Inotersen sodium

– European and FDA approval of Sephience™ (sepiapterin) with broad labeling for PKU – – Global launch underway in Europe and U.S. – – Total Q2 Revenue of $179M – WARREN, N.J., Aug. 7, 2025 /PRNewswire/ -- PTC Therapeutics, Inc., (NASDAQ: PTCT) today announced a corporate update and financial results for the second quarter ended June 30, 2025. "We had another strong quarter highlighted by the first approvals of Sephience for the treatment of children and adults with PKU," said Matthew B. Klein, M.D., Chief Executive Officer. "We have initiated the global launch and expect Sephience to be the foundational product for PTC's future growth and path to profitability." Key Corporate Updates: Second quarter 2025 total net product, collaboration and royalty revenue of $179 million Second quarter 2025 revenue for the DMD franchise of $96 million, including net product revenue for Translarna™ of $59 million and for Emflaza® of $36 million Initiated global launch of Sephience™ in the U.S. and Germany as well as in other countries through early access and named patient programs Entered into agreement to purchase the Sephience annual percentage-based global net sales obligation owed to former Censa shareholders in exchange for an upfront payment of $225 million and future sales milestone payments Key Clinical and Regulatory Milestones: Sephience™ (sepiapterin) Marketing authorization granted by the EC on June 19, 2025 with broad label inclusive of all disease subtypes and all ages FDA approval on July 28, 2025 with broad label inclusive of all disease subtypes and all ages, from 1 month of age upwards Japan NDA review is ongoing with decision expected in Q4 2025 NDA reviews for vatiquinone (Friedreich's ataxia) and Translarna (nonsense mutation DMD) are ongoing, with regulatory action date of August 19, 2025 for vatiquinone In May 2025, reported positive Phase 2 PIVOT-HD study results for votoplam (PTC518) in Huntington's Disease patients. PTC continues to collaborate with Novartis on next steps and aims to meet with FDA in Q4 2025 to discuss Phase 3 clinical trial design and potential accelerated approval pathway. Second Quarter 2025 Financial Highlights: Total revenues were $178.9 million for the second quarter of 2025, compared to $186.7 million for the second quarter of 2024. Total revenue includes net product revenue across the commercial portfolio of $118.3 million for the second quarter of 2025, compared to $133.2 million for the second quarter of 2024. Total revenue also includes royalty, collaboration and license, and manufacturing revenue of $60.5 million in the second quarter of 2025, compared to $53.5 million for the second quarter of 2024. Translarna net product revenues were $59.5 million for the second quarter of 2025, compared to $70.4 million for the second quarter of 2024. Emflaza net product revenues were $36.4 million for the second quarter of 2025, compared to $47.3 million for the second quarter of 2024. Roche reported Evrysdi® first half 2025 sales of approximately 869 CHF million, resulting in royalty revenue of $57.6 million to PTC for second quarter 2025, as compared to $53.2 million for second quarter 2024. Based on U.S. GAAP (Generally Accepted Accounting Principles), GAAP R&D expenses were $113.0 million for the second quarter of 2025, compared to $132.2 million for the second quarter of 2024. Non-GAAP R&D expenses were $104.0 million for the second quarter of 2025, excluding $9.0 million in non-cash, stock-based compensation expense, compared to $122.7 million for the second quarter of 2024, excluding $9.4 million in non-cash, stock-based compensation expense. GAAP SG&A expenses were $85.3 million for the second quarter of 2025, compared to $69.5 million for the second quarter of 2024. Non-GAAP SG&A expenses were $75.7 million for the second quarter of 2025, excluding $9.5 million in non-cash, stock-based compensation expense, compared to $59.7 million for the second quarter of 2024, excluding $9.8 million in non-cash, stock-based compensation expense. Net loss was $64.8 million for the second quarter of 2025, compared to net loss of $99.2 million for the second quarter of 2024. Cash, cash equivalents, and marketable securities were $1,989.2 million as of June 30, 2025, compared