Patisiran sodium

编者按：2025年诺贝尔奖即将在下周揭晓。作为全球科学研究领域的至高荣誉之一，诺贝尔奖已走过一个多世纪，见证了无数推动人类文明进步的伟大突破。从基础科学的前沿探索到造福患者的临床应用，许多诺奖获奖成果已成为现代医学发展的基石，催生出改变疾病治疗格局的创新疗法。在这些成就中，RNA干扰（RNAi）机制的发现堪称里程碑，不仅深化了我们对基因表达调控的理解，也直接催生了一类创新药物——RNAi疗法。如今，已有7款RNAi药物获批上市，为全球患者带来切实的治疗希望。作为全球创新的赋能者，药明康德旗下独特的CRDMO平台WuXi TIDES，围绕包括RNAi在内的寡核苷酸药物建立了一体化服务平台，覆盖从药物发现、CMC开发，到商业化生产的全生命周期，加速将合作伙伴的创新构想转化为现实，造福全球病患。在今天的文章中，我们将回顾RNAi如何从实验室走向临床，从基础研究转化为惠及人类健康的现实成果，并展示WuXi TIDES赋能平台如何帮助合作伙伴有效克服RNAi药物开发中的多重挑战。 意外而至的诺贝尔奖 2006年10月2日凌晨2点30分，斯坦福大学的Andrew Fire教授接到一通来电。电话那头，一个略带口音的声音向他表示祝贺——诺贝尔奖委员会决定，由他与马萨诸塞大学的Craig Mello教授共同分享当年的诺贝尔生理学或医学奖。 ▲2006年诺贝尔生理学或医学奖授予Andrew Fire和Craig Mello教授（图片来源：NobelPrize.org） 和许多获奖者相似，Fire教授的第一反应是“非常惊讶”，甚至一度怀疑对方拨错了号码。这种惊讶并非没有原因：自上世纪80年代起，诺贝尔生理学或医学奖得主的平均年龄多在60岁以上，但他当年只有47岁，Mello教授更是只有45岁。而且，距离他们合作发表的关键论文问世，也只有短短8年的时间。这一切都来得太快，太不真实了。 许多生物学家指出，正是这些“不同寻常”的数字，印证了他们发现的非凡价值。“他们的发现是一个再明显不过的诺贝尔奖，”诺奖得主Thomas Cech教授直言：“它在所有人的诺奖候选名单上。”几乎没有人质疑他们的贡献，这份荣誉实至名归。 这项不同寻常的成果，正是RNA干扰机制的发现——一种通过双链RNA实现基因沉默的机制。诺贝尔奖委员会称，这是控制遗传信息流的一个根本性机制，广泛存在于植物、动物与人类体内，并在生物技术与医学领域拥有广阔的应用前景。 什么是RNAi？ 有趣的是，这两位科学家并非最早注意到RNAi现象的人。在他们之前，植物学家就已观察到一系列难以解释的现象。1990年，两名研究者报道了一个令他们大感意外的发现：在矮牵牛花中，查尔酮合成酶（chalcone synthase）是一种在花青素合成通路里起到限速作用的酶。他们原以为提高这种酶的表达，就能加速花青素的合成，让矮牵牛花的颜色变得更深。 但实验结果与他们的预期截然相反。在引入表达查尔酮合成酶的基因后，矮牵牛花的颜色非但没有变深，反而还变浅了！看着眼前的白色花朵，植物学家们感到无比困惑。后续的研究发现，经过改造的矮牵牛花里头，查尔酮合成酶的含量竟要比野生型低上50倍。这也让研究人员们猜测，外源RNA的引入可能会使具有同源序列的基因“沉默”。 尽管这些植物学家做出了重要的观察，并提出了潜在的作用机制，但他们却一直没有把这个发现转化为实际应用的技术。这也正是Fire教授与Mello教授的贡献所在。在线虫中，他们发现，只有注射与目标基因序列一致或高度相近的双链RNA，才能实现有效沉默。这原本可能是生物体的抗病毒机制，却在演化的长河中被用作调控自身基因的手段。两位科学家领导的工作，使研究者得以用更简便的方法精准调控基因，为生命科学研究开辟新路径。 可以说，这项突破性的技术，打开了一扇通往新天地的大门。这一创新工具得到了许多生物实验室的青睐，也加速了生物学的发展。更重要的是，它让我们看到了通过“基因沉默”治疗疾病的希望。正如诺贝尔奖官方新闻稿中所言，“RNA干扰已经在基础科研中广泛应用，用于研究基因功能，并有望在未来带来全新的疗法。” “我相信这一技术将在未来10年里，在抗癌领域得到广泛应用。”时任冷泉港实验室主席，美国科学院院士Bruce Stillman博士说道。 热情与现实 人们的乐观并不是没有理由：在诺贝尔奖颁发的5年前，人类基因的测序工作已经完成。许多研究人员早就开始在哺乳动物细胞里尝试应用RNAi，生物技术公司如雨后春笋般涌现，争当第一款RNAi新药的发明人。 这一热潮背后有清晰的逻辑：许多疾病源于致病蛋白的出现，而传统小分子药物的作用机理，正是结合这些蛋白，抑制其功能。使用RNAi技术则有望从源头抑制蛋白表达，将这些致病蛋白扼杀在萌芽之中。由于双链RNA易于合成，若能成功，既可避免漫长的化合物筛选，也可能攻克“不可成药”靶点带来的难题。因此，产业界对RNAi疗法有着极为高涨的研发热情，一些大型药企亦相继入局。 然而，热潮之下，问题逐渐浮现出来。其中，研究人员们无法解决的一大难题，在于如何在特定细胞内精准启动RNAi。更糟糕的是，部分项目在仅有初步实验依据时便匆忙进入人体试验。 “早期许多临床试验并不明智，很多人只是为了抢第一，”斯坦福大学的基因疗法专家Mark Kay教授说道：“大部分保持理性且深谙这一领域的人都知道，这些试验难以成功。” 不久之后，这些隐患逐渐显现，一些RNAi疗法在人体中暴露出意料之外却在情理之中的严重副作用。由于无法递送到人体内的正确细胞，这些疗法要么没有效果，要么反而对人体有害。 整个RNAi领域迅速降温，诸多生物医药公司选择退出。2014年，一家名为Sirna Therapeutics的RNAi技术公司被折价出售。而购买它的，则是一家名为Alnylam Pharmaceuticals的生物技术公司。 最亮的星 Alnylam成立于2002年，恰处于RNAi从科学突破（1998年）到斩获诺奖（2006）的中点。它的名字源于“Alnilam”，中文名是“参宿二”，指的是夜空中距离我们2000光年外的猎户座腰带中点。 如同漫天群星一般，在10多年前，到处都能看到研发RNAi技术的新锐公司，Alnylam看起来并不起眼；但在RNAi疗法跌入低谷时，Alnylam却是少数坚持者之一。这并不代表它未曾经历过阵痛。在Alnylam公司官网上写道，其成立早期也曾遇到过许多挑战：合作伙伴的离去、外界对于技术的丧失信心，都给Alnylam带来了不小的打击。只有在公司内部，才能看到将RNAi疗法变成现实的信念与乐观。 ▲这篇论文改变了RNAi疗法的进程 当然，无数案例证明，仅凭信念与乐观是不够的。真正推动Alnylam前进的，是其在RNAi疗法“至暗时刻”取得的关键技术突破。2010年，这家公司发表了一篇足以影响整个RNAi疗法领域的论文。这项研究不但阐述了脂质纳米颗粒（LNP）靶向递送RNAi药物的机制，还介绍了基于N-乙酰半乳糖胺（GalNAc）偶联的靶向递送策略。利用LNP和GalNAc偶联技术，人们终于能对RNAi疗法进行肝脏靶向递送。横亘在科学家们前进道路上的最大阻碍自此被移除，通往首款RNAi疗法的道路逐渐清晰。 首款RNAi疗法 找到解决问题的关键后，Alnylam迅速建立起一系列研发管线，聚焦多种罕见的遗传疾病。其中，领先项目patisiran用于治疗的是一种叫做遗传性转甲状腺素蛋白介导（hATTR）淀粉样变性的疾病。这种疾病的根源在于编码转甲状腺素蛋白的基因发生突变，导致淀粉样蛋白在人体内的异常积累，对器官和组织造成损伤。这是一种严重而致命的罕见病，患者从症状发作起，预期寿命只有2-15年。 而patisiran则能发挥RNAi对基因的“沉默”效果。通过抑制特定mRNA的表达，这款疗法能有效阻止变异转甲状腺素蛋白的生成，清除组织里的淀粉样蛋白沉积，恢复组织功能。 2017年9月，Alnylam与其合作伙伴赛诺菲（Sanofi）公布了patisiran在3期临床试验中的积极顶线结果。研究表明，这款新药达到了主要临床终点以及所有次要临床终点。在18个月时，与安慰剂相比，patisiran显著减少了患者的神经病变，提高了他们的生活质量。 2个月后，Alnylam启动了滚动递交上市申请，以加速上市进程。美国FDA也授予patisiran突破性疗法认定和孤儿药资格。8月3日，英国授予patisiran“早期获取”（Early Access）资格，允许患者在这款疗法正式问世前，就能得到治疗。在2018年，人类终于迎来了首款RNAi疗法的获批。 GalNAc偶联技术催生多款获批疗法 首款RNAi疗法获批之后，GalNAc偶联技术因其卓越的肝脏靶向性、高效的细胞摄取率和良好的安全性特征，成为肝脏靶向寡核苷酸疗法开发的首选递送策略。迄今为止获批的7款RNAi疗法中，6款使用GalNAc偶联技术完成肝脏特异性递送。 自问世以来，GalNAc偶联技术不断迭代升级，无论是在化学修饰方式还是多价分子的设计合成方面，均取得显著进展。