Arrowhead Pharmaceuticals, Inc.

2025 年 6 月 9 日，随着多家药企在 RNA 干扰（RNAi）领域的持续突破，小干扰 RNA（siRNA）疗法正站在关键转折点。继 Alnylam 在肝脏靶向治疗中取得显著成功后，行业正全力攻克多器官递送难题，一场从 "肝脏专属" 到 "全身布局" 的技术革命已然拉开序幕。一、肝脏靶向的辉煌：Alnylam 奠定行业基石2025 年 3 月，Alnylam 再获两项 FDA 批准：Amvuttra 用于转甲状腺素蛋白介导的淀粉样变性，与赛诺菲合作的 Qfitlia 则针对血友病 A 和 B。这一成就延续了该公司的创新轨迹 ——2018 年，其首款 siRNA 药物 Onpattro 获批，标志着 RNAi 疗法从实验室走向临床的重大突破。回顾技术演进，1998 年 Craig Mello 发现 RNA 干扰机制，2002 年 Alnylam 成立，直至 2014 年 GalNAc 配体技术问世，才真正解决了 siRNA 的肝脏靶向难题。Onpattro 通过 GalNAc 偶联技术，首次实现了在肝脏细胞中特异性沉默致病基因，不仅缓解遗传性转甲状腺素蛋白淀粉样变性多发性神经病的症状，更实现了功能改善，被行业分析师 Myles Minter 称为 "革命性突破"。目前，Alnylam 已有多款药物获批，涵盖高胆固醇血症（与诺华合作的 Leqvio）、急性肝卟啉症（Givlaari）等领域。诺和诺德的 Rivfloza 也于 2023 年获批，共同构建了 siRNA 在肝脏疾病中的治疗版图。威廉・布莱尔高级分析师 Minter 指出："siRNA 在罕见病领域已展现变革性潜力，而更广泛适应症的突破才刚刚开始。"二、多器官靶向：从实验室到临床的突破尝试尽管现有 siRNA 疗法均聚焦肝脏，但多家药企已在非肝脏组织靶向中取得进展。Alnylam 首席技术官 Vasant Jadhav 表示，公司正攻关脑、脂肪、肺等组织的递送技术，其候选药物 mivelsiran 已进入 II 期临床试验，用于治疗脑淀粉样血管病，并启动阿尔茨海默病的 I 期研究。礼来的分子发现副总裁 Andrew Adams 强调，GalNAc 仍是目前最成功的靶向工具，但团队正探索脑靶向递送："一旦突破新组织的递送瓶颈，将开启类似肝脏靶向的适应症拓展浪潮。"Arrowhead Pharmaceuticals 的研究同样引人注目：其 siRNA 候选药物在小鼠实验中成功减少体脂并保留瘦肌肉，其中靶向脂肪细胞 ALK7 基因的疗法已启动早期临床；另一款靶向肺部的 ARO-RAGE 在哮喘患者中使目标蛋白水平降低 88%，展现出呼吸系统疾病的治疗潜力。三、技术边界与行业竞争格局siRNA 疗法仍面临固有挑战：无法完全敲除基因表达，仅能下调；且无法直接补充缺失蛋白。Jadhav 以 Givlaari 为例解释 workaround 策略：通过沉默代谢通路中上游的 GO 酶，降低急性肝卟啉症的毒性中间产物，而非直接修复突变酶。基因编辑技术的崛起也带来竞争压力。礼来的 Adams 指出，当 siRNA 长期数据证明敲低特定蛋白的安全性后，基因编辑可能成为永久性解决方案，如 Verve Therapeutics 已针对 PCSK9 基因开展编辑疗法的临床试验。但 Jadhav 强调 siRNA 的独特优势："兼具持久活性与可逆性，这是基因编辑无法同时实现的。"行业并购热潮反映了资本对 siRNA 的信心。2024 年 1 月，勃林格殷格翰与中国苏州瑞博生物达成 20 亿美元合作，开发非酒精性脂肪性肝炎（MASH）疗法；2025 年 5 月，GSK 以 12 亿美元收购 Boston Pharmaceuticals 的 FGF21 类似物，同样瞄准 MASH。据预测，到 2030 年 MASH 将影响 2700 万美国人，这类代谢疾病正成为 siRNA 的下一个战场。四、未来展望：技术迭代与市场扩容的双重机遇Minter 将 siRNA 的当前阶段形容为 "站在悬崖边缘"：一方面，肝脏靶向的成功奠定了坚实基础；另一方面，多器官递送的突破将开启黄金时代。Alnylam 设定了 2030 年 "靶向任意器官" 的目标，而礼来、Arrowhead 等企业的管线进展印证了这一愿景的可行性。从科学意义看，siRNA 不仅是药物开发的新工具，更重塑了基因调控的治疗逻辑 —— 通过 "基因开关" 而非传统小分子或抗体，实现更精准的疾病干预。随着递送技术的突破，神经系统、免疫系统等复杂疾病的治疗有望迎来革新。对患者而言，siRNA 的长效性（部分药物每半年给药一次）和高特异性，意味着更便捷的治疗方案和更少的副作用。而对行业来说，这场从肝脏到全身的技术跨越，可能催生数千亿美元的市场，重塑生物医药的竞争格局。站在 2025 年的技术临界点，siRNA 疗法的下一个十年注定充满挑战与机遇。正如 Minter 所言："未来五到十年，这个领域必将激动人心，我们正见证一场医学革命的序幕。" 当 Alnylam 等先驱者突破组织屏障，siRNA 或将成为继单克隆抗体、基因编辑之后，又一个改变疾病治疗范式的颠覆性技术。参考来源：https://www.biospace.com/drug-development/sirna-on-the-precipice-as-candidates-reach-beyond-the-liver识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

iStock, Love Employee As multiple companies vie to expand on Alnylam’s success in commercializing RNAi therapeutics, the pioneering company has set a goal of targeting small interfering RNA to any organ by 2030. In March, Alnylam chalked up two FDA approvals, for Amvuttra in transthyretin-mediated amyloidosis and, with Sanofi, Qfitlia in hemophilia A and B. Such approvals have become par for the course for Alnylam, leading multiple other companies—including GSK , AbbVie , Boehringer Ingelheim and Eli Lilly —to follow suit in pursuing therapies based on small interfering RNA (siRNA). And it’s not just the number of companies involved that’s expanding: while all siRNA therapies approved so far target the liver, Alnylam and others are now seeing some success in targeting other organs as well. The past two years have seen billions of dollars change hands in a bid to be part of this rapidly growing field. In January 2024, for example, Boehringer Ingelheim announced an agreement potentially worth more than $2 billion with Chinese biotech Suzhou Ribo Life Science and its Swedish unit Ribocure Pharmaceuticals to develop siRNA-based treatments for nonalcoholic or