同行致遠 | 數十年來首款！這款曾被放棄的“老藥”，如何為患者帶來“新生”？

編者按：精神分裂癥是一種常見且復雜的嚴重精神疾病，根據世界衛生組織的統計，全球約有2400萬人受到影響。患者常常面臨幻覺、妄想、思維障礙和社交退縮等癥狀，不僅剝奪了他們的正常生活，也給家庭和社會帶來沉重負擔。現有治療手段雖能在一定程度上緩解癥狀，但仍存在療效有限、耐藥性和副作用顯著等難題。近年來，精神疾病新藥研發迎來突破，不僅為精神分裂癥患者帶來了數十年來首款新機制療法，也開辟了精神疾病治療的新方向。長期以來，藥明康德始終支持精神疾病藥物的研發，依托“一體化、端到端”的CRDMO模式，助力合作伙伴將科學突破高效轉化為創新藥物。本文將通過一名患者的故事，走近這一領域的探索與希望。

點亮大腦中的“燈泡”

蒂姆（Tim）是一位20多歲的年輕人，自青少年時期便被確診為精神分裂癥。多年來，他接受過多種抗精神病藥物治療，但效果始終有限。藥物還帶來多種副作用：體重增加、過度嗜睡以及難以忍受的靜坐不能（akathisia）。這讓他逐漸失去了堅持服藥的意愿。隨著用藥依從性下降，他的癥狀越來越難以控制。家人形容他越來越沉默寡言，陷入自己的世界，眼神空洞，又經常出現情緒激動并難以控制行為。蒂姆的生活似乎陷入了反復住院和生活狀態紊亂的循環之中。

直到2024年，蒂姆開始使用Cobenfy（xanomeline/trospium）。他的變化幾乎是立竿見影，短短數周，家人發現他眼中的空洞感消失了，取而代之的是久違的神采。醫生將這種轉變形容為“燈泡效應”（the light bulb effect）：就像一盞久未點亮的燈突然被點亮，蒂姆的個性與活力被重新照亮，他的家人也第一次看到了希望。而這款給蒂姆和他的家人帶來希望的新藥也曾走過漫長而曲折的開發路程。

圖片來源：123RF

原本用于治療阿爾茨海默病，卻發現意外療效

讓我們回到上世紀90年代，諾和諾德（Novo Nordisk）和禮來（Eli Lilly and Company）合作在臨床試驗中評估一款M1/M4型毒蕈堿乙酰膽堿受體（mAChR）激動劑xanomeline治療阿爾茨海默病（AD）的效果。當時，膽堿能假說是科學家們提出的AD病理機制之一，認為刺激膽堿能系統可能改善患者的認知功能。Xanomeline的設計構想是在患者的神經遞質乙酰膽堿缺乏的情況下，通過直接激活M1/M4型毒蕈堿受體來刺激膽堿能系統，從而改善患者癥狀。

這款藥物被推進到治療AD的2期臨床試驗中，不過結果卻不夠理想，雖然它對患者的記憶能力有一定的改善，但是刺激外周毒蕈堿受體帶來了一系列不良反應，包括惡心、嘔吐和過度唾液分泌等。最終，xanomeline的研發進程被擱置。“因為我們覺得它在AD患者中沒有表現出足夠的安全性和耐受性。”當時負責這一研發項目的Steve Paul博士回憶道。

▲Xanomeline的化學結構（圖片來源：PubChem）

不過，作為臨床試驗的一部分，研究人員發現xanomeline在治療與AD相關的精神病發作（包括幻覺和妄想）方面表現出顯著的效果。“這完全是意外的發現，”Paul博士表示，“我們沒有想過它會發生。”研究人員在1997年發表了這一研究結果。

受到這項研究的啟發，研究人員在一項小型臨床試驗中檢驗了xanomeline治療精神分裂癥患者的效果。在這些患者中xanomeline同樣顯示出療效，不過不良反應仍然是阻止進一步研發的“攔路虎”。Xanomeline在精神分裂癥方面的研發同樣被擱置。而讓這款藥物“起死回生”的轉機來自一位沒有接受過正式神經科學和心理學培訓的年輕人。

從被擱置到重獲新生

2008年，Andrew Miller博士加入PureTech Health公司，他最初的任務是閱讀文獻和與研發人員交流，積累在新藥研發方面的專長。在閱讀和探索的過程中，他被精神分裂癥導致長期嚴重殘疾的特征深深觸動。

Miller博士對精神分裂癥的興趣讓他從文獻中找到了被擱置的xanomeline，他和PureTech公司的同事意識到如果能夠將xanomeline與不能穿過血腦屏障的毒蕈堿受體阻斷劑聯用，就可能在保留xanomeline在大腦中的抗精神病效力的同時，降低因為激活外周毒蕈堿受體帶來的不良反應。

