编者按:随着神经系统疾病在全球范围内负担的持续加重,人们对有效治疗复杂中枢神经系统(CNS)疾病的疗法需求日益迫切。作为世界领先的神经科学转化研究创新企业之一,罗氏(Roche)站在应对这一挑战的第一线——过去十年间,罗氏在为患者带来创新疗法方面取得了重大进展,其针对多发性硬化、脊髓性肌萎缩、视神经脊髓炎和杜氏肌营养不良的新药近期相继获批。2025年4月,罗氏宣布启动新一代阿尔茨海默病治疗药物trontinemab的3期临床试验项目,该药物运用了罗氏的“脑穿梭(brain shuttle)”技术平台,能更高效地穿越血脑屏障——这一直是神经系统药物研发领域的重大难题。在这篇文章中,我们与罗氏医药研究与早期开发(pRED)神经科学及罕见病领域全球负责人Azad Bonni博士进行了独家对话,探讨罗氏如何加速研发进程,以及为何我们有望迎来一个为严重中枢神经系统疾病患者带来实质性突破的新纪元。Azad Bonni博士现任医药研究与早期开发(pRED)神经科学及罕见病领域全球负责人,全面领导这些领域的研发战略与管线布局。在罗氏任职期间,他成功推动多项突破性疗法从实验室走向临床,包括阿尔茨海默病药物trontinemab、多发性硬化疗法Brain Shuttle-CD20、天使综合征治疗药物rugonersen等。此外,他还积极推动罗氏在神经科学领域的全球合作与并购、参与创立罗氏人类生物学研究所(原罗氏转化生物工程研究所)并担任其科学顾问。加入罗氏前,Azad Bonni博士曾任华盛顿大学圣路易斯分校医学院神经科学系主任,并领导McDonnell细胞和分子神经生物学中心。Azad Bonni博士兼具基础科研与产业领导的复合背景,在学术创新与药物研发转化领域具有深远影响力。感谢您接受我们的采访。作为神经科学领域的全球领导者之一,罗氏在推动复杂CNS疾病治疗方面,如何规划实现真正的突破性进展?Azad Bonni博士:神经科学治疗领域长期以来被视为医学界最具挑战的领域之一。但我认为,我们正站在这一领域重大突破的临界点上。如果从罗氏自身的经历来回顾神经科学疗法的发展史,便能很好地印证这一点。20世纪60年代,罗氏从Librium和Valium作为起点开始研发苯二氮䓬类药物;此后又历经十年,才推出帕金森病治疗药物Madopar;又过了二十年,才通过基因泰克公司(现属罗氏)推出急性卒中治疗药物tPA。在整个20世纪的大部分时间里,神经科学领域的新疗法类别寥寥无几——大约每十年甚至二十年才有一种。自2017年起,这个现象发生了显著转变。我们相继推出了治疗多发性硬化的Ocrevus、治疗脊髓性肌萎缩的Evrysdi、以及治疗视神经脊髓炎谱系障碍的Enspryng,现在又推出了治疗杜氏肌营养不良的Elevidys。在相对较短的时间内实现了四款重要疗法上市——这在此前的中枢神经治疗领域是前所未有的。这绝非偶然,它预示着我们已经迎来了一个真正的转折点。更令人振奋的是,我们正在阿尔茨海默病和帕金森病等重大常见疾病领域取得实质性进展——这些领域历来被视为难以攻克的医学高峰。在阿尔茨海默病领域,我们正推进采用创新脑穿梭技术的trontinemab,以及γ分泌酶调节剂nivegacetor的研发;在帕金森病领域,我们正在开发靶向聚集态α-突触核蛋白的prasinezumab——该靶点正是帕金森病的一个关键病理标志。这一突破性进展主要得益于三大驱动因素:首先,人类遗传学的进展为疾病机制研究提供了关键洞见;其次,我们对疾病生物学的认知取得了显著提高;再者,新型技术平台正加速药物发现与开发进程。这些进步共同奠定了坚实的基础,也正因如此,我们相信神经科学治疗领域正在迈入一个具有实质进展的新纪元。您提到了小分子药物和抗体疗法,在针对中枢神经系统疾病时,罗氏在选择治疗模式方面有什么考量?Azad Bonni博士:长期以来,小分子药物一直是神经科学领域的主要治疗手段,未来也必将持续发挥重要作用。这类药物具有多重优势,且近年来已在神经科学领域取得了显著进展。与此同时,生物制品等大分子药物的临床价值正日益凸显。其在神经科学领域应用的核心挑战始终在于血脑屏障——虽然这一屏障对保护大脑功能至关重要,却也使治疗药物难以到达脑组织。这正是我们开发"脑穿梭"等创新技术的意义所在。该技术平台能有效突破血脑屏障限制,将治疗药物直接输送到大脑,为神经系统疾病的治疗开辟全新的可能性。所以,简而言之——并不存在放之四海皆准的方案。我们需要运用多种治疗模式,充分利用不断扩展的治疗手段,才能应对神经系统疾病的复杂挑战。而这正是罗氏乃至整个行业正在践行的研发策略。许多药企都在转化研究的“死亡谷”中苦苦挣扎。罗氏采取了哪些差异化策略来更好地衔接早期药物发现与临床开发?Azad Bonni博士:得益于我刚才提到的那些科学突破,我们现在可以用一种全新的、更加现代的方式来开展神经科学领域的药物研发。这意味着,我们会将重点放在那些有确凿遗传证据、致病机制研究较为透彻、并能应用尖端技术平台的疾病上。换言之,我们优先选择生物学置信度较高的靶点和疾病领域。在神经科学领域,我们虽然仍处于这些发现转化为经临床验证靶点的早期阶段,但正在取得稳步进展。另一个关键因素是提高临床前模型的预测有效性——确保实验数据能更准确地反映在人类身上的实际效果。这是一项持续推进的工作。同样重要的是开发更好的生物标志物,可靠的标志物对研发全链条的决策至关重要。这三个要素——选择高置信度靶点、优化转化模型、开发优质生物标志物——正是跨越你所说的“死亡谷”的核心策略。许多企业曾深耕神经科学领域,但随后这一领域的研发热潮逐渐消退。然而近期,我们看到行业重焕活力与热情。在您看来,这次复兴与以往有何本质区别?我们又该如何避免重蹈覆辙?Azad Bonni博士:这是个很好的问题,我完全同意你的说法——神经科学确实正经历一场明显的复兴浪潮,我预计这股势头将在未来二十年持续加速。特别要强调的是生物标志物在其中的关键作用。以阿尔茨海默病为例,虽然针对β淀粉样蛋白的疗法研发历经25年并曾屡遭挫折,但这些经验进一步深化了我们对疾病的理解,并推动了生物标志物的发展。这些标志物彻底改变了药物的研发模式:它们让我们能在临床前研究和临床试验中提出更精准的科学问题,开展机制验证研究——从而在投入大量时间和资源进行后期研发之前,尽早确定药物是否起效。这种实验医学方法对阿尔茨海默病领域的近期进展功不可没,现在我们需要将这种思维扩展到帕金森病等其他疾病领域。尽管阿尔茨海默病研究仍有很长的路要走,但医药企业、生物科技公司和学术机构已通过生物标志物的开发建立起坚实的基础。这样的合作模式不仅可以,也应当推广到其他复杂的神经系统疾病中。除生物标志物外,您认为罗氏还在探索哪些有望在未来五年彻底改变药物发现和转化范式的技术?Azad Bonni博士:首先我想要重点介绍我们的"脑穿梭"技术平台。虽然当前有许多前沿技术正在研发中,但我相信这项技术有可能彻底革新脑部药物递送方式。如先前所述,血脑屏障会阻止抗体等大分子入脑——传统抗体通常只有约0.1%能进入大脑,且多富集于脑室周围,难以均匀分布至全脑组织。“脑穿梭”技术通过利用天然的胞吞转运机制(生物体跨屏障运输物质的自然途径)解决了这一难题。通过先进的蛋白质工程技术,我们开发出例如trontinemab这样的创新抗体分子——该药物靶向阿尔茨海默病的淀粉样蛋白斑块,其特殊结构域可与转铁蛋白受体结合,通过触发转胞吞转运作用主动穿越血脑屏障。值得注意的是,这种设计能确保抗体在外周循环和入脑后均能保持正常功能,避免在血管内皮细胞中异常蓄积。