Tovorafenib

编者按：中枢神经系统（CNS）疾病由于病理机制复杂，且药物入脑受到血脑屏障（BBB）的限制，一直被认为是药物研发领域的重大挑战。尽管困难重重，但FDA已在CNS领域先后批准多款小分子药物的临床批件或上市，凸显了小分子疗法在CNS治疗中的重要作用。与此同时，靶向蛋白降解（TPD）等新兴技术的出现，为下一代疗法开辟了全新的可能。在这一不断演进的研发趋势下，药明康德作为全球医药及生命科学行业值得信赖的合作伙伴，已构建起完善的CNS能力体系，覆盖从早期筛选到IND申报的全流程。凭借丰富经验与深厚积累，药明康德致力于加速全球合作伙伴的CNS药物研发进程，携手为患者带来改变生命的创新疗法。在医药领域，CNS药物研发一直被视为最具挑战性的任务之一。其主要障碍在于BBB——这一高度选择性的生理“守门人”仅允许分子量约在400–600 Da以下的脂溶性分子被动扩散进入大脑。正因如此，药物在脑内的递送效率往往受限，导致疗效不足；如果提高用药剂量，药物在其他器官和组织中的非靶向分布又会引发更多副作用。除了BBB，CNS疾病本身的高度异质性与复杂病理机制，以及缺乏可靠生物标志物，也让研发难度进一步加大。图片来源：123RF在这样的背景下，小分子疗法展现出一定的优势。凭借较低的分子量，它们更容易穿透BBB；再加上固有的药代动力学优势以及较高的口服生物利用度，使小分子药物成为CNS治疗的重要选择。近期多款小分子药物获FDA批准用于CNS疾病，进一步印证其临床价值。2024年9月，Cobenfy®（xanomeline/trospium chloride）获批，成为首个通过靶向胆碱能通路（而非多巴胺通路）的口服小分子抗精神病药物，为该领域开辟了全新的作用机制。同年8月，可穿透血脑屏障的“first-in-class”小分子Voranigo®（vorasidenib）获FDA批准，用于治疗2级异柠檬酸脱氢酶1（IDH1）或异柠檬酸脱氢酶2（IDH2）突变型胶质瘤。而在同年4月，Ojemda（tovorafenib）获批用于治疗携带BRAF重排的儿童低级别胶质瘤，显示系统性小分子激酶抑制剂在CNS治疗上的潜力。除已上市的疗法外，目前还有多款小分子药物处于3期临床试验阶段，适应症涵盖阿尔茨海默病、肌萎缩侧索硬化症（“渐冻症”）等重大疾病。与此同时，新兴技术也在不断拓展CNS的治疗版图。以“降解而非抑制”靶蛋白的独特机制为特点的靶向蛋白降解，正逐步进入CNS药物研发的视野。与传统抑制剂相比，蛋白降解剂无需在组织（如大脑）达到高水平暴露；鉴于TPD不依赖药物饱和，且可在较低配体浓度下累积药理效应，这为需跨越血脑屏障而又常受分子量限制的疾病（如多发性硬化、脑转移）带来新的治疗可能。目前，Arvinas的口服蛋白降解靶向嵌合体（proteolysis-targeting chimera，PROTAC®）降解剂ARV-102已在1期CNS临床试验中展现出穿透BBB的能力，并在脑脊液（CSF）中实现了显著的靶点蛋白降解。在这一持续发展的领域中，药明康德成为全球创新者推动CNS药物研发的重要合作伙伴。针对该领域的特殊挑战，药明康德建立了多项CNS专属的药物代谢与药代动力学（DMPK）能力。例如，其独特的“漏斗（Funnel）”体外检测模型展现出高度准确性，能够有效区分可穿透血脑屏障的药物与因被动扩散能力不足或受外排转运蛋白影响而无法进入的药物，帮助合作伙伴快速识别潜力候选疗法，从而高效推进研发进程。▲药明康德“Funnel”检测模型用于小分子体外脑渗透性评估除了早期筛选，药明康德还为合作伙伴提供多样化的定制化研究策略，包括脑室内或鞘内给药、微透析技术、在啮齿类和大型动物模型中进行脑脊液连续采样、精确解剖和分离近20种不同脑区组织，以及利用全身自显影（QWBA）全面展示药物在脑内的分布。这些能力不仅应用于小分子药物，也广泛支持蛋白质、寡核苷酸等大分子药物，从早期筛选直至IND申报。小分子药物近期在CNS治疗领域的进展，充分展现了科学创新与产业协作的力量。而随着靶向蛋白降解等新兴技术的加入，CNS研发管线将迎来更多活力。在这一充满机遇的时代，药明康德始终坚持赋能全球合作伙伴，提供先进而可靠的CNS研发平台，加速创新疗法的落地。秉持“让天下没有难做的药，难治的病”的愿景，药明康德将继续支持CNS药物研发进步，造福全球患者。The Resurgence of Small-Molecule Drugs in CNS TherapeuticsCentral nervous system (CNS) diseases have long represented one of the greatest challenges in drug development, owing to their complex pathophysiology and the protective barrier of the blood–brain barrier (BBB). Despite these difficulties, the FDA has recently approved several small-molecule drugs in the CNS field, highlighting recent progress of small-molecule therapies in CNS treatment. At the same time, the emergence of new technologies such as targeted protein degradation (TPD) is opening up entirely new possibilities for future innovation. In this evolving landscape, WuXi AppTec serves as an enabler of innovation and a trusted partner, offering a suite of CNS-specific capabilities to support partners from early screening through IND filing and clinical stage. With these resources, WuXi AppTec is dedicated to accelerating CNS drug discovery, empowering global partners to deliver life-changing therapies for patients worldwide. Developing CNS drugs has long been one of the most challenging tasks in the biopharmaceutical field. A principal barrier is the BBB, a highly selective physiological gatekeeper that generally allows only lipophilic molecules under ~400–600 Da to passively diffuse into the brain. This limitation often leads to inefficient delivery of therapeutic agents, resulting in low efficacy and increased side effects due to off-target drug distribution in other organs and tissues. Beyond the BBB, the heterogeneity and complex pathophysiology of many CNS disorders, along with the scarcity of reliable biomarkers, further complicate drug development.In this