今年一季度，多款這類療法在罕見疾病領(lǐng)域持續(xù)取得監(jiān)管突破

編者按：寡核苷酸藥物已成為全球新藥開發(fā)的重要熱點(diǎn)，近年來在多個(gè)領(lǐng)域獲得快速應(yīng)用。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，藥明康德圍繞寡核苷酸及其相關(guān)化學(xué)偶聯(lián)藥物構(gòu)建了一體化解決方案，覆蓋定制合成、共價(jià)連接、工藝開發(fā)以及CMC等關(guān)鍵環(huán)節(jié)，為寡核苷酸及復(fù)雜偶聯(lián)藥物的發(fā)現(xiàn)與開發(fā)提供有力支持。本文將盤點(diǎn)2026年第一季度寡核苷酸領(lǐng)域的重要進(jìn)展，帶您了解這一快速發(fā)展領(lǐng)域的最新動(dòng)態(tài)與趨勢(shì)。

多款療法遞交上市申請(qǐng)，寡核苷酸進(jìn)展橫跨罕見病與常見疾病

2026年第一季度，多款寡核苷酸療法在罕見疾病領(lǐng)域持續(xù)取得監(jiān)管突破。例如，歐盟委員會(huì)（EC）在1月批準(zhǔn)Dawnzera（donidalorsen）在歐盟上市，用于成人及12歲以上青少年遺傳性血管性水腫（HAE）反復(fù)發(fā)作的常規(guī)預(yù)防。Dawnzera是一款反義寡核苷酸配體偶聯(lián)（LICA）藥物，旨在通過沉默前激肽釋放酶（PKK）的表達(dá)，中斷導(dǎo)致HAE發(fā)作的相關(guān)信號(hào)通路。在OASISplus開放標(biāo)簽延長(zhǎng)期研究中，用藥一年后患者的總體平均月發(fā)作率降低達(dá)94%。

與此同時(shí)，Ionis Pharmaceuticals用于治療亞歷山大病（AxD）的反義寡核苷酸（ASO）療法zilganersen（ION373）也在本季度迎來監(jiān)管進(jìn)展。該療法的新藥申請(qǐng)（NDA）已獲美國FDA受理，并被授予優(yōu)先審評(píng)資格，PDUFA日期為2026年9月22日。AxD是一種罕見、進(jìn)行性且最終致命的神經(jīng)系統(tǒng)疾病。研究顯示，在兒童及成人AxD患者中，50 mg zilganersen在第61周時(shí)相較對(duì)照組，在主要終點(diǎn)10米步行測(cè)試（10MWT）評(píng)估的步行速度方面實(shí)現(xiàn)了具有統(tǒng)計(jì)學(xué)意義且臨床意義明確的穩(wěn)定效果（最小二乘均值差異33.3%，P=0.0412），同時(shí)展現(xiàn)出良好的安全性和耐受性。

在臨床研究方面，Wave Life Sciences旗下ASO療法WVE-N531在FORWARD-53 2期臨床研究中也取得積極進(jìn)展。數(shù)據(jù)顯示，接受治療的杜氏肌營(yíng)養(yǎng)不良癥（DMD）患者在24至48周期間，經(jīng)肌肉含量校正后的肌營(yíng)養(yǎng)不良蛋白表達(dá)水平保持穩(wěn)定，平均達(dá)到7.8%。肌肉組織學(xué)分析進(jìn)一步顯示，肌纖維從再生階段向成熟階段轉(zhuǎn)變，同時(shí)肌肉纖維化顯著減少（24至48周期間降低28.6%；p<0.01）。該公司計(jì)劃于今年向美國FDA遞交新藥申請(qǐng)，尋求WVE-N531的加速批準(zhǔn)。