metabolic dysfunction-associated steatohepatitis (MASH), a disease expected to afflict 27 million Americans by 2030. And just last month, GSK plunked down $1.2 billion for Boston Pharmaceuticals’ investigational FGF21 analog efimosfermin alfa, also targeting MASH. “I think the siRNA space, for rare disease predominantly, has been revolutionary in a handful of cases,” said Myles Minter, a senior biotech analyst at William Blair. “And I do think that the large promise of the field to go into broader, more prevalent indications and to get more approvals is largely ahead of us.” A Genetic On/Off Switch The term RNA interference dates back to a 1998 paper by Craig Mello and colleagues, who found that double-stranded RNA was more effective than single strands in silencing genes with corresponding sequences in C. elegans . The mechanism turned out to also work in mammalian cells , and in 2002, multiple researchers who’d led key studies of the phenomenon, including Mello, teamed up with investors to found Alnylam. It took 16 years to gain FDA approval for the first siRNA drug, Onpattro, for polyneuropathy of hereditary transthyretin-mediated amyloidosis, a rare genetic disorder caused by mutations in the transthyretin ( TTR ) gene. One challenge Alnylam faced in the intervening years was in designing siRNAs that could escape degradation within the body for long enough to be effective, explained Vasant Jadhav, the company’s chief technology officer. But the biggest hurdle—one not unique to siRNAs—was getting the nucleic acid payloads where they needed to go. Then, in 2014, Alnylam researchers and their academic colleagues reported that linking siRNAs with a ligand called GalNAc would get them into cells in the liver, but not into other organs. Onpattro, approved in 2018, is a GalNac-linked siRNA. The drug “was pretty revolutionary at the time,” Minter said, because rather than simply treating symptoms or even slowing the toll of polyneuropathy of hereditary transthyretin-mediated amyloidosis, it elicited functional improvement. “The way I like to think about siRNA is that it’s a way that you can titrate, so you can dose at a genetic level. And it’s really one of the only modalities that you can do that with,” Minter told BioSpace . Other therapies followed from Alnylam for hypercholesterolemia (Leqvio, developed and commercialized by Novartis), acute hepatic porphyria (Givlaari) and primary hyperoxaluria type 1 (Oxlumo). Apart from Alnylam and its partners Sanofi and Novartis, the only other company to get an siRNA drug onto the market so far is Novo Nordisk, whose Rivfloza (nedosiran), approved by the FDA in 2023, treats the rare genetic disease primary hyperoxaluria type 1 (PH1). Testing the Limits So far, all of these therapies have targeted processes in the liver—including Amvuttra, which takes aim at cardiac outcomes via knocking down transthyretin (TTR) in hepatic cells. But experts who spoke with BioSpace said that could soon change. “Where we’re starting to see innovation—and it still is early stage, although it looks very promising—is trying to deliver to new tissues,” Minter said. That targeting problem is “the major question in the field that we’re working on right now.” Andrew Adams, Eli Lilly’s group vice president, molecule discovery and director of the Lilly Institute for Genetic Medicines, echoed this. GalNAc has thus far been a “unicorn” in the field in terms of its specific and safe delivery, and “we have a lot of work to do to open up si[RNA]beyond the