Dextromethorphan Hydrobromide Hydrate

//  从1期临床至上市成功率仅有5.9%的CNS药物，AI为其开辟了新机遇，包括难以在CNS领域应用的靶向疗法。“知识驱动的常规药物研发模式在CNS领域遭遇瓶颈期，加之过去15年积累的疾病组学和药物临床大数据，因而给予了数据驱动CNS药物研发新契机。”普百思生物创始人包杨欢如是分析。利用AI驱动CNS疾病研发，目前国内外均已有企业布局，且已有部分成果出现：一是从已有研究数据中筛选和验证老药的新途径，预测药物联用组合的疗效和副作用；二是发现新靶点和新机理；三是为特定患者亚群匹配更可能有效的药物。筛选生物标志物多年的基因组和遗传学研究表明，除了ALS、亨廷顿病、家族性AD等只有少数几种亚型，大部分CNS疾病的风险基因有上百个，每个都对发病产生一定程度的贡献，且各致病基因间相互关系并不清楚。这也意味着，类似针对“驱动基因”的肿瘤靶向疗法在CNS领域很难推广开来，给CNS疾病新机理的开发增加了更多难度。但也正是各类CNS疾病之间存在很强的关联性，底 层生物学致病机制存在相通之处，包杨欢认为，CNS药物研发应着重靶向这些机制，即CNS疾病的“靶向疗法”。连接这些疾病的底层机制是什么？包杨欢做出解释。普百思创始人 包杨欢在中枢神经上游的压力应激、神经免疫炎症和下游的神经突触损伤三个通路中，各类疾病都存在相同之处，例如抑郁症、精神分裂、双向情感障碍、阿尔茨海默病等疾病，压力激素失调、神经免疫炎症指标偏高、神经突触损伤导致的认知受损，在相当一部分患者中能检测出来，这正是“靶向疗法”瞄准的精准亚群。以“房屋着火”解释三个通路的原理。“房屋着火”时，最明显标志是中游的“火焰”，这是目前研究较多的方向，例如精神类药物靶向的神经递质和AD药物靶向的错误折叠蛋白。而如果只针对火焰，可能暂时扑灭，但无法完全解决问题。上游没被熄灭的“火源”（应激和炎症）容易复燃，下游对房屋造成的损伤没被修复（突触、神经、髓鞘损伤），疾病也不能完全被治愈。以神经突触损伤通路为例。当突触功能损伤后易导致认知功能障碍，斯坦福大学研究人员在重度抑郁症（MDD）中发现一类认知受损亚群，占MDD患者约27%，且对常规治疗反应不佳。该领域中已有企业开启研究，Alto Neuroscience公司的ALTO-100就是治疗以神经认知损伤为特征的MDD患者。由此也体现出生物标志物筛选的重要性，富集出与有效药物发挥疗效相匹配的亚群。富集用药人群越精准，临床获益越好。ALTO-100的2a数据显示，单药治疗时，81%神经认知受损的患者获得临床应答，而一般患者只有38%。另一款以脑电生物标志物为特征的ALTO-300，其2a期临床试验发现，通过生物标志物识别的患者与无生物标志物的患者，两者的临床缓解分别是47%与27%。而生物标志物的应用并非一帆风顺，但在不断研究中也给临床进展不顺的项目带来了希望。索元生物2017年从BMS引入治疗难治性抑郁症的DB104后，历经3年至2020年才发现生物标志物DGM4。在DGM4阳性的病人中，DB104的抗抑郁效果极为显著。用于治疗重度抑郁症（MDD）的zelquistinel同样充满波折，产品最初由Naurex发现，后辗转经过艾尔建、艾伯维，最后被Gate Neurosciences引进，目前已经完成了多项1期脑电图生物标志物研究，将在2a期临床中利用EEG生物标志物平台，深入探索产品对MDD亚群的疗效。挑战老药新用相比针对精准亚群的靶向疗法，“老药新用”研发策略是更多CNS企业选择的开发思路。事实上，很多老机制老靶点只是在临床阶段被研究多年，并未上市，只是科学研究意义上的“老”。例如KarXT中的组分xanomeline，最早于上世纪90年代开发，因不良反应被放弃，2018年才被Karuna重启与trospium组成复方制剂。包杨欢认为，未来5~8年有可能上市的新药将还是这些“老面孔”。老药新用是建立在过往几十年积累的大量试验数据和临床经验基础上，寻找有初步疗效数据的老靶点、老分子的机会。另外，鲁白教授和管小明博士共同创立的福贝生物，在与英矽智能2021年达成的AI平台合作中，也采用了老药新用策略。由英矽智能PandaOmics平台开发的FB1006，已启动IIT并完成64例患者入组。拓展阅读中国新药猎手｜遇见鲁白（上）中国新药猎手｜遇见鲁白（下）英矽智能：AI全程推动研发的样本根据普百思的统计，2019年至今，已有6款老药新用获批的CNS药物（见下表）。如，治疗产后抑郁症（PPD）的zuranolone由四氢孕酮改良而来，先改良为注射液brexanolone于2019年获批，后再制成口服制剂zuranolone于2023年批准上市。zuranolone是老药新用中微改良的典型案例。另一种常见模式是联用，受访两位专家也更看重联用方式。阿斯诺来创始人周显波谈到，老药的联用主要解决两类问题。一类是利用其中一个药物解决另一个药物的缺陷和副作用。例如被BMS收购的KarXT，是利用trospium缓解蕈毒胆碱M1/M4受体双激动剂xanomeline的毒副作用，1期临床数据显示加入trospium后确实能使药物副作用下降46%。另一款药物Axsome的Auvelity，是利用安非他酮解决右美沙芬的代谢问题，提高右美沙芬的生物利用度。阿斯诺来创始人 周显波另一类是两个药物协同发挥作用。AMX0035是苯丁酸钠+牛磺酸二醇两个组分联合的老药，两款老药获批多年，因此安全性已获得验证，联合后发现产品能改善线粒体功能和内质网的健康状态、延缓神经细胞死亡，在ALS治疗中看到积极疗效，从而获得FDA批准。“联用效果更好的原因是，CNS疾病具有致病位点多、患者异质性高的特点，同时靶向多个位点的药物或者不同机制的药物联用，往往效果更好，副作用更小，复发率更低。”包杨欢如是解释。而两款老药如何在增加疗效同时减少副作用，发挥协同效果，是周显波谈到的老药新用在实际研究过程中遇到的挑战之一。例如近期AMX0035被宣布3期验证性研究失败，开发公司Amylyx表示将撤市该产品。拓展阅读Relyvrio失败对渐冻症药物试验设计的启示另一项挑战是专利问题，包括如何获取老药专利，以及联用后的新组合药物的专利保护问题。包杨欢认为，很多人把老药等同于没有专利保护，事实上国际已上市的老药新用都有一整套IP保护策略，也就是说，其他公司很难在近期简单仿制。新趋势：表型筛选目前进入临床阶段的大多数企业还是从老机制、老靶点出发，但总有企业致力于寻找新机理、新靶点，并在原始创新途中获得关注和机遇。成立于2015年的AI药物发现公司Verge Genomics，就不断获得MNC青睐：2021年与礼来达成价值近7亿美元的合作，共同开发ALS创新疗法；2023年9月，与阿斯利康的罕见疾病部门Alexion建立高达8.4亿美元的合作，寻找和验证不常见的新药物靶点。不仅如此，礼来和默克还参与了Verge近1亿美元B轮融资。吸引MNC不断加码的是Verge的ConVERGE平台，其特点是利用机器学习直接分析源于人体组织的基因组数据以发现新兴靶点，而不是动物模型数据。首个研发产品VRG50635创新性靶向PIKfyve，是治疗ALS的潜力靶点，可恢复ALS患者神经元的内溶酶体功能，并在ALS相关运动神经元变性模型中的多项临床前研究中显示出疗效，2024年1月启动了1b期概念验证研究。