对话 | 融资2亿美元、创立多家公司，她将如何重塑脑部疾病的治疗版图？ | Bilingual

编者按：在充满挑战且快速发展的神经科学领域，鲜有领导者能像Stacie Weninger博士这般在塑造行业格局方面发挥关键作用。作为F-Prime生物医学研究倡议（FBRI）主席兼F-Prime风险合伙人，她活跃于基础科学与企业创建的交汇点：发掘颠覆性研究成果，并组建顶尖团队将其转化为创新药物。凭借联合创立Denali Therapeutics和Neumora等行业中坚企业的经历，以及近期联合主导Tenvie Therapeutics完成2亿美元融资的成果，Weninger博士逐步形成了清晰的成功法则：降低创新靶点研发风险，深耕小分子药物的持久潜力，并将临床试验重心重新聚焦于生物标志物与真实世界数据。近日，我们与Weninger博士展开对话，深入探讨她构建新一代神经科学企业的策略，以及开创脑部重大疾病治疗新纪元的愿景。

Stacie Weninger博士现任F-Prime生物医学研究倡议主席及F-Prime风险合伙人。她拥有深厚的神经科学背景，职业生涯横跨学术研究、风险投资与科研管理等多个领域。作为神经退行性疾病与精神疾病领域创新疗法研发的重要推动者，她还担任Target ALS等疾病基金会的董事会成员，持续支持生物医学界的研究协作。

感谢您接受我们的采访。我们想首先从您近期的工作谈起，特别是您共同主导Tenvie Therapeutics完成的2亿美元融资。在您看来，这个项目最突出的亮点是什么？它又体现了您在评估神经科学领域企业时关注的哪些关键特质？

Stacie Weninger博士：对我而言，成功始终来源于科学基础与团队能力的有机结合。此前我曾共同领导创立Denali公司，其中令人振奋之处在于其广阔的发展前景：新技术不断涌现，我们对疾病生物学机制的理解也在持续加深。当Denali决定重点发展其突破性的血脑屏障穿越技术平台时，公司还拥有极具潜力的小分子药物研发项目。我们认为这些项目更适合通过私募融资独立发展，于是我们组建了一支顶尖团队将其独立孵化出来，使它们获得足够的资源与专注度。这样就形成了理想的组合：卓越的团队搭配极具前景的基础研发项目。

当前神经科学领域正迎来蓬勃发展的阶段，创新治疗模式不断涌现。然而从长远来看，小分子药物仍将是理想治疗方案之一。一旦我们能够成功降低靶点风险，并证实调控靶点能改变疾病进程，那么最终目标便是研发出具有同等疗效的口服药物。

您清晰阐述了重新聚焦小分子药物的重要性，但同时您也提及了对新型治疗模式的高度关注。在脑衰老治疗领域，您认为还有哪些治疗策略最具潜力？

Stacie Weninger博士：穿越血脑屏障的递送技术正展现出强大潜力。最初我们主要考虑如何递送那些无法轻易穿越血脑屏障的抗体药物，但现在我们意识到其应用远不止于此，比如寡核苷酸和酶等大分子都能通过该技术递送。Denali公司通过递送患者缺失的蛋白酶来治疗亨特综合征（Hunter syndrome）的数据就十分令人振奋。此外，通过RNAi等技术来调控基因表达也展现出巨大前景。随着这些技术在中枢神经系统直接给药模式下不断获得概念验证，若未来能与其他递送技术结合，实现外周给药即可作用于大脑，将会是极具突破性的进展。

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如果我们聚焦于阿尔茨海默病这一富有挑战性的领域，您认为过去十年中最具影响力的进展是什么？未来投资的重大机遇又在哪里？

Stacie Weninger博士：首先，如果靶点本身不正确，就无法开发有效的药物。因此，推进我们对这类复杂、多因素疾病的生物学理解至关重要。同时，我认为研究影响疾病进展速度的基因将带来变革性影响。迄今为止，大多数遗传学研究都聚焦于疾病风险因素，但对于已出现症状的患者而言，影响疾病进展速度的生物通路和基因或许才是更可行的治疗靶点。这方面我们才刚刚开始。

生物标志物同样正在重塑药物研发，其重要性怎么强调都不为过。基于在医生诊所进行的认知测试来评估药效的策略面对噪音大，难度高的挑战。诸多因素都会影响测试结果，比如睡眠质量、通勤压力等等。我们需要建立针对疾病亚型和进展程度的客观、量化生物标志物体系。这一点至关重要，因为阿尔茨海默病存在显著异质性：某些患者可能主要表现为免疫介导的病理特征，而另一些患者则存在溶酶体系统功能障碍。运用生物标志物精准筛选试验对象并量化治疗效果，将真正改变研发格局。

