今年一季度，多款這類療法在罕見疾病領域持續取得監管突破

編者按：寡核苷酸藥物已成為全球新藥開發的重要熱點，近年來在多個領域獲得快速應用。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，藥明康德圍繞寡核苷酸及其相關化學偶聯藥物構建了一體化解決方案，覆蓋定制合成、共價連接、工藝開發以及CMC等關鍵環節，為寡核苷酸及復雜偶聯藥物的發現與開發提供有力支持。本文將盤點2026年第一季度寡核苷酸領域的重要進展，帶您了解這一快速發展領域的最新動態與趨勢。

多款療法遞交上市申請，寡核苷酸進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域持續取得監管突破。例如，歐盟委員會（EC）在1月批準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）反復發作的常規預防。Dawnzera是一款反義寡核苷酸配體偶聯（LICA）藥物，旨在通過沉默前激肽釋放酶（PKK）的表達，中斷導致HAE發作的相關信號通路。在OASISplus開放標簽延長期研究中，用藥一年后患者的總體平均月發作率降低達94%。

與此同時，Ionis Pharmaceuticals用于治療亞歷山大?。ˋxD）的反義寡核苷酸（ASO）療法zilganersen（ION373）也在本季度迎來監管進展。該療法的新藥申請（NDA）已獲美國FDA受理，并被授予優先審評資格，PDUFA日期為2026年9月22日。AxD是一種罕見、進行性且最終致命的神經系統疾病。研究顯示，在兒童及成人AxD患者中，50 mg zilganersen在第61周時相較對照組，在主要終點10米步行測試（10MWT）評估的步行速度方面實現了具有統計學意義且臨床意義明確的穩定效果（最小二乘均值差異33.3%，P=0.0412），同時展現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展。數據顯示，接受治療的杜氏肌營養不良癥（DMD）患者在24至48周期間，經肌肉含量校正后的肌營養不良蛋白表達水平保持穩定，平均達到7.8%。肌肉組織學分析進一步顯示，肌纖維從再生階段向成熟階段轉變，同時肌肉纖維化顯著減少（24至48周期間降低28.6%；p<0.01）。該公司計劃于今年向美國FDA遞交新藥申請，尋求WVE-N531的加速批準。

除了罕見病領域，寡核苷酸療法在常見疾病中的應用也在不斷取得突破。FDA在本季度受理Ionis旗下ASO療法olezarsen用于治療嚴重高甘油三酯血癥（sHTG）的補充新藥申請（sNDA），并授予優先審評資格。該申請的PDUFA日期設定為2026年6月30日。研究數據顯示，olezarsen可實現最高達72%的安慰劑校正甘油三酯水平降低，同時急性胰腺炎事件減少85%，并表現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險閾值。這些結果表明，該療法不僅能夠顯著降低甘油三酯水平，也有望降低與嚴重高甘油三酯血癥相關的臨床風險。

在疫苗領域，Moderna也在推進其mRNA技術平臺的應用。該公司在2月與美國FDA就其季節性流感疫苗候選產品mRNA-1010的修訂申報策略達成共識。根據更新后的計劃，Moderna將為50至64歲成年人申請完全批準，并為65歲及以上成年人尋求加速批準。在提交修訂申請后，FDA已正式受理該生物制品許可申請（BLA），并設定2026年8月5日為目標審評完成日期。mRNA-1010是一款基于mRNA技術的季節性流感疫苗，旨在針對流感A型和B型多種毒株提供更廣泛且更高效的免疫保護。

在肝炎領域，寡核苷酸療法也迎來新的監管進展。日本厚生勞動省（MHLW）已受理Ionis與GSK聯合開發的潛在“first-in-class”ASO療法bepirovirsen的新藥申請，用于治療成人慢性乙型肝炎（CHB）。這是該療法在全球范圍內首次向監管機構遞交上市申請。Bepirovirsen是一種具有三重作用機制的ASO療法，可識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重新獲得對病毒感染的控制能力。研究顯示，與單純標準治療相比，bepirovirsen聯合標準治療在所有預設層級終點中均實現更高的功能性治愈率，且差異具有統計學意義和臨床意義。

