Prasinezumab

A protein called alpha-synuclein that accumulates and ravages the brains of some people with Parkinson’s disease is the target of several experimental drugs. Until recently, the only way to detect it was by opening someone’s brain when they died. That’s starting to change. Amprion, a 30-person biotech based in San Diego, has developed a way to detect small amounts of alpha-synuclein from spinal fluid. A study published last year in The Lancet Neurology suggests the method could help confirm suspected diagnoses and even predict Parkinson’s before common symptoms arise. And now Amprion is scaling up to commercialize the test. CEO and co-founder Russell Lebovitz told Endpoints News in an exclusive interview that Amprion has raised $6 million in the first portion of its Series B, which will help it hire 15 more employees and expand its salesforce and operations throughout the US. The round was led by Formation Venture Engineering, with participation from Eli Lilly. Lilly’s interest is notable because the pharma company helped pioneer the use of diagnostics to detect amyloid in the brains of people with Alzheimer’s disease. The drugmaker is also developing drugs for Parkinson’s, and the company’s scientific leaders have mentioned alpha-synuclein as an area of interest for future neurodegenerative research at the company. “They have recognized, as have a lot of the drug companies, that this is going to be important in the future,” Lebovitz said. The technology underlying Amprion’s test was forged in the early 2000s in the aftermath of the mad cow disease crisis. Claudio Soto, a biochemist and professor of neurology at the UT Health Houston McGovern Medical School in Houston, developed a way to detect prions, the misfolded proteins that cause bovine spongiform encephalopathy in cattle and Creutzfeldt-Jakob disease in humans. The infectious proteins cause natural versions of the proteins to misfold, leaving tainted and toxic prions in their wake as they spread through the brain. That natural amplification formed the basis of Soto’s test. He added highly purified and properly folded proteins to spinal fluid or blood from a patient suspected of having the disease. If prions were present in the sample, they would quickly convert the normal proteins into diseased ones. He compared the method to PCR, the technique used to make many copies of DNA for easier sequencing. Soto formed a startup with Lebovitz in 2007 that aimed to refine the technique, now dubbed a seed amplification assay. The mad cow crisis abated, but the duo believed the technique would be valuable to help detect other misfolded proteins, such as amyloid and tau in Alzheimer’s and alpha-synuclein in Parkinson’s. The first ten years were slow going. The test originally took nearly two weeks to run, but they got it down to 20 hours. And a fluorescent dye that only lights up in the presence of misfolded proteins made the results easy to interpret. The tests are currently run out of its CLIA-certified lab in San Diego. The company is developing a simplified kit of the test that other labs can run, and hopes to submit it to the FDA in about 18 months. By 2019, Amprion had developed an alpha-synuclein test for Parkinson’s that it believed would be scalable. The company raised a $13.7 million Series A over the next three years and began offering the test to doctors at major medical centers and research institutions in 2023, Lebovitz said. The study published last year revealed that the test had a sensitivity of about 88%, meaning that about 12 in 100 people with Parkinson’s had a false negative result. Among the 1,100 healthy volunteers, the test had a 97% specificity, meaning about 3 in 100 people without the disease had a false positive. The test performed more poorly for certain subsets of Parkinson’s disease, including those with mutations in the LRRK2 gene linked to the disease. Drugmakers and regulators alike are increasingly turning to biomarkers to decide which patients to include in a clinical trial and how to assess whether the drug is working. In August, the FDA issued a letter of support encouraging “further study and use of” seed amplification assays for alpha-synuclein. Amprion has worked on similar amplification assays for amyloid and tau, but these tests are still experimental. The company offers clinical tests for amyloid, tau and another brain biomarker called neurofilament using machines sold by Fujirebio. With the new funding, Leboviz said “we can hit every major medical center doing cognitive and motor disorders in the US.” He’s hoping to raise another $9 million in the Series B round this year to help the company open a lab in Europe. But Amprion’s efforts to scale up come at a challenging time. About two weeks ago, an investigation published in Science cast doubt on several research papers supporting the role of alpha-synuclein in Parkinson’s disease. More than 130 papers published by National Institutes of Health neuroscientist Eliezer Masliah had “suspect images,” including doctored and duplicated results, according to the report. Some of the questionable studies were cited as evidence underpinning the alpha-synuclein-targeting antibody prasinezumab, which is being developed by Prothena Biosciences and Roche. Lebovitz said that other scientists have consistently demonstrated alpha-synuclein’s role in Parkinson’s and other neurodegenerative diseases irrespective of Masliah’s studies. “None of Amprion’s data relies on any work ever performed or published by Eliezer Masliah,” Lebovitz said. “We have never met with Dr. Masliah, and he has never provided any advice or other counsel.”