从Verge身上能看到，致力于新靶点的CNS药物研发还存在潜力和机遇。同时，国内的原始创新企业也在冉冉升起。国内企业中，卓凯生物的05061是全球首个抑制遗忘分子Rac1活性的阿尔茨海默症新药，通过果蝇表型筛选平台以表型筛选的方式研发而来。阿斯诺来引进的AN1001同样是通过表型筛选而来，是全球唯一口服通过肠道分布GPCR靶向迷走神经的多肽药物，2022年已在澳洲完成1期临床。据周显波介绍，AN1001是通过迷走神经脑肠轴起效，因此能避开血脑屏障阻碍，1期临床结果显示，产品已观察到脑电波量效关系的改变，安全性和生物学活性已得到初步验证。可以看到，卓凯生物和阿斯诺来药物研发的共同特点是通过表型筛选发现新药，也代表了目前CNS药物研发的新趋势。海外进展较快从已公开信息发现，在CNS新药研发应用AI并取得初步积极的临床数据方面，海外企业的进展较快。Alto Neuroscience管线中有6款产品进入临床阶段，其中ALTO-100和ALTO-300已分别在超过200名患者完成临床2a期试验，并均推进至2b期。两款均已在2a期研究中取得积极结果，以ALTO-300为例，产品给药后，通过脑电生物标志物识别出的部分患者在抑郁症状上观察到明显的临床改善和更高的缓解率。Neumora Therapeutics公司有4款产品进入临床阶段，其中治疗重度抑郁症（MDD）的NMRA-140已启动3期临床，另一项治疗精神分裂症的NMRA-266，分子机制与艾伯维收购Cerevel的潜力药物emraclidine相同，靶向新型毒蕈碱M4受体。有意思的是，这两家公司均成立于2019年，仅成立4年后已成功推动产品进入临床，且Neumora于2023年在纳斯达克上市，Alto则于近期成功登陆纽交所。产品的快速推进和IPO进度，将为其他CNS开发企业提供参考的样本。编辑 | 姚嘉yao.jia@PharmaDJ.com 总第2081期访问研发客网站可浏览更多文章www.PharmaDJ.com

Pictured: Fractured time and melting clock/Taylor Tieden for BioSpace While the past few decades have seen a focus on treating Alzheimer's disease at the source, which is widely considered to be the build-up of amyloid fibrils and tau tangles, many companies are also chasing the first approval of a drug to treat the related psychosis. Anti-amyloid drugs like Eisai and Biogen’s Leqembi and Eli Lilly’s donanemab represent a leap forward, but many experts say success rates are modest, and Aduhelm, Biogen and Eisai’s first anti-amyloid treatment, was discontinued in January. Against this backdrop, companies are increasingly focusing on symptomatic treatments, said Graig Suvannavejh, a senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas. Using a financial model, Suvannavejh estimated that 35% of Alzheimer’s patients have psychosis. Even discounting patients who may not be diagnosed or have access to treatments, this translates to roughly 1 million patients in the U.S. alone, making for a large market opportunity, he told BioSpace. Unconventional Targets According to ClinicalTrials.gov, there are more than 600 active trials studying interventional treatments for Alzheimer’s disease, but fewer than 30 that focus on Alzheimer’s-related psychosis. Given the lack of options, Alzheimer’s patients who experience psychosis may be prescribed off-label antipsychotics approved for schizophrenia, said Christoph Correll, a professor of psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. Most antipsychotics target the receptors of dopamine and serotonin, neurotransmitters that are common to many processes in the body. Because of this overlap between molecular pathways in the brain and the rest of the body, the drugs can cause side effects like excessive sleepiness, swallowing difficulties and uncontrolled movements. These effects make compliance an issue for Alzheimer’s patients in particular, who are likely on other medications and may be unwilling to tolerate additional side effects, Correll said. Christiana Bardon, a co-managing partner at MPM BioImpact, told BioSpace that the side effects associated with all antipsychotics are a significant complaint. “Patients who need the antipsychotics discontinue the drugs because