由于去唾液酸糖蛋白受体（ASGPR）对GalNAc的亲和力与其配体数目密切相关，研究人员广泛探索并开发了多种三价、四价GalNAc簇（cluster）及其在寡核苷酸上的偶联策略，以提高递送效率。 随着技术不断成熟，GalNAc偶联药物的合成与工艺开发日益复杂。WuXi TIDES团队在合成GalNAc分子方面拥有丰富经验，已合成100多种GalNAc分子及其衍生物，包括单-GalNAc、三-GalNAc、四-GalNAc、GalNAc酰胺、GalNAc PFP酯、GalNAc N3和GalNAc-PEG偶联物等。借助全面的平台能力，WuXi TIDES能够提供GalNAc定制合成、工艺开发和生产一体化服务，支持从药物发现到临床开发再到商业化生产。下面的案例将介绍WuXi TIDES如何帮助合作伙伴加速推进GalNAc偶联siRNA药物的开发。 14个月完成两款GalNAc偶联siRNA药物IND申报准备 一家生物技术公司在开发用于治疗心血管疾病的GalNAc偶联siRNA候选药物时，由于缺乏成熟的GalNAc分子来源，加上产率和粗纯度低下等问题，项目推进受阻。他们找到了WuXi TIDES，寻求解决方案。 首先要解决的便是非常规GalNAc分子的供应问题。针对合作伙伴提出的特殊需求，团队迅速建立合成路线，采用先进的流动化学技术，并优化了溶剂体系，使重结晶收率高达94.8%，4个月内成功交付4.5公斤高纯度定制GalNAc分子，有效保障了项目的原料供应。 随后，在关键的偶联环节，凭借在多种偶联类型、偶联化学和修饰策略上的积累，WuXi TIDES团队选择了具有高度选择性的“点击化学”策略，显著降低副产物产生，简化合成和纯化流程，使最终收率从13%提升至62%，粗品纯度从18%提高到75%，确保了适合临床试验的高纯度和稳定性。 同时，基于一体化CMC服务能力，WuXi TIDES团队平行开展了分析方法、制剂开发等多项工作，同时利用先进的无菌灌装生产线和优化的生产流程设计，在GMP批次的生产中达到99%的产率，显著降低了API的损失。多团队的全方位协作使两款siRNA候选药物在14个月内顺利完成了IND申报准备，加速推进至临床阶段。 以上案例只是WuXi TIDES一体化CRDMO平台能力的一个缩影。除了GalNAc偶联寡核苷酸，WuXi TIDES也可为GalNAc偶联多肽药物提供一站式开发支持。随着越来越多GalNAc偶联药物进入临床开发阶段，像这样的产业协同将成为加快研发步伐的重要推动力。 展望未来 在首款RNAi疗法获批之后的7年中，又有6款RNAi疗法获批上市，治疗的疾病类型也从罕见病扩展到患者人数众多的常见病，有望变革高血压、高血脂和肥胖症等慢性病的治疗模式。据统计，截至今年7月，全球在研RNAi疗法接近400款，其中约三分之一已进入临床开发阶段。RNAi领域的“明星公司”Alnylam表示，预计在2030年前解决主要组织的递送挑战，最大限度地释放RNAi技术的潜力。面向未来，WuXi TIDES将持续基于其一体化CRDMO平台，赋能包括RNAi在内的寡核苷酸药物开发，助力合作伙伴加快将科学创新转化为新药、好药，造福全球病患。 Two Decades On: How RNAi Evolved from Nobel Discovery to New Medicines The 2025 Nobel Prizes will be announced next week. As one of the top honors in global scientific research, the Nobel Prize has, for more than a century, recognized discoveries that have propelled human civilization forward. From frontier explorations in basic science to clinical applications that improve lives, Nobel-winning breakthroughs have laid the foundation of modern medicine and inspired therapies that transform how we treat disease. Among these achievements, the discovery of RNA interference (RNAi) stands as a milestone. It not only deepened our understanding of gene regulation but also directly led to the creation of a new class of medicines—RNAi therapies. Today, seven RNAi therapies have been approved worldwide, offering real treatment hope for patients. WuXi TIDES, an integral part of WuXi AppTec, has established a CRDMO platform for RNAi and other oligonucleotide therapies. The platform provides high-throughput library synthesis and custom synthesis, covering all types of oligonucleotides, their monomers, linkers, ligands and conjugates. It supports all stages of development, from drug discovery and CMC development to commercial-scale manufacturing, accelerating the translation of innovative ideas into clinical reality for partners worldwide. In this article, we trace RNAi’s journey from the laboratory to the clinic and highlight how the WuXi TIDES platform helps overcome the critical challenges of RNAi drug development. A Nobel Prize Arrives Unexpectedly At 2:30 a.m. on October 2, 2006, Stanford University professor Andrew Fire received a call. On the line was a voice with a slight accent offering congratulations: the Nobel Committee had decided that he and Dr. Craig Mello of the University of Massachusetts would share that year’s Nobel Prize in Physiology or Medicine. Like many laureates, Fire’s first reaction was disbelief—he even wondered whether the caller had dialed the wrong number. His surprise was understandable. Since the 1980s, Nobel laureates in Physiology or Medicine had typically been in their 60s or older. Fire was only 47, and Mello just 45. What’s more, their landmark paper had been published only eight years earlier. It all seemed too sudden, almost unreal. Scientists quickly pointed out that these unusual numbers only underscored the significance of their discovery. “Their discovery is as obvious a Nobel as you can get,” remarked Nobel laureate Dr. Thomas