Everolimus

寡核苷酸是近年来发展迅速的一类新兴分子类型。随着技术演进，肝外递送正成为新的研发趋势，有望将这类疗法的应用拓展至更广泛的疾病领域。脂质偶联作为实现肝外递送的关键技术路径之一，在从实验室走向临床的过程中仍面临诸多挑战。 一家生物技术公司曾就其管线中的一款寡核苷酸脂质偶联（siRNA-lipid conjugate）药物，与药明康德建立合作。彼时，该候选药物正处于从临床前候选化合物（PCC）阶段向新药临床试验申请（IND）阶段推进的准备过程中。 这类药物本身的复杂性，已经让这项工作充满挑战。而客户提出的一个特殊要求则进一步加大了项目的难度——在不到九个月的紧急时间内，完成公斤级siRNA脂质偶联药物的工艺放大及生产并提交IND。 这一时间要求远超行业常规节奏。通常，一个典型的siRNA脂质偶联药物从PCC到完成IND申请准备的各项CMC工作，大约需要11个月。这意味着，项目核心开发阶段的时间需大幅压缩。 面对这一极具挑战的目标，药明康德旗下WuXi TIDES以灵活的策略以及高效的执行力，在8个月内便完成了从临床前候选化合物到临床试验申请所需的整套CMC资料，项目顺利通过客户验收。 图片来源：123RF 丰富的化学经验，为客户解决关键工艺挑战 故事，要从寡核苷酸药物的递送说起。 过去十年，寡核苷酸药物的临床成功高度集中于肝脏适应症。以GalNAc偶联为代表的肝脏递送技术，凭借其对肝细胞的高效靶向，极大地推动了siRNA与反义寡核苷酸（ASO）药物的快速发展。然而，当治疗靶点拓展至肌肉、心脏或中枢神经系统（CNS）等肝外组织时，递送难度显著增加。以CNS为例，血脑屏障、组织特异性屏障以及靶细胞受体分布的差异性，共同构成了核酸药物“肝外递送”领域亟待突破的核心挑战。 在这一背景下，寡核苷酸脂质偶联药物应运而生。通过选用具有不同化学结构的脂质分子与寡核苷酸偶联，可调控其在血液中的蛋白结合特性，从而实现肝外组织的靶向递送。因此，这类偶联物被视为实现肝外递送的重要工具之一。 然而，这一新型递送工具的开发并非坦途。脂质自身水溶性较低，使得这类偶联物在化学设计、合成纯化、分析表征、制剂开发等环节均面临相应的技术挑战。同时，其开发涉及小分子、寡核苷酸、偶联化学等多领域的技术能力，要求研发团队具备深厚的技术深度，同时平台拥有较高的全链条整合能力。此外，核酸药物在杂质控制与遗传毒性评估等方面面临更严格的监管，对质量管控提出更高要求。 面对上述挑战，药明康德通过一体化、端到端的CRDMO平台，助力全球客户加速这类新型寡核苷酸偶联药物的开发。 多年来，药明康德在化学领域持续深耕，为解决偶联化学的复杂性奠定了坚实基础。在寡核苷酸浪潮兴起初期，公司就开始进行能力布局，逐步搭建起专注于寡核苷酸、多肽及相关化学偶联药物的WuXi TIDES平台。通过建立全面的能力，该平台能够为复杂的寡核苷酸偶联药物提供一体化解决方案。 针对寡核苷酸脂质偶联药物这一细分领域，团队同样在技术兴起之初便积极投入，通过持续的项目经验积累，已形成了成熟的技术体系和复杂问题解决能力。 公开数据显示，仅在2025年，WuXi TIDES就合成并交付了超过7000个寡核苷酸脂质偶联化合物。这背后是团队对多种偶联位点（如寡核苷酸链的3′端和5′端）以及各类修饰（包括核苷酸的碱基、糖骨架和磷骨架）的全面掌握。针对siRNA、双靶点siRNA、ASO等不同类型的脂质偶联，平台已开发出超过20种可供偶联的脂质类型。 在工艺开发层面，WuXi TIDES平台对酰胺偶联、酰胺缩合、点击化学、氧化磷酰胺化等多种偶联技术均积累了丰富的实操经验。此外，公司的原料药及制剂基地空间距离近，且遵守统一的质量体系，也为高质量、快速交付项目奠定了重要基础。 故事回到前述的客户项目中。正是这些从大量实践中沉淀下来的技术、能力和经验，让WuXi TIDES团队能够快速响应客户需求。 面对紧迫的时间窗口和复杂的技术要求，团队决定不再沿用原本的寡核苷酸固相合成策略——那条路可以说是障碍重重。原工艺策略中，先将脂质固定在固相载体（树脂）上，然后在其上进行寡核苷酸固相合成。然而，定制化脂质载体的交付周期往往长达两到三个月，项目还没开始合成，就卡在了供应瓶颈上。而脂质本身的疏水性和空间位置，又让反应效率大打折扣，粗品纯度低、收率也不理想。更麻烦的是，与脂质相关的杂质或残留物（如游离脂质、脂质降解产物、脂质siRNA的聚集体等）使下游纯化和内毒素控制更加棘手，很可能在IND阶段引发监管风险。 时间、合成效率、质量——多重压力集中在同一个项目上。 为克服上述挑战，团队重新设计了整条路线。他们放弃了原来的方案，转而采用一种新策略：先完成寡核苷酸固相合成，后进行液相脂质偶联。这一调整立刻释放了项目的灵活性——脂质由内部同步合成，与寡核苷酸的生产并行推进。仅此一举，开发周期就缩短了约两个月。由于脂质不再依赖外部采购，质量和供应稳定性也更加可控。 新的偶联工艺带来了高达95%的转化率，粗品纯度提升了约20%。下游也同步简化，原本需要两步的纯化被缩减成一步。团队还成功开发并实施了有效的内毒素控制策略，覆盖原料、设备、纯化流程等方面，最终使API中的内毒素水平稳定控制在0.05 EU/mg以下，远低于监管要求。 一体化CRDMO平台助力项目开发“加速度” 如果说技术能力和经验决定了这个项目“能做多好”，那么一体化平台则决定了“能做多快”。 完成工艺重构后，WuXi TIDES团队以一体化模式推进项目——脂质合成、工艺开发、分析方法验证，以及制剂开发，所有环节都在同一平台下并行推进，无缝衔接。 具体而言，在原料药团队完成Demo批次后，工艺优化立即开启，处方前研究及制剂开发、原料药GLP批次生产也在同步推进中。制剂工程批次生产紧随其后，原料药GMP批次很快并行推进，为临床供应做好准备。分析方法开发与验证则贯穿整个周期。 这种协同并非简单的“同时工作”。它建立在团队对上下游各环节技术逻辑的深度理解之上——大家都清楚上游将交付什么、下游需要什么，从而压缩等待时间和沟通成本，更建立在一体化平台体系下，工艺、分析方法、质量体系的一致性，从工艺放大到分析方法转移，都大大提高了成功率，减少在方法转移时出现的偏差和重复验证工作，使数据完整性更好，有助于CMC资料的一致性与监管接受度。由专职项目管理人员负责整个项目的协调，进一步提升了执行效率与风险控制。 简而言之，跨阶段、跨团队、跨基地所产生的摩擦及风险大幅降低，让项目更快、更稳地往前推进。这背后，是一体化平台将技术能力与协同机制真正融合在一起的力量，也是它区别于传统碎片化协作的核心价值所在。 从肝脏靶向到肝外组织递送，寡核苷酸脂质偶联药物展现出广阔的前景。尽管研发之路充满挑战，但正是这些挑战，才更能彰显创新技术和疗法造福患者的真正价值。在本案例中，药明康德将阶段性研发周期从11个月缩短到8个月——这不仅是效率的提升，更是公司持续践行“让天下没有难做的药，难治的病”这一愿景的生动缩影。 