多款新療法接連獲批！治療動脈粥樣硬化、帕金森病、血友病等，寡核苷酸療法迎來新突破

編者按：寡核苷酸藥物是全球新藥開發(fā)的重要熱點，近年來在罕見病等多個領(lǐng)域得到快速應用。當前，全球共有超過300項寡核苷酸療法相關(guān)臨床試驗正在進行之中，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，藥明康德旗下WuXi TIDES平臺圍繞寡核苷酸、多肽及其相關(guān)化學偶聯(lián)藥物建立了一體化解決方案，覆蓋定制合成、共價連接、工藝開發(fā)和CMC等關(guān)鍵環(huán)節(jié)，賦能創(chuàng)新項目加速進入臨床階段。本文將盤點2025年寡核苷酸產(chǎn)業(yè)的重要進展，并分享一則具體賦能案例，助您了解該領(lǐng)域的最新動態(tài)與發(fā)展方向。

臨床與監(jiān)管進展

今年3月，賽諾菲（Sanofi）與Alnylam Pharmaceuticals聯(lián)合開發(fā)的潛在重磅siRNA療法Qfitlia（fitusiran）獲美國FDA批準，用于治療血友病患者。兩項3期臨床試驗結(jié)果顯示，fitusiran可將患者的年化出血率降低約90%，部分患者的給藥頻率還可減少至每兩個月一次。幾乎同期，Alnylam的另一款siRNA藥物Amvuttra（vutrisiran）也獲得FDA批準，用于治療伴心肌病的轉(zhuǎn)甲狀腺素蛋白淀粉樣變性（ATTR-CM）成人患者。

圖片來源：123RF

進入7月，美國FDA批準諾華（Novartis）每年兩次給藥的siRNA療法Leqvio（inclisiran）擴展適應癥，允許其作為單藥并聯(lián)合飲食控制和運動，用于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。值得注意的是，此次標簽更新源于該

PCSK9

靶向療法在降低LDL-C方面的積極臨床數(shù)據(jù)，是FDA主動要求進行的調(diào)整。隨后在8月，FDA又批準反義寡核苷酸配體偶聯(lián)（LICA）藥物Dawnzera（donidalorsen），用于預防12歲及以上成人及兒童患者的遺傳性血管性水腫（HAE）發(fā)作。根據(jù)新聞稿，Dawnzera是首款獲批用于HAE的RNA靶向藥物。今年11月，F(xiàn)DA批準Arrowhead Pharmaceuticals旗下靶向APOC3的“first-in-class”RNAi療法Redemplo（plozasiran），作為飲食控制的輔助治療，用于降低家族性乳糜微粒血癥綜合征成人患者的甘油三酯（TG）水平。

除藥物獲批，多項寡核苷酸療法的后期臨床試驗數(shù)據(jù)也在今年公布。例如，安進（Amgen）開發(fā)的siRNA療法olpasiran在一項2期試驗中，可使動脈粥樣硬化性心血管疾病合并高脂蛋白a——Lp（a）水平升高患者的Lp（a）濃度降低約92%，且療效可持續(xù)超過一年，該療法目前已進入3期臨床階段。此外，開發(fā)用以治療代謝功能障礙相關(guān)脂肪性肝炎（MASH）的ASO療法ION224也在今年獲得積極的2期臨床試驗結(jié)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(shù)值在安慰劑組僅為19%。

在罕見疾病方面，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(lián)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(guān)鍵試驗中顯著改善罕見神經(jīng)系統(tǒng)疾病亞歷山大病（AxD）患者的步行能力。根據(jù)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(guān)監(jiān)管申請。

研發(fā)合作與融資進展

2025年，多家大型醫(yī)藥企業(yè)在寡核苷酸領(lǐng)域持續(xù)加碼，通過戰(zhàn)略合作與并購進一步完善布局。5月，渤健（Biogen）與City Therapeutics達成一項潛在總額高達10億美元的合作協(xié)議，初期聚焦于開發(fā)針對中樞神經(jīng)系統(tǒng)關(guān)鍵靶點的新型RNAi療法。此前在2月，渤健還與Stoke Therapeutics簽署協(xié)議，就其反義寡核苷酸療法zorevunersen的開發(fā)與商業(yè)化達成最高3.85億美元的合作。諾華（Novartis）于4月宣布擬以最高約17億美元收購Regulus Therapeutics。Regulus專注于靶向microRNA的療法開發(fā)，其核心產(chǎn)品farabursen是一款靶向miR-17的下一代寡核苷酸藥物，用于治療常染色體顯性多囊腎病（ADPKD），并已完成一項1b期多劑量遞增臨床試驗。

今年9月，諾華接連達成兩項大額siRNA療法授權(quán)合作。其一，諾華與Arrowhead Pharmaceuticals就后者開發(fā)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(xié)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(nèi)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(lǐng)域的布局。

展望未來，寡核苷酸療法有望成為一類改變醫(yī)學格局的關(guān)鍵治療模式。作為該領(lǐng)域的先驅(qū)之一，Alnylam公司創(chuàng)始首席執(zhí)行官John Maraganore博士在接受美國化學會旗下