Cech, “It was on everyone’s shortlist.” Few questioned the importance of their work. The honor was widely regarded as inevitable. That work was the discovery of RNA interference, a mechanism by which double-stranded RNA silences gene expression. The Nobel Committee described it as a fundamental biological process for controlling genetic information, present in plants, animals, and humans, with vast potential in biotechnology and medicine. What Is RNAi? Fire and Mello were not the first to observe RNAi-like effects. In the early 1990s, plant scientists noticed puzzling phenomena. In 1990, researchers working on petunias hypothesized that overexpressing chalcone synthase, an enzyme in anthocyanin biosynthesis, would deepen flower color. Instead, the modified plants became lighter. Later studies showed that chalcone synthase levels in the altered petunias were up to 50 times lower than in wild-type plants, suggesting that the introduced RNA had “silenced” homologous genes. Although these researchers proposed possible mechanisms, they did not develop a practical technology. Fire and Mello did. In C. elegans, they discovered that gene silencing occurred only when double-stranded RNA identical to, or closely resembling, the target sequence was introduced. What may have evolved as an antiviral defense had been co-opted to regulate genes. Their discovery provided researchers with a simple yet powerful tool for gene control, opening new directions in biology. The implications were enormous. RNAi quickly became a staple in laboratories, accelerating biological research. More importantly, it opened the door to treating diseases through “gene silencing.” As the Nobel press release noted, “RNA interference is already widely used in basic research to study gene function and may lead to novel therapies in the future.” Dr. Bruce Stillman, then president of Cold Spring Harbor Laboratory, predicted, “This technology will find broad application in the next 10 years in the fight against cancer.” Enthusiasm and Reality The optimism had a strong foundation. The human DNA had been sequenced, and biotech startups rushed to harness RNAi, hoping to deliver the first therapeutic. The rationale was compelling: many diseases are caused by pathogenic proteins, and while small molecules act by inhibiting proteins, RNAi promised to silence them at the source. Because double-stranded RNA is easy to synthesize, RNAi offered a faster route to therapy and a way around “undruggable” targets. The field attracted intense industry interest, including from large pharmaceutical companies. But enthusiasm soon collided with reality. A central challenge was how to trigger RNAi precisely in the right cells. Despite limited preclinical validation, some programs advanced hastily into human trials. "Many early trials were unwise. People just wanted to be first," recalled Stanford gene therapy expert Dr. Mark Kay, "Those who stayed rational knew they wouldn’t succeed." It didn’t take long for problems to surface. Some RNAi therapies proved ineffective, or even harmful, because they couldn’t reach the intended cells. The field cooled quickly, and many companies exited. In 2014, an RNAi company called Sirna Therapeutics was sold at a discount. The buyer was a small biotech: Alnylam Pharmaceuticals. The Brightest Star Founded in 2002, midway between the 1998 breakthrough and the 2006 Nobel Prize, Alnylam took its name from “Alnilam”, the central star in Orion’s Belt. A decade ago, amid a crowded field of RNAi startups, Alnylam did not stand out. But when the field hit its low point, it endured while many others disappeared. Alnylam’s survival was not without difficulty. As the company has recalled, it faced partner withdrawals and waning external confidence in RNAi. What sustained it was