Trontinemab是我们目前利用该技术所开发进展最快的项目。在一项2a期临床试验中,它表现出了快速而强大的淀粉样蛋白斑块清除能力,远超传统抗体。更令人振奋的是,它引发的淀粉样蛋白相关影像学异常(ARIA)发生率更低——这是传统淀粉样蛋白疗法常见的不良反应,我们认为其安全性优势可能是由于其独特的入脑途径所致。但“脑穿梭”技术的潜力远不止于淀粉样蛋白和阿尔茨海默病。该平台可适配其他抗体、并拓展至多种神经系统疾病,甚至有望应用于抗体之外的其他治疗模式,为脑部疾病的治疗开辟全新的可能性。最后一个问题——如果您有机会在神经科学领域实现一个愿望,您最希望达成的目标是什么?Azad Bonni博士:这是一个很好的问题。我最近一直在思考“预防神经病学”这个领域。例如,在心脏病学领域,预防措施已相当成熟——降压药、他汀类药物、再到如今的GLP-1激动剂,这些干预手段都专注于在严重疾病发生之前解决风险因素。我相信神经病学领域也将迎来类似的转折点。以阿尔茨海默病为例:研究显示,60岁及以上人群中约40%的人已出现脑内淀粉样蛋白病理改变,尽管尚未表现症状。设想这样一个未来——精准诊断技术可以及早识别这些人,我们也有针对性的疗法来阻止其病情发展到有症状的地步。这正是我为之振奋的未来图景,而我相信,这样的未来正越来越接近现实。罗氏同时拥有制药和诊断两大业务板块,这使我们能推进精准预防策略,从根本上改变神经系统疾病的管理模式。当然,这并不意味着我们不再关注对已表现出症状患者的治疗——只要存在未被满足的医疗需求,这一方向仍然至关重要。但随着社会越来越重视保持健康和生活质量,二级预防——即在症状出现之前进行干预,必将成为未来医学越来越重要的一部分。能参与塑造这样的未来,着实令人振奋。Advancing the New Era of Neuroscience: A Conversation with Dr. Azad Bonni, SVP and Global Head of Neuroscience & Rare Diseases, Roche Pharma Research & Early DevelopmentEditor’s Note: As the global burden of neurological diseases continues to rise, the need for effective treatments for complex CNS (central nervous system) disorders has never been more urgent. At the forefront of addressing this challenge is Roche, one of the world’s leading innovators in neuroscience translational research. Over the past decade, Roche has made significant progress in bringing new therapies to patients, with recent approvals for conditions including multiple sclerosis, spinal muscular atrophy, neuromyelitis optica, and Duchenne muscular dystrophy. In a major step forward, Roche announced in April 2025 the initiation of a Phase III program for trontinemab, a next-generation Alzheimer’s therapy that leverages the company’s brain shuttle platform to more effectively cross the blood-brain barrier—a long-standing hurdle in neurological drug development. With this momentum, we sat down for an exclusive conversation with Dr. Azad Bonni, SVP and Global Head of Neuroscience & Rare Diseases at Roche pRED, to discuss how Roche is accelerating research and development and why we may be entering a new era of meaningful breakthroughs for patients affected by devastating CNS diseases.Thank you for joining us, Dr. Bonni. As a global leader in neuroscience, how does Roche envision making meaningful progress in addressing complex CNS diseases?Azad Bonni: Neuroscience therapeutics has long been considered one of the most challenging areas in medicine—often described as a “graveyard for pharma.” But I believe we are now on the cusp of major breakthroughs in this field. If you look at the history of neuroscience therapeutics—from the lens of Roche—it illustrates this point well. In the 1960s, Roche developed benzodiazepines, starting with Librium and Valium. It then took another decade before launching Madopar for Parkinson’s disease, and two more decades before introducing tPA for acute stroke through Genentech, now part of Roche. For much of the 20th century, new classes of therapies in neuroscience were sparse—perhaps one every decade or two.Starting in 2017, that pace changed dramatically. We launched Ocrevus for multiple sclerosis, Evrysdi for spinal muscular atrophy, Enspryng for neuromyelitis optica spectrum disorders, and