Mike Wilson | 06 February 2024
阿尔兹海默症是全球范围内最常见的死亡原因之一。阿尔兹海默症和其他痴呆症多发于老年阶段，已经成为高收入国家排名第三的死亡原因（如果将癌症分开统计，则是第二大死亡原因）。根据世卫组织的最新数据，阿尔兹海默症已经取代脑中风，成为排名第二的死亡原因，仅次于缺血性心脏病。
在过去20年里，高收入国家中因痴呆症死亡的总人数翻了两番，对此医学界至今仍未取得突破性进展。这并不是因为该领域未受到重视，事实上科学家们多年来投入了大量的时间和金钱来研究这种神经系统退行性疾病，寻找能够预防、治疗或至少延缓其进展的方法。
本文将探讨近期备受关注的几款治疗阿尔兹海默症的药品。
曙光初现
几十年来，科学家们一直在努力研究阿尔兹海默症的病因，以期研发出能够阻止或减缓病程发展的药物，然而却始终未能完全破译阿尔兹海默症的发病机制。阿尔兹海默症通常被认为是多种因素的共同结果，其中，有一种病因假说多年来一直占据主导地位。
那就是 "淀粉样蛋白假说 "，许多科学家认为阿尔兹海默症是由于大脑中的蛋白质异常沉积导致的。这个理论是这样来解释阿尔兹海默症的：由于脑内β淀粉样蛋白生成并聚集，形成被称为淀粉样蛋白的沉积物。随着时间的推移，最终聚集形成淀粉样蛋白斑，这些斑块的体积大到足以阻断脑神经细胞之间的信息传导。蛋白沉积还会激活免疫细胞，引起炎症，并最终破坏脑细胞。
如果阿尔茨海默症的诱因确实是蛋白质异常沉积的话，那么理论上清除淀粉样蛋白沉积物就可以延缓病程发展。最近，三种通过靶向β淀粉样蛋白新药备受关注，有可能成为阿尔茨海默症治疗的破局者。
第一款药品是阿杜卡尼单抗（Aducanemab），于 2021 年在美国附条件获批上市(1)。阿杜卡尼单抗能够有效清除淀粉样蛋白斑块，但其治疗效果差强人意，并不能显著改善患者的临床症状（如记忆力减退）。因此，该药的获批上市一直备受争议。由于缺乏证据证明使用阿杜卡尼单抗能让患者明显获益，所以很多医生拒绝开具处方。美国联邦政府为65岁以上老年人提供的医疗保险 Medicare以及包括英国和欧盟在内的多地监管机构尚未批准使用这款药物。
紧接着登场的是仑卡奈单抗（Lecanemab）。与阿杜卡尼单抗相比，仑卡奈单抗对减少大脑中的淀粉样蛋白斑块同样效果显著，同时这款药品的临床疗效更为优秀。临床试验表明，在接受仑卡奈单抗治疗18 个月后，患者的记忆力和思维能力的衰退减缓了 27%。有了阿杜卡尼单抗获批的先例，仑卡奈单抗毫无意外地于 2023 年 7 月在美国获批上市2。其他地区的监管机构仍在继续评估试验结果，以决定是否批准使用这款药物。
最近，多奈单抗（Donanemab）成为第三种在该领域取得成功的药物。多奈单抗在减少淀粉样蛋白斑块方面同样表现优异，在约 80% 的入组患者中均观察到可测量的斑块大幅减少。
然而多奈单抗在改善患者的临床症状（如记忆力减退）方面未能取得实质突破，临床试验显示其治疗效果与仑卡奈单抗相当。从不同对照组的数据来看，如果仅观察脑内的 tau蛋白量较少的患者，那么多奈单抗治疗将患者病程进展的速度减缓约三分之一。如果把脑内tau蛋白量较多的患者也包括在内，上述数据则降低为22%。目前多奈单抗在美国的上市申请仍在审批中，十分有望获得批准。
前路漫漫
医学界在治疗阿尔兹海默症领域所取得的突破着实令人欣喜。然而，我们必须同时认识到这些药物的局限性。其中最根本的一点是，这几款药物并不能显著改善阿尔茨海默症患者的临床症状，而且通常仅对早期患者有效。以多奈单抗为例，我们本对其寄予厚望，但该药品的临床试验结果并不如预期。
从统计学角度看，多奈单抗确实改善了患者的症状。数据显示服用多奈单抗的患者比服用安慰剂的对照组治疗效果更好，从而证明了多奈单抗的有效性。
然而，多奈单抗治疗的临床意义仍不明朗，比如如何证明患者认知能力的改善。与许多其他疾病不同，阿尔茨海默症的疾病进展很难界定，而且更多基于主观判断。通常我们会使用各种测试量表来评估阿尔兹海默症，包括测试患者在单词记忆、方向识别、长时记忆和单词查找等多方面的能力。在多奈单抗的临床试验中使用过一项测试，当该测试的评分提高至少 5 分时才被认为具有临床意义3，而多奈单抗的治疗结果只提高了约 3 分4。这就意味着，尽管统计学角度多奈单抗已证实有效，但在使用该药物 18 个月后，患者本人或其家人很可能不会发现疾病有任何改善。
多奈单抗的长期疗效尚未得到检验。同时目前所有的治疗效果都基于将参与的患者分组试验后获得的。
这些新药同时也带来了一些实际问题。首先，它们有一定的副作用。罕见严重不良反应包括脑肿胀和小中风。在多奈单抗试验中，有 1.6% 的患者出现了严重不良反应，还有 24% 的患者出现了其他不太严重的药物反应。另外，目前这几款药物都需通过静脉滴注的方式注射给药，患者每周需要到诊所接受长达一小时的药物治疗。好消息是，一种新的在研药物Remternetug正在实验皮下注射是否可行，类似于糖尿病患者使用的胰岛素笔。
结语
最后，上述多项药品临床试验结果皆为喜忧参半。这几款药物的原理都是通过清除淀粉样蛋白沉积来改善阿尔茨海默症的疾病进展。事实上，这些药物都实现了有效清除淀粉样蛋白，但其治疗效果却十分有限，这样的结果难以令人满意。我们可以这样理解，这些药物在减少淀粉样蛋白斑块方面已经做得足够好，达到了预期效果；所以继续从这个方向改进药品并不能提升其临床疗效。这意味着我们可能一直忽略了除蛋白质异常沉积之外的其他致病因素。