internal conviction that RNAi medicines could be made a reality. What ultimately propelled Alnylam forward was a critical technical advance. In 2010, the company published a landmark paper describing how lipid nanoparticles (LNPs) could deliver RNAi therapies, and how N-acetylgalactosamine (GalNAc) conjugation could achieve precise liver targeting. With these innovations, the biggest obstacle, effective delivery, was finally overcome. The path to the first RNAi therapy became clear. The First RNAi Therapy With the delivery problem solved, Alnylam built a pipeline focused on rare genetic diseases. Its lead program, patisiran, targeted hereditary transthyretin-mediated (hATTR) amyloidosis, a fatal disorder caused by transthyretin mutations that lead to amyloid buildup in tissues. Patients typically survive only 2–15 years after symptom onset. Patisiran silences the mutant gene, preventing production of faulty transthyretin protein, clearing amyloid deposits, and restoring function. In September 2017, Alnylam and Sanofi reported positive Phase 3 results: patisiran met all endpoints, significantly reduced neuropathy, and improved quality of life over 18 months compared with placebo. Two months later, Alnylam began a rolling submission to accelerate approval. The FDA granted Breakthrough Therapy and Orphan Drug designations. In 2018, the world welcomed the first approved RNAi therapy. GalNAc Conjugation Enables Multiple Approvals Since then, GalNAc conjugation has become the gold standard for liver-targeted oligonucleotide delivery, offering high uptake and good safety. Of the seven approved RNAi therapies, six use GalNAc conjugation. Since its introduction, GalNAc conjugation has evolved significantly through advances in chemical modification and the development of multivalent GalNAc clusters. Research shows that asialoglycoprotein receptor (ASGPR) binding affinity improves with the number of GalNAc ligands present, prompting the development of tri- and tetra-valent GalNAc constructs and optimized strategies for their conjugation to oligonucleotides.  As the technology matures, the synthesis and process development of GalNAc-conjugated drugs have grown increasingly complex. WuXi TIDES brings extensive experience in this area, having synthesized more than 100 types of GalNAc molecules and derivatives—including mono-GalNAc, tri-GalNAc, tetra-GalNAc, GalNAc amidites, GalNAc PFP esters, GalNAc N3, and GalNAc-PEG conjugates. Through the company’s comprehensive capabilities and capacity, WuXi TIDES offers GalNAc custom synthesis, process development, and manufacturing support from the discovery phase to commercial launch. The following case study illustrates how WuXi TIDES helped a biotech partner rapidly advance a GalNAc-siRNA candidate. Fast-Track to Phase 1: Two siRNA IND CMC Packages Completed in 14 Months One biotech company developing a GalNAc-siRNA therapy for cardiovascular disease faced multiple challenges—including limited supply of a unique GalNAc molecule, low yield, and poor purity—which stalled their program. To overcome these hurdles, they partnered with WuXi TIDES. The priority was to ensure a stable supply of the GalNAc molecule. WuXi TIDES quickly designed a customized synthetic route tailored to the client’s specifications. Using advanced flow chemistry and an optimized solvent system, the team achieved a 94.8% recrystallization yield. Within just four months, they successfully delivered 4.5 kilograms of high-purity, custom GalNAc—effectively securing the supply of the starting material for the GalNAc-siRNA conjugate and shortening development timelines. Next came the critical conjugation step. Drawing on extensive expertise in conjugation chemistries and modification strategies, the WuXi TIDES team adopted a highly selective “Click Chemistry” approach, minimizing byproduct formation and simplifying synthesis and purification. As a result, the overall yield increased from 13% to 62%, and crude purity improved from 18% to 75%, ensuring the production of clinical-grade material with superior purity and stability. In parallel, WuXi TIDES leveraged its integrated CMC capabilities to advance analytical method development and formulation optimization. Together with an advanced sterile fill-finish line and optimal process design, we achieved a batch yield of >99% in GMP production, significantly minimizing the overall loss of costly API. These coordinated efforts enabled two siRNA candidates to complete IND-enabling activities within just 14 months, accelerating progress toward the clinic. This case is just one example of the capabilities of WuXi TIDES’ integrated CRDMO platform. In addition to oligonucleotides, WuXi TIDES also provides comprehensive development solutions for GalNAc-conjugated peptide therapeutics. As more GalNAc-conjugated drugs advance into clinical development, integrated collaboration will be essential to accelerating innovation and bringing therapies to patients faster.  Looking Ahead As of July this year, nearly 400 RNAi candidates are in development globally, with about one-third already in clinical stages. Alnylam, a recognized leader, has stated its goal of solving delivery challenges across major tissues by 2030 to unlock the full potential of RNAi. Looking forward, WuXi AppTec will continue to leverage its integrated, end-to-end CRDMO platform to support partners in accelerating the transformation of scientific innovation into impactful medicines that improve lives worldwide. 参考资料： [1] 2 American ‘Worm People’ Win Nobel for RNA Work. Retrieved, September 5, 2025, from https://www.nytimes.com/2006/10/03/science/03nobel.html [2] Andrew Fire shares Nobel Prize for discovering how RNA can switch off genes. Retrieved September 5, 2025, from https://news.stanford.edu/news/2006/october4/nobel-100206.html [3] When a Nobel Prize brings a shower of hype: the roller coaster ride of RNAi. Retrieved September 5, 2025, from https://www.statnews.com/2016/09/29/nobel-prize-rnai-biotech/ [4] Average Age for for Nobel Laureates in Physiology or Medicine. Retrieved September 5, 2025, from https://www.nobelprize.org/nobel_prizes/lists/laureates_ages/medicine_ages.html [5] Sen and Blau (2006). A brief history of RNAi: the silence of the genes. The FASEB Journal. https://doi.org/10.1096/fj.06-6014rev [6] Suhr et al., (2015). Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet Journal of Rare Diseases. https://doi.org/10.1186/s13023-015-0326-6 [7] Akinc et al., (2010). Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Molecular Therapy. https://doi.org/10.1038/mt.2010.85 [8] Alnylam and Sanofi Report Positive Topline Results from APOLLO Phase 3 Study of Patisiran in Hereditary ATTR (hATTR) Amyloidosis Patients with Polyneuropathy. Retrieved September 5, 2025, from http://investors.alnylam.com/news-releases/news-release-details/alnylam-and-sanofi-report-positive-topline-results-apollo-phase [9] "Press Release: The 2006 Nobel Prize in Physiology or Medicine". Nobelprize.org. Nobel Media AB 2014. Retrieved September 5, 2025, from http://www.nobelprize.org/nobel_prizes/medicine/laureates/2006/press.html [10] Cui et al., (2021). Liver-Targeted Delivery of Oligonucleotides with N-Acetylgalactosamine Conjugation. ACS Omega, DOI:10.1021/acsomega.1c01755. [11] Gene, Cell, & RNA Therapy Landscape Report. Q2 2025 Quarterly Data Report. Retrieved September 5, 2025, from https://www.asgct.org/global/documents/cl-080125report-asgct-citeline-q2-2025-jn7765-fina.aspx 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