now Elevidys for Duchenne muscular dystrophy. That’s four major launches within a relatively short period—something we hadn’t seen before in this space. And this isn’t a coincidence; it signals that we’ve reached a real turning point.What excites me even more is that we’re now making meaningful progress in major prevalent disorders like Alzheimer’s disease and Parkinson’s disease—areas that have historically been incredibly challenging. In Alzheimer’s, we’re advancing trontinemab, which utilizes our innovative brain shuttle technology, and nivegacetor, a gamma secretase modulator. In Parkinson’s, we’re developing prasinezumab, which targets aggregated alpha-synuclein, a key pathological hallmark of the disease.Several factors are driving this progress. First, advances in human genetics have provided critical insights into disease mechanisms. Second, our understanding of disease biology has significantly improved. And third, new technological platforms are accelerating discovery and development. Together, these advances create a strong foundation for why we believe neuroscience therapeutics is entering a new era of meaningful progress.You mentioned both small molecules and antibodies. How does Roche approach modality selection when targeting CNS diseases?Azad Bonni: For a long time, small molecules have been the primary therapeutic approach in neuroscience, and they will certainly continue to play an important role. Small molecules offer several advantages, and there have been significant advances in this area in recent years.At the same time, large molecules—such as biologics—are becoming increasingly relevant. The main challenge with large molecules in neuroscience has always been the blood-brain barrier, which, while essential for protecting brain function, also makes it incredibly difficult for therapeutics to reach brain tissue. That’s where innovations like our brain shuttle technology come in. This platform allows us to effectively bypass the blood-brain barrier and deliver therapies directly to the brain, opening up entirely new possibilities for treating neurological diseases.So, to answer your question directly—there’s no one-size-fits-all approach. We need to apply multiple modalities and fully leverage the expanding range of therapeutic options to address the complex challenges of nervous system disorders. And that’s exactly what we’re doing at Roche and across the field.Many drug developers struggle with the translational ‘valley of death.’ What does Roche do differently to more effectively bridge early discovery and clinical development?Azad Bonni: Thanks to the scientific advances I mentioned earlier, we can now approach drug development in neuroscience in a fundamentally different—and more modern—way than in the past. This means focusing on diseases where there’s strong genetic evidence and a decent biological understanding of disease pathogenesis, and where we can apply cutting-edge technological platforms. In other words, we prioritize disease areas and targets that offer relatively high biological confidence. While we’re still in the early stages of translating that into clinically