除了罕見病領(lǐng)域，寡核苷酸療法在常見疾病中的應(yīng)用也在不斷取得突破。FDA在本季度受理Ionis旗下ASO療法olezarsen用于治療嚴(yán)重高甘油三酯血癥（sHTG）的補(bǔ)充新藥申請(qǐng)（sNDA），并授予優(yōu)先審評(píng)資格。該申請(qǐng)的PDUFA日期設(shè)定為2026年6月30日。研究數(shù)據(jù)顯示，olezarsen可實(shí)現(xiàn)最高達(dá)72%的安慰劑校正甘油三酯水平降低，同時(shí)急性胰腺炎事件減少85%，并表現(xiàn)出良好的安全性和耐受性。此外，近90%接受olezarsen治療的患者甘油三酯水平降至500 mg/dL以下，低于急性胰腺炎的風(fēng)險(xiǎn)閾值。這些結(jié)果表明，該療法不僅能夠顯著降低甘油三酯水平，也有望降低與嚴(yán)重高甘油三酯血癥相關(guān)的臨床風(fēng)險(xiǎn)。

在疫苗領(lǐng)域，Moderna也在推進(jìn)其mRNA技術(shù)平臺(tái)的應(yīng)用。該公司在2月與美國FDA就其季節(jié)性流感疫苗候選產(chǎn)品mRNA-1010的修訂申報(bào)策略達(dá)成共識(shí)。根據(jù)更新后的計(jì)劃，Moderna將為50至64歲成年人申請(qǐng)完全批準(zhǔn)，并為65歲及以上成年人尋求加速批準(zhǔn)。在提交修訂申請(qǐng)后，F(xiàn)DA已正式受理該生物制品許可申請(qǐng)（BLA），并設(shè)定2026年8月5日為目標(biāo)審評(píng)完成日期。mRNA-1010是一款基于mRNA技術(shù)的季節(jié)性流感疫苗，旨在針對(duì)流感A型和B型多種毒株提供更廣泛且更高效的免疫保護(hù)。

在肝炎領(lǐng)域，寡核苷酸療法也迎來新的監(jiān)管進(jìn)展。日本厚生勞動(dòng)省（MHLW）已受理Ionis與GSK聯(lián)合開發(fā)的潛在“first-in-class”ASO療法bepirovirsen的新藥申請(qǐng)，用于治療成人慢性乙型肝炎（CHB）。這是該療法在全球范圍內(nèi)首次向監(jiān)管機(jī)構(gòu)遞交上市申請(qǐng)。Bepirovirsen是一種具有三重作用機(jī)制的ASO療法，可識(shí)別并靶向乙肝病毒的遺傳成分（即RNA），從而幫助患者免疫系統(tǒng)重新獲得對(duì)病毒感染的控制能力。研究顯示，與單純標(biāo)準(zhǔn)治療相比，bepirovirsen聯(lián)合標(biāo)準(zhǔn)治療在所有預(yù)設(shè)層級(jí)終點(diǎn)中均實(shí)現(xiàn)更高的功能性治愈率，且差異具有統(tǒng)計(jì)學(xué)意義和臨床意義。

與此同時(shí)，Wave Life Sciences還公布了其長(zhǎng)效GalNAc修飾siRNA療法WVE-007在INLIGHT首次人體試驗(yàn)（1期部分）的最新數(shù)據(jù)。隨訪6個(gè)月結(jié)果顯示，單次240 mg給藥即可持續(xù)改善超重或肥胖患者的身體成分結(jié)構(gòu)，在減少脂肪的同時(shí)實(shí)現(xiàn)肌肉保留。此外，WVE-007還能夠持續(xù)、劑量依賴性地抑制血清靶蛋白水平，這一效應(yīng)至少可維持7個(gè)月，為每年一次或兩次給藥提供了依據(jù)。

另一家企業(yè)Tangram Therapeutics則在本季度完成其主打候選藥物TGM-312的1/2期臨床試驗(yàn)首例受試者給藥。TGM-312是一種基于Tangram專有RNAi化學(xué)平臺(tái)GalOmic開發(fā)的GalNAc-siRNA療法，旨在特異性沉默肝細(xì)胞中的一個(gè)新靶點(diǎn)基因，用于治療代謝功能障礙相關(guān)脂肪性肝炎（MASH）。該藥物有望實(shí)現(xiàn)每季度一次的皮下給藥，從而提升患者的用藥便利性。

