每月一針，持久降血脂！2025年第三季度，這類療法有哪些新進展？

編者按：寡核苷酸藥物是全球新藥開發的重要熱點，近年來在罕見病等多個領域得到快速應用。當前，全球共有超過300款寡核苷酸療法管線已進入臨床開發階段，未來有望造福更多病患。為幫助合作伙伴更高效地推動寡核苷酸藥物從實驗室走向臨床，藥明康德化學業務旗下WuXi TIDES平臺圍繞寡核苷酸、多肽及其相關化學偶聯藥物建立了一體化解決方案，覆蓋定制合成、共價偶聯、工藝開發和CMC等關鍵環節，賦能創新項目加速進入臨床階段。本文將回顧2025年第三季度寡核苷酸領域的最新進展，并介紹藥明康德的一體化CRDMO平臺如何高效助力該領域藥物的開發。

寡核苷酸療法在罕見病領域獲得持續進展

寡核苷酸療法正成為突破罕見病治療的重要力量。2025年第三季度，寡核苷酸療法也持續迎來多項進展。美國FDA在8月批準反義寡核苷酸配體偶聯（LICA）藥物Dawnzera（donidalorsen），用于預防12歲及以上成人和兒童患者的遺傳性血管性水腫（HAE）發作。根據新聞稿，Dawnzera是獲批用于HAE的首個RNA靶向藥物。歐盟（EU）則在9月批準反義寡核苷酸（ASO）療法Tryngolza（olezarsen）作為飲食控制的輔助療法，用于治療經遺傳學確認的家族性乳糜微粒血癥（FCS）成人患者。值得一提的是，該療法用于治療重度高甘油三酯血癥（sHTG）的3期試驗也在同月迎來積極結果，每月一次的olezarsen使患者的空腹甘油三酯相較安慰劑平均降低72%，急性胰腺炎事件減少85%。由此可見，起初定位于罕見病的寡核苷酸療法，具潛力拓展應用于非罕見疾病治療。

圖片來源：123RF

此外，補體C5靶向siRNA療法cemdisiran，在用以治療成人全身性重癥肌無力（gMG）的NIMBLE臨床3期試驗中達到試驗終點。分析顯示，每三個月皮下注射一次的cemdisiran單藥顯示出平均74%的補體活性抑制，而cemdisiran與C5抗體pozelimab的聯合療法則達成近99%的補體活性抑制。與此同時，ASO療法zilganersen也在關鍵試驗中顯著改善罕見神經系統疾病亞歷山大病（AxD）患者的步行能力。根據新聞稿，zilganersen是在AxD患者中顯示出改變疾病進程影響的首款在研療法。以上兩款療法皆預計于2026年第一季度提交相關監管申請。另一方面，用以治療Dravet綜合征的在研ASO療法zorevunersen在為期3年的擴展研究中，顯示可持續降低癲癇發作，并伴隨認知與行為的持續改善。該療法已在今年8月完成3期試驗的首位患者給藥。

同時，本季度FDA還向多款寡核苷酸療法授予突破性療法認定（BTD），適應癥涵蓋多種罕見疾病。其中，抗體/抗體片段-寡核苷酸偶聯療法del-zota與DYNE-251分別用于治療適用外顯子44與51跳躍的杜氏肌營養不良癥（DMD）；同時，用于治療天使綜合征的ASO療法apazunersen與ION582也獲此認定。

寡核苷酸療法在常見適應癥的突破

寡核苷酸療法的進展也逐漸從罕見病擴展至常見疾病。今年7月，美國FDA批準諾華（Novartis）每年兩次給藥的siRNA療法Leqvio（inclisiran）的擴展適應癥，允許其作為單藥，與飲食控制和運動聯合使用，以降低成人高膽固醇血癥患者的低密度脂蛋白膽固醇（LDL-C）水平。值得一提的是，根據新聞稿，這次的標簽更新是美國FDA根據該PCSK9靶向療法降低LDL-C的積極數據，主動要求更新該藥品的標簽。而開發用以治療代謝功能障礙相關脂肪性肝炎（MASH）的ASO療法ION224也在本季度獲得積極的2期臨床試驗結果。有近60%的最高劑量組患者達到主要終點，顯示出在MASH疾病活動上的改善，而此數值在安慰劑組僅為19%。