of the intolerable side effects,” she said, and the dearth of tolerable treatments for Alzheimer’s patients with psychosis is “a huge unmet medical need.” This is particularly true as the prevalence of the condition increases. “We're having more and more patients develop not just agitation but also psychosis,” Bardon said. With this in mind, many companies are working to make better schizophrenia medicines, and some are repurposing these candidates for Alzheimer's-related psychosis. Karuna Therapeutics is developing KarXT for both schizophrenia and Alzheimer’s-related psychosis. KarXT combines xanomeline, which activates muscarinic receptors, and trospium, which prevents xanomeline from affecting muscarinic receptors outside the brain. This combination helps to prevent side effects like nausea, vomiting and diarrhea, according to the company. Having shown positive clinical trial results in schizophrenia, KarXT is now being tested in Phase III trials for Alzheimer’s-related psychosis. Andrew Miller, Karuna’s founder and president of research and development, told BioSpace the company has seen a “broad spectrum of benefits,” in Alzheimer’s patients, including a lessening of hallucinations and delusions and a reduction in aggression and vocal outbursts. Cerevel Therapeutics’ emraclidine also targets the muscarinic pathway. The candidate selectively binds only one type of muscarinic receptor and, like KarXT, affects the balance of neurotransmitters in the brain. Emraclidine is currently in Phase II trials for schizophrenia and is also in development for Alzheimer’s-related psychosis. A third candidate with an unconventional target is Axsome’s AXS-05, a combination of two drugs: dextromethorphan, which blocks NMDA receptors, and bupropion, which increases the bioavailability of dextromethorphan. Originally conceived as an antidepressant, AXS-05 is now in Phase III trials for Alzheimer’s-related agitation. Agitation usually comes across as physical restlessness or aggression, whereas psychosis involves hallucinations and delusion. The two can often overlap in Alzheimer’s patients but cannot be treated alike, Bardon said. “Agitation is the broader subset that we have to address, and then as the disease progresses, psychotic features may emerge as well,” she explained. Clinical Development Considerations A key sticking point when developing drugs for Alzheimer’s-related psychosis is a lack of biological information. “We don’t really know what the underlying biological mechanism of psychosis and Alzheimer’s is,” Correll said. Unlike in Alzheimer’s disease, there are no clear or unique molecular targets for the related psychosis, according to a 2022 article published in Nature Reviews Neurology. Some studies suggest that genes like APOEε4 and SUMF1 may be involved, but these links have not been substantiated. A lack of good animal models compounds this difficulty, hindering basic research, Bardon said. These uncertainties mean that drug-makers have no concrete targets to aim for. Even when repurposing known antipsychotics, companies must cater