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YACOO:AD领域蒙阴影——安斯泰来终止$7.6亿研发合作
2014-10-20
来源:转载自第三方
导读:阿尔茨海默氏症(AD)一直是新药研发的重灾区,据PhRMA统计,1998-2011年,13年中新医药研发战绩3胜101败,满满都是失败的惨淡景象。强生/辉瑞和礼来投资超$10亿的单抗均在III期失败,在AD领域是非常沉重的打击。但业界从未放弃。目前,BACE抑制剂已取代单抗站在了AD新药研发的舞台中心,默沙东是该领域的领导者,其BACE抑制剂MK-8931首批III期数据将于2017年获得。礼来今年9月又投5亿美元,押注阿斯利康BACE抑制剂AZD3293,该药成功几率仅9%。然而,安斯泰来近日终止一份高达7.6亿美元的AD研发协议,为BACE抑制剂研发领域蒙上了一层阴影。
安斯泰来(Astellas)近日宣布,终止与CoMentis长达6年的阿尔茨海默氏症(AD)研发合作协议。双方于2008年签署了一份高达7.6亿美元的协议,开发和商业化β-分泌酶(BACE)抑制剂用于AD的治疗。该协议包括一笔1亿美元的现金和股权投资以及6.8亿美元的里程碑款项。
安斯泰来表示,终止合作的决定,是基于该项研发合作所取得的成果,但未详细说明。CoMentis公司网站上列出了其主导产品——口服小分子BACE抑制剂CTS-21166(ASP1720),但定义为“机密”状态。CTS-21166旨在抑制β-淀粉样蛋白(Aβ)片段在大脑淀粉样斑块中的累积。据报道,该产品已在2项I期临床研究中取得了可喜的结果。在2008年公布的一项I期研究中,CTS-21166以高达225mg剂量静脉注射AD患者体内时,表现出了良好的安全性,数据表明,在一段延长期内,血浆β-淀粉样蛋白(Aβ)水平呈现剂量依赖性降低,显著抑制血浆Aβ持续超过72小时。在2012年公布的另一项I期研究中,口服200mg CTS-21166也取得了相似的研究数据。此外,在一项为期6周的小鼠实验中,AD小鼠模型大脑中Aβ水平降低了1/3。
CoMentis公司给出的理由是,可通过血脑屏障的BACE抑制剂有望能够阻止AD疾病的进程。CTS-21166针对的是AD的根本疾病机制,有望成为首个AD疾病修饰疗法。然而,该化合物并未出现在安斯泰来更新的管线药物名单中。安斯泰来于8月1日更新了列表,上面只列出了其内部研发的一个AD化合物——ASP3662。
BACE站在AD研发舞台中心
阿尔茨海默氏症(AD)的特征是,淀粉样蛋白斑块(由β淀粉样蛋白组成)在大脑中积累。BACE是与β淀粉样蛋白形成相关的蛋白酶,抑制BACE有望阻止淀粉样蛋白斑块的形成,并最终减缓疾病的进展。
2年前,强生和辉瑞的单抗药物bapineuzumab以及礼来的单抗药物solanezumab均在III期临床惨遭失败,这2种药物研发投入均超过10亿美元,在AD新药研发领域,是非常沉重的打击。而BACE抑制剂是另一种很有前途的新方法,已取代单抗药物站在了阿尔茨海默氏症药物研发的舞台中心。当前,默沙东(Merck & Co)是BACE抑制剂领域的领导者,其实验性药物MK-8931的首批III期临床数据预计将于2017年左右获得。
阿尔茨海默氏症(AD)是一种进行性发展的致死性神经退行性疾病,临床表现为认知和记忆功能不断恶化,日常生活能力进行性减退,并有各种神经精神症状和行为障碍。阿尔茨海默氏症是最常见形式的老年痴呆症,约占老年痴呆症病例的60%-80%。根据阿尔茨海默氏症协会数据,目前全球范围内约有4400万人患有老年痴呆症,每年的医疗费用已达到2000亿美元,鉴于当前AD治疗选择仅限于疗效欠佳的对症治疗药物,AD患者总数预计将在2030年达到7500万,在2050年达到1.35亿,治疗费用更将达到12000亿美元。
目前,市面上仅有5种药物获批用于阿尔茨海默氏症的对症症状,尚无一种药物能够逆转疾病进程,这也造就了巨大的医疗需求以及新药的重磅销售潜力。
AD研发惨淡,不抛弃,不放弃
阿尔茨海默氏症(AD)一直是新药研发的重灾区,据美国药品研究与制造商协会(PhRMA)统计,1998-2011年这13年中,已取消或终止101个新药开发,只有3种药物上市,研发战绩3胜101败,满满都是失败的惨淡景象。已上市的3种新药也仅限于对症治疗。
尽管新药研发路途艰难,但尚无迹象表明,生物医药行业将要放弃阿尔茨海默氏症领域的新药研发。今年9月,礼来(Eli Lilly)又投5亿美元,押注阿斯利康(AZN)成功几率仅9%的AD新药AZD3293,该药也是一种口服β-淀粉样前体蛋白裂解酶(BACE或β分泌酶)抑制剂,正调查用于早期阿尔茨海默氏症(AD)的治疗。
阿尔茨海默氏症领域的诸多挫折确实令很多人失望,包括开展研究的科学家,但这些不成功的尝试却是至关重要的垫脚石,帮助推动对这种极其复杂疾病的认识,同时也在帮助重新定向研究,提供新的线索,让科学不断向前迈进。(生物谷Bioon.com)
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英文原文:Astellas backs out of a $760M Alzheimer's deal with CoMentis
Astellas Pharma has terminated its six-year collaboration with CoMentis to develop and commercialize beta-secretase inhibitors for Alzheimer’s disease, the companies said—a partnership that had been expected to generate up to $760 million for CoMentis.
Astellas said its decision came “based on the outcome of the research and development collaboration,” without elaborating. The pharma giant said it recognized impairment losses on other intangible asset of ¥8.1 billion (about $59.5 million) in the first three months of the company’s current fiscal year, which began April 1.
CoMentis’ website lists the status of the company’s lead product, identified only as “BACE inhibitor” as “confidential.”