C&EN

雜志采訪時表示，未來醫(yī)學發(fā)展亟需包括寡核苷酸在內(nèi)的更復雜治療手段，以更好地滿足不同患者的臨床需求。這類新型分子療法有望在多個疾病領(lǐng)域發(fā)揮關(guān)鍵作用。我們期待這些前沿技術(shù)不斷取得突破，早日轉(zhuǎn)化為真正惠及全球患者的創(chuàng)新藥物。

▲2025年寡核苷酸領(lǐng)域>5000萬美元B輪及以下部分投融資信息

一體化平臺高效賦能寡核苷酸藥物研發(fā)

作為醫(yī)藥創(chuàng)新的賦能者，藥明康德化學業(yè)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(fā)及生產(chǎn)的一站式服務平臺，覆蓋從藥物發(fā)現(xiàn)、CMC開發(fā)，到商業(yè)化生產(chǎn)的全生命周期，加速將合作伙伴的創(chuàng)新構(gòu)想轉(zhuǎn)化為現(xiàn)實，更好地造福全球病患。以下案例將展示W(wǎng)uXi TIDES的一體化平臺如何加速合作伙伴ASO藥物的開發(fā)進程。

2023年，一家生物技術(shù)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(xié)助確定最具前景的分子。然而，早期研究發(fā)現(xiàn)，創(chuàng)新骨架修飾導致候選化合物中出現(xiàn)新的雜質(zhì)。在最初的合成過程中，這些雜質(zhì)占比高達25%，不僅降低了產(chǎn)率和純化效率，還可能帶來潛在毒性，給后續(xù)臨床開發(fā)帶來挑戰(zhàn)。

面對這一難題，WuXi TIDES藥物化學團隊和工藝研發(fā)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(zhì)產(chǎn)生的潛在原因，設(shè)計出定制化的amidite和分子砌塊，規(guī)避雜質(zhì)產(chǎn)生的關(guān)鍵合成機制，并快速生產(chǎn)這些新分子砌塊，協(xié)助工藝研發(fā)團隊加速驗證工藝設(shè)計策略，以有效地控制雜質(zhì)。此外，工藝研發(fā)團隊通過優(yōu)化工藝參數(shù)，系統(tǒng)性地降低了雜質(zhì)的產(chǎn)生。最終，經(jīng)過持續(xù)工藝優(yōu)化，雜質(zhì)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(xié)作，不僅在12個月內(nèi)完成了先導化合物的優(yōu)化、工藝開發(fā)及GMP生產(chǎn)，更幫助合作伙伴基于數(shù)據(jù)進行快速決策，選出綜合效力、穩(wěn)定性和開發(fā)潛力俱佳的ASO候選化合物，為后續(xù)臨床研究奠定了堅實基礎(chǔ)。隨著越來越多的ASO以及其他寡核苷酸藥物進入臨床開發(fā)，這種產(chǎn)業(yè)協(xié)同模式將成為加快研發(fā)步伐的重要推動力。

Multiple FDA Approvals for Oligonucleotide Therapeutics in 2025

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 clinical trials are ongoing 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 (“TIDES” drugs). The platform greatly simplifies the 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 in 2025 and share a case study that illustrates how WuXi TIDES helps accelerate progress in this dynamic area.

Clinical and Regulatory Progress

In March this year,Qfitlia (fitusiran), a potentially best-in-class siRNA therapy jointly developed by Sanofi and Alnylam Pharmaceuticals, received approval from the U.S. Food and Drug Administration (FDA) for the treatment of patients with hemophilia.Results from two Phase 3 clinical trials demonstrated that fitusiran reduced annualized bleeding rates by approximately 90%, with dosing frequency reduced to once every two months in a subset of patients. Around the same time, Amvuttra (vutrisiran), another siRNA therapy from Alnylam, was also approved by the FDA, becoming the first RNAi therapeutic indicated for the treatment of adult patients with transthyretin amyloid cardiomyopathy (ATTR-CM).

In July, the FDA approved an expanded indication for Leqvio (inclisiran), a twice-yearly siRNA therapy from Novartis, allowing its use as monotherapy in combination with diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) levels in adults with hypercholesterolemia. Notably, this label update was initiated by the FDA based on positive clinical data demonstrating LDL-C reduction with this

PCSK9

-targeting therapy. Subsequently, in August,the FDA approved Dawnzera (donidalorsen), an antisense oligonucleotide LIgand-Conjugated Antisense (LICA) therapy, for the prevention of hereditary angioedema (HAE) attacks in adults and pediatric patients aged 12 years and older.According to the company, Dawnzera is the first RNA-targeted therapy approved for HAE. In November, the FDA approved Redemplo (plozasiran), a first-in-class APOC3-targeting RNAi therapy developed by Arrowhead Pharmaceuticals, as an adjunct to diet to reduce triglyceride (TG) levels in adults with familial chylomicronemia syndrome.