to $1,139.7 million as of December 31, 2024. Shares issued and outstanding as of June 30, 2025, were 79,378,145. PTC Full-Year 2025 Financial Guidance: PTC anticipates full-year 2025 revenue to be between $650 million and $800 million, which includes in-line products, new and potential product launches, and royalty revenue from Evrysdi. PTC anticipates full-year 2025 GAAP R&D and SG&A expense to be between $805 and $835 million. PTC anticipates full-year 2025 non-GAAP R&D and SG&A expense to be between $730 and $760 million, excluding estimated non-cash, stock-based compensation expense of $75 million. Non-GAAP Financial Measures: In this press release, the financial results of PTC are provided in accordance with GAAP and using certain non-GAAP financial measures. In particular, the non-GAAP R&D and SG&A expense financial measures exclude non-cash, stock-based compensation expense. These non-GAAP financial measures are provided as a complement to financial measures reported in GAAP because management uses these non-GAAP financial measures when assessing and identifying operational trends. In management's opinion, these non-GAAP financial measures are useful to investors and other users of PTC's financial statements by providing greater transparency into the historical and projected operating performance of PTC and the company's future outlook. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. Quantitative reconciliations of the non-GAAP financial measures to their respective closest equivalent GAAP financial measures are included in the table below. Acronyms: CHF: Confoederatio Helvetica Francs (Swiss francs) DMD: Duchenne Muscular Dystrophy EC: European Commission FDA: U.S. Food and Drug Administration GAAP: Generally Accepted Accounting Principles NDA: New Drug Application nmDMD: Nonsense mutation Duchenne muscular dystrophy PKU: Phenylketonuria R&D: Research and Development SG&A: Selling, General, and Administrative Today's Conference Call and Webcast Reminder: To access the call by phone, please click here to register and you will be provided with dial-in details. To avoid delays, we recommend participants dial in for the conference call 15 minutes prior to the start of the call. The webcast conference call can be accessed on the Investors section of the PTC website at . A replay of the call will be available approximately two hours after completion of the call and will be archived on the company's website for 30 days. About PTC Therapeutics, Inc. PTC is a global biopharmaceutical company dedicated to the discovery, development and commercialization of clinically differentiated medicines for children and adults living with rare disorders. PTC is advancing a robust and diversified pipeline of transformative medicines as part of its mission to provide access to best-in-class treatments for patients with unmet medical needs. The company's strategy is to leverage its scientific expertise and global commercial infrastructure to optimize value for patients and other stakeholders. To learn more about PTC, please visit and follow on Facebook, X, and LinkedIn. For more information please contact: Investors: Ellen Cavaleri +1 (615) 618-8228 [email protected] Media: Jeanine Clemente +1 (908) 912-9406 [email protected] Forward-Looking Statements: This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this release, other than statements of historic fact, are forward-looking statements, including the information provided under the heading "PTC Full Year 2025 Financial Guidance", including with respect to (i) 2025 total revenue guidance and (ii) 2025 GAAP and non-GAAP R&D and SG&A expense guidance, and statements regarding: the future expectations, plans and prospects for PTC, including with respect to the expected timing of clinical trials and studies, availability of data, regulatory submissions and responses, commercialization and other matters with respect to its products and product candidates; PTC's strategy, future operations, future financial position, future revenues, projected costs; and the objectives of management. Other forward-looking statements may be identified by the words, "guidance," "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," "aim," and similar