編者按：寡核苷酸藥物是全球新藥開發(fā)的重要熱點(diǎn)，近年來在罕見病等多個(gè)領(lǐng)域得到快速應(yīng)用。當(dāng)前，全球共有超過300款寡核苷酸療法管線已進(jìn)入臨床開發(fā)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(dòng)寡核苷酸藥物從實(shí)驗(yàn)室走向臨床，藥明康德化學(xué)業(yè)務(wù)旗下WuXi TIDES平臺(tái)圍繞寡核苷酸、多肽及其相關(guān)化學(xué)偶聯(lián)藥物建立了一體化解決方案，覆蓋定制合成、共價(jià)偶聯(lián)、工藝開發(fā)和CMC等關(guān)鍵環(huán)節(jié)，賦能創(chuàng)新項(xiàng)目加速進(jìn)入臨床階段。本文將回顧2025年第三季度寡核苷酸領(lǐng)域的最新進(jìn)展，并介紹藥明康德的一體化CRDMO平臺(tái)如何高效助力該領(lǐng)域藥物的開發(fā)。

寡核苷酸療法在罕見病領(lǐng)域獲得持續(xù)進(jìn)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(xù)迎來多項(xiàng)進(jìn)展。美國FDA在8月批準(zhǔn)反義寡核苷酸配體偶聯(lián)（LICA）藥物Dawnzera（donidalorsen），用于預(yù)防12歲及以上成人和兒童患者的遺傳性血管性水腫（HAE）發(fā)作。根據(jù)新聞稿，Dawnzera是獲批用于HAE的首個(gè)RNA靶向藥物。歐盟（EU）則在9月批準(zhǔn)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(jīng)遺傳學(xué)確認(rèn)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(yàn)也在同月迎來積極結(jié)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(yīng)用于非罕見疾病治療。

圖片來源：123RF

此外，補(bǔ)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(yàn)中達(dá)到試驗(yàn)終點(diǎn)。分析顯示，每三個(gè)月皮下注射一次的cemdisiran單藥顯示出平均74%的補(bǔ)體活性抑制，而cemdisiran與C5抗體pozelimab的聯(lián)合療法則達(dá)成近99%的補(bǔ)體活性抑制。與此同時(shí)，ASO療法zilganersen也在關(guān)鍵試驗(yàn)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(jìn)程影響的首款在研療法。以上兩款療法皆預(yù)計(jì)于2026年第一季度提交相關(guān)監(jiān)管申請(qǐng)。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(kuò)展研究中，顯示可持續(xù)降低癲癇發(fā)作，并伴隨認(rèn)知與行為的持續(xù)改善。該療法已在今年8月完成3期試驗(yàn)的首位患者給藥。

同時(shí)，本季度FDA還向多款寡核苷酸療法授予突破性療法認(rèn)定（BTD），適應(yīng)癥涵蓋多種罕見疾病。其中，抗體/抗體片段-寡核苷酸偶聯(lián)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(yǎng)不良癥（DMD）；同時(shí)，用于治療天使綜合征的ASO療法apazunersen與ION582也獲此認(rèn)定。

寡核苷酸療法在常見適應(yīng)癥的突破

寡核苷酸療法的進(jìn)展也逐漸從罕見病擴(kuò)展至常見疾病。今年7月，美國FDA批準(zhǔn)諾華（Novartis）每年兩次給藥的siRNA療法Leqvio（inclisiran）的擴(kuò)展適應(yīng)癥，允許其作為單藥，與飲食控制和運(yùn)動(dòng)聯(lián)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(jù)新聞稿，這次的標(biāo)簽更新是美國FDA根據(jù)該P(yáng)CSK9靶向療法降低LDL-C的積極數(shù)據(jù)，主動(dòng)要求更新該藥品的標(biāo)簽。而開發(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也在本季度獲得積極的2期臨床試驗(yàn)結(jié)果。有近60%的最高劑量組患者達(dá)到主要終點(diǎn)，顯示出在MASH疾病活動(dòng)上的改善，而此數(shù)值在安慰劑組僅為19%。