圖片來源：123RF

他們通過文獻查詢發現了上百種毒蕈堿受體阻斷劑，最終選擇了trospium作為與xanomeline匹配的毒蕈堿受體阻斷劑。這一組合成為了后來的KarXT。PureTech Health創建了Karuna Therapeutics公司，致力于推動KarXT的臨床開發。而與這一分子頗有淵源的Steve Paul博士在從禮來公司退休后，也在2018年加入Karuna Therapeutics，成為該公司的首席執行官。

2019年，KarXT在2期臨床試驗（EMERGENT-1）中達到主要終點，不但顯著改善了患者的精神分裂癥陽性和陰性癥狀量表（PANSS）總分，還顯示出良好的耐受性，患者因不良事件停藥率與安慰劑組類似，未出現嗜睡或體重增加等其他常見抗精神病藥物相關的不良反應。

2023年12月，百時美施貴寶（Bristol Myers Squibb）斥資140億美元收購了Karuna公司。2024年，KarXT獲得（商品名Cobenfy），成為幾十年來首個具有創新作用機制的抗精神病藥物。

精神疾病藥物研發的新方向

伴隨著Cobenfy的成功，毒蕈堿乙酰膽堿受體靶向療法的開發也成為神經系統疾病的重要研發方向之一。2024年在

Nature Reviews Drug Discovery

百時美施貴寶正在多項3期臨床試驗中評估Cobenfy用于治療阿爾茨海默病患者的精神病發作和激越癥狀的效果。與Cobenfy的作用機制類似，MapLight Therapeutics開發的ML-007C-MA同樣由M1/M4受體激動劑與外周作用的mAChR阻斷劑組成，目前處于2期臨床開發階段，用于治療精神分裂癥及阿爾茨海默病相關精神病發作。

為了提高mAChR藥物的亞型選擇性，研究者轉向別構調節劑。這些藥物不與乙酰膽堿的活性結合位點結合，而是通過作用于mAChR的別構位點來調節受體活性。由于不同亞型的別構位點差異更大，這種方法有望帶來選擇性更強的新藥。

在這一方向上，Neumora公司開發的NMRA-861是一款潛在“best-in-class”M4亞型mAChR正向別構調節劑（PAM），已經進入1期臨床開發階段。艾伯維（AbbVie）公司計劃在臨床試驗中探索M4選擇性PAM emraclidine作為附加療法，與現有療法聯用治療神經精神疾病的效果。

對mAChR結構更為詳盡的解析，也推動了基于結構的藥物設計。Nxera Pharma與Neurocrine Biosciences合作開發了一系列高選擇性的mAChR激動劑。用于治療精神分裂癥的direclidine（M4亞型選擇性激動劑）目前處于3期臨床試驗階段。Neurocrine還有多款M1/M4激動劑在1期臨床開發階段。

改變精神疾病患者的生命

讓我們回到文章開頭的蒂姆，在接受Cobenfy治療后，他開始主動與家人交談，積極參加治療小組，并提出想要嘗試找一份兼職工作。更重要的是，他不再因不良反應而拒絕服藥，終于能夠穩定地堅持治療了。他的醫生，塔夫茨大學（Tufts University）神經科學系轉化研究主任Michael Halassa博士表示，對于蒂姆來說，Cobenfy不只是另一款新藥，而是一條生命線。

作為全球醫藥創新的賦能者，藥明康德很高興能助力合作伙伴，加速多款治療精神疾病的創新療法問世，造福病患。長期以來，藥明康德都在支持全球合作伙伴從藥物研究（R）、開發（D）到商業化生產（M）各個階段的需求，通過獨特的一體化、端到端CRDMO模式，助力更多藥物加速從實驗室來到患者身邊。

以治療精神疾病的小分子藥物為例，藥明康德化學服務平臺能支持各種化學藥物的分子形式及類別，滿足從藥物發現到商業化生產各個階段、各個規模的各種物料需求。藥明康德生物學業務平臺作為綜合性的早期發現和轉化生物學賦能平臺，能為包括精神疾病在內的多個疾病領域的新藥研發提供從早期發現到臨床研究階段的生物學解決方案。藥明康德測試業務平臺可提供全生命周期的一體化研發測試服務及全方位的臨床研究服務，助力合作伙伴的藥物成功申報IND、NDA以及通過核查上市。

在這個世界精神衛生日，讓我們向科學家、患者和所有推動創新的力量致敬。正是這些不懈努力，讓越來越多的患者看到希望的曙光。藥明康德將繼續依托其“一體化、端到端”的CRDMO平臺，加速合作伙伴的更多創新療法問世，讓科學的力量惠及每一位患者。

First in Decades! How a Once-Abandoned "Old Drug" Is Giving Patients New Hope

Schizophrenia is a common yet complex and serious mental illness that affects about 24 million people worldwide, according to the World Health Organization. Patients often suffer from hallucinations, delusions, disorganized thinking, and social withdrawal, symptoms that not only rob them of a normal life but also impose a heavy burden on families and society. Existing treatments can alleviate symptoms to some degree, but they remain limited by modest efficacy, treatment resistance, and significant side effects.