validated targets in neuroscience, we’re making steady progress.Another critical factor is improving the predictive validity of preclinical models—ensuring that what we learn in research better reflects what will happen in humans. That’s an ongoing effort. Equally important is the development of better biomarkers. Robust biomarkers are essential to guide decision-making along the value chain. Together, these factors—targeting high-confidence biology, improving translational models, and developing better biomarkers—are key to overcoming the “valley of death” you described.Many companies have historically focused on neuroscience, but over time the field lost momentum. Recently, however, we’ve seen a resurgence of activity and renewed enthusiasm. In your view, what’s fundamentally different this time, and what steps can be taken to avoid repeating the cycles of attrition we’ve seen in the past?Azad Bonni: That’s a great question, and I fully agree with you—there’s a clear renaissance happening in neuroscience, and I believe it will continue to accelerate throughout this decade and the next.One critical factor I want to highlight is the role of biomarkers. Take Alzheimer’s disease as an example. Despite more than 25 years of work on amyloid-targeting therapies and many high-profile failures, those setbacks led to significant advances in our understanding of the disease and in developing biomarkers. These biomarkers have fundamentally changed how we approach drug development. They allow us to ask precise scientific questions, both preclinically and in clinical trials, and enable proof-of-mechanism studies—helping us determine early on whether a drug is doing what it’s supposed to do before committing significant time and resources to later-stage development.This experimental medicine approach has been critical to the recent progress in Alzheimer’s, and we now need to apply that same mindset to other diseases—Parkinson’s and beyond. While there’s still more to do even in Alzheimer’s, the collaborative efforts of pharma, biotech, and academia have created a strong foundation through biomarker development. That model can—and should—be extended to other complex neurological diseases.Beyond biomarkers, what other technologies is Roche exploring that you believe could fundamentally transform how we discover and translate medicines over the next five years?Azad Bonni: One technology I’d really like to highlight is our brain shuttle platform. While there are many exciting technologies in development, I believe this one has the potential to fundamentally change how we deliver therapies to the brain. As I mentioned earlier, the blood-brain barrier prevents large molecules like antibodies from entering the brain. With conventional antibodies, typically only about 0.1% reaches the brain, and even then, the distribution is limited, often concentrated around the ventricles rather than throughout the brain tissue.The brain shuttle technology addresses this challenge by leveraging natural transcytosis mechanisms—the body’s way of transporting substances across the barrier. Through advanced protein engineering, we’ve developed