One dose of nex-z led to rapid, deep and durable TTR reductions, with mean reductions of at least 90% from baseline sustained through three years Stabilization or improvement in disease-related clinical measures observed at 24 months Continue to observe generally favorable safety data with no new drug-related events within the follow-up period Data presented today at the 5th International ATTR Amyloidosis Annual Meeting for Patients and Doctors with simultaneous publication in the New England Journal of Medicine Expect to complete enrollment in multi-national Phase 3 MAGNITUDE-2 trial in first half 2026 to support a potential BLA filing by 2028 CAMBRIDGE, Mass., Sept. 25, 2025 (GLOBE NEWSWIRE) -- Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading clinical-stage gene editing company focused on revolutionizing medicine with CRISPR-based therapies, today announced longer-term follow-up data from the ongoing Phase 1 study of investigational nexiguran ziclumeran (nex-z) for the treatment of hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN). Results were presented in an oral session on Thursday, September 25 at the 5th International ATTR Amyloidosis Annual Meeting for Patients and Doctors in Baveno, Italy. The results were simultaneously published in the New England Journal of Medicine, and the presentation will be available on the Scientific Publications & Presentations section of intelliatx.com. "After receiving a one-time treatment of nex-z, patients continue to experience durable TTR reductions, including those who have reached three years of follow-up,” said Intellia President and Chief Executive Officer John Leonard, M.D. “The results from our ongoing Phase 1 study of nex-z support our belief that deeper and more consistent reductions in TTR translate to better outcomes for patients. Our Phase 3 MAGNITUDE-2 study is progressing swiftly, and we are eagerly anticipating the results, which we believe will demonstrate nex-z’s potential to halt or reverse disease progression in people living with ATTRv-PN.” Continuation of Deep and Durable Serum TTR Reduction Deep, durable and consistent TTR reductions continue to be observed. Across patients who received a one-time dose of 0.3 mg/kg or higher (n=33), the mean serum TTR reduction at 24 months was 92% (corresponding mean absolute serum TTR level of 17.3 g/mL [Mean 95% CI, 12.5 – 22.2]). Among the 12 patients who had reached 36 months of follow-up, the mean serum TTR reduction was 90% (corresponding mean absolute serum TTR level of 20 g/mL [Mean 95% CI, 11.2 – 28.8]). Evidence of Stability or Improvement on Clinical and Biomarker Measures Favorable trends indicating stability or improvement were observed in most patients with ATTRv-PN after a single dose of nex-z. Stability or improvement was based on evaluation of multiple clinical and biomarker measures, including Neuropathy Impairment Score (NIS), modified Neuropathy Impairment Score +7 (mNIS+7), modified body mass index (mBMI), Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire, neurofilament light chain (NfL), and polyneuropathy disability (PND) score. Among the 18 patients in whom a 24-month mNIS+7 assessment was completed by the data cutoff date (April 11, 2025), 13 (72%) showed improvements of a clinically meaningful threshold of ≥4 points, including most of the patients in the cohort who had progressed on patisiran. Among all 36 patients enrolled in the Phase 1 trial, mean values of the secondary endpoints mBMI, QoL-DN and NfL all trended toward disease improvement and 89% of patients showed improvement or stability in PND scores through 24 months compared to baseline. Safety Summary Nex-z has been generally well tolerated as of the data cutoff date across all patients and at all dose levels tested. The most commonly reported treatment-related adverse