investigators have already noted a 20% reduction in the risk of dying--the key measure behind a full slate of upbeat peak sales estimates. The pharma giant's ($NVS) biggest challenge now is living up to some heady expectations. And today we learned that there was also a 30% dro in ER visits, a 16% overall slide in hospitalizations as well as a significant reduction in the need for intense therapy at home when compared to patients taking the ACE inhibitor enalapril.

When hospitalized, Novartis reported, "LCZ696 and enalapril patients remained under care for approximately the same time, but those on LCZ696 had 18% fewer stays in intensive care and were 31% less likely to need IV drugs to help their heart pump. Patients' reports of how well they felt and doctors' assessments of disease severity were also significantly better with LCZ696 than enalapril."

Add it all up, says David Epstein, division head of Novartis Pharmaceuticals, and there's a growing body of evidence that this drug can "reduce or slow the decline in their heart function, potentially altering the progression of their disease." The new numbers are being reviewed at the annual meeting of the American Heart Association (AHA).

Novartis needs all the upbeat pharmacoeconomic data that it can get on this drug. The company has to put significant clinical distance between its new treatment and the cheap generic enalapril. Analysts estimate that Novartis could charge $7 a day for LCZ696--more than many people's copay for a month's worth of generics.

Designed to be taken twice a day by a massive group of patients suffering from chronic heart failure, the treatment is a dual-acting angiotensin receptor-neprilysin inhibitor, taking a one-two punch with valsartan and AHU-377. AHU-377 blocks a mechanism of action that threatens two peptides responsible for lowering blood pressure while valsartan improves vasodilation, spurring the body to excrete sodium and water.

LCZ696 has been living up to its rep as the next big thing in Novartis's cardiovascular pipeline--a big factor in getting over the profound disappointment caused by the failure of serelaxin with regulators.

"I've done many trials, and you just don't get things that look like this," says principal investigator John McMurray, a professor at the University of Glasgow. "Every single measure we looked at, we did something good."

The clinical work for this drug is being divided into two basic segments, says McMurray. This first part covered at the AHA involves prompting the heart to contract and empty more normally for heart failure patients. The next step, to be covered in an upcoming trial, will examine its ability to complete another essential task for the heart muscle: relaxation and filling.

An initial approval for this drug would open up a huge and growing market in the heart failure field. But further success has the potential to make this drug a player in the lives of 75% to 80% of the entire patient population, says the investigator, one reason why Novartis execs are estimating peak sales at $5 billion or more.

Investigators had to compare their new drug with a standard of care for patients. But by extrapolating data from enalapril, they found a "really impressive 32%-34% reduction in cardio mortality and a 45%-50% reduction in hospitalizations."

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安进Humira仿制药ABP501临床三期研究成功

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发布日期：2014-11-18  来源：生物谷  

安进公司最近公布了其关于仿制药安全性和有效性评价的临床三期研究数据，引起了生物医药界的广泛关注。

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安进公司开发的这一药物ABP501的原版药物是艾伯维公司治疗斑块性银屑病畅销药物Humira（adalimumab）。在这项随机双盲对照实验中，研究人员对比了中度-重度患者从接受治疗开始到治疗16周后，ABP501和adalimumab治疗组的银屑病部位和严重程度指数。结果显示达到了预期重点。

同时，安进公司表示ABP501的安全性和免疫原性也和adalimumab相仿。这一研究也是安进公司为为将ABP501提交全球市场管理审核，安进公司设计了两个临床三期研究，此次进行的是第一个临床三期研究。

此次安进公司在加拿大、澳大利亚和欧洲招募了350名患者，随机分为ABP501治疗组(n = 174)和adalimumab治疗组(n = 173)。其中ABP501组的一名患者和adalimumab的两名患者被随机选出并且未接受任何调查药物产品的治疗。安进公司表示对任意患者PASI百分数改善的评估都尽可能由同一观察者得出。

据安进副总裁兼仿制药部门主管Scott Foraker介绍，治疗16周时PASI指数保持在50以上的患者的治疗将自动延长至52周，以收集数据判断研究是否达到次级安全终点。根据Cortellis临床试验情报(CTI)的规定，这其中包括了任何不良反应或严重副作用的发生，实验室评价中的临床显着变化和产生抗药性抗体的明显现象。

在研究中治疗时间超过16周的患者以双盲方式重新随机分组。此前ABP501组患者继续接受药物不变，adalimumab组患者随机按照1：1比例随机分入两组。患者在48周接受最后一次药物治疗，并于第50周进行疗效评价。根据Cortellis CTI规定，这一研究计划于2015年第一季度末完成。

作为抗TNF-α单抗药物，adalimumab在多个国家被批准用于治疗包括风湿性关节炎、斑块状银屑病、幼年特发性关节炎、牛皮癣关节炎、强直性脊柱炎、克罗恩氏病和溃疡性结肠炎疾病在内的多种炎症疾病。而Amgen公司ABP501的第二个临床三期研究就是关于其治疗风湿性关节炎的效果，这一研究目前已经筹备完成并计划于明年完成。据安进公司负责全球仿制药研发的医疗行政总监Richard Markus透露，一旦两个临床三期研究完成，安进公司将会同相关管理机构寻求ABP501的全球上市。