在癌癥領域，PD-1靶向siRNA療法PH-762在治療皮膚癌的1b期試驗中也獲得積極結果。入組的13名皮膚鱗狀細胞癌（cSCC）患者中有6人在接受治療后達到病理學完全緩解或接近完全緩解。另外，DNA癌癥疫苗SCIB1與其改良版iSCIB1+在晚期不可切除黑色素瘤患者中展現亮眼療效。臨床2期試驗結果顯示，當兩者與當前標準免疫檢查點抑制劑聯用時，患者的疾病控制率（DCR）高達88.0%。

與此同時，在9月，兩款分別設計用以治療肥胖與阿爾茨海默病的siRNA療法RN3161與ARO-MAPT，也分別在澳洲與新西蘭遞交臨床試驗申請，標志著寡核苷酸療法在更廣泛適應癥上的進一步拓展。

商業研發合作進展

今年9月，諾華接連達成兩項大額siRNA療法授權合作。其一，諾華與Arrowhead Pharmaceuticals就后者開發的α-突觸核蛋白靶向siRNA療法ARO-SNCA簽署總額高達20億美元的全球許可與合作協議。該療法目前處于臨床前階段，擬用于治療包括帕金森病在內的突觸核蛋白病。其二，諾華與Argo Biopharma圍繞多項心血管siRNA管線達成合作，交易總額最高可達52億美元，進一步夯實其在心血管代謝領域的布局。

與此同時，Arrowhead Pharmaceuticals控股子公司維亞臻（Visirna Therapeutics）亦與賽諾菲（Sanofi）達成最高2.65億美元的合作：賽諾菲將獲得潛在“first-in-class”的siRNA療法plozasiran（VSA001）在大中華區的開發與商業化獨家權利。該療法通過抑制載脂蛋白C-III（APOC3）的產生，用于治療家族性乳糜微粒血癥綜合征及重度高甘油三酯血癥。

▲部分2025年第三季度寡核苷酸療法相關合作交易與融資事件

此外，本季度Arnatar Therapeutics宣布結束隱匿模式并正式亮相。該公司已于2024年完成5200萬美元A輪融資，其專有的DARGER平臺將siRNA沉默技術與基于ASO的基因上調技術相結合，開發具雙重作用機制的RNA療法，面向心臟代謝、肝、腎及中樞神經系統等疾病領域。

綜上，2025年第三季度，寡核苷酸療法持續展現出從罕見病到常見疾病的進展。多款ASO和siRNA療法迎來關鍵監管批準與積極臨床數據，不僅推動了遺傳性血管性水腫、家族性乳糜微粒血癥、重癥肌無力及亞歷山大病等罕見病治療的進展，也在高膽固醇血癥、MASH及皮膚癌等常見適應癥中展現突破。同時，部分藥企通過多項高額合作進一步加碼siRNA布局，顯示產業對該領域的信心。

一體化平臺高效賦能寡核苷酸藥物研發

作為醫藥創新的賦能者，藥明康德化學業務旗下WuXi TIDES平臺圍繞siRNA、ASO等寡核苷酸療法，建立了化合物合成、工藝開發及生產的一站式服務平臺，覆蓋從藥物發現、CMC開發，到商業化生產的全生命周期，加速將合作伙伴的創新構想轉化為現實，更好地造福全球病患。以下案例將展示WuXi TIDES的一體化平臺如何加速合作伙伴ASO藥物的開發進程。

2023年，一家生物技術公司與WuXi TIDES合作進行ASO藥物的早期篩選研究，WuXi TIDES的藥物化學團隊為其提供了超過400種攜帶骨架化學修飾的ASO化合物，以協助確定最具前景的分子。然而，早期研究發現，創新骨架修飾導致候選化合物中出現新的雜質。在最初的合成過程中，這些雜質占比高達25%，不僅降低了產率和純化效率，還可能帶來潛在毒性，給后續臨床開發帶來挑戰。