events were infusion-related reactions, which were mild or moderate and did not result in any discontinuations. As previously reported, three participants had Grade >3 liver enzyme elevations that were not considered serious, were asymptomatic and resolved spontaneously without medical intervention or sequelae. Phase 3 MAGNITUDE-2 Trial Advancing Rapidly Intellia began dosing patients in the Phase 3 MAGNITUDE-2 trial in April 2025. Patient screening is advancing rapidly, and enrollment completion is expected in the first half of 2026. Intellia anticipates submitting a biologics license application (BLA) for ATTRv-PN by 2028. MAGNITUDE-2 is a randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of nexiguran ziclumeran (nex-z) in approximately 50 patients with hereditary transthyretin ATTR amyloidosis with polyneuropathy (ATTRv-PN). The primary endpoints of the study are a change in modified neuropathy impairment score and a change in serum TTR levels. Adult patients with ATTRv-PN are randomized 1:1 to receive a single 55 mg infusion of nex-z or placebo. For more information on MAGNITUDE-2 (NCT06672237), please visit clinicaltrials.gov. About the Nexiguran Ziclumeran (nex-z) Phase 1 Clinical Trial The global Phase 1 trial is an ongoing open-label, multi-center, two-part study of nex-z in adults with hereditary transthyretin ATTR amyloidosis with polyneuropathy (ATTRv-PN) or transthyretin ATTR amyloidosis with cardiomyopathy (ATTR-CM). Part 1 of the ATTRv-PN arm of the study is an open-label, single-ascending dose escalation cohort and Part 2 is an open-label, single-dose expansion cohort. Visit clinicaltrials.gov (NCT04601051) for more details. About Nex-z Based on Nobel Prize-winning CRISPR/Cas9 gene editing technology, nex-z has the potential to become the first one-time treatment for transthyretin (ATTR) amyloidosis. Nex-z is designed to inactivate the TTR gene that encodes for the transthyretin (TTR) protein. Interim Phase 1 clinical data showed the administration of nex-z led to consistent, deep and long-lasting TTR reduction. Intellia leads development and commercialization of nex-z as part of a multi-target discovery, development and commercialization collaboration with Regeneron Pharmaceuticals, Inc. About Transthyretin (ATTR) Amyloidosis Transthyretin amyloidosis, or ATTR amyloidosis, is a rare, progressive and fatal disease. Hereditary ATTR (ATTRv) amyloidosis occurs when a person is born with mutations in the TTR gene, which causes the liver to produce structurally abnormal transthyretin (TTR) protein with a propensity to misfold. These damaged proteins build up as amyloid in the body, causing serious complications in multiple tissues, including the heart, nerves and digestive system. ATTRv amyloidosis predominantly manifests as polyneuropathy (ATTRv-PN), which can lead to nerve damage, or cardiomyopathy (ATTRv-CM), which can lead to heart failure. Some individuals without the genetic mutation produce non-mutated, or wild-type TTR proteins that become unstable over time, misfolding and aggregating in disease-causing amyloid deposits. This condition, called wild-type ATTR (ATTRwt) amyloidosis, primarily affects the heart. There are an estimated 50,000 people worldwide living with ATTRv amyloidosis and between 200,000 and 500,000 people with ATTRwt amyloidosis. There is no known cure for ATTR amyloidosis and currently available medications are limited to slowing accumulation of misfolded TTR protein. About Intellia Therapeutics Intellia Therapeutics, Inc. (NASDAQ:NTLA) is a leading clinical-stage gene editing company focused on revolutionizing medicine with CRISPR-based therapies. Since its inception, Intellia has focused on leveraging gene editing technology to develop novel, first-in-class medicines that address important