Markus在接受BioWorld Today采访时表示，"我们认为及时为全球股东提供这些研究的相关信息很重要。"同时他还强调了安进公司不单希望给出令管理部门满意的数据，还希望用自己的研究数据吸引处方医生和消费者。

同时Foraker还补充，通过和相关管理部门的沟通，安进公司有信心利用三期研究的数据推动ABP501的广泛批准，而无需像Humira那样逐个获得批准。

安进公司的生物仿制药活性成分是与adalimumab序列相同的抗TNF-α单抗。这一药物的处方形式和强度都与adalimumab保持一致并已获得美国和欧盟的批准。

Foraker表示，这对公司和公司的仿制药部门来说都是令人激动的一天，因为Humira是目前世界上销售额最大的畅销药物。

推荐的英文原文：

Humira is in the Crosshairs as Amgen gets its First Phase III Biosimilars Win

Amgen Inc. put the biopharma world on notice by disclosing positive findings from the first phase III study evaluating efficacy and safety of its lead biosimilar candidate. The randomized， double-blind， active-controlled study of ABP 501， whose reference drug is Humira (adalimumab， Abbvie Inc.)， met its primary endpoint： improving the Psoriasis Area and Severity Index (PASI) within a prespecified equivalence margin， compared to adalimumab， from baseline to week 16 in patients with moderate to severe plaque psoriasis.

Officials at Amgen said the safety and immunogenicity of ABP 501 also were comparable to adalimumab. The study was the first of two phase III trials designed to move ABP 501 into global regulatory submissions.

The phase III trial enrolled 350 patients at sites in Canada， Australia and Europe， randomized to ABP 501 (n = 174) or adalimumab (n = 173). One patient in the ABP 501 group and two in the adalimumab group were randomized but did not receive any investigational product. Amgen said assessments of PASI percent improvement for any given patient were made by the same observer whenever possible.

Patients with a PASI 50 or above response at week 16 will remain on the study for up to 52 weeks so the company can collect data on key secondary safety endpoints， according to Scott Foraker， Amgen’s vice president and general manager of biosimilars. Those include the occurrence of any adverse and serious adverse events， clinically significant changes in laboratory values and vital signs and the incidence of anti-drug antibodies， according to Cortellis Clinical Trials Intelligence (CTI).

Patients who continued on the study beyond week 16 were re-randomized in a blinded fashion. Those initially randomized to ABP 501 are continuing to receive the study drug， while those on adalimumab either continued on adalimumab or switched to ABP 501 in a 1-to-1 fashion. Patients will receive the last dose at week 48， with final efficacy assessments conducted at week 50. The study is expected to be completed at the end of the first quarter of 2015， according to Cortellis CTI.

An anti-TNF-alpha monoclonal antibody (MAb)， adalimumab is approved in numerous countries to treat inflammatory diseases， including rheumatoid arthritis (RA)， plaque psoriasis， polyarticular juvenile idiopathic arthritis， psoriatic arthritis， ankylosing spondylitis， Crohn’s disease and ulcerative colitis. RA is the target of Amgen’s second phase III for ABP 501， with the fully enrolled study also expected to be completed next year. once Amgen has data from both studies in hand， it will seek meetings with regulatory agencies and submit global filings， according to Richard Markus， Amgen’s executive medical director for global biosimilars development.

“We thought it important to satisfy global stakeholders to have some data available in both of these indications，” Markus told BioWorld Today， citing Amgen’s desire to provide a compelling data package not only to regulators but also to payers and prescribing physicians.

based on discussions with regulators， Amgen is confident that it can extrapolate data from the phase III studies to seek broad approval for ABP 501 without having to study “every single labeled indication that Humira enjoys，” Foraker added.

The active ingredient of the Amgen biosimilar is an anti-TNF-alpha MAb with the same amino acid sequence as adalimumab. The drug also has the same pharmaceutical dosage form and strength as adalimumab， as approved in the U.S. and European unio.

“This is a really， really exciting day for us on the biosims team and for the company， in general，” Foraker said. “After all， this is the largest-selling drug in the world right now.”