Beyond regulatory approvals, several late-stage clinical readouts for oligonucleotide-based therapies were also reported this year. In a Phase 2 study, olpasiran, an siRNA therapy developed by Amgen, reduced lipoprotein(a) [Lp(a)] levels by approximately 92% in patients with atherosclerotic cardiovascular disease and elevated Lp(a), with effects sustained for more than one year. The program has since advanced into Phase 3 development. In parallel, ION224, an antisense oligonucleotide therapy under development for metabolic dysfunction-associated steatohepatitis (MASH), reported positive Phase 2 results. Nearly 60% of patients in the highest-dose group achieved the primary endpoint, demonstrating improvement in MASH disease activity, compared with 19% in the placebo group.

In the rare disease space, the complement C5-targeting siRNA therapy cemdisiran met its primary endpoint in the Phase 3 NIMBLE trial evaluating treatment in adults with generalized myasthenia gravis (gMG). Data showed that cemdisiran monotherapy, administered via subcutaneous injection once every three months, achieved an average 74% inhibition of complement activity, while combination therapy with the C5 antibody pozelimab resulted in nearly 99% complement inhibition. Meanwhile, the antisense oligonucleotide therapy zilganersen demonstrated significant improvement in walking ability in patients with the rare neurological disorder Alexander disease (AxD) in a pivotal trial. According to company disclosures,zilganersen is the first investigational therapy to show potential disease-modifying effects in AxD.Both programs are expected to submit regulatory applications in the first quarter of 2026.

R&D Collaboration & Financing Progress

In 2025, major pharmaceutical companies continued to deepen their commitment to the oligonucleotide space through strategic partnerships and acquisitions. In May,Biogen entered into a collaboration with City Therapeutics with a potential total value of up to $1 billion, initially focused on developing novel RNAi therapies targeting key central nervous system targets.Earlier in February, Biogen also signed a collaboration agreement with Stoke Therapeutics, valued at up to $385 million, for the development and commercialization of the antisense oligonucleotide therapy zorevunersen.

In April, Novartis announced its intention to acquire Regulus Therapeutics for up to approximately $1.7 billion. Regulus specializes in microRNA-targeted therapies, and its lead asset farabursen, a next-generation oligonucleotide targeting miR-17, is being developed for the treatment of autosomal dominant polycystic kidney disease (ADPKD). The program has completed a Phase 1b multiple-ascending-dose clinical trial.

In September, Novartis further expanded its siRNA portfolio through two major licensing transactions. First,Novartis entered into a global licensing and collaboration agreement with Arrowhead Pharmaceuticals for ARO-SNCA, an α-synuclein-targeting siRNA therapy, with a total deal value of up to $2 billion.The therapy is currently in preclinical development and is intended for the treatment of synucleinopathies, including Parkinson’s disease. Second,Novartis formed a broad collaboration with Argo Biopharma covering multiple cardiovascular siRNA programs, with a potential total transaction value of up to $5.2 billion, further strengthening its strategic position in cardiovascular and metabolic diseases.

Looking ahead, oligonucleotide therapies are poised to emerge as a transformative class of treatments with the potential to reshape the medical landscape. As one of the pioneers in the field, Dr. John Maraganore, founding Chief Executive Officer of Alnylam, noted in an interview with

C&EN

, the magazine of the American Chemical Society, that the future of medicine will require more sophisticated therapeutic modalities—including oligonucleotides—to better address the diverse clinical needs of patients. These novel molecular therapies are expected to play a critical role across a wide range of disease areas. We look forward to continued breakthroughs in these cutting-edge technologies and to their rapid translation into innovative medicines that deliver meaningful benefits to patients worldwide.

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] Oligonucleotide Synthesis Market Industry Trends and Global Forecasts Report 2025-2035: Market Strengthens With 110+ Providers, North America Leads, Clinical Pipeline Exceeds 300 Trials - ResearchAndMarkets.com. Retrieved December 21, 2025 from https://www.businesswire.com/news/home/20251203559059/en/Oligonucleotide-Synthesis-Market-Industry-Trends-and-Global-Forecasts-Report-2025-2035-Market-Strengthens-With-110-Providers-North-America-Leads-Clinical-Pipeline-Exceeds-300-Trials---ResearchAndMarkets.com

[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] Biogen’s Investigational Tau-Targeting Therapy BIIB080 Receives FDA Fast Track Designation for the Treatment of Alzheimer’s Disease. Retrieved June 18, 2025 from https://investors.biogen.com/news-releases/news-release-details/biogens-investigational-tau-targeting-therapy-biib080-receives

[4] Alys Pharmaceuticals Announces Dosing of First Patient in Phase IIa Trial of ALY-101 for Alopecia Areata. Retrieved June 18, 2025 from https://alyspharma.com/alys-pharmaceuticals-announces-dosing-of-first-patient-in-phase-iia-trial-of-aly-101-for-alopecia-areata/

[5] Is this the decade of RNA? Retrieved June 19, 2025 from https://cen.acs.org/pharmaceuticals/decade-RNA/97/web/2019/01?utm_source=chatgpt.com

[6] 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

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