Zuranolone

Pictured: A brain surrounded by falling pills/Taylor Tieden for BioSpace While large pharmaceutical companies turn their attention to neurodegenerative diseases like Alzheimer’s and amyotrophic lateral sclerosis, the business case for neuropsychiatric R&D doesn’t appear to fit as neatly with their objectives. Blockbuster drugs like Prozac and Zoloft for depression and atypical antipsychotics like Risperdal and Abilify are all products of the big pharma engine from the 1980s and 1990s, said Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas. “Large pharma liked these diseases because there are lots of patients,” he told BioSpace. This was in the days of pharmaceutical sales forces selling a wide portfolio of primary care products, Suvannavejh said. However, in the late 2000s and 2010s, many of these successful products went generic, “and that coincided with a time where oncology and the emergence of monoclonal antibodies took off,” he explained, driving many big pharma companies to exit psychiatry, putting more focus on Alzheimer’s and other neurological diseases. To some extent, this trend still holds today. For example, a representative from Eli Lilly, a big player in the Alzheimer’s space, told BioSpace in an email that the company does not have any clinical programs in psychiatry and it is not a focus area for R&D. Meanwhile, neuropsychiatric drug development has been left to smaller biotech companies like Sage Therapeutics, whose Zurzuvae was approved in August 2023 for postpartum depression, and Intra-Cellular Therapies, which recently scored a Phase III victory in major depressive disorder. Amit Etkin, founder and CEO of Alto Neuroscience, told BioSpace it is “critical” that big pharma get back into neuropsychiatric R&D. “The need is massive,” he said. “Fundamentally, there’s a huge need that needs to be addressed and needs to be addressed in a different way.” A Risky Proposition In a LinkedIn poll conducted by BioSpace, 25% of respondents said that lack of pharma R&D investment is the biggest challenge facing the neuropsychiatric space. There are several reasons why large pharma companies may steer clear of neuropsychiatric R&D. First, most neuropsychiatric drugs are small molecules, which are much easier to make generic versions of than large molecules, Suvannavejh said. Hence, large pharmas pivoted to large molecules and monoclonal antibodies where revenue is extended. The Inflation Reduction Act, which came into law in 2022 and makes small molecule drugs eligible for price negotiations four years sooner than biologics, is reinforcing this trend. Additionally, the neuropsychiatric space is risky. “The likelihood of clinical trial success . . . is probably the lowest in neuroscience,” Suvannavejh said, noting a “big placebo effect” and the complexity of the brain. “Everyone these days needs to optimize for capital efficiency . . . and I think that large pharma has, on purpose, chosen to limit their exposure to neuroscience because they know clinical trial failure rates are high.” Daniel Karlin, chief medical officer at MindMed, which is developing psychedelic therapies for neuropsychiatric and other disorders, agreed. He noted that depression is a “phenomenological shared