context, small-molecule drugs offer clear advantages. Their relatively low molecular weight allows them to more effectively penetrate the BBB, while their inherent pharmacokinetic properties and high oral bioavailability further strengthen their therapeutic value. Taken together, these attributes support consideration of small molecules as one viable therapeutic option in the treatment of CNS disorders.Several recent FDA approvals in the CNS field have included small-molecule therapies. For example, Cobenfy® (xanomeline/trospium chloride), the first antipsychotic designed to target cholinergic rather than dopaminergic pathways, was approved in September 2024 as an oral small-molecule combination for schizophrenia, introducing a new mechanistic class in the field. Similarly, Voranigo® (vorasidenib) received FDA approval in August 2024 for grade 2 IDH1- or IDH2-mutant gliomas, providing a first-in-class brain-penetrant small molecule that inhibits mutant enzymes IDH1 and IDH2. Adding to this progress, Ojemda (tovorafenib) was cleared in April 2024 for pediatric low-grade glioma harboring BRAF rearrangements, representing another systemic small-molecule kinase inhibitor capable of navigating the CNS to reach its target. Beyond these approvals, several investigational small-molecule therapies are currently in phase 3 clinical trials for conditions such as Alzheimer’s disease and amyotrophic lateral sclerosis.At the same time, emerging technologies are continuously expanding the landscape of CNS therapeutics. Targeted protein degradation, distinguished by its unique mechanism of degrading rather than inhibiting target proteins, is gradually entering the field of CNS drug development. Unlike traditional inhibitors, protein degraders do not need to reach high concentrations in target tissues such as the brain. Because TPD does not rely on target saturation and can deliver sustained pharmacology at low ligand exposure, it opens new avenues for diseases that must cross the blood–brain barrier yet are often constrained by molecular size, including multiple sclerosis and brain metastases. Notably, oral proteolysis-targeting chimera (PROTAC®) degraders have demonstrated the ability to penetrate the BBB in phase 1 CNS clinical trials and have achieved significant target protein degradation in cerebrospinal fluid (CSF).In this evolving landscape, WuXi AppTec serves as a trusted partner for global innovators pursuing CNS drug development. Recognizing the unique hurdles in this space, WuXi AppTec has established CNS-specific DMPK capabilities. Its distinctive “Funnel” model has demonstrated remarkable accuracy, effectively distinguishing between CNS-penetrant small-molecule drugs and those hindered by poor passive diffusion. This enables partners to rapidly identify promising candidates and move them forward with confidence.▲WuXi AppTec's "Funnel" model for in vitro brain permeability evaluation of small moleculesBeyond early screening, WuXi AppTec provides tailored experimental strategies such as lateral ventricular or intrathecal administration, microdialysis, serial CSF sampling in rodent and large animal models, precise separation and collection of approximately 20 brain regions, and quantitative whole-body autoradiography (QWBA) to comprehensively map drug distribution. These tools are applied not only to small molecules but also to proteins and oligonucleotides, supporting partners from discovery through IND filings.Recent advances