In recent years, breakthroughs in psychiatric drug development have reshaped the field, delivering the first novel mechanism therapy for schizophrenia in decades. This progress not only offers new hope for patients but also points to a broader shift in treatment approaches for mental illness. WuXi AppTec has long supported psychiatric drug discovery and development, leveraging its fully integrated, end-to-end CRDMO model to help partners efficiently transform scientific advances into innovative medicines. On this World Mental Health Day, we share the story of one patient to illustrate the possibilities that new therapies are bringing to this challenging area.

Lighting Up the "Light Bulb" in the Brain

Tim, a man in his twenties, was diagnosed with schizophrenia as a teenager. Over the years, he tried multiple antipsychotics, but the benefits were limited. Worse still, side effects such as weight gain, excessive drowsiness, and intolerable akathisia gradually eroded his willingness to stay on medication. As adherence declined, his symptoms spiraled out of control. His family described him as increasingly withdrawn, trapped in his own world, with a vacant gaze and bouts of agitation that he could not manage. His life became a cycle of hospitalizations and instability.

Everything changed in 2024 when Tim began treatment with Cobenfy (xanomeline/trospium). Within weeks, the "emptiness" in his eyes disappeared, replaced by vitality his family had not seen in years. Doctors referred to this as "the light bulb effect," as if a long-darkened bulb had suddenly switched on, revealing Tim’s personality and energy once more. For his family, it was the first real glimmer of hope. Yet the therapy that transformed Tim’s life had itself traveled a long and winding road to approval.

Originally Developed for Alzheimer’s Disease, with an Unexpected Effect

The story of Cobenfy begins in the 1990s, when Novo Nordisk and Eli Lilly and Company collaborated on clinical trials of xanomeline, an M1/M4 muscarinic acetylcholine receptor (mAChR) agonist, for Alzheimer’s disease (AD). At the time, the cholinergic hypothesis, suggesting that stimulating the cholinergic system could improve cognition, was widely studied. Xanomeline was designed to directly activate M1/M4 muscarinic receptors to compensate for acetylcholine deficiency, thereby improving symptoms.

Although xanomeline was advanced into Phase 2 trials, the results were mixed. While memory improved to some extent, activation of peripheral muscarinic receptors triggered adverse effects such as nausea, vomiting, and excessive salivation. Ultimately, the program was shelved. "We felt it didn’t show sufficient safety and tolerability in AD patients," recalled Dr. Steve Paul, who led the project at the time.

Yet amid these disappointing results, researchers noticed something surprising: xanomeline had a significant effect on AD-related psychosis, including hallucinations and delusions. "It was completely unexpected," Dr. Paul noted. "We didn’t think it would happen." The findings, published in 1997, sparked further curiosity.

Encouraged, xanomeline was tested in a small group of schizophrenia patients. The drug again showed signs of efficacy, but intolerable side effects halted further development. Once more, xanomeline was shelved, until an unlikely champion emerged: a young scientist without formal training in neuroscience or psychology.

From Shelved to Reborn

In 2008, Dr. Andrew Miller joined PureTech Health, initially tasked with reviewing literature and engaging with researchers to build expertise in drug development. While doing so, he was struck by the profound disability caused by schizophrenia.

Digging deeper, Dr. Miller rediscovered xanomeline. He and colleagues at PureTech recognized that pairing xanomeline with a peripherally acting muscarinic antagonist, one unable to cross the blood-brain barrier, might retain its antipsychotic activity in the brain while reducing peripheral side effects.

After screening hundreds of candidates, they identified trospium as the best match. This combination became KarXT. To advance it, PureTech Health founded Karuna Therapeutics. In 2018, Dr. Steve Paul, who had once led the xanomeline development, joined Karuna as CEO, bringing the story full circle.

In 2019, KarXT met its primary endpoint in the Phase 2 EMERGENT-1 trial, significantly improving the Positive and Negative Syndrome Scale (PANSS) scores. Importantly, tolerability was favorable: discontinuation rates due to adverse events were similar to placebo, and the common side effects of traditional antipsychotics, such as somnolence and weight gain, were not observed.