Conquering Oligonucleotide-Lipid Conjugate Process Challenges: How WuXi AppTec Accelerates Client Timelines Oligonucleotides represent a rapidly emerging modality. As the technology evolves, extrahepatic delivery is becoming a new trend, with the potential to expand oligonucleotide-based therapies into a broader range of disease areas. Lipid conjugation, as one of the key approaches for achieving extrahepatic delivery, still presents considerable challenges during the transition from laboratory to clinical development. A biotechnology company collaborated with WuXi AppTec to advance an oligonucleotide-lipid conjugate drug candidate. At that time, the candidate (siRNA-lipid conjugate) was preparing to advance from the preclinical candidate compound (PCC) stage toward investigational new drug (IND) application. The intrinsic complexity of this class of therapeutics had already made the program highly challenging. A specific client requirement further increased the level of difficulty: completing kilogram-scale manufacturing of a siRNA-lipid conjugate and achieving IND submission within an accelerated timeline of fewer than 9 months. This timeline was significantly faster than the industry norm. Under typical circumstances, an oligonucleotide-lipid conjugate program generally requires approximately 11 months to progress from PCC to IND-enabling CMC readiness. In this case, the core development timeline had to be substantially compressed. Faced with this highly demanding objective, the integrated WuXi TIDES team adopted a flexible development strategy combined with rapid execution, ultimately delivering the program at high quality. Within 8 months, the team completed the full set of CMC activities required to advance the program from preclinical candidate to IND submission, and the project successfully passed client acceptance. Image source: 123RF Chemistry Expertise Solves Critical Process Challenges for Clients The story begins with oligonucleotide drug delivery. Over the past decade, the clinical success of oligonucleotide drugs has been largely limited to liver-related indications. Liver-directed delivery technologies, such as GalNAc conjugation, have enabled efficient targeting of hepatocytes, driving the rapid development of siRNA and antisense oligonucleotide (ASO) therapies.  However, when therapeutic targets shift to extrahepatic tissues — such as muscle, heart, and the central nervous system (CNS) — additional challenges arise. The blood-brain barrier in the CNS, tissue-specific barriers, and differences in target cell receptor distribution have made extrahepatic delivery one of the major challenges in the field of nucleic acid therapeutics. In this context, oligonucleotide-lipid conjugates have been explored as a potential solution. By conjugating oligonucleotides with lipid molecules of different chemical structures, it may be possible to modulate protein binding properties in the blood and thereby direct drug distribution to extrahepatic tissues. These conjugates are