to older patients, who have different metabolic rates, require more tightly controlled doses and often have lower tolerability, Bardon explained. It is paramount to ensure safe side effect pro especially because older patients are more likely to also be on other medications, she said. Suvannavejh added that it is also imperative in developing these therapies to recruit a patient population that is as homogeneous as possible, whether by age or the severity of their Alzheimer’s disease or psychosis. When it comes to evaluating the endpoints of a trial, placebo effects are a major concern, Suvannavejh said. This is especially true for neuropsychiatric conditions, as patients may be more suggestible than in other disease areas. Companies must ensure that raters, who track patient responses and behaviors, are trained well and follow the same protocols across sites, Suvannavejh said. Finally, when using existing or new antipsychotics to treat Alzheimer’s-related psychosis, physicians must look closely at the trial data. Correll prioritizes safety and efficacy and then looks at the effect size, which he said is an indicator of the study’s strength. He is also keen to explore new mechanisms that can sidestep the rather overused dopamine and serotonin pathways. A drug with a novel mechanism may be worth testing even if it comes with some side effects, Correll said, as it would allow physicians to tackle the issue from new angles. Correll noted three key aspects of clinical trials in this space: testing drugs first on a small scale, selecting sites and patient populations to reflect the actual medical need and performing thorough follow-ups. These precautions inevitably translate to reliable and sound results, allowing physicians and regulatory bodies to make informed decisions, he said. Precedent Needed The increase in drug development in this space is emblematic of a renewed interest in neuroscience overall, Suvannavejh said. Small companies can focus exclusively on specific problems yet pivot when needed. This combination of focus and flexibility allows them to pursue neglected questions, he noted, paving the way for larger companies to take the solutions forward. Frontrunners Karuna and Cerevel have each been acquired by pharma giants, with Bristol-Myers Squibb paying $14 billion for Karuna and AbbVie putting up $8.7 billion for Cerevel in December 2023. Despite the increased activity, regulatory guidelines are still being established in this space. Although the FDA is working closely with companies, Miller said there is room for improvement. “I think having more clarity and understanding when you work with [regulators] is really important,” he said. Miller looks forward to seeing the first drug approval for Alzheimer’s-related psychosis. “It would establish a clear clinical trial and endpoint precedent,” he said. “I think it would also, importantly, be an example of success.” Sruthi S. Balakrishnan is a freelance academic editor, science writer and fact-checker based in Santa Barbara, California. She can be reached at sruthisb@sciscriber.com.