多家大藥企達(dá)成上億美元寡核苷酸療法合作

在產(chǎn)業(yè)合作方面，多家大型制藥企業(yè)在本季度達(dá)成多項(xiàng)規(guī)模可觀的寡核苷酸合作交易。今年2月，羅氏（Roche）旗下基因泰克（Genentech）與圣因生物（SanegeneBio）達(dá)成全球研發(fā)合作與許可協(xié)議，雙方將基于圣因生物專有的RNA干擾（RNAi）藥物研發(fā)平臺(tái)共同推進(jìn)一款RNAi療法的開發(fā)。根據(jù)協(xié)議條款，圣因生物將獲得2億美元首付款，并有權(quán)收取開發(fā)和銷售里程碑付款，總金額最高可達(dá)15億美元。該公司平臺(tái)整合了新型藥物化學(xué)修飾與遞送技術(shù)，其中包括具有組織選擇性的LEAD肝外遞送技術(shù)，可支持多個(gè)疾病領(lǐng)域具有“best-in-class”或“first-in-class”潛力的RNAi藥物開發(fā)。

同月，Madrigal Pharmaceuticals也與瑞博生物及其子公司Ribocure Pharmaceuticals達(dá)成最高達(dá)44億美元的全球獨(dú)家許可協(xié)議。雙方將基于瑞博生物的肝靶向RiboGalSTAR平臺(tái)，共同開發(fā)6款針對(duì)MASH的創(chuàng)新siRNA療法。此外，GSK與前沿生物（Frontier Biotechnologies）也達(dá)成超過10億美元的合作。根據(jù)協(xié)議，GSK將獲得兩款siRNA管線產(chǎn)品在全球范圍內(nèi)的獨(dú)家開發(fā)、生產(chǎn)及商業(yè)化權(quán)利，其中一款候選藥物已進(jìn)入新藥臨床試驗(yàn)申請(qǐng)（IND）階段，另一款仍處于臨床前研究階段。

與此同時(shí)，禮來（Eli Lilly and Company）也與Orna Therapeutics達(dá)成收購協(xié)議，交易金額最高可達(dá)24億美元。Orna正在推進(jìn)其細(xì)胞療法平臺(tái)，該平臺(tái)基于工程化環(huán)狀RNA，并結(jié)合新型脂質(zhì)納米顆粒技術(shù)，使患者自身能夠在體內(nèi)生成具有治療作用的免疫細(xì)胞，從而靶向疾病的根本機(jī)制。Orna的主打項(xiàng)目為ORN-252，這是一款即將進(jìn)入臨床試驗(yàn)的體內(nèi)CD19靶向嵌合抗原受體T細(xì)胞（CAR-T）療法，擬用于治療由B細(xì)胞驅(qū)動(dòng)的自身免疫性疾病。

由以上進(jìn)展可以發(fā)現(xiàn)，本季度多項(xiàng)大型交易均圍繞siRNA療法展開。而在siRNA藥物快速發(fā)展的背景下，如何通過體外研究準(zhǔn)確預(yù)測(cè)其體內(nèi)代謝行為，是核酸藥物研發(fā)中的關(guān)鍵科學(xué)挑戰(zhàn)之一。由于siRNA在體內(nèi)主要經(jīng)歷核酸酶介導(dǎo)的逐步降解，其代謝過程高度依賴生物環(huán)境差異，傳統(tǒng)體外模型往往難以真實(shí)反映體內(nèi)代謝路徑，進(jìn)而影響候選分子的評(píng)價(jià)與開發(fā)效率。為滿足客戶的持續(xù)需求，藥明康德DMPK團(tuán)隊(duì)通過系統(tǒng)性研究與方法論優(yōu)化，建立了能夠顯著提升體外-體內(nèi)相關(guān)性（IVIVC）的siRNA代謝評(píng)價(jià)體系，為體外模型預(yù)測(cè)能力提供了堅(jiān)實(shí)的科學(xué)基礎(chǔ)。