therefore considered as a promising tool for achieving extrahepatic delivery. Nevertheless, the development of such conjugates is technically challenging. Due to the poor water solubility of lipids, these molecules present hurdles in chemical design, synthesis and purification, analytical characterization, and formulation development. Furthermore, developing oligonucleotide-lipid conjugates requires expertise across small molecules, oligonucleotides, and conjugation chemistry, placing high demands on both technical depth and end-to-end integration capabilities. In addition, oligonucleotide drugs face tighter regulatory scrutiny for impurity control and genotoxicity assessment, imposing higher demands on quality control. In response to these challenges, WuXi AppTec's integrated CRDMO platform supports clients in accelerating the development of such novel conjugates. Over the years, WuXi AppTec has continuously built extensive chemistry expertise, laying a solid foundation for tackling the complexities of conjugation chemistry. Early in the rise of oligonucleotides, WuXi AppTec began building the WuXi TIDES platform, which focuses on oligonucleotides, peptides, and related chemical conjugation drugs, with established capabilities to provide end-to-end solutions for complex oligonucleotide conjugates. For oligonucleotide-lipid conjugates, the team made early strategic investments as the technology emerged. Through ongoing project work, the team has established a comprehensive technical framework and accumulated extensive experience in addressing complex development and manufacturing challenges. In 2025 alone, the platform delivered over 7,000 oligonucleotide-lipid conjugates. This figure reflects the team's experience with various conjugation sites on the 3′ and 5′ ends of strands, base or sugar skeleton of nucleotide, and phosphorus backbone. For lipid conjugates of various modalities, including siRNA, dual-targeting siRNA, and ASO, the platform has developed more than 20 lipid moieties suitable for conjugation. At the process development level, the platform has accumulated extensive hands-on experience with various conjugation technologies, including amide coupling, amide condensation, click chemistry, and oxidative phosphoramidation. The close proximity of drug substance and drug product sites, together with a unified quality system, provides a strong foundation for high-quality, rapid project delivery. The story returns to the client program described earlier. It was precisely this accumulation of technical expertise, platform capability, and hands-on experience that enabled the WuXi TIDES team to respond rapidly to the client’s needs. Faced with an aggressive timeline and complex technical requirements, the team decided not to continue with the original solid-phase oligonucleotide synthesis strategy — a route that had become increasingly constrained. Under the initial process design, the customized lipid-functionalized