disease” without a shared underlying biology. “You take a drug that has a distinct biological action and you test it in all [depressed patients]—it’s no surprise that we get low mean effect sizes because why would one biological intervention work for a bunch of different biologies?” This makes it “extraordinarily difficult” to develop new psychiatric drugs, he told BioSpace. “The enterprise of psychiatric drugs is high risk and potentially low reward. So the pursuit of novel psychiatric drugs has been sort of offloaded onto biotechs to take on that early development risk.” Suvannavejh concurred. He characterized big pharma’s mentality as, “Let them figure it out on their dime . . . and then we’ll buy them.” And that appears to be what is happening. In December, Bristol Myers Squibb acquired Karuna Therapeutics and its investigational schizophrenia drug, KarXT, for $14 billion, and AbbVie picked up Cerevel Therapeutics and its neuropsychiatric pipeline for $8.7 billion. And last month, AbbVie—which has previously been active in the space—inked a potentially $2 billion deal with Gilgamesh Pharmaceuticals to develop psychedelic therapies for psychiatric disorders. Greater Speed and Scalability Beyond these deals, a handful of other large pharmaceutical companies do have neuropsychiatric programs. Johnson & Johnson’s Janssen has two assets, seltorexant and aticaprant, in Phase III studies for depression. Meanwhile, Merck has a Phase IIb program in schizophrenia, and Denmark-based Lundbeck is developing a Phase III asset in post-traumatic stress disorder, in partnership with Otsuka Pharmaceutical. While there is significant innovation stemming from the efforts of smaller biotechs, Etkin said that big pharma’s greater involvement “would lend enthusiasm, energy, more money, more opportunity, like we see in other areas.” Development can also occur more quickly with the help of larger companies. “When you have big pharma get involved in a space, there is a capacity for scale and for speed that’s much harder to do in biotech.” Etkin said there is not one ideal marriage between pharma and biotech in the neuropsychiatric space. While the traditional alliance has been through M&A, “There could be many other forms in terms of collaborations, trying to bring expertise in different ways at different stages,” he said. Whatever form it takes, he added, the key is to establish those connections. “Because a lot of those people over the years went to biotech, [collaboration] becomes a natural way to kind of reconstitute that field within those big pharmas.” Even when big pharma companies aren’t actively developing neuropsychiatric therapies, they can still be involved. Etkin noted that Novartis and Eli Lilly joined the Series B and Series C rounds, respectively, for Alto, which has had several mid-stage wins in depression over the past two years. Karlin said that big pharma companies need to “be brave and be thoughtful.” Specifically, he said the industry needs to move away from the style of drug development based on the Diagnostic and Statistical Manual of Mental Disorders, where one psychiatric drug needs to address a single diagnosis. “Big Pharma has always looked at this space as really important, just not knowing how to innovate,” Etkin said. “At the end of the day, it’s probably big pharma with biotech coming together to bring that innovation.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