基于對(duì)代表性GalNAc偶聯(lián)siRNA藥物inclisiran的深入研究，團(tuán)隊(duì)系統(tǒng)比較了多種體外模型在模擬體內(nèi)血液與肝臟代謝方面的表現(xiàn)，包括血清、不同抗凝條件下的血漿、肝勻漿、S9組分、tritosomes及貼壁肝細(xì)胞等模型，并結(jié)合體內(nèi)數(shù)據(jù)驗(yàn)證其預(yù)測(cè)能力。研究結(jié)果表明，經(jīng)肝素抗凝處理的血漿與血清能夠較好模擬體內(nèi)血液中的核酸酶代謝，而在肝臟代謝方面，特定pH條件下的肝勻漿、tritosomes以及優(yōu)化培養(yǎng)條件下的肝細(xì)胞模型可有效重現(xiàn)體內(nèi)代謝特征，從而顯著提升體外研究對(duì)體內(nèi)結(jié)果的預(yù)測(cè)準(zhǔn)確性。此外，研究還發(fā)現(xiàn)實(shí)驗(yàn)條件如緩沖體系與pH值對(duì)代謝結(jié)果具有關(guān)鍵影響，強(qiáng)調(diào)了針對(duì)siRNA分子特性進(jìn)行模型優(yōu)化的重要性。

藥明康德DMPK團(tuán)隊(duì)已經(jīng)構(gòu)建了涵蓋血液、亞細(xì)胞組分及細(xì)胞模型的多層級(jí)體外代謝研究平臺(tái)，可系統(tǒng)解析siRNA在循環(huán)系統(tǒng)與靶組織中的降解路徑及代謝特征，并支持跨物種比較以提高臨床轉(zhuǎn)化可靠性。通過將機(jī)制研究與標(biāo)準(zhǔn)化實(shí)驗(yàn)流程相結(jié)合，該能力幫助研發(fā)團(tuán)隊(duì)更早識(shí)別代謝風(fēng)險(xiǎn)、優(yōu)化分子設(shè)計(jì)策略，并降低從體外研究到體內(nèi)驗(yàn)證過程中的不確定性，為siRNA藥物高效邁向臨床開發(fā)提供關(guān)鍵支撐。

Multiple Billion-Dollar siRNA Partnerships and Regulatory Breakthroughs Signal New Progress in Oligonucleotide Therapies

Editor’s Note:Oligonucleotide therapeutics have become a major focus of global drug development and have seen rapid adoption in recent years across multiple therapeutic areas. To help partners more efficiently advance oligonucleotide drugs from the laboratory to the clinic, WuXi AppTec has built an integrated solution centered on oligonucleotides and related chemically conjugated modalities. This solution covers key stages including custom synthesis, covalent conjugation, process development, and CMC, providing strong support for the discovery and development of oligonucleotides and complex conjugated drugs. This article reviews major developments in the oligonucleotide field in the first quarter of 2026 and highlights the latest trends in this rapidly evolving area.

Multiple Therapies File for Approval as Oligonucleotide Advances Span Rare and Common Diseases

In the first quarter of 2026, several oligonucleotide therapies continued to achieve regulatory breakthroughs in rare diseases. For example, in January theEuropean Commission approved Dawnzera (donidalorsen) in the European Union for routine prevention of recurrent attacks of hereditary angioedema (HAE) in adults and adolescents aged 12 years and older.Dawnzera is a ligand-conjugated antisense oligonucleotide (LICA) designed to interrupt signaling pathways that trigger HAE attacks by silencing the expression of prekallikrein (PKK). In the OASISplus open-label extension study, the overall average monthly attack rate decreased by 94% after one year of treatment.

Meanwhile, an antisense oligonucleotide (ASO) therapy developed by Ionis Pharmaceuticals for Alexander disease (AxD),zilganersen (ION373), also reached an important regulatory milestone this quarter.Its New Drug Application (NDA) has been accepted by the U.S. Food and Drug Administration and granted Priority Review, with a PDUFA date set for September 22, 2026. AxD is a rare, progressive, and ultimately fatal neurological disease. Studies showed that in both pediatric and adult AxD patients, 50 mg zilganersen demonstrated a statistically and clinically meaningful stabilization in walking speed at Week 61 as measured by the 10-meter walk test (10MWT) compared with the control group (least squares mean difference 33.3%, P=0.0412), while also showing good safety and tolerability.