support typically required a procurement lead time of two to three months, creating a supply bottleneck before synthesis could even begin. At the same time, the poor solubility and steric hindrance of the lipid significantly reduced coupling efficiency, resulting in low crude purity and unsatisfactory yield. Lipid-associated materials (such as free lipids, lipid degradation products, aggregates of siRNA-lipid complexes, etc.) also complicated downstream purification and endotoxin control, potentially introducing regulatory risk at the IND stage. Timeline pressure, synthetic efficiency, and manufacturing quality all converged within a single program. To overcome these challenges, the team redesigned the entire process route. Instead of following the original strategy, they adopted a new approach: completing oligonucleotide synthesis first, followed by solution-phase lipid conjugation. This change immediately improved operational flexibility. Lipid building blocks were synthesized in-house in parallel with oligonucleotide production, shortening the overall development timeline by approximately 2 months. By eliminating dependence on external lipid supply, the team also gained greater control over quality and supply reliability. The new conjugation process achieved up to 95% homogeneous conversion, increased the crude purity by approximately 20%. Downstream processing was streamlined as well, with two purification steps consolidated into one. The team also developed and implemented a dedicated endotoxin control strategy across raw materials, equipment, and purification workflow, ultimately maintaining endotoxin levels in the final API below 0.05 EU/mg — well within regulatory expectations. The Integrated CRDMO Platform Supports Acceleration of Project Development If technical expertise and execution determined how well the project could be delivered, the integrated platform determined how quickly it could move forward. Following the process redesign, the WuXi TIDES team advanced the program under an integrated development model. Lipid synthesis, process development, analytical method validation, and formulation development were all executed in parallel on a unified platform, enabling seamless coordination across functions. Specifically, once the API team delivered the demo batch, process optimization began immediately, with pre-formulation/formulation development and API GLP production running in parallel. Drug product engineering batches followed, and API GMP batches were quickly advanced alongside to prepare clinical supply. Analytical method development and validation continued throughout the entire cycle. This synergy is more than “working in parallel.” It rests on a deep, shared understanding of technical dependencies across upstream and downstream activities: each team knows what the prior stage will deliver and what the next stage needs, which cuts wait time and reduces communication inefficiencies. Built on an