在癌癥領(lǐng)域，PD-1靶向siRNA療法PH-762在治療皮膚癌的1b期試驗(yàn)中也獲得積極結(jié)果。入組的13名皮膚鱗狀細(xì)胞癌（cSCC）患者中有6人在接受治療后達(dá)到病理學(xué)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(xiàn)亮眼療效。臨床2期試驗(yàn)結(jié)果顯示，當(dāng)兩者與當(dāng)前標(biāo)準(zhǔn)免疫檢查點(diǎn)抑制劑聯(lián)用時(shí)，患者的疾病控制率（DCR）高達(dá)88.0%。

與此同時(shí)，在9月，兩款分別設(shè)計(jì)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(yàn)申請(qǐng)，標(biāo)志著寡核苷酸療法在更廣泛適應(yīng)癥上的進(jìn)一步拓展。

商業(yè)研發(fā)合作進(jìn)展

今年9月，諾華接連達(dá)成兩項(xiàng)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(dá)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(xiàng)心血管siRNA管線達(dá)成合作，交易總額最高可達(dá)52億美元，進(jìn)一步夯實(shí)其在心血管代謝領(lǐng)域的布局。

與此同時(shí)，Arrowhead Pharmaceuticals控股子公司維亞臻（Visirna Therapeutics）亦與賽諾菲（Sanofi）達(dá)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(qū)的開發(fā)與商業(yè)化獨(dú)家權(quán)利。該療法通過抑制載脂蛋白C-III（APOC3）的產(chǎn)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(guān)合作交易與融資事件

此外，本季度Arnatar Therapeutics宣布結(jié)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(tái)將siRNA沉默技術(shù)與基于ASO的基因上調(diào)技術(shù)相結(jié)合，開發(fā)具雙重作用機(jī)制的RNA療法，面向心臟代謝、肝、腎及中樞神經(jīng)系統(tǒng)等疾病領(lǐng)域。

綜上，2025年第三季度，寡核苷酸療法持續(xù)展現(xiàn)出從罕見病到常見疾病的進(jìn)展。多款A(yù)SO和siRNA療法迎來關(guān)鍵監(jiān)管批準(zhǔn)與積極臨床數(shù)據(jù)，不僅推動(dòng)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(jìn)展，也在高膽固醇血癥、MASH及皮膚癌等常見適應(yīng)癥中展現(xiàn)突破。同時(shí)，部分藥企通過多項(xiàng)高額合作進(jìn)一步加碼siRNA布局，顯示產(chǎn)業(yè)對(duì)該領(lǐng)域的信心。

一體化平臺(tái)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(xué)業(yè)務(wù)旗下WuXi TIDES平臺(tái)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(wù)平臺(tái)，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(shí)，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(tái)如何加速合作伙伴ASO藥物的開發(fā)進(jìn)程。

2023年，一家生物技術(shù)公司與WuXi TIDES合作進(jìn)行ASO藥物的早期篩選研究，WuXi TIDES的藥物化學(xué)團(tuán)隊(duì)為其提供了超過400種攜帶骨架化學(xué)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(dǎo)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(dá)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(duì)這一難題，WuXi TIDES藥物化學(xué)團(tuán)隊(duì)和工藝研發(fā)團(tuán)隊(duì)密切配合，從兩個(gè)方向入手解決問題。一方面，藥物化學(xué)團(tuán)隊(duì)與合作伙伴共同探索雜質(zhì)產(chǎn)生的潛在原因，設(shè)計(jì)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(jī)制，并快速生產(chǎn)這些新分子砌塊，協(xié)助工藝研發(fā)團(tuán)隊(duì)加速驗(yàn)證工藝設(shè)計(jì)策略，以有效地控制雜質(zhì)。此外，工藝研發(fā)團(tuán)隊(duì)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(shí)最終收率也從最初的0.5 g/mol提高到3.4 g/mol。

在該項(xiàng)目中，WuXi TIDES各團(tuán)隊(duì)高效協(xié)作，不僅在12個(gè)月內(nèi)完成了先導(dǎo)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(jìn)行快速?zèng)Q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(jiān)實(shí)基礎(chǔ)。隨著越來越多的ASO以及其他寡核苷酸藥物進(jìn)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(dòng)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

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