In clinical development, the ASO therapyWVE-N531from Wave Life Sciences also reported positive progress in the Phase 2 FORWARD-53 study. Data showed that in patients with Duchenne muscular dystrophy (DMD), dystrophin expression adjusted for muscle content remained stable at an average of 7.8% between Weeks 24 and 48.Histological analyses further demonstrated that muscle fibers transitioned from regeneration to maturation, while muscle fibrosis significantly decreased (28.6% reduction from Weeks 24 to 48; p<0.01). The company plans to submit an NDA to the U.S. FDA this year seeking accelerated approval for WVE-N531.

Beyond rare diseases, oligonucleotide therapies are also making progress in more common conditions.The FDA accepted a supplemental New Drug Application (sNDA) this quarter for the Ionis ASO therapy olezarsen for the treatment of severe hypertriglyceridemia (sHTG), granting Priority Review.The PDUFA date is set for June 30, 2026. Data show thatolezarsen achieved up to a 72% placebo-adjusted reduction in triglyceride levels, while reducing acute pancreatitis events by 85%and demonstrating favorable safety and tolerability. Additionally, nearly 90% of patients receiving olezarsen achieved triglyceride levels below 500 mg/dL, which is lower than the risk threshold for acute pancreatitis. These findings suggest that the therapy not only significantly lowers triglycerides but may also reduce clinical risks associated with sHTG.

In the vaccine field, Moderna is also advancing applications of its mRNA technology platform. In February, the company reached agreement with the U.S. FDA on a revised regulatory submission strategy for itsseasonal influenza vaccine candidate mRNA-1010.Under the updated plan, Moderna will seek full approval for adults aged 50 to 64 and accelerated approval for adults aged 65 and older. Following submission of the revised application,the FDA accepted the Biologics License Application (BLA) and set a target review completion date of August 5, 2026.mRNA-1010 is an mRNA-based seasonal influenza vaccine designed to provide broader and more effective immune protection against multiple influenza A and B strains.

In the hepatitis field, oligonucleotide therapies have also achieved regulatory progress.The Ministry of Health, Labour and Welfare in Japan has accepted the NDA for the potential first-in-class ASO therapy bepirovirsen, jointly developed by Ionis and GSK, for the treatment of adults with chronic hepatitis B (CHB).This marks the first global regulatory filing for the therapy. Bepirovirsen is an ASO therapy with a triple mechanism of action that recognizes and targets the genetic components (RNA) of the hepatitis B virus, potentially enabling patients’ immune systems to regain control over the infection. Studies showed that compared with standard of care alone, bepirovirsen combined with standard therapy achieved higher functional cure rates across all prespecified hierarchical endpoints, with statistically and clinically significant differences.

Wave Life Sciences also reported new data from the first-in-human trial (Phase 1 portion) of itslong-acting GalNAc-modified siRNA therapy WVE-007in the INLIGHT study. Six-month follow-up results showed thata single 240 mg dose produced sustained improvements in body composition in overweight or obese individuals, reducing fat while preserving muscle mass.In addition, WVE-007 produced sustained, dose-dependent suppression of serum target protein levels for at least seven months, supporting potential once- or twice-yearly dosing.

Another company, Tangram Therapeutics, completed first patient dosing in the Phase 1/2 clinical trial of its lead candidate TGM-312 this quarter.TGM-312 is a GalNAc-siRNA therapy developed using Tangram’s proprietary RNAi chemistry platform GalOmic, designed to specifically silence a novel target gene in hepatocytes for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). The drug may enable once-quarterly subcutaneous dosing, improving treatment convenience for patients.