integrated platform with consistent processes, analytical methods, and quality systems, this approach increases success rates, minimizes deviations and repetitive re-validation during method transfers, and strengthens data integrity—supporting CMC consistency and regulatory acceptance. One dedicated project manager coordinates program end-to-end, further improving execution efficiency and risk control. In short, cross-stage, cross-team, and cross-site frictions and risks are substantially reduced, enabling faster, more reliable project progression. This seamless integration of technical capability and collaborative mechanisms is the platform’s core value and differentiator versus traditional fragmented models. Oligonucleotide-lipid conjugates offer a promising route from liver-targeted to extrahepatic delivery, though development remains technically challenging. In this case, reducing the R&D timeline from 11 to 8 months reflects not only improved efficiency but also the value of integrated capabilities in addressing complex development hurdles. This is consistent with WuXi AppTec’s vision: every drug can be made, and every disease can be treated.  参考资料： [1] Chaudhari (2026). Evolution of the psoriasis therapy landscape. Nature Reviews Drug Discovery, Doi: https://doi.org/10.1038/d41573-026-00097-3 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

2026 年第三季度，美国食品药品监督管理局（FDA）将对三款重点药物做出获批决定：用于注意缺陷多动障碍（ADHD）的 centanafadine、用于胃肠胰神经内分泌肿瘤（GEP-NETs）的177Lu-edotreotide，以及用于非小细胞肺癌（NSCLC）的 zidesamtinib。Centanafadine：ADHD 全新非兴奋剂治疗方案Centanafadine 是大冢制药开发的每日一次缓释型去甲肾上腺素-多巴胺-5-羟色胺再摄取抑制剂，适应症覆盖儿童、青少年及成人 ADHD。该药的新药申请（NDA）已获 FDA 优先审评受理，《处方药使用者付费法案》（PDUFA）目标审批日期为 2026 年 7 月 24 日。 本次申报基于 4 项关键 III 期临床试验，覆盖全年龄段人群的疗效与安全性验证。结果显示：与安慰剂相比，centanafadine 可使 ADHD 症状得到统计学显著、且具备临床意义的改善（儿童采用 ADHD 评定量表第 5 版评估，成人采用成人 ADHD 研究者症状评定量表评估）。 4-17 岁儿童群体：高剂量方案可稳定减轻症状，低剂量组疗效一致性较差； 18-55 岁成人群体：每日 200mg、400mg 两个剂量组的症状评分均显著优于安慰剂。若顺利获批，centanafadine 将成为 ADHD 领域全新的非兴奋剂治疗选择，进一步丰富患者的治疗方案。177Lu-edotreotide：胃肠胰神经内分泌肿瘤核药新选择177Lu-edotreotide（研发代号 ITM-11）由 ITM 慕尼黑同位素技术公司开发，是一款靶向生长抑素受体（SSTR）2、SSTR5 的放射性治疗药物，适应症为不可切除、进展性 1 级/2 级胃肠胰神经内分泌肿瘤。 该药 NDA 已获 FDA 受理，PDUFA 目标日期为 2026 年 8 月 28 日。申报核心依据为 III 期 COMPETE 研究（随机、对照、开放标签，纳入 309 例患者）：与标准治疗药物依维莫司相比，177Lu-edotreotide 显著延长患者中位无进展生存期（23.9 个月 vs 14.1 个月），同时客观缓解率大幅提升（21.9% vs 4.2%），且安全性良好可控。 若获批，该药将与诺华 2018 年上市的 SSTR 靶向核药 177Lu-dotatate（Lutathera）形成市场竞争。Zidesamtinib：ROS1 阳性肺癌下一代靶向药目前已获批的 ROS1 阳性 NSCLC 靶向药（克唑替尼、恩曲替尼、瑞波替尼）仍存在临床局限：中枢神经系统活性不足、G2032R 等耐药突变无法覆盖。 Zidesamtinib 是 Nuvalent 公司开发的高选择性 ROS1 酪氨酸激酶抑制剂，设计上针对性解决了上述痛点：保留对 G2032R 等耐药突变的活性，同时具备血脑屏障穿透能力，适应症为既往接受过 ROS1 靶向治疗的局部晚期/转移性 ROS1 阳性 NSCLC。 该药 PDUFA 审批日期为 2026 年 9 月 18 日。申报数据来自全球 ARROS-1 I/II 期试验（纳入大量经多线治疗患者）： 既往接受过 ROS1 抑制剂治疗的患者中，客观缓解率约 44%； 脑转移患者颅内缓解率达 48%，填补了该领域的临床空白。若获批，zidesamtinib 将成为 ROS1 阳性肺癌的下一代治疗方案，为耐药、脑转移患者提供新的治疗选择。值得一提的是，2026 年 6 月 9 日葛兰素史克已宣布以 106 亿美元收购 Nuvalent，将 zidesamtinib 与同处于 FDA 审评阶段的 ALK 抑制剂 neladalkib 一并纳入管线。 原文来源： DOI：https://doi.org/10.1038/d41573-026-00103-8