in CNS therapeutics—including small-molecule medicines—underscore steady scientific progress and strong industry collaboration. In parallel, novel modalities such as targeted protein degradation are bringing fresh momentum to CNS pipelines and expanding the range of viable treatment approaches. In this era of opportunity, WuXi AppTec remains committed to empowering its global partners, offering advanced CNS-focused platforms that accelerate translational progress. Guided by the vision that “every drug can be made and every disease can be treated,” WuXi AppTec continues to enable CNS drug discovery for the ultimate benefit of patients worldwide.参考资料：[1] The future of CNS drug development: signs of real progress. Retrieved September 2, 2025 from https://www.drugtargetreview.com/article/168079/the-future-of-cns-drug-development-signs-of-real-progress/[2] Central Nervous System (CNS) Drugs DMPK Services. Retrieved September 4, 2025 from https://dmpkservice.wuxiapptec.com/central-nervous-system-drugs-dmpk-services.html[3] First-in-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of ARV-102, a PROTAC LRRK2 Degrader, in Healthy Volunteers. Retrieved September 4, 2025 from https://arvinasmedical.com/wp-content/uploads/2025/04/AD-PD-2025-ARV-102-Phase-1-Oral_Final.pdf[4] Bexobrutideg (NX-5948) is a CNS-Penetrant Catalytic Bruton’s Tyrosine Kinase (BTK) Degrader That Breaks Established Design Rules for CNS Drugs. Retrieved September 9, 2025 from https://www.nurixtx.com/wp-content/uploads/2025/04/Bexobrutideg-NX-5948-CNS-Penetrant-Catalytic-BTK-Degrader-that-Breaks-Established-Design-Rules-for-CNS-Drugs.pdf免责声明：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：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

编者按：中枢神经系统（CNS）疾病由于病理机制复杂，且药物入脑受到血脑屏障（BBB）的限制，一直被认为是药物研发领域的重大挑战。尽管困难重重，但FDA已在CNS领域先后批准多款小分子药物的临床批件或上市，凸显了小分子疗法在CNS治疗中的重要作用。与此同时，靶向蛋白降解（TPD）等新兴技术的出现，为下一代疗法开辟了全新的可能。在这一不断演进的研发趋势下，药明康德作为全球医药及生命科学行业值得信赖的合作伙伴，已构建起完善的CNS能力体系，覆盖从早期筛选到IND申报的全流程。凭借丰富经验与深厚积累，药明康德致力于加速全球合作伙伴的CNS药物研发进程，携手为患者带来改变生命的创新疗法。 在医药领域，CNS药物研发一直被视为最具挑战性的任务之一。其主要障碍在于BBB——这一高度选择性的生理“守门人”仅允许分子量约在400–600 Da以下的脂溶性分子被动扩散进入大脑。正因如此，药物在脑内的递送效率往往受限，导致疗效不足；如果提高用药剂量，药物在其他器官和组织中的非靶向分布又会引发更多副作用。除了BBB，CNS疾病本身的高度异质性与复杂病理机制，以及缺乏可靠生物标志物，也让研发难度进一步加大。 在这样的背景下，小分子疗法展现出一定的优势。凭借较低的分子量，它们更容易穿透BBB；再加上固有的药代动力学优势以及较高的口服生物利用度，使小分子药物成为CNS治疗的重要选择。 近期多款小分子药物获FDA批准用于CNS疾病，进一步印证其临床价值。2024年9月，Cobenfy®（xanomeline/trospium chloride）获批，成为首个通过靶向胆碱能通路（而非多巴胺通路）的口服小分子抗精神病药物，为该领域开辟了全新的作用机制。同年8月，可穿透血脑屏障的“first-in-class”小分子Voranigo®（vorasidenib）获FDA批准，用于治疗2级异柠檬酸脱氢酶1（IDH1）或异柠檬酸脱氢酶2（IDH2）突变型胶质瘤。而在同年4月，Ojemda（tovorafenib）获批用于治疗携带BRAF重排的儿童低级别胶质瘤，显示系统性小分子激酶抑制剂在CNS治疗上的潜力。除已上市的疗法外，目前还有多款小分子药物处于3期临床试验阶段，适应症涵盖阿尔茨海默病、肌萎缩侧索硬化症等重大疾病。 与此同时，新兴技术也在不断拓展CNS的治疗版图。以“降解而非抑制”靶蛋白的独特机制为特点的靶向蛋白降解，正逐步进入CNS药物研发的视野。与传统抑制剂相比，蛋白降解剂无需在组织（如大脑）达到高水平暴露；鉴于TPD不依赖药物饱和，且可在较低配体浓度下累积药理效应，这为需跨越血脑屏障而又常受分子量限制的疾病（如多发性硬化、脑转移）带来新的治疗可能。目前，Arvinas的口服蛋白降解靶向嵌合体（proteolysis-targeting chimera，PROTAC®）降解剂ARV-102已在1期CNS临床试验中展现出穿透BBB的能力，并在脑脊液（CSF）中实现了显著的靶点蛋白降解。 在这一持续发展的领域中，药明康德成为全球创新者推动CNS药物研发的重要合作伙伴。针对该领域的特殊挑战，药明康德建立了多项CNS专属的药物代谢与药代动力学（DMPK）能力。例如，其独特的“漏斗（Funnel）”体外检测模型展现出高度准确性，能够有效区分可穿透血脑屏障的药物与因被动扩散能力不足或受外排转运蛋白影响而无法进入的药物，帮助合作伙伴快速识别潜力候选疗法，从而高效推进研发进程。 ▲药明康德“Funnel”检测模型用于小分子体外脑渗透性评估 除了早期筛选，药明康德还为合作伙伴提供多样化的定制化研究策略，包括脑室内或鞘内给药、微透析技术、在啮齿类和大型动物模型中进行脑脊液连续采样、精确解剖和分离近20种不同脑区组织，以及利用全身自显影（QWBA）全面展示药物在脑内的分布。这些能力不仅应用于小分子药物，也广泛支持蛋白质、寡核苷酸等大分子药物，从早期筛选直至IND申报。 小分子药物近期在CNS治疗领域的进展，充分展现了科学创新与产业协作的力量。而随着靶向蛋白降解等新兴技术的加入，CNS研发管线将迎来更多活力。在这一充满机遇的时代，药明康德始终坚持赋能全球合作伙伴，提供先进而可靠的CNS研发平台，加速创新疗法的落地。