hepatocyte, but . . . probably once we crack it is going to be similar to when Alnylam and others initially cracked GalNAc, and you’ll just sort of walk your way down the list of indications in the new tissue that you open up,” he told BioSpace . “I think probably the most interesting space for the field right now is in delivery to the brain and going after diseases of the brain,” he said, citing Alnylam’s candidate mivelsiran, currently in Phase II for cerebral amyloid angiopathy and Phase I for Alzheimer’s disease. Lilly, too, is pursuing neurodegenerative targets with siRNA, Adams added. Other tissues with promising early data include adipose and lung. In a March conference presentation, for example, Arrowhead Pharmaceuticals released mouse data on two siRNA candidates devised to reduce body fat while preserving lean muscle mass. One targets hepatic cells’ expression of a gene, INHBE , that is involved in metabolic processes, while the other silences expression of ALK7 , a gene needed for fat storage, in lipocytes. Early clinical studies on both candidates have begun. And last spring, Arrowhead announced interim results of a Phase I/II study of ARO-RAGE, an siRNA that targets lung tissue and silences the receptor for advanced glycation end-products, a mediator of type 2 inflammation. In study participants with asthma, two doses of the candidate reduced serum levels of the target protein by up to 88%, the company reported. siRNA’s limitations don’t end at targeting. It can’t be used to completely knock out expression of a gene, only knock it down, and it can’t by itself be used against multiple genetic targets, Jadhav noted. In addition, RNAi can only dial gene expression down, so it can’t be used to directly boost levels of a deficient protein. Researchers have found workarounds for this in some cases, though. Jadhav cited the example of Givlaari, which treats acute hepatic porphyria. “In this metabolic pathway, the heme biosynthesis, one of the enzymes is mutated, and because of that, you have toxic intermediates that build up,” he said. Since siRNA can’t replace the mutated enzyme, the therapy instead targets a different enzyme, GO, that’s upstream of the toxic intermediates, lowering their levels. siRNA’s successes could pave the way for a more permanent treatment option, Adams said. “Once you’ve generated enough evidence over a long enough period of time in enough patients that getting rid of this protein [via siRNA] has no negative consequences in an adult . . . Probably at that point you start to feel confident to permanently change something, but I think the bar should be and is high for things that people will tolerate permanent genetic changes for,” he said. He raised the example of Leqvio, which targets the enzyme PCSK9 in order to lower cholesterol levels. Verve Therapeutics now has a gene editor targeting the same enzyme in early clinical trials. Jadhav allowed that gene editing could become a competitor to siRNA in some cases. “I think at the end of the day, any solution . . . biopharma brings for the patients would be great,” he said. “At the same time, we feel that with RNAi, we can achieve [a] durable level of activity and still be reversible. You kind of get the best of both things. So we remain very confident and very optimistic about the future of RNAi.” Looking ahead, Minter summarized what he sees as the prospects for siRNA: “we’re at the precipice where we’re waiting, but it’s an exciting five to ten years ahead for the field, no doubt.”