面對這一難題，WuXi TIDES藥物化學團隊和工藝研發團隊密切配合，從兩個方向入手解決問題。一方面，藥物化學團隊與合作伙伴共同探索雜質產生的潛在原因，設計出定制化的amidite和分子砌塊，規避雜質產生的關鍵合成機制，并快速生產這些新分子砌塊，協助工藝研發團隊加速驗證工藝設計策略，以有效地控制雜質。此外，工藝研發團隊通過優化工藝參數，系統性地降低了雜質的產生。最終，經過持續工藝優化，雜質占比成功從25%降低至5%，同時最終收率也從最初的0.5 g/mol提高到3.4 g/mol。

在該項目中，WuXi TIDES各團隊高效協作，不僅在12個月內完成了先導化合物的優化、工藝開發及GMP生產，更幫助合作伙伴基于數據進行快速決策，選出綜合效力、穩定性和開發潛力俱佳的ASO候選化合物，為后續臨床研究奠定了堅實基礎。隨著越來越多的ASO以及其他寡核苷酸藥物進入臨床開發，這種產業協同模式將成為加快研發步伐的重要推動力。

CRDMO: Q3 2025 Review of Oligonucleotide Therapeutics

Oligonucleotide-based therapeutics continue to stand out as a key area in global drug development, with rapid progress seen across rare diseases and beyond. Currently, over 300 oligonucleotide pipelines are in clinical development worldwide, offering hope to a growing number of patients. To support partners in efficiently advancing these innovative therapies from discovery to clinic, WuXi TIDES offers efficient, flexible, and high-quality solutions for the drug development of oligonucleotides, peptides and related synthetic conjugates. The platform greatly simplifies TIDES drug development by providing all discovery, CMC development and the entire manufacturing supply chain under one roof. Here, we summarize key developments in the oligonucleotide space during Q3 2025 and share a case study that illustrates how WuXi TIDES helps accelerate progress in this dynamic area.

Oligonucleotide Therapies Continue to Advance Across Rare Diseases

Oligonucleotide therapies have emerged as a powerful tool in transforming the treatment landscape for rare diseases. In the third quarter of 2025, the field marked several major milestones. In August, the U.S. FDA approved Dawnzera (donidalorsen), an antisense oligonucleotide ligand conjugate (LICA), for the prevention of hereditary angioedema (HAE) attacks in patients aged 12 and older. According to the press release,Dawnzera is the first RNA-targeted prophylactic treatment for HAE.In September, the European Union (EU) granted marketing authorization to the antisense oligonucleotide (ASO) therapy Tryngolza (olezarsen) as an adjunct to diet for adults with genetically confirmed familial chylomicronemia syndrome (FCS). Notably,olezarsen also achieved positive results in a Phase 3 trial in severe hypertriglyceridemia (sHTG), demonstrating a 72% average reduction in fasting triglycerides versus placebo and an 85% reduction in acute pancreatitis events.These findings underscore the potential of oligonucleotide therapies, originally developed for rare diseases, to expand into more common conditions.

Further progress was seen with siRNA therapy cemdisiran, which achieved the primary endpoint in the Phase 3 NIMBLE trial for generalized myasthenia gravis (gMG). Results showed that subcutaneous cemdisiran given every three months as monotherapy suppressed complement activity by an average of 74%, while in combination with the C5 antibody pozelimab, suppression approached 99%. Meanwhile, the ASO therapy zilganersen demonstrated meaningful improvements in the 10-Meter Walk Test (10MWT) for patients with Alexander disease (AxD)—the first investigational therapy to show disease-modifying potential in this indicationaccording to the company. Both therapies are expected to be submitted for regulatory review in Q1 2026. In parallel, investigational ASO zorevunersen for Dravet syndrome continued to show durable seizure reduction and cognitive and behavioral improvements in a three-year extension study, with dosing of the first patient in its Phase 3 program beginning in August.

In addition, the FDA granted multiple Breakthrough Therapy Designations (BTD) to oligonucleotide candidates addressing rare diseases this quarter. These include the antibody/antibody fragment-oligonucleotide conjugates del-zota and DYNE-251 for Duchenne muscular dystrophy (DMD) exon 44 and 51 skipping, respectively, and the ASO therapies apazunersen and ION582 for Angelman syndrome.