秉持“让天下没有难做的药，难治的病”的愿景，药明康德将继续支持CNS药物研发进步，造福全球患者。 The Resurgence of Small-Molecule Drugs in CNS Therapeutics Central nervous system (CNS) diseases have long represented one of the greatest challenges in drug development, owing to their complex pathophysiology and the protective barrier of the blood–brain barrier (BBB). Despite these difficulties, the FDA has recently approved several small-molecule drugs in the CNS field, highlighting recent progress of small-molecule therapies in CNS treatment. At the same time, the emergence of new technologies such as targeted protein degradation (TPD) is opening up entirely new possibilities for future innovation. In this evolving landscape, WuXi AppTec serves as an enabler of innovation and a trusted partner, offering a suite of CNS-specific capabilities to support partners from early screening through IND filing and clinical stage. With these resources, WuXi AppTec is dedicated to accelerating CNS drug discovery, empowering global partners to deliver life-changing therapies for patients worldwide.  Developing CNS drugs has long been one of the most challenging tasks in the biopharmaceutical field. A principal barrier is the BBB, a highly selective physiological gatekeeper that generally allows only lipophilic molecules under ~400–600 Da to passively diffuse into the brain. This limitation often leads to inefficient delivery of therapeutic agents, resulting in low efficacy and increased side effects due to off-target drug distribution in other organs and tissues. Beyond the BBB, the heterogeneity and complex pathophysiology of many CNS disorders, along with the scarcity of reliable biomarkers, further complicate drug development. In this context, small-molecule drugs offer clear advantages. Their relatively low molecular weight allows them to more effectively penetrate the BBB, while their inherent pharmacokinetic properties and high oral bioavailability further strengthen their therapeutic value. Taken together, these attributes support consideration of small molecules as one viable therapeutic option in the treatment of CNS disorders. Several recent FDA approvals in the CNS field have included small-molecule therapies. For example, Cobenfy® (xanomeline/trospium chloride), the first antipsychotic designed to target cholinergic rather than dopaminergic pathways, was approved in September 2024 as an oral small-molecule combination for schizophrenia, introducing a new mechanistic class in the field. Similarly, Voranigo® (vorasidenib) received FDA approval in August 2024 for grade 2 IDH1- or IDH2-mutant gliomas, providing a first-in-class brain-penetrant small molecule that inhibits mutant enzymes IDH1 and IDH2. Adding to this progress, Ojemda (tovorafenib) was cleared in April 2024 for pediatric low-grade glioma harboring BRAF rearrangements, representing another systemic small-molecule kinase inhibitor capable of navigating the CNS to reach its target. Beyond these approvals, several investigational small-molecule therapies are currently in phase 3 clinical trials for conditions such as Alzheimer’s disease and amyotrophic lateral sclerosis. At the same time, emerging technologies are continuously expanding the landscape of CNS therapeutics. Targeted protein degradation, distinguished by its unique mechanism of degrading rather than inhibiting target proteins, is gradually entering the field of CNS drug development. Unlike traditional inhibitors, protein degraders