近期，全球多肽和寡核苷酸（TIDES）领域迎来系列进展。Zealand Pharma公司宣布向欧洲药品管理局（EMA）递交其多肽疗法glepaglutide的上市申请，用于治疗短肠综合征（SBS）成人患者。用于治疗真性红细胞增多症（PV）的多肽疗法rusfertide达3期临床试验终点，需放血治疗的患者比例显著降低。治疗胶质母细胞瘤（GBM）的C/EBPβ拮抗剂lucicebtide（ST101）获积极2期临床试验结果。Glepaglutide：向EMA提交上市申请Zealand Pharma公司宣布向EMA递交其长效胰高血糖素样肽-2（GLP-2）类似物glepaglutide的上市许可申请（MAA），用于治疗SBS成人患者。Glepaglutide是一种装于自动注射器中的液体产品，设计用于每周两次的皮下给药，旨在减少或消除SBS患者对肠外营养支持（PS）的需求。美国FDA已授予该疗法治疗SBS的孤儿药资格。该递交主要是基于随机双盲关键3期试验EASE-1的结果，并得到两项正在进行的长期扩展试验EASE-2和EASE-3的中期结果和机制试验EASE-4的结果支持。EASE-1研究中，与安慰剂相比，每周两次glepaglutide给药在第24周显著降低患者每周PS所需总液体体积（P=0.0039）。第24周时，每周两次接受glepaglutide治疗患者的PS液体体积较基线平均降低5.13公升/周。安慰剂治疗仅导致所需PS液体体积降低2.85公升/周。对于接受每周两次glepaglutide治疗的患者，14%的患者（n=5）实现不再需要PS辅助治疗，而安慰剂治疗患者均不能停用PS。Rusfertide：公布3期临床试验的新数据Protagonist Therapeutics公司与武田（Takeda）公布了3期研究VERIFY的积极新结果。该试验主要评估每周一次的rusfertide自我给药皮下注射，在那些标准治疗下仍血容量控制不佳且依赖放血疗法的真性红细胞增多症患者中的疗效与安全性。Rusfertide是一种潜在“first-in-class”的在研天然激素铁调素的多肽模拟物，已获得美国FDA的孤儿药资格和快速通道资格。此次公布的分析结果显示，该研究达到了其主要终点，rusfertide联合当前标准治疗在高危和低危PV患者中使临床缓解率较安慰剂联合当前标准治疗组患者翻倍（76.9%对比32.9%），显著降低需放血治疗的患者比例。所有关键次要终点也均达到统计学显著差异，包括rusfertide联合治疗组需放血治疗的患者比例显著下降（27%对比78%），保持血细胞比容水平低于45%的患者比例显著提升（62.6%对比14.4%），患者报告的结局也有所改善。此外，未报告任何与rusfertide相关的严重不良事件。EO4010：公布1/2期联合治疗试验数据Enterome公司公布了其在研免疫疗法EO4010的1/2期临床试验AUDREY的积极数据。该研究旨在评估EO4010联合纳武利尤单抗（nivolumab）±贝伐珠单抗（bevacizumab）治疗微卫星稳定（MSS）/错配修复功能正常（pMMR）转移性结直肠癌（mCRC）的效果。EO4010是一种由五种微生物衍生肽组成的疫苗，这些肽模拟了五种常见于结直肠癌患者的肿瘤相关抗原（TAA）——BIRC5、FOXM1、UBE2C、CDC20和KIF2C，旨在激活患者的肿瘤特异性CD8阳性T细胞，引导其识别并杀死表达这些抗原的癌细胞。此次公布的结果显示，EO4010显示出良好的安全性和耐受性。中位随访时间为15.4个月时，20名MSS/pMMR mCRC患者的12个月生存率为40%，中位生存时间为11.3个月。目前，患者的生存曲线已趋于平稳，34%（7/20）的患者仍存活。此外，80%接受EO4010联合纳武利尤单抗治疗的患者体内检测到针对肿瘤相关抗原的特异性免疫反应。这些积极结果支持进一步开发EO4010治疗结直肠癌的潜力。Lucicebtide：公布2期临床试验结果Sapience Therapeutics公司公布了其潜在“first-in-class”的C/EBPβ拮抗剂lucicebtide治疗胶质母细胞瘤的2期临床试验数据。Lucicebtide已获得美国FDA授予用于治疗复发性GBM的快速通道资格，以及美国FDA和欧盟委员会授予的孤儿药资格，用以治疗神经胶质瘤。此次公布的结果显示，lucicebtide作为单一疗法和与标准护理（SoC）联合使用具有良好的耐受性。截至2025年5月6日的数据，新确诊的GBM队列中，9名患者中有5名尚未出现疾病进展（10-24+个月），6名患者在数据截止时仍然存活；复发性GBM队列中，9名患者中有4名获得疾病控制，其中2名为部分缓解（PR），3名患者在数据截止时仍然存活。[212Pb]VMT-α-NET：公布1/2a期临床试验的中期数据Perspective Therapeutics公司公布了其候选多肽偶联核素疗法[212Pb]VMT-α-NET的1/2a期临床试验的最新中期数据。该研究旨在评估[212Pb]VMT-α-NET在表达SSTR2的不可切除/转移性神经内分泌瘤（NET）患者中的疗效和安全性，这些患者既往未接受过放射性药物治疗（RPT），并且放射学证据显示其肿瘤在入组前12个月内已发生疾病进展。截至2025年4月30日的数据，该疗法安全性良好，在接受至少一种治疗的总共42名患者中，没有观察到剂量限制性毒性，也没有因不良事件而停药。在队列2的7名患者中，有4名达到了研究者评估的客观缓解，其中3名缓解已确认并持续维持，1名需进一步确认；而在队列1和2的共计9名患者中，有7名在超过一年的随访期内保持无疾病进展。ARO-ALK7：启动1/2a期临床试验Arrowhead Pharmaceuticals公司宣布，其用于治疗肥胖的在研小干扰RNA（siRNA）疗法ARO-ALK7的1/2a期临床试验已为第一批受试者给药。ARO-ALK7旨在沉默脂肪细胞中ACVR1C基因的表达，以减少激活素受体样激酶7（ALK7）的产生，ALK7在调节脂肪组织能量稳态的通路中充当受体。在临床前研究中，ARO-ALK7抑制了脂肪组织中ALK7的表达，从而能在保留瘦肌肉的同时减少体重和脂肪质量。新闻稿指出，ARO-ALK7是首个进入临床研究、靶向脂肪组织中表达基因的RNA干扰（RNAi）治疗药物。