您特别强调了生物标志物的重要性，尤其是多重检测组合这一发展趋势。在开发这类复杂诊断工具的过程中，在科研以及患者可及性层面，我们面临哪些关键挑战？

Stacie Weninger博士：我认为多重生物标志物检测组合是未来发展趋势。单一标志物远远不够，我们需要的是能够一次性检测数十种不同标志物的血液检测方案。鉴于共存病理是普遍现象，我们真正需要的是能检测与神经退行性病变相关的关键蛋白及多种生物系统的广谱检测组合，而非单一的"阿尔茨海默病检测"或"帕金森病检测"。

至于可及性，我并不担忧这项技术。当我们依赖PET和MRI扫描这类昂贵影像学检查手段时，我确实曾为可及性问题忧虑。然而，我毫不怀疑我们将获得具有可及性的血液生物标志物检测组合。

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您关注的另一个关键挑战是临床试验本身。我们应如何重新设计神经病学试验，使其能更真实地反映患者的日常生活状态？

Stacie Weninger博士：在医生诊所里进行的低频认知评估很难反映疾病的真实波动。我在照顾患有神经退行性疾病的父母期间，深切体会到患者病情每天的波动有多么剧烈，更不用说频繁就诊带来的负担。我们需要转向使用可穿戴设备等技术采集的持续真实世界数据，并结合客观生物标志物，作为临床试验终点。

能持续监测患者活动的无创可穿戴设备可能会非常有效，尤其是对于帕金森病等需要监测运动功能的疾病。相比医生诊所里三分钟的评估，全天24小时监测用药期与停药期的活动数据能提供更全面的信息。我们确实需要更积极地采纳这些创新工具。

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现在，让我们将视角转向企业构建与商业策略。考虑到神经科学领域研发周期长、成本高的特点，您认为哪些融资与合作模式最为有效？

Stacie Weninger博士：对小型生物技术公司而言，独立将神经退行性疾病疗法推进至3期临床试验非常困难，因此需要多元化的融资与合作模式。从早期阶段的私募资金，到公开市场投资者，当然还包括大型药企的合作，需要与各方建立合作关系。我们始终需要依靠大型药企来开展大规模3期试验。

慈善资金在降低早期风险方面也发挥着重要作用。神经科学研究难度高，往往需要漫长周期才能达到关键价值拐点。来自家族办公室或大型公益慈善机构的额外资金，不仅能帮助降低早期项目风险，还能增强其他投资者的信心。关键在于组建能够推动项目进展的顶尖团队，而慈善资金能够激励这些顶尖团队挑战高风险靶点，而一旦成功，这些靶点或将带来变革性突破。

回顾这一领域的发展，自《时代》周刊著名的阿尔茨海默病封面报道问世已过去25年。回顾往昔，您认为我们在哪些方面尚未达到预期？展望未来，神经退行性疾病与精神疾病领域有哪些进展最令您振奋？

Stacie Weninger博士：展望未来，让我振奋的是我们对神经退行性疾病靶点的生物学理解不断深化，尤其是外周免疫系统在大脑中的作用，这一方向长期以来被严重低估。在精神病学领域，令我欣喜的是我们正在超越过去"重锤式"的用药方式。如今我们正逐步厘清关键受体的作用，进而设计出在保持疗效的同时大幅降低副作用的治疗方案。

回望过去，我希望我们当时能够更快一些。然而，那时我们缺乏如今掌握的诸多技术手段。以有些早期阿尔茨海默病临床试验为例，我们甚至无法准确诊断患者，部分试验招募了大脑中不存在淀粉样蛋白沉积的受试者，因为当时缺乏可靠的检测手段。PET扫描技术和现今的血液检测改变了这一格局。通过生物标志物更早筛选受试者并缩短验证药物疗效的临床试验时间，我们能够全面加速研发进程。

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从个人经历来看，您曾与家人共同面对这些疾病。基于这样的体验，您认为我们应当如何思考工作的最终目标？是延长寿命，还是致力于缩短寿命与健康寿命之间的差距？