Breakthroughs in Common Diseases

Encouragingly, oligonucleotide therapies are now extending their impact beyond rare diseases into more prevalent conditions. In July, the FDA approved an expanded indication for Novartis’s Leqvio (inclisiran), the twice-yearly siRNA therapy, allowing its use as monotherapy in combination with diet and exercise to lower LDL-C in adults with hypercholesterolemia. According to the company,this label expansion was proactively initiated by the FDA following compelling data on LDL-C reduction with this PCSK9-targeting therapy.Also in Q3, the ASO therapy ION224 for metabolic dysfunction-associated steatohepatitis (MASH) delivered positive Phase 2 data, with nearly 60% of patients in the highest-dose group achieving the primary endpoint, compared to just 19% in the placebo arm.

In oncology, PD-1-targeting siRNA therapy PH-762 achieved positive results in a Phase 1b trial in cutaneous squamous cell carcinoma (cSCC), where 6 out of 13 treated patients achieved either complete or near-complete pathological responses. Meanwhile, the DNA cancer vaccines SCIB1 and its modified version iSCIB1+ demonstrated promising efficacy in advanced, unresectable melanoma. Phase 2 results showed that,when combined with standard immune checkpoint inhibitors, the disease control rate (DCR) reached 88.0%.

In September, siRNA therapies also expanded into new frontiers, with clinical trial applications submitted in Australia for RN3161 (obesity) and in New Zealand for ARO-MAPT (Alzheimer’s disease)—signaling the growing scope of oligonucleotide-based innovation.

Momentum in Strategic Partnerships

September was also marked by high-profile collaborations in the siRNA space. Novartis announced two major licensing agreements: one with Arrowhead Pharmaceuticals for global rights to ARO-SNCA, an α-synuclein-targeting siRNA currently in preclinical development for synucleinopathies including Parkinson’s disease, in a deal worth up to USD 2 billion; and another with Argo Biopharma for multiple cardiovascular siRNA programs, valued at up to USD 5.2 billion, further strengthening its position in cardiovascular and metabolic diseases.

In parallel, Arrowhead’s majority-owned subsidiary Visirna Therapeutics entered into a partnership with Sanofi, granting Sanofi exclusive rights in Greater China to develop and commercialize plozasiran (VSA001). This potential first-in-class siRNA therapy targets APOC3 to treat familial chylomicronemia syndrome and severe hypertriglyceridemia.

Additionally, Arnatar Therapeutics emerged from stealth this quarter, following a USD 52 million Series A financing in 2024. Leveraging its proprietary DARGER platform, the company is developing RNA therapies that combine siRNA silencing with ASO-based gene upregulation, addressing cardiovascular, hepatic, renal, and central nervous system diseases.

Overall, Q3 2025 underscored the accelerating momentum of oligonucleotide therapies, with significant advances spanning both rare and common diseases. Multiple ASO and siRNA candidates achieved key regulatory approvals and delivered positive clinical data, advancing treatment options for hereditary angioedema, familial chylomicronemia syndrome, myasthenia gravis, and Alexander disease, while also demonstrating potential in hypercholesterolemia, MASH, and oncology. Alongside these scientific breakthroughs, landmark licensing and collaboration deals highlighted the industry’s confidence and investment in the promise of oligonucleotide medicines.

WuXi TIDES Accelerates Oligonucleotide Drug Development for Global Partners

WuXi TIDES has built an end-to-end service platform for oligonucleotide therapeutics, including siRNA and ASO, encompassing compound synthesis, process development, and manufacturing. Covering the full lifecycle—from drug discovery and CMC development to commercial production—the platform enables partners to rapidly transform innovative ideas into reality and bring benefits to patients worldwide. The following case study highlights how WuXi TIDES’ fully integrated platform is accelerating the development of an ASO therapy for one of our partners.