这些药物的成功研发是一个好的开始，证明了阿尔茨海默症是可以被治疗的，同时也为今后的发展带来了希望。显然，短期内阿尔茨海默症仍无可能成为一种可以控制的疾病。想要真正解决阿尔兹海默症带来的疾病负担，我们还需要在更多方面取得突破，特别是那些尚未研发出任何药品的领域。
参考资料
01. alzint.org
FDA approves Biogen’s aducanumab | Alzheimer’s Disease International (ADI)
02. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval | FDA
03. Integrated Alzheimer’s Disease Rating Scale: Clinically meaningful change estimates - Wessels - 2022 - Alzheimer’s & Dementia: Translational Research & Clinical Interventions - Wiley Online Library
04. Meaningful Clinical Changes in Alzheimer Disease Measured With the iADRS and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings | Neurology Clinical Practice
Pacific Life Re Limited (No. 825110) is registered in England and Wales and has its registered office at Tower Bridge House, St Katharine’s Way, London, E1W 1BA. Pacific Life Re Limited is authorised and regulated by the Financial Conduct Authority and Prudential Regulatory Authority in the United Kingdom (Reference Number 202620). The material contained in this booklet is for information purposes only. Pacific Life Re gives no assurance as to the completeness or accuracy of such material and accepts no responsibility for loss occasioned to any person acting or refraining from acting on the basis of such material.
©2024 Pacific Life Re Limited. All rights reserved.
Mike Wilson
Director, Medical Analytics
Discover more Vital Insights
Protection
Changing regulations an area of opportunity for reinsurers
When asked what opportunities life reinsurers in Asia have, Pacific Life Re's Vasan Errakiah was quick to cite demand for insurance, changing regulations and the adoption of new technologies.
.png)
.png)
Protection
Solving the implementation puzzle of machine learning
Asia Insurance Review spoke to Pacific Life Re's Mr Ong Qian Hao and FWD Group's Ms Fiona Hermans to understand how strategic partnerships can effectively address these challenges and lead to successful outcomes.
Medical Advances
Update on COVID-19 and Long Covid
Read our update on the impact of mortality from COVID-19.
Medical Advances
Lung cancer screening, marginal gains or a game changer?
Lung cancer is often diagnosed at a late stage leading to poor prognosis for the individual. We look at how screening could have an impact.