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辉瑞与默克签订28亿美元合作协议进入肿瘤免疫疗法研究领域

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发布日期：2014-11-18  来源：生物谷

最近辉瑞公司表示已经决定进入肿瘤免疫疗法研究领域并已经和默克公司签订了价值28亿美元的研发协议。

                               
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今年以来，辉瑞公司频频登上生物医药产业乃至金融界的头条。先是今年早些时候宣布准备收购阿斯利康而被后者和英国政府联合送了一张"好人卡"，后来又频频传出准备和阿斯利康再续前缘的消息。甚至就在上周，还有消息称辉瑞公司可能会转而寻求收购Actavis公司。可以说公司在资本市场上十分活跃。

最近辉瑞公司表示已经决定进入肿瘤免疫疗法研究领域并已经和默克公司签订了价值28亿美元的研发协议。其中包括8亿5千万美元的预付经费和高达20亿美元的里程碑资金。这一协议将使辉瑞有资格分享默克公司目前正在开发研究的热门肿瘤免疫疗法药物MSB0010718C以及可能由此衍生而来的其他药物。

同时，默克公司还会协助辉瑞公司进行其自有的抗PD-1药物Xalkori 尽快完成临床前研究进入临床一期研究。作为回报，默克公司在未来可分享这种药物在美国以及其他热点市场的版权。默克公司生物制药部门主管Belén Garijo介绍说，2015年将有20多种肿瘤免疫疗法药物开始研究，而默克公司与辉瑞等公司建立起的全球广泛合作体系将有助于默克公司在这一大背景下占据优势。

而这一协议也创下了合作公司预付经费的新纪录。此前，Celgene公司向Nogra公司支付7亿1千万美元的预付经费以获得其治疗克劳恩氏症药物而被业界看做"土豪中的战斗机"。不过这一协议也使得此前辉瑞公司可能再次收购阿斯利康的谣言不攻自破。因为辉瑞收购阿斯利康公司的一个重要原因就是希望获得其肿瘤免疫药物MEDI-4736。

对于默克公司来说，这一协议同样是一个重要转折点，此前数年公司都一直处于痛苦的研发机构转型阶段中，前不久公司还被迫放弃了进行数年之久的肿瘤疫苗的研发。此次被两家巨头寄予厚望的MSB0010718C在前不久已经完成了治疗m-Merkel细胞癌（一种罕见皮肤癌）的临床一期研究。它主要是通过破坏肿瘤细胞的隐藏机制，使其能够暴露在免疫系统的监控下进而使机体能够快速清除肿瘤细胞。

详细英文报道：

Pfizer ($PFE) is determined to be a major player in the fast-emerging field ofimmuno-oncology, and the pharma giant is paying handsomely to buy its way into an anti-PD-L1 program now underway at Merck KGaA. In a deal announced Monday Pfizer outlined plans to pay a whopping $850 million upfront and up to $2 billion in milestones for the right to co-develop and co-market MSB0010718C and any other IO drugs they put in the pipeline.

This is a broad collaboration on the cancer front for both Pfizer and Merck KGaA. In addition to launching combination studies using their existing cancer therapies, they'll work together to push Pfizer's preclinical anti-PD-1 antibody into Phase I. And Merck KGaA also gets the right to co-promote Xalkori in the U.S. and other "key" markets.

These partners--which both have plenty to prove on the R&D side of the business--won't be wasting any time.

"Up to 20 high priority immuno-oncology clinical development programs are expected to commence in 2015, including pivotal registration studies," noted Belén Garijo, who heads up the biopharmaceutical division of Merck KGaA. "On top of that, the global alliance will enable Merck to gain an early entry into the US oncology market as well as to strengthen our existing oncology business in several other important global markets."

The big upfront part of this deal is rare and may well garner criticism for being too much for Pfizer to pay out at this point. The pact immendiately vaults to the front of the line as the biggest upfront deal payment in the industry, a list that had been topped byCelgene's $710 million payout to Nogra for commercial rights on its Crohn's drug.

This deal may well help douse persistent rumors that Pfizer will make another run at AstraZeneca ($AZN), wher one of the main attractions was an immuno-oncology program for MEDI-4736. Buying into this program would make an AstraZeneca deal, bitterly opposed in the U.K. and now less appealing due to new M&A rules in the U.S., look somewhat redundant. And it will also enhance Pfizer's R&D prospects, which have been limited to a few major efforts, including the cancer drug palbociclib.

The pact also marks a turning point for Merck KGaA, which has been struggling in R&D for years. The company recently decided to terminate an ill-fated second shot at developing a cancer vaccine. And it made some serious missteps in multiple sclerosis earlier. But its decision to enter the hot IO field - which has inspired billions of dollars in deals and rivals emerge to begin competing with the leaders: Bristol-Myers ($BMY), Merck ($MRK), Roche ($RHHBY) and AstraZeneca.

MSB0010718C has finished a Phase I study and is currently in a Phase II trial for m-Merkel cell carcinoma, a rare form of skin cancer. These drugs are designed to dismantle a key mechanism that cancer cells use to stay hidden from the immune system. Merck and Bristol-Myers have already gained pioneering approvals for their lead drugs, and analysts believe that the market will be worth tens of billions of dollars.

Karl-Ludwig Kley, chairman of Merck KGaA in Darmstadt, Germany, stated: "We live up to our promise to strengthen all three pillars of our business: Healthcare, Performance Materials and Life Science. After this year's acquisition of AZ Electronic Materials and the proposal to acquire Sigma-Aldrich, we have now turned the focus on healthcare. The agreement with Pfizer is a very important milestone in taking our pharma pipeline forward."

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