molecules like trontinemab, an antibody that targets aggregated amyloid plaques in Alzheimer’s disease. Trontinemab is engineered to include a moiety that binds to the transferrin receptor, enabling it to actively cross the blood-brain barrier through transcytosis. Importantly, this engineering ensures that the antibody behaves properly both in peripheral circulation and once inside the brain, avoiding unwanted accumulation in endothelial cells lining the blood vessels.Trontinemab is currently our most advanced asset using this technology. In a Phase 2a trial, it demonstrated rapid and robust depletion of amyloid plaques, dramatically more than conventional antibodies. What’s also exciting is that it showed a lower incidence of ARIA (amyloid-related imaging abnormalities)—a common adverse effect seen with traditional amyloid therapies. We believe this may be related to the different route of entry into the brain.But the potential of the brain shuttle goes far beyond amyloid and Alzheimer’s disease. This platform can be applied to other antibodies, a range of neurological diseases, and even beyond antibodies to other modalities, opening up entirely new possibilities for treating diseases of the brain.For my final question—if you had a magic wand and could make one wish come true in neuroscience, what would it be?Azad Bonni: That’s a great question. One area I’ve been thinking about lately is preventive neurology. In cardiology, for example, prevention is already well established—with treatments like antihypertensives, statins, and now GLP-1 agonists aimed at addressing risk factors before serious disease develops. I believe we will approach a similar turning point in neurology.To give some context in the example of Alzheimer’s, by the sixth decade of life, it’s estimated that up to 40% of people already have amyloid pathology in the brain, even if they show no symptoms. Now imagine a future where accurate diagnostic tests identify these individuals early, and we have targeted therapies to prevent progression to symptomatic disease. This is the kind of future I’m excited about—and one I believe is increasingly within reach.At Roche, we’re uniquely positioned to lead this transformation because we have both a pharmaceutical and diagnostics division, and we’re global leaders in neurology across both areas. This gives us a unique ability to advance precision-type, preventive approaches that could fundamentally change how we manage neurological diseases. Of course, this doesn’t mean we’ll stop focusing on treatments for people who already have symptoms—that remains critical as long as unmet medical needs exist. But as societies become more focused on maintaining health and quality of life, secondary prevention—intervening before symptoms emerge—will become an increasingly important part of the future of medicine. And I’m truly excited to be part of shaping that future.免责声明:药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的,文中观点不代表药明康德立场,亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导,请前往正规医院就诊。版权说明:本文来自药明康德内容团队,欢迎个人转发至朋友圈,谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”,获取转载须知。分享,点赞,在看,聚焦全球生物医药健康创新