作者｜YY 渤健（Biogen Inc）刚刚公布的第一季度财报显示其利润超过预期，尤其是备受关注的阿尔茨海默病Leqembi的销售业绩也高于预期。  01  渤健Q1财报，Leqembi开始上位 图片来源：卫材Leqembi去年1月获得FDA加速批准，并于当年7月迅速升级为全面批准。虽然开发商渤健和卫材并没有急于将Leqembi推向市场，但上市后市场吸收率在今年第一季度突然提速，获得了1900万美元的销售额，几乎是去年第四季度销售额的三倍，高于分析师预测的1100万美元，也超过了去年1000万美元业绩。公布财报后，渤健的股价立即上涨了6%。据渤健称，自 2023 年底以来，接受Leqembi的患者数量增加了近 2.5 倍，3 月份开始新患者数量激增，占总患者人数的20% 以上。对于Leqembi患者人数增加的背后原因，渤健认为随着医生团体和医疗中心诊断、监测所需的所有后勤设置的到位，Leqembi 的迅速上位自然就是水到渠成的事情。但Leqembi的壮大道路也并非一番坦途。卫材设定了3月底吸引1万名美国患者的“小目标”，但CMS  (医疗保险和医疗补助服务中心) 提供的信息显示，截至4月初，只有5600 名患者获准接受治疗。繁缛的治疗过程、高昂的费用和对副作用的担心限制了Leqemi大展宏图。患者在18个月的疗程中需要接受38次输注，但首先需要进行 PET 脑部扫描和定期 MRI 扫描，五分之一的患者会受到破坏性副作用的影响。除此之外，Medicare不愿意为65 岁以上的人支付昂贵的扫描费用，而一些神经科医生掣肘于Leqembi背后的风险和有限的疗效而选择不开具Leqembi处方。渤健和卫材2021 年推出的阿尔茨海默病药物Aduhelm 的黯然收场令很多医生和患者对此类药物可能的副作用非常忌惮。除此之外，Leqembi 的售价为每年 26500 美元，并且带有脑水肿和脑出血ARIA（Amyloid related imaging abnormalities）黑框警告。FDA 3月份推迟了礼来的阿尔茨海默病药物Donanemab的批准决定，这突显了他们在批准此类药物时的谨慎态度。临床试验发现，donanemab需要每月输注以清除患者大脑中的淀粉样蛋白，因此脑水肿的发生率更高。尽管面临着高成本、高风险和有限疗效的限制，但考虑到700万美国患者和5000万全球患者，分析师预计leqembi和donanemab未来的销售量将保持高水准。据彭博社数据，到 2030 年，Leqembi 和 donanemab 预计每年将分别产生 22 亿美元和 55 亿美元的收入（图1）。 图1. 阿尔茨海默病药物Leqembi和donanemab预计销售量走势图。（图片来源：Financial Times）尽管新一代阿尔茨海默病疗法在研究和治疗领域取得了一些进展，但简化给药过程中所需的管理任务仍然有待解决。渤健和卫材四月初决定推迟每周皮下注射版 Leqembi 的监管申请，这主要是因为 FDA 要求提供三个月的额外免疫反应数据。从监测方面来看，分析β淀粉样蛋白片段的血液检测无需花费 5000 美元的 PET 扫描，商业化后并未广泛使用，然而大约一半患者最初会被 Medicare Advantage 计划拒绝接受 PET 扫描承保。对于Leqembi的未来地位，CMS发言人最近发表了一番预测，预计Leqembi 2024年的Medicare成本将为5.5亿美元，到2025年将猛增至35亿美元。考虑到Medicare精算师在预测方面众所周知的保守性，35亿美元的预测尤其令人意外。这甚至超过了卫材自己的预测，他们3月刚刚宣称，Leqembi到2026财年（2026年4月到2027年3月）在北美洲和南美洲的销售额合计将达到13亿美元，这只是CMS 2025年预测值的三分之一多。  02  渤健Q1表现如何？虽然Leqembi传来捷报，但渤健本季度22.9亿美元的销售额同比下降 7%。第一季度净利润为 3.934 亿美元，略高于去年同期的净利润 3.879 亿美元。Skyclarys渤健7 月份收购 Reata Pharmaceuticals 带来的 资产Skyclarys在今年第一季度收入了7800 万美元，高于FactSet分析师预计的6880万美元。FDA去年批准的Skyclarys是史上首款获批的弗里德赖希共济失调症疗法。这是一种罕见的遗传性退行性疾病，可损害年仅 5 岁儿童的行走和协调能力。今年2 月获得了欧盟委员会批准。渤健表示，美国和欧盟目前分别有1100名和300名患者正在使用Skyclarys。首款产后抑郁症药物Zurzuvae去年8月，Biogen 与 Sage Therapeutics 合作开发的首款产后抑郁症药物Zurzuvae获得FDA批准，但针对更大适应症重度抑郁症的申请遭到了拒绝。Zurzuvae第一季度销售额达 1200 万美元，远高于FactSet分析师此前500万美元的预估。受到仿制药竞争带来的影响，渤健第一季度多发性硬化症产品收入下降 4% ，跌至10.8 亿美元。渤健曾经的重磅炸弹Tecfidera第一季度的销售额为 2.543 亿美元，低于去年第一季度的2.745 亿美元。复发型多发性硬化症的口服药物Vumerity第一季度的销售额达 1.275 亿美元。罕见病药物类渤健的罕见病药物销售额为 4.239 亿美元，低于去年同期的 4.433 亿美元。罕见神经肌肉疾病脊髓性肌萎缩症疗法Spinraza第一季度销售额为 3.413 亿美元，低于分析师预计的 4.151 亿美元。生物类似药生物类似药方面，渤健第一季度的销售额为1.969亿美元，高于去年同期的1.924亿美元。Ref.Constantino, A. K. Biogen tops profit estimates as cost cuts take hold, Alzheimer’s drug Leqembi launch picks up. CNBC. 24. 04. 2024.Feuerstein, A. Biogen’s Alzheimer’s drug launch on ‘steady pace’ as logistical hurdles recede. STAT. 24. 04. 2024.Barnes, O. Alzheimer’s drug Leqembi falls short of blockbuster status in faltering US rollout. Fanancial Times. 22. 04. 2024.Herman, B. et al. Medicare expects to spend $3.5 billion on new Alzheimer’s drug in 2025. STAT. 11. 04. 2024.  BiG 十周年预告  本次BiG十周年庆典，将首次分为国内和国际篇章，以原创科学和临床需求为出发点，讨论创新技术平台和创新疗法（PROTACT/分子胶、双抗/ADC、siRNA/ASO、CGT、AI制药）的重大进展和发展前景，十年一药曙光现，大浪淘沙始见金！▼报名参会 会议门票：审核制(免费)；含主论坛+分论坛，不含餐；优先biotech/Pharma、临床、院校科学家共建Biomedical创新生态圈！如何加入BiG会员？