Stacie Weninger博士：这是一个让我深有感触的话题。今年一月，我的父亲因帕金森病相关痴呆离世，目前我也在照料患有额颞叶痴呆的母亲。有时，人们会将延长痴呆症患者寿命几个月与肿瘤学领域的生存期延长相比较，但我认为二者之间存在巨大差异。正如你提到健康寿命与自然寿命之间的区别，我们的目标应该是延长健康寿命。当患者处于痴呆症晚期时，在我看来，重点并不是延长寿命本身。

我希望我们能在预防和早期干预领域投入更多努力。这意味着我们需要更早开始治疗，往往在症状显现之前就采取行动。如果能将神经退行性疾病症状的出现推迟五到十年，那么即便对患者最终寿命影响有限，也足以显著改善他们的健康寿命。对我来说，让患者在认知功能完好、能够独立生活的状态下度过更多时间，才应该是我们的目标。

De-Risking the Brain: A Conversation with Dr. Stacie Weninger, President of the F-Prime Biomedical Research Initiative

Editor’s Note:In the high-stakes, rapidly advancing field of neuroscience, few leaders have been as instrumental in shaping the landscape as Dr. Stacie Weninger. As President of the F-Prime Biomedical Research Initiative (FBRI) and a Venture Partner at F-Prime, she operates at the nexus of foundational science and company creation,identifying transformative research and building world-class teams to translate it into new medicines. With a track record that includes co-founding industry pillars like Denali Therapeutics and Neumora, and recently co-leading a $200 million financing for Tenvie Therapeutics, Dr. Weninger has developed a clear thesis for success:de-risk novel targets, double down on the enduring power of small molecules, and re-focus clinical trials on biomarkers and real-world data. We spoke with Dr. Weninger to understand her strategy for building the next generation of neuroscience companies, and her vision for ushering in a new era of therapies for devastating brain disorders.

Stacie, thank you for speaking with us. We'd like to start with your recent work, beginning with a $200 million round for Tenvie Therapeutics that you co-led. What made that specific opportunity stand out, and what does it say about the key characteristics you look for in neuro-focused companies?

Stacie Weninger:To me, it’s always a combination of science and team.Previously, I co-led the founding of Denali, and part of the excitement there was the broad scope: new technologies were emerging and our understanding of the biology was improving. While Denali decided to double down on its exciting blood-brain barrier platform, it also had a promising program of small molecules. We decided those programs would be better financed privately, so we spun them out with a stellar team to give them the attention they deserved. That created the ideal combination: a phenomenal team and exciting foundational programs.

There's a lot of excitement in neuroscience right now as new modalities emerge. For instance, I was just listening to the latest Huntington's disease data from uniQure, which involves an MRI-guided neurosurgical administration of gene therapy. While that kind of therapy is a heavy lift and challenging to scale, it's an incredible proof of concept showing we can affect these diseases.Ultimately, however, small molecules are going to be among the best drugs.Once we de-risk targets and show that modulating them affects the disease, the ultimate goal will be a pill that can do the same.

You've made a strong case for refocusing on small molecules. At the same time, you mentioned the excitement around new modalities. What other therapeutic approaches for brain aging do you find most promising?

Stacie Weninger:Blood-brain barrier technology is proving to be quite powerful.The original idea was to deliver antibodies that can’t otherwise easily cross into the brain. We've since realized there's so much more we can deliver, such as oligos and enzymes. The data Denali has shown on delivering the missing enzyme to treat Hunter syndrome is very exciting. In addition,the ability to manipulate gene expression through technologies such as RNAi holds great promise.As these technologies achieve further POC with direct CNS administration, it will be exciting if we could further combine technologies to allow peripheral administration.

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If we could zoom in on a specific and challenging area like Alzheimer's, what do you see as the most impactful advances over the past decade, and where are the next big opportunities for investment?

Stacie Weninger:First,if we don't have the right targets, we can’t make the right drugs.The advancements in our biological understanding of these complex, multifactorial disorders have been key.I also think examining genes that affect the rate of disease progression will be transformational.To date, most genetic research has focused on what increases disease risk. But the biological pathways and genes that affect rate of progression might be more tractable as therapeutic targets for patients who are already symptomatic. We've barely scratched the surface there.

Biomarkers are also completely changing drug development. I can't stress their importance enough.Trying to measure a drug's efficacy based on a cognitive test in a doctor's office is extremely noisy and difficult. Many factors influence the result, like how well you slept or how stressful traffic was getting there.We need objective, quantitative biomarkers of disease subtypes and disease progression. This is crucial because Alzheimer's isn’t the same across all patients;for example some may have a more immune-mediated disease while others have issues with their endolysosomal system.Using biomarkers to identify the right patients for a trial and measure the therapeutic effect will be truly game-changing.