In 2023, a biotech company partnered with WuXi TIDES to conduct early-stage ASO screening. The discovery synthesis team undertook extensive SAR (Structure-Activity Relationship) exploration—screening more than 400 ASO variants with various types of backbone and ribose modifications to help identify the most promising candidates. However, early-stage studies revealed that novel backbone modifications introduced new impurities—up to 25% in some initial batches—significantly lowering yield and purification efficiency, while raising concerns about potential toxicity that could hinder clinical development.

To address these challenges, WuXi TIDES’ Discovery Chemistry team and Process Development (PRD) team collaborated closely on two fronts. The Discovery Chemistry Team worked with the client to investigate the source of impurities and designed specialized amidites and building blocks to circumvent the pathway leading to key impurities. In parallel, the PRD team rapidly synthesized these components and supported swift validation of the optimized strategy. Additionally, the PRD team systematically optimized multiple process parameters to further reduce impurities.

Ultimately, through a series of process refinements,the impurity level was reduced from 25% to just 5%, and the final yield increased from 0.5 g/mol to 3.4 g/mol.

Thanks to efficient cross-functional collaboration, WuXi TIDES completed hit-to-lead optimization, process development, and GMP manufacturing within 12 months. The partner was able to make data-driven decisions and select a lead ASO candidate with optimal potency, stability, and development potential—laying a strong foundation for clinical studies. As more ASO therapies enter development, this model of collaborative development will be critical for accelerating future breakthroughs.

Advances in chemical modification and delivery technology have enabled oligonucleotide therapeutics to reach previously inaccessible tissue targets—offering new hope for rare and hard-to-treat diseases. Looking ahead, the continued evolution of this field is expected to deliver more innovative treatments to benefit patients worldwide. WuXi TIDES remains committed to leveraging its integrated CRDMO platform to empower the development of oligonucleotide therapeutics, helping partners translate scientific innovation into life-changing medicines.

參考資料：

[1] Oligonucleotides Clinical Trial Pipeline Analysis Demonstrates 280+ Key Companies at the Horizon Expected to Transform the Treatment Paradigm, Assesses DelveInsight. Retrieved June 18, 2025 from https://www.globenewswire.com/news-release/2025/06/17/3100992/0/en/Oligonucleotides-Clinical-Trial-Pipeline-Analysis-Demonstrates-280-Key-Companies-at-the-Horizon-Expected-to-Transform-the-Treatment-Paradigm-Assesses-DelveInsight.html

[2] Olezarsen significantly reduces triglycerides and acute pancreatitis events in landmark pivotal studies for people with severe hypertriglyceridemia (sHTG). Retrieved September 30, 2025 from https://ir.ionis.com/news-releases/news-release-details/olezarsen-significantly-reduces-triglycerides-and-acute

[3] Arrowhead Pharmaceuticals and Novartis Enter into a Global License and Collaboration Agreement. Retrieved October 1, 2025 from https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-and-novartis-enter-global-license-and

[4] Argo Biopharma Announces Multi-Asset License and Option Agreements with Novartis for Novel Molecules for Cardiovascular Diseases. Retrieved October 1, 2025 from https://www.prnewswire.com/news-releases/argo-biopharma-announces-multi-asset-license-and-option-agreements-with-novartis-for-novel-molecules-for-cardiovascular-diseases-302544452.html

[5] 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

[6] Oligonucleotides Clinical Trial Pipeline Analysis Demonstrates 280+ Key Companies at the Horizon Expected to Transform the Treatment Paradigm, Assesses DelveInsight. Retrieved October 10, 2025, from https://www.globenewswire.com/news-release/2025/06/17/3100992/0/en/Oligonucleotides-Clinical-Trial-Pipeline-Analysis-Demonstrates-280-Key-Companies-at-the-Horizon-Expected-to-Transform-the-Treatment-Paradigm-Assesses-DelveInsight.html

免責聲明：本文僅作信息交流之目的，文中觀點不代表藥明康德立場，亦不代表藥明康德支持或反對文中觀點。本文也不是治療方案推薦。如需獲得治療方案指導，請前往正規醫院就診。

版權說明：歡迎個人轉發至朋友圈，謝絕媒體或機構未經授權以任何形式轉載至其他平臺。轉載授權請在「藥明康德」微信公眾號回復“轉載”，獲取轉載須知。