Multiple Large Pharmaceutical Companies Announce Billion-Dollar Oligonucleotide Partnerships

In terms of industry collaboration, several major pharmaceutical companies entered large oligonucleotide-focused deals this quarter. In February, Roche subsidiaryGenentech signed a global research collaboration and license agreement with SanegeneBio to jointly develop an RNAi therapy based on SanegeneBio’s proprietary RNAi drug discovery platform.Under the agreement, SanegeneBio will receive an upfront payment of $200 million and may earn development and commercial milestone payments totaling up to $1.5 billion. The company’s platform integrates novel chemical modification and delivery technologies, including the tissue-selective LEAD extrahepatic delivery technology, enabling the development of breakthrough RNAi drugs with potential best-in-class or first-in-class profiles across multiple disease areas.

In the same month,Madrigal Pharmaceuticals signed a global exclusive licensing agreement worth up to $4.4 billion with RiboLife Science and its subsidiary Ribocure Pharmaceuticals.The companies will jointly develop six innovative siRNA therapies targeting MASH using RiboLife’s liver-targeted RiboGalSTAR platform. In addition,GSK and Frontier Biotechnologies entered a collaboration exceeding $1 billion.Under the agreement, GSK will obtain global exclusive rights to develop, manufacture, and commercialize two siRNA pipeline candidates, one of which has entered the Investigational New Drug (IND) stage while the other remains in preclinical development.

Meanwhile,Eli Lilly and Company also reached an acquisition agreement with Orna Therapeutics valued at up to $2.4 billion.Orna is advancing a cell therapy platform based on engineered circular RNA combined with novel lipid nanoparticle technology, enabling patients to generate therapeutic immune cells in vivo to target the underlying mechanisms of disease. Orna’s lead program, ORN-252, is an in vivo CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy approaching clinical trials, intended for the treatment of B-cell-driven autoimmune diseases.

Advancing Predictive Metabolism Research to Support siRNA Drug Development

These developments show that many of the major transactions this quarter were centered around siRNA therapies. As siRNA therapeutics continue to advance rapidly, establishing reliable in vitro metabolic models has become essential for accurately predicting in vivo behavior and enabling efficient development decisions. Unlike traditional small molecules, oligonucleotides, particularly GalNAc-conjugated siRNAs, undergo complex nuclease-mediated metabolism that varies significantly across biological compartments, making conventional in vitro systems insufficient for translational prediction. To better meet clients’ need,WuXi AppTec DMPK team has developed a comprehensive framework for building and validating predictive in vitro metabolic models tailored specifically for oligonucleotide therapeutics, integrating mechanistic experimentation with translational pharmacokinetic insight.

As shown from a recent peer-reviewed study investigating the metabolism of a representative GalNAc-conjugated siRNA, WuXi AppTec scientists systematically evaluated multiple biological systems to determine which models most accurately replicate in vivo metabolism. The research demonstrated that carefully selected matrices, such as serum and heparin-anticoagulated plasma for blood metabolism, along with optimized liver homogenates, tritosomes, and plated hepatocytes for hepatic metabolism, can closely reproduce metabolite profiles observed in vivo, significantly improving in vitro–in vivo correlation (IVIVC) for oligonucleotide candidates . Importantly, the study also revealed how experimental conditions, including buffer composition and pH, influence nuclease activity and metabolic outcomes, underscoring the need for modality-specific model optimization rather than reliance on conventional assay formats.

Building upon these insights, WuXi AppTec DMPK platform incorporates a diverse panel of validated in vitro stability and metabolism systems, including plasma, tissue homogenates, subcellular fractions, and hepatocyte models, to characterize degradation pathways, metabolite formation, and compartment-specific disposition mechanisms. Cross-species evaluation strategies further support translational relevance by identifying metabolic differences between animal models and humans, helping reduce clinical uncertainty early in development.

Through the integration of mechanistic metabolism studies, advanced bioanalysis, and model validation workflows, WuXi AppTec DMPK enables developers to better predict oligonucleotide stability, optimize molecular design, and refine development strategies with greater confidence. These capabilities provide a robust scientific foundation for understanding oligonucleotide biotransformation and accelerate the progression of RNA-based therapeutics from discovery toward clinical application.

參考資料：

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