unmet medical needs and advance the treatment paradigm for patients. Intellia’s deep scientific, technical and clinical development experience, along with its people, is helping set the standard for a new class of medicine. To harness the full potential of gene editing, Intellia continues to expand the capabilities of its CRISPR-based platform with novel editing and delivery technologies. Learn more at intelliatx.com and follow us @intelliatx. Forward-Looking Statements This press release contains “forward-looking statements” of Intellia Therapeutics, Inc. (“Intellia” or the “Company”) within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding Intellia’s beliefs and expectations regarding: the safety, tolerability, efficacy, success and advancement of its clinical programs for nexiguran ziclumeran or “nex-z” (also known as NTLA-2001) for transthyretin (“ATTR”) amyloidosis, including the ability to successfully complete its global Phase 3 MAGNITUDE-2 study for hereditary transthyretin ATTR amyloidosis with polyneuropathy (“ATTRv-PN”) pursuant to its clinical trial applications and investigational new drug submissions; its expectation to complete enrollment in the MAGNITUDE-2 trial in the first half of 2026; its belief that a single dose of nex-z leads to deep, durable and consistent reductions in serum TTR and that increasingly deep reductions in TTR levels translate to better outcomes for patients; its belief that the MAGNITUDE-2 trial will demonstrate nex-z’s potential to halt or reverse disease progression in people living with ATTRv-PN; and its expectation to submit a biologics license application for nex-z for the treatment of ATTRv-PN by 2028. Any forward-looking statements in this press release are based on management’s current expectations and beliefs of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: risks related to Intellia’s ability to protect and maintain its intellectual property position; risks related to valid third party intellectual property; risks related to Intellia’s relationship with third parties, including its licensors and licensees; risks related to the ability of its licensors to protect and maintain their intellectual property position; uncertainties related to regulatory agencies’ evaluation of regulatory filings and other information related to our product candidates, including nex-z; uncertainties related to the authorization, initiation and conduct of studies and other development requirements for our product candidates, including uncertainties related to regulatory approvals to conduct clinical trials; the risk that any one or more of Intellia’s product candidates, including nex-z, will not be successfully developed and commercialized; the risk that the results of preclinical studies or clinical studies will not be predictive of future results in connection with future studies for the same product candidate or Intellia’s other product candidates; and risks related to Intellia’s reliance on collaborations, including that its collaboration with Regeneron Pharmaceuticals, Inc. will not continue or will not be successful. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause Intellia’s actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in Intellia’s most recent annual report on Form 10-K and quarterly report on Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in Intellia’s other filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Intellia undertakes no duty to update this information unless required by law. Intellia Contacts: Investors: Jason Fredette Vice President, Investor Relations and Corporate Communications jason.fredette@intelliatx.com Media: Matt Crenson Ten Bridge Communications media@intelliatx.com mcrenson@tenbridgecommunications.com Source: Intellia Therapeutics, Inc.