You've highlighted the power of biomarkers, particularly the move towards multiplexed panels. As we develop these complex diagnostics, what are the key challenges, both in terms of the science and in ensuring they remain affordable for patients?

Stacie Weninger:I think the future is multiplexed panels of biomarkers.It’s not going to be one single marker; you're going to want a blood test that can measure dozens of different markers at once. As co-pathologies are the norm, not the exception, we really need broad neurodegeneration panels that examine key proteins and various biological systems, not just an "Alzheimer's panel" or a "Parkinson's panel".

As for affordability, I’m not worried about that with this technology. I was worried about how to keep things affordable when we were relying on PET scans and MRI scans, which are very expensive. But I have no doubt that we will have affordable blood biomarker panels.

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Another hurdle you’ve focused on is the clinical trial itself. How can we redesign neurology trials to better reflect the day-to-day reality of living with a disease?

Stacie Weninger:Infrequent cognitive tests in a doctor's office aren't particularly meaningful.Having cared for both my parents with neurodegenerative diseases, I've seen how massive the daily fluctuations are, not to mention the burden of care appointments.We need to move toward using continuous, real-world data from technologies such as wearables, combined with objective biomarkers, as our endpoints.

Noninvasive wearables that continuously measure activity could be very effective, particularly for diseases like Parkinson’s where you want to monitor motor function. Measuring activity 24 hours a day, on meds, off meds, etc., is much better than a three-minute assessment in a doctor’s office. We really need to embrace these tools.

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Shifting to the business side, let’s discuss the strategy behind building these companies. Given the notoriously long and expensive timelines in neuroscience, what financing and partnership models do you see working best?

Stacie Weninger:It's difficult for small biotech companies to take a therapy all the way through a Phase III trial in a neurodegenerative disease, so it requires a combination of models.You need a partnership among everyone, from private investment in early-stage work to public investors and, of course, big pharma. We will always rely on big pharma for large Phase III trials.

Philanthropy also plays a big role in early-stage de-risking.Neuroscience is hard, and it can be a long time before you reach those high-value inflection milestones. Additional financing, whether from family offices or large public charities, helps de-risk projects in the early stages and convinces other investors this is worth investing in. It’s about assembling an A-plus team that can move the needle, and philanthropic funding can encourage these A-plus teams to work on higher-risk targets that could be transformative if they succeed.

Looking at the state of the field, it’s been 25 years since that famous Time Magazine cover on Alzheimer's. When you look back at that time, where do you feel we have fallen short? And when you look forward, what developments in neurodegeneration and psychiatry get you most excited?

Stacie Weninger:When I look forward, I'm excited by our improved biological understanding of targets in neurodegeneration, especially the role of the peripheral immune system in the brain,which has been woefully underappreciated. In psychiatry, I’m excited that we’re moving beyond the "sledgehammer" drugs of the past. We're now understanding the specific receptors that matter, so we can design therapies that maintain efficacy with far fewer side effects.

When I look back, I wish we had been faster. However, we were lacking so many tools that we have now. In some of the early Alzheimer's trials, for example, we couldn't even definitively diagnose someone; some trials enrolled people who didn’t have amyloid in their brains because we didn't have the tools to detect it. PET scans, and now blood tests, have changed that.Using biomarkers to enroll people earlier and run shorter trials to see if a drug is working will accelerate everything.

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On a more personal note, you’ve spoken about your family’s experience with these diseases. From that perspective, how should we think about the ultimate goal of our work? Is it about extending lifespan or closing the gap between lifespan and healthspan?

Stacie Weninger:This is very personal to me. I lost my dad in January to Parkinson's Disease Dementia, and I care for my mother, who has Frontotemporal Dementia. People sometimes compare extending life by a few months in dementia to doing so in oncology, and I think there's a huge difference.To your point on healthspan versus lifespan, we want to extend healthy life. When someone is in the late stages of dementia, to me, it is not about extending life.

I want to see us doing more prevention and early-stage slowing. That means we need to be treating people earlier, often before symptoms appear.If we could delay the onset of neurodegenerative disease symptoms by five or ten years, it would significantly change an individual’s healthspan, even if it doesn't dramatically alter their lifespan.To me, giving people more years of being cognitively intact and living independently should be our goal.

参考资料：

[1] A Trailblazer in Neuroscience and Biotech Leadership. Retrieved JNovember 4, 2025, from https://www.targetals.org/2025/03/28/a-trailblazer-in-neuroscience-and-biotech-leadership/

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