與此同時，Wave Life Sciences還公布了其長效GalNAc修飾siRNA療法WVE-007在INLIGHT首次人體試驗（1期部分）的最新數據。隨訪6個月結果顯示，單次240 mg給藥即可持續改善超重或肥胖患者的身體成分結構，在減少脂肪的同時實現肌肉保留。此外，WVE-007還能夠持續、劑量依賴性地抑制血清靶蛋白水平，這一效應至少可維持7個月，為每年一次或兩次給藥提供了依據。

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

多家大藥企達成上億美元寡核苷酸療法合作

在產業合作方面，多家大型制藥企業在本季度達成多項規?？捎^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）達成全球研發合作與許可協議，雙方將基于圣因生物專有的RNA干擾（RNAi）藥物研發平臺共同推進一款RNAi療法的開發。根據協議條款，圣因生物將獲得2億美元首付款，并有權收取開發和銷售里程碑付款，總金額最高可達15億美元。該公司平臺整合了新型藥物化學修飾與遞送技術，其中包括具有組織選擇性的LEAD肝外遞送技術，可支持多個疾病領域具有“best-in-class”或“first-in-class”潛力的RNAi藥物開發。

同月，Madrigal Pharmaceuticals也與瑞博生物及其子公司Ribocure Pharmaceuticals達成最高達44億美元的全球獨家許可協議。雙方將基于瑞博生物的肝靶向RiboGalSTAR平臺，共同開發6款針對MASH的創新siRNA療法。此外，GSK與前沿生物（Frontier Biotechnologies）也達成超過10億美元的合作。根據協議，GSK將獲得兩款siRNA管線產品在全球范圍內的獨家開發、生產及商業化權利，其中一款候選藥物已進入新藥臨床試驗申請（IND）階段，另一款仍處于臨床前研究階段。

與此同時，禮來（Eli Lilly and Company）也與Orna Therapeutics達成收購協議，交易金額最高可達24億美元。Orna正在推進其細胞療法平臺，該平臺基于工程化環狀RNA，并結合新型脂質納米顆粒技術，使患者自身能夠在體內生成具有治療作用的免疫細胞，從而靶向疾病的根本機制。Orna的主打項目為ORN-252，這是一款即將進入臨床試驗的體內CD19靶向嵌合抗原受體T細胞（CAR-T）療法，擬用于治療由B細胞驅動的自身免疫性疾病。

由以上進展可以發現，本季度多項大型交易均圍繞siRNA療法展開。而在siRNA藥物快速發展的背景下，如何通過體外研究準確預測其體內代謝行為，是核酸藥物研發中的關鍵科學挑戰之一。由于siRNA在體內主要經歷核酸酶介導的逐步降解，其代謝過程高度依賴生物環境差異，傳統體外模型往往難以真實反映體內代謝路徑，進而影響候選分子的評價與開發效率。為滿足客戶的持續需求，藥明康德DMPK團隊通過系統性研究與方法論優化，建立了能夠顯著提升體外-體內相關性（IVIVC）的siRNA代謝評價體系，為體外模型預測能力提供了堅實的科學基礎。

基于對代表性GalNAc偶聯siRNA藥物inclisiran的深入研究，團隊系統比較了多種體外模型在模擬體內血液與肝臟代謝方面的表現，包括血清、不同抗凝條件下的血漿、肝勻漿、S9組分、tritosomes及貼壁肝細胞等模型，并結合體內數據驗證其預測能力。研究結果表明，經肝素抗凝處理的血漿與血清能夠較好模擬體內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以及優化培養條件下的肝細胞模型可有效重現體內代謝特征，從而顯著提升體外研究對體內結果的預測準確性。此外，研究還發現實驗條件如緩沖體系與pH值對代謝結果具有關鍵影響，強調了針對siRNA分子特性進行模型優化的重要性。

藥明康德DMPK團隊已經構建了涵蓋血液、亞細胞組分及細胞模型的多層級體外代謝研究平臺，可系統解析siRNA在循環系統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化可靠性。通過將機制研究與標準化實驗流程相結合，該能力幫助研發團隊更早識別代謝風險、優化分子設計策略，并降低從體外研究到體內驗證過程中的不確定性，為siRNA藥物高效邁向臨床開發提供關鍵支撐。

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：

[1] 各公司官網

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