Underwriting & Claims
From Barrier to Benefit: Rethinking the Future of Underwriting
Underwriting has been going through significant transformation over the last few years and continues to accelerate at an unprecedented pace. Traditionally seen as a barrier, there is now a growing opportunity to position underwriting as a strategic asset.
Protection
Leveraging big data insights in reinsurance
Big data analytics has been instrumental for (re)insurers aiming to boost performance, efficiency, and effectiveness.
Medical Advances
Vital Insights Issue 2
From emerging drugs which battle obesity to a review of the effectiveness of new blood tests both to detect cancer and to help slow down Alzheimer’s, we hope these insights help keep you up to date with the latest in medical research.
Medical Advances
Vaping vs. smoking: what are the risks?
Vaping is generally considered less harmful than smoking, however longer-term risks have not had time to emerge and could prove considerable.
Medical Advances
Gut Check: the concerning rise of bowel cancer among young adults
Despite broadly improving cancer mortality, some types of the disease are increasing in incidence
Protection
Serving the Underserved
Consumer Duty has put increased focus on how much value different customers get from financial products. But how well is the protection industry serving different customer groups? Who are the most underserved groups, and what can the industry do to help serve these groups better?
Underwriting & Claims
The future of underwriting is now... are we ready?
Underwriting processes, practices and philosophies are changing with faster pace than we have ever experienced before.
Medical Advances
Tackling the obesity crisis
A new generation of drugs has now well and truly arrived aiming to improve weight loss. The drugs are heavily touted by celebrities and influencers, despite many of them having no medical need to lose weight. Obesity contributes significantly to some of the most common causes of death including heart disease and cancer, as well as affecting quality of life for millions. In this article we look at these increasingly available drugs offering hope to more people with obesity. We consider their potential to broadly improve health, and their limitations.
Medical Advances
New drug may slow down multiple sclerosis
Scientists successfully conducted early-stage trials which provide hope of a future cure for some of the most severe types of multiple sclerosis (MS).
Medical Advances
Exploring the latest medical advances in cancer detection
The world’s largest conference dedicated to the science and treatment of cancer took place in Chicago in early June. The American Society of Clinical Oncology’s annual meeting is a popular forum at which new scientific developments are often revealed.
Medical Advances
Pituitary Neuroendocrine Tumour (PitNET)
A recent review by WHO resulted in reclassification of pituitary adenoma as described in the article
Medical Advances
Climate change and its impact on mortality and morbidity
In 2023 we’ve seen soaring temperatures across the globe along with devastating storms and wildfires. Why is our climate changing and what impact is it having?
Medical Advances
Vital Insights Issue 1
Welcome to our first edition of Vital Insights. Here we’ve put together a collection of articles covering some of the major issues of the day with a specific focus on how they will impact mortality and morbidity.
Medical Advances
Deep dive: Alzheimer's
Total deaths from dementias in high-income countries have almost quadrupled in the last 20 years, yet so far medical science has very few answers. This article looks at the recent emergence of the first drugs which may be able to modify the effects of this terrifying disease
Medical Advances
New Respiratory Syncytial Virus Vaccine
COVID-19 has stolen the limelight from other respiratory viruses in recent years. However there are plenty of other common viruses which can have serious health consequences, among them Respiratory Syncytial Virus, or RSV.
Medical Advances
An end in sight for AIDS
A new UN report reveals optimism about a possible end to the global AIDS epidemic
Medical Advances
Anti-vaccine sentiment increases risk of measles outbreaks
Vaccine technologies have continued to improve greatly in recent years. However, vaccines are little use if people refuse to use them. Here we look at the precarious position of measles, a well-known but little-understood serious condition, which is held in check in most countries only because of high vaccine uptake.
Medical Advances
Does a common sweetener cause cancer
The International Agency for Research on Cancer (IARC), the cancer research arm of the WHO, recently classified the common sweetener aspartame as a possible cause of cancer in humans.
Protection
Building a sustainable protection market
Beneath the Surface report 2023 We explored some of the key drivers of sustainability for the protection market. We undertook consumer research which combined with our medical and underwriting expertise and our deep understanding of the market, enabled us to create this report.
.png)
Protection
Navigating the ocean of Value-Added Services
Beneath the Surface report 2022 In this report, we analyse the current VAS landscape in the UK & Irish protection markets. Look to understand the views and experiences of customers, with the aim of assessing how much value these services are really adding today. Look at what insurers say, and consider what the future might hold for the development of VAS.