Momentum built quickly. In December 2023, Bristol Myers Squibb acquired Karuna for $14 billion. By 2024, KarXT was approved by the FDA under the brand name Cobenfy, marking the first antipsychotic with a novel mechanism in decades.

A New Direction for Psychiatric Drug Development

Cobenfy’s approval signaled more than the success of one drug; it reignited interest in muscarinic receptor-based therapies. A 2024 article in

Nature Reviews Drug Discovery

Bristol Myers Squibb is now conducting multiple Phase 3 trials to assess Cobenfy in AD-related psychosis and agitation. Similarly, MapLight Therapeutics is developing ML-007C-MA, a combination of an M1/M4 agonist with a peripherally acting muscarinic receptor antagonist, now in Phase 2 for schizophrenia and AD-related psychosis.

To further refine the approach, researchers are focusing on subtype selectivity. Allosteric modulators, agents that bind to receptor sites distinct from acetylcholine’s binding site, are emerging as a promising solution, as differences among allosteric sites can allow for greater subtype specificity.

Neumora’s NMRA-861, a potentially "best-in-class" M4 positive allosteric modulator (PAM), is already in Phase 1. AbbVie, meanwhile, plans to explore the M4-selective PAM emraclidine as an add-on therapy in neuropsychiatric disease trials.

Advances in mAChR structural biology are also fueling structure-based drug design. Nxera Pharma and Neurocrine Biosciences are co-developing a portfolio of highly selective agonists, including direclidine (an M4-selective agonist) now in Phase 3 for schizophrenia. Neurocrine also has multiple M1/M4 agonists in Phase 1 development.

Changing Patients’ Lives

Returning to Tim’s story, the impact of Cobenfy has been profound. He began conversing with his family again, actively joined therapy groups, and even expressed interest in part-time work. Most importantly, he no longer refused medication due to side effects and could finally remain on consistent treatment. For Tim, said Dr. Michael Halassa, director of Translational Research in the Department of Neuroscience at Tufts University, Cobenfy was not just another drug, but a lifeline.

As a trusted partner to innovators worldwide, WuXi AppTec plays a vital role in advancing the next generation of therapies for neurological and psychiatric diseases, including schizophrenia, through its integrated CRDMO platform. By combining scientific expertise with integrated global infrastructure, WuXi AppTec enables faster, more efficient progress across the entire drug development lifecycle.

For small-molecule innovation, WuXi AppTec’s Chemistry Services Platform supports all categories of chemical compounds and production scales. This infrastructure helps partners meet material needs from lead optimization to clinical supply and beyond. Meanwhile, WuXi AppTec’s Biology Business Unit offers an integrated platform for early discovery and translational biology, empowering researchers to evaluate new targets and mechanisms in neurological diseases with precision and speed.

WuXi AppTec’s Testing Division enhances these capabilities with comprehensive R&D testing and clinical research services. From preclinical safety assessments to IND/NDA-enabling studies, the team helps streamline regulatory submissions and approval processes. This integrated model not only accelerates timelines but also enhances efficiency—helping transform innovative ideas into life-saving therapies.

Looking Forward

On this World Mental Health Day, we honor the scientists, patients, and all those driving innovation forward. Through their tireless efforts, more and more patients are seeing a brighter future. WuXi AppTec will continue to leverage its fully integrated, end-to-end CRDMO platform to help partners bring more groundbreaking therapies to life, ensuring that the power of science reaches every patient.

參考資料：

[1] 世界精神衛生日：10月10日. Retrieved September 23, 2025, from https://www.who.int/zh/campaigns/world-mental-health-day

[2] Early Experience with Cobenfy: A Promising Schizophrenia Treatment for Specific Cases. Retrieved September 23, 2025, from https://michaelhalassa.com/early-experience-with-cobenfy-a-breakthrough-in-schizophrenia-treatment-for-resistant-cases/

[3] The inside story of Cobenfy. Retrieved September 23, 2025, from https://www.healio.com/news/psychiatry/20241003/the-inside-story-of-cobenfy

[4] The Making of BMS’ Cobenfy: From Alzheimer’s to Schizophrenia. Retrieved September 23, 2025, from https://www.biospace.com/drug-development/the-making-of-bms-cobenfy-from-alzheimers-to-schizophrenia

[5] Schizophrenia. Retrieved September 23, 2025, from https://www.who.int/news-room/fact-sheets/detail/schizophrenia

[6] Fierce 50 of 2025 / Breakthrough Honorees / Andrew Miller. Retrieved September 25, 2025, from https://www.fiercepharma.com/fierce-50/andrew-miller

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