9月26日，美国国立卫生研究院（NIH）发表声明称，已经发现下辖机构国家衰老研究所（NIA）的神经科学主任Eliezer Masliah博士论文造假。NIH表示造假的发现涉及Eliezer Masliah博士合著的两项研究中的图像。目前Eliezer Masliah已经不再担任神经科学主任，由副主任履职。 Eliezer Masliah的履历和背景 Eliezer Masliah博士是在2016年加入NIH的附属机构NIA的。 2016年其实是个很微妙的时间点，这是奥巴马政府的最后一年，而因为阿片药物泛滥，当时美国国会通过了一项叫做《21世纪治愈法案》的生物制药相关法案，这一法案旨在减少药物滥用，并拨款给老年痴呆症和癌症的相关基础研究（所谓的“癌症登月计划”就包括在其中）。为了筹足这一法案的宣称的48亿美元经费，甚至削减了35亿美元奥巴马政府当时试图推出平价医疗法案经费并出售10多亿美元战略石油储备。（石油：？？？） 因此大量资金注入了阿尔兹海默症的相关研究，而Eliezer Masliah博士就是在这一背景下受聘加入NIA的。该部门的预算占到了惊天动地的26亿美元，可以说让其他NIH部门的经费总和都相形见绌。 加入NIA后，Eliezer Masliah博士就担任NIA主任Richard Hodes的首席顾问兼联邦领衔大使，以及神经科学主任。不过从当时来看，聘用Masliah博士看起来没什么问题。 Masliah博士是神经科学领域的大牛，他最初于1982年墨西哥国立自治大学，1986年，他在墨西哥城国立卫生研究院完成了病理学的研究生住院医师培训。在那里他娶了一位也在UNAM大学学医的美国居民。 图：Eliezer Masliah 来源：NIH官网 在加州大学圣地亚哥分校(UCSD)获得神经病理学和神经退行性疾病奖学金后，他就一直留在那里担任了几十年的加州大学圣地亚哥分校（UCSD）医学中心的神经科学教授和尸检服务主任，他是一位高产的作者，大约贡献了阿尔兹海默症和帕金森领域800篇研究论文，是所在领域被引用最多的科学家。（下图为Science给出的被引用情况） 300页的档案，132篇论文存在问题 根据NIH的阐述，NIH会将他们的发现递交给两家期刊，让他们采取正确行动。在NIH发表声明之际，Science发表的文章应证了这一点。 Science的文章显然比NIH简短的声明更加具体，而Science方面由外部专家撰写的指控就不单单是两项研究了，他们出具了一份300页的档案。 档案中，他们详细阐述了1997年至2023年期间发表的132篇研究论文中对可疑图像的指控，其中一些论文在许多药物的早期开发中发挥了作用，而这些论文是由Masliah合著的。 在与Science交谈之前，档案的合著者实际并不知道NIH方面的调查，他们强调自己并没有指责Eliezer Masliah或其同事欺诈或行为不端。 他们当时表示，已识别出的一些图像问题可能只是简单的错误，而在为出版准备图像时，一些图像可能会获得看似不正当变动的其实没什么大不了的视觉伪影。区分这两者有时需要与原始的高分辨率图像和其他数据进行比较，而档案材料的作者并不具备这些条件。虽然有些伪影确实很难区别，但他们表示，还是值得进行正式调查的。 可直到调查后，他们才被调查内容惊掉了下巴。 令人震惊的是，大多数可疑的工作都无法合理解释为粗心大意的错误或出版异常，西奈山阿尔茨海默病研究中心主任、著名神经学家Samuel Gandy表示，就连公交车司机都看得出来发表于不同主题文章，不同期刊的线粒体图像是同一张图复制黏贴。 而令人担忧的，还不只是学术造假那么简单，一些在研管线也因为这次造假风波受到了波及。 涉及罗氏管线 Masliah的研究有助于获得美国食品药品监督管理局（FDA）对一种名为prasinezumab的抗体进行帕金森病临床试验的批准。这种药物由Prothena公司开发，还是和罗氏共同开发的合作项目，旨在靶向α突触核蛋白（α-syn）来治疗帕金森。 2022年NEJM上发表的300人作用样本临床表明，这种抗体似乎效果和安慰剂差不多，患者还有额外的头痛恶心等副作用。 虽然临床效果甚微，目前罗氏还想要依靠次要终点的运动症状评分改善为方向进行开发。 考虑到之前FDA的前争议神经科学部门负责人Billy Dunn（之前力排众议批准Aduhelm）加入了Prothena公司董事会，这可能就让人怀疑prasinezumab是否想要依靠Billy Dunn的旋转门关系推动上市了。毕竟Prothena公司财力雄厚，根据Q2财报，账上有5.65亿美元现金及其等价物。 参考来源： https://www.science.org/content/article/research-misconduct-finding-neuroscientist-eliezer-masliah-papers-under-suspicion#sidebar https://apnews.com/article/misconduct-alzheimers-parkinsons-research-nih-297a61dc69cb18965015381a911197ec