That product, CTS-21166 (ASP1720), was reported to have shown promising results in two Phase I trials. In one such trial, for which findings were published in 2008, the oral small-molecule BACE inhibitor was reported to be safe when injected intravenously into Alzheimer’s patients with doses as high as 225 mg. Results showed a dose-dependent reduction of plasma beta-amyloid (Aβ) levels for an extended period of time, with significant inhibition of plasma Aβ persisted beyond 72 hours.
Similar results were obtained from a second phase I trial on subjects receiving an oral liquid solution of 200 mg CTS-21166, for which results were published in 2012. A six-week trial in 13-month-old transgenic mice with Alzheimer’s showed a one-third reduction in brain Aβ—though chronic dosing produced no detectable change on myelination in peripheral nerves.
CTS-21166 was designed to inhibit the accumulation of Aβ fragments into plaques within the brain. The fragments are made through the cutting of larger proteins called amyloid precursor protein (APP) by two enzymes, the enzyme BACE and γ-secretase. CoMentis reasoned that inhibition of BACE through compounds that could pass the blood-brain barrier could stop the progression of Alzheimer’s.
“CoMentis’s approach of BACE inhibition targets the underlying disease mechanism and has the possibility of being one of the first disease-modifying therapies for Alzheimer’s disease,” CoMentis states on its website.
However, the compound had not appeared on Astellas’ updated lists of pipeline drugs. In an updated listing of its R&D pipeline as of Aug. 1, Astellas lists only one Alzheimer’s compound—ASP3662, developed in-house.
Under their deal, announced in April 2008, Astellas agreed to pay CoMentis $80 million upfront, plus a $20 million equity investment; the pharma giant bought CoMentis’ Series D preferred stock. CoMentis was eligible for up to $660 million in payments tied to development milestones, plus commercialization milestone payments.
CoMentis also received the right to development milestone payments for next-generation beta-secretase inhibitors discovered under the research collaboration. Astellas also agreed to fund 100% of the pre-Phase III global development costs, with CoMentis sharing Phase III development costs.
In return, Astellas won exclusive worldwide commercialization rights to CTS-21166, while CoMentis retained the right to co-promote the drug in the U.S., where the companies agreed to share profits. The companies also agreed that CoMentis would receive royalties on sales outside the U.S.
The memory-robbing ailment has long eluded drug discovery efforts, with the failure rate for experimental treatments between 2002-2012 an astounding 99.6%, researchers at the Cleveland Clinic Lou Ruvo Center for Brain Health and Touro University Nevada College of Osteopathic Medicine reported in “Alzheimer's Disease Drug Development Pipeline: Few Candidates, Frequent Failures,” published online July 3 in the journal Alzheimer's Research & Therapy.
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