expressions. PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of pricing, coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC commercializes or may commercialize in the future; PTC's ability to maintain its marketing authorization of Translarna for the treatment of nmDMD in Brazil, Russia and other regions; the effect of the European Commission's adoption of the negative opinion from the Committee for Medicinal Products for Human Use (CHMP) on Translarna on other regulatory bodies; PTC's ability to use the results of Study 041, a randomized, 18-month, placebo-controlled clinical trial of Translarna for the treatment of nmDMD followed by an 18-month open-label extension, and from its international drug registry study to support a marketing approval for Translarna for the treatment of nmDMD in the United States; whether investigators agree with PTC's interpretation of the results of clinical trials and the totality of clinical data from its trials in Translarna; expectations with respect to PTC's license and collaboration agreement with Novartis Pharmaceuticals Corporation including its right to receive development, regulatory and sales milestones, profit sharing and royalty payments from Novartis; expectations with respect to Upstaza/Kebilidi, including commercialization, manufacturing capabilities, and the potential achievement of sales milestones and contingent payments that PTC may be obligated to make; expectations with respect to Sephience, including any regulatory submissions and potential approvals, commercialization, and the potential achievement of regulatory and sales milestones and contingent payments that PTC may be obligated to make; expectations with respect to vatiquinone, including any regulatory submissions and potential approvals, commercialization, and the potential achievement of regulatory and sales milestones and contingent payments that PTC may be obligated to make; expectations with respect to the commercialization of Evrysdi under PTC's SMA collaboration; expectations with respect to the commercialization of Tegsedi and Waylivra; significant business effects, including the effects of industry, market, economic, political or regulatory conditions; changes in tax and other laws, regulations, rates and policies; the eligible patient base and commercial potential of PTC's products and product candidates; PTC's scientific approach and general development progress; PTC's ability to satisfy its obligations under the terms of its lease agreements; the sufficiency of PTC's cash resources and its ability to obtain adequate financing in the future for its foreseeable and unforeseeable operating expenses and capital expenditures; and the factors discussed in the "Risk Factors" section of PTC's most recent Quarterly Report on Form 10-Q and Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in any territory, or prove to be commercially successful, including Sephience, Translarna, Emflaza, Upstaza, Kebilidi, Evrysdi, Tegsedi, Waylivra or vatiquinone. The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law. SOURCE PTC Therapeutics, Inc. 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点击上方的 行舟Drug ▲ 添加关注全球小核酸药物的上市及临床研究现状分析来源《中国新药杂志》 2025年 第34卷 第12期作者杜慧，肖宇锋，张玢中国医学科学院/北京协和医学院医学信息研究所/图书馆摘要目的: 本研究旨在分析总结全球小核酸药物的上市及临床研究现状，探索其未来发展方向。方法: 利用药物早期研发情报数据库检索上市及临床在研的小核酸药物并对这些药物的分类、研发国家及机构、靶点、适应证和递送系统等信息进行详细分析。结果: 截至2024年9月18日，全球共有17个小核酸药物获批上市、192个小核酸药物处于临床研究状态，其中反义寡核苷酸药物和小干扰RNA药物数量较多。大多数临床在研的小核酸药物仍处于早期研发阶段，适应证已逐渐从早期的遗传病拓展到肿瘤、心血管疾病等慢性病领域，其中N-乙酰半乳糖胺偶联物是应用最广泛的递送系统。我国小核酸药物发展态势良好，企业管线布局以乙型肝炎和慢性病为主。结论: 小核酸药物已成为继小分子药物、抗体药物后的第三大类药物，其研发潜力巨大，市场前景广阔。未来的发展方向包括探索新的治疗靶点、多学科合作开发肝外递送系统以及加强产学研的深度合作，共同助力推进临床转化。关键词小核酸药物; 反义寡核苷酸; 小干扰RNA; 临床研究_正文_小核酸药物是由十几个到几十个核苷酸串联组成的短链核酸，通过干扰或调控基因表达实现疾病治疗目的。与传统的小分子化学药和抗体类药物相比，小核酸药物具有研发周期短、研发成功率高、候选靶点丰富、适应证分布广泛和治疗精准化等优点。小核酸药物主要包括反义寡核苷酸(antisense oligonucleotide，ASO)、小干扰RNA(small interfering RNA，siRNA)、微小RNA(microRNA，miRNA)、小激活RNA(small activating RNA，saRNA)、向导RNA(small-guide RNA，sgRNA)、适配体(aptamer)以及抗体核酸偶联药物(antibody-oligonucleotide conjugates，AOCs)、多肽核酸偶联药物(peptide-oligonu cleotide conjugates，POCs)等[1]。ASO是一类化学合成的单链寡核苷酸分子，通常由13~30个核苷酸组成，ASO通过沃森-克里克(Watson-Crick)碱基配对原则与靶标序列形成双链结构，从而影响靶基因的表达[2]。RNA干扰(RNA interference，RNAi)是将外源或内源RNA导入细胞后与靶基因的信使RNA(messenger RNA，mRNA)结合，从而阻断靶基因mRNA的翻译，进而抑制靶基因表达的一种技术。基于RNAi的小核