do not need to reach high concentrations in target tissues such as the brain. Because TPD does not rely on target saturation and can deliver sustained pharmacology at low ligand exposure, it opens new avenues for diseases that must cross the blood–brain barrier yet are often constrained by molecular size, including multiple sclerosis and brain metastases. Notably, oral proteolysis-targeting chimera (PROTAC®) degraders have demonstrated the ability to penetrate the BBB in phase 1 CNS clinical trials and have achieved significant target protein degradation in cerebrospinal fluid (CSF). In this evolving landscape, WuXi AppTec serves as a trusted partner for global innovators pursuing CNS drug development. Recognizing the unique hurdles in this space, WuXi AppTec has established CNS-specific DMPK capabilities. Its distinctive “Funnel” model has demonstrated remarkable accuracy, effectively distinguishing between CNS-penetrant small-molecule drugs and those hindered by poor passive diffusion. This enables partners to rapidly identify promising candidates and move them forward with confidence. ▲WuXi AppTec's "Funnel" model for in vitro brain permeability evaluation of small molecules Beyond early screening, WuXi AppTec provides tailored experimental strategies such as lateral ventricular or intrathecal administration, microdialysis, serial CSF sampling in rodent and large animal models, precise separation and collection of approximately 20 brain regions, and quantitative whole-body autoradiography (QWBA) to comprehensively map drug distribution. These tools are applied not only to small molecules but also to proteins and oligonucleotides, supporting partners from discovery through IND filings. Recent advances in CNS therapeutics—including small-molecule medicines—underscore steady scientific progress and strong industry collaboration. In parallel, novel modalities such as targeted protein degradation are bringing fresh momentum to CNS pipelines and expanding the range of viable treatment approaches. In this era of opportunity, WuXi AppTec remains committed to empowering its global partners, offering advanced CNS-focused platforms that accelerate translational progress. Guided by the vision that “every drug can be made and every disease can be treated,” WuXi AppTec continues to enable CNS drug discovery for the ultimate benefit of patients worldwide. 参考资料： [1] The future of CNS drug development: signs of real progress. Retrieved September 2, 2025 from https://www.drugtargetreview.com/article/168079/the-future-of-cns-drug-development-signs-of-real-progress/ [2] Central Nervous System (CNS) Drugs DMPK Services. Retrieved September 4, 2025 from https://dmpkservice.wuxiapptec.com/central-nervous-system-drugs-dmpk-services.html [3] First-in-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of ARV-102, a PROTAC LRRK2 Degrader, in Healthy Volunteers. Retrieved September 4, 2025 from https://arvinasmedical.com/wp-content/uploads/2025/04/AD-PD-2025-ARV-102-Phase-1-Oral_Final.pdf [4] Bexobrutideg (NX-5948) is a CNS-Penetrant Catalytic Bruton’s Tyrosine Kinase (BTK) Degrader That Breaks Established Design Rules for CNS Drugs. Retrieved September 9, 2025 from https://www.nurixtx.com/wp-content/uploads/2025/04/Bexobrutideg-NX-5948-CNS-Penetrant-Catalytic-BTK-Degrader-that-Breaks-Established-Design-Rules-for-CNS-Drugs.pdf 免责声明：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：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。