阿尔茨海默病组合药物（老药新用）

[原文来自：www.ii77.com]

[好文分享：www.ii77.com]

近日，刚刚卸任Voyager首席执行官的Steven Paul正在与一些知名投资者完成一轮4200万美元的投资，支持美国生物技术公司Karuna制药，该公司找到了两种“老药”的新组合疗法，可以尽量减少阿尔茨海默病治疗中不必要的副作用，并最大发挥药物效果。此次投资也吸引了Arch公司、Wellcome信托及其他投资者的参与。作为该轮融资的一部分，Karuna制药正在将2200万美元的债务转换为股权。

此前，Karuna制药一直在利用种子基金以推进其战略理念，其主要项目KarXT是针对毒蕈碱乙酰胆碱受体的临床阶段计划，公司正在研究占诺美林（Xanomeline）与曲司氯铵（trospium chloride）组合在大脑中发挥治疗效果，他们相信该药物组合可以在精神分裂症和阿尔茨海默病治疗中产生显著效果。

Karuna制药研发概念（来自Karuna制药官网）

占诺美林是一种毒蕈碱M1受体选择性激动剂，对M2、M3、M4、M5受体作用很弱，易透过血脑屏障，且皮质和纹状体的摄取率较高，是目前发现的选择性最高的M1受体激动剂之一，并已获美国FDA批准上市。服用该药物后，阿尔茨海默病患者的认知功能和动作行为有明显改善。但因存在胃肠不适以及心血管方面的不良反应，部分患者往往会选择中断治疗。曲司氯铵则是一种季铵盐化合物，又称为毒蕈碱受体拮抗剂，具有抗胆碱作用和解痉作用。

凭借公司投资者Steven Paul早期在礼来公司及中枢神经系统（CNS）领域研究工作的基础，以及Wellcome信托支持下的临床工作，Karuna正在调查新的临床试验数据，以证明其药物组合用于阿尔茨海默病可以获批。

Steven Paul，一位明星级的CNS研究员

过去20年来，神经退行性疾病研究几乎全军覆没。礼来、阿斯利康、强生、辉瑞、罗氏等制药巨头的多个单抗药物均在III期临床惨遭失败，这为阿尔茨海默病的新药研发领域蒙上了厚厚的阴云。

2012年，强生/辉瑞的单抗药物bapineuzumab在III期临床惨遭失败。2014年，罗氏不幸中招，该公司单抗药物gantenerumab在大型III期也以失败告终，其药物旨在清除AD患者大脑中的β-淀粉样蛋白斑块。2016年，礼来广受瞩目的阿尔茨海默病新药solanezumab在III期临床试验中功亏一篑。2017年，默沙东宣布停止开发BACE抑制剂药物verubecestat。2018年，强生宣布终止了BACE抑制剂atabecestat的II/III期研究，礼来/阿斯利康宣布终止口服BACE抑制剂lanabecestat治疗阿尔茨海默病的全球III期项目，包括治疗早期AD的III期研究AMARANTH、治疗轻度AD痴呆的III期研究DAYBREAK-ALZ、AMARANTH的扩展研究。这些无疑均为阿尔茨海默病的新药研发带来了致命的打击。

不过，药企也未曾放弃对该领域药物的研发工作。2016年春季，艾尔建以23亿美元的价格收购了来自Heptares的M1和M4靶向药物，并表示要积极推进该药物的研发进展。2018年6月，..卫材公司宣布决定在美国马萨诸塞州剑桥市成立Eisai Center for Genetics Guided Dementia Discovery (G2D2)，是一个新的专注于基于人类遗传学的免疫-失智症的探索性研究设施，旨在研发失智症领域创新药物。这些又为AD新药的研发带来了曙光。

目前，Karuna制药的主要候选药物具有治疗精神疾病和认知障碍的独特作用机制，此外其非阿片类药物疼痛的治疗效果也令人兴奋，这些适应症都是目前临床需求尚未得到充分满足的领域，因此市场前景巨大。

文章参考来源：

Can two old drugs — including an Eli Lilly flop — make one good treatment for Alzheimer’s? Karuna has $42M to find out

新浪医药编译：范东东

Back when Steven Paul was a star CNS researcher who had jumped to industry at Eli Lilly back in ’93, he boasted of abroad pipeline of intriguing new drugs he was working on — including apromising muscarinic acetylcholine receptor agonist called xanomeline. But that drug, like so many others at Lilly, was scuttled — in this case by the adverseevents triggered by off-target effects.

Today, Paul — who recently stepped down as CEO of Voyager — is investing in a $42 million round with some high-profile investors to back a company that believes it has found a way to make xanomeline work the way they had seen in the clinic, without the onerous side effects that killed the earlier project.

The biotech is Boston-based Karuna Pharmaceuticals, a PureTech venture that has also attracted Bob Nelsen at Arch,along with the Wellcome Trust and some other unnamed investors. As part of theround, the company is converting $22 million in debt into equity.

So what’s the big idea here? 

Karuna has been working with seed money to advance its notion that their combination of xanomeline with trospium chloridecan allow the therapy to do its work in the brain, where they believe it canhave a significant effect as an antipsychotic for schizophrenia and Alzheimer’s disease. Xanomeline targets M1 receptors in the brain, for possible cognitiveand antipsychotic effects, while the old drug trospium chloride (Sanctura) works as a muscarinic antagonist to counter the side effects.

They’ve dubbed the combination KarXT.Karuna is helmed by MIT graduate Andrew Miller, and Paul is chairman of theboard.

Building off of Paul’s earlier work at EliLilly along with the clinical work they’ve done with backing by the WellcomeTrust, they’re shooting for new human data to prove that the crew at Karuna could have the first viable new drug for Alzheimer’s in more than a decade. And that’s one very tall order that has now defeated a long lineup of researchers.

They’re not alone in the field, though.Allergan in-licensed M1 and M4 targeted drugs from Heptares in the spring of2016 in a $3.3 billion deal, interested in pushing ahead here as well. And researchers at Vanderbilt told me a couple of years ago about their own clinical plans. There are others.