SC-102：IND申请获得FDA许可星联肽生物宣布，其EphA2靶向多肽偶联药物（PDC）SC-102的IND申请获得了美国FDA许可，可开展临床试验评估SC-102治疗表达EphA2的晚期或转移性实体瘤患者的安全性和有效性。SC-102通过特异性结合表达EphA2的肿瘤细胞，释放毒性载荷，从而抑制肿瘤生长。EphA2在多种肿瘤细胞表面高表达，SC-102有望治疗包括卵巢癌、乳腺癌、胰腺癌在内的多种实体瘤。此前，SC-102已在中国获批开展临床试验，目前正处于剂量递增研究阶段。已有临床数据显示，SC-102初步展现出良好的疗效和安全性。参考资料：[1] Arrowhead Pharmaceuticals Initiates Phase 1/2a Study of ARO-ALK7 for the Treatment of Obesity. Retrieved June 5, 2025, from https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-initiates-phase-12a-study-aro-alk7[2] Perspective Therapeutics Highlights Updated Interim Data from its Ongoing Phase 1/2a Clinical Trial of [212Pb]VMT-α-NET at the 2025 ASCO Annual Meeting. Retrieved June 5, 2025, from https://www.globenewswire.com/news-release/2025/05/30/3091346/0/en/Perspective-Therapeutics-Highlights-Updated-Interim-Data-from-its-Ongoing-Phase-1-2a-Clinical-Trial-of-212Pb-VMT-%CE%B1-NET-at-the-2025-ASCO-Annual-Meeting.html[3] Zealand Pharma submits Marketing Authorization Application to the European Medicines Agency for glepaglutide in short bowel syndrome. Retrieved June 5, 2025, from https://www.globenewswire.com/news-release/2025/06/02/3091534/0/en/Zealand-Pharma-submits-Marketing-Authorization-Application-to-the-European-Medicines-Agency-for-glepaglutide-in-short-bowel-syndrome.html[4] Protagonist and Takeda Announce ASCO Plenary Presentation Highlighting Full 32-Week Results from Phase 3 VERIFY Study of Rusfertide, Showing Reductions in Phlebotomy, Improved Hematocrit Control in Polycythemia Vera. Retrieved June 5, 2025, from https://www.takeda.com/newsroom/newsreleases/2025/polycythemia-vera-rusfertide-study/[5] Sapience Therapeutics Provides Data Update from Phase 2 Trial of Lucicebtide in Patients with Glioblastoma at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. Retrieved June 5, 2025, from https://www.prnewswire.com/news-releases/sapience-therapeutics-provides-data-update-from-phase-2-trial-of-lucicebtide-in-patients-with-glioblastoma-at-the-2025-american-society-of-clinical-oncology-asco-annual-meeting-302470177.html[6] Enterome presents positive Phase 1/2 MSS/pMMR metastatic colorectal cancer data in patients treated with EO4010 OncoMimics™ immunotherapy plus nivolumab at ASCO 2025. Retrieved June 5, 2025, from https://www.globenewswire.com/news-release/2025/05/30/3090836/0/en/Enterome-presents-positive-Phase-1-2-MSS-pMMR-metastatic-colorectal-cancer-data-in-patients-treated-with-EO4010-OncoMimics-immunotherapy-plus-nivolumab-at-ASCO-2025.html[7] 星联肽EphA2靶向PDC药物SC-102获批美国临床. Retrieved June 5, 2025, from https://mp.weixin.qq.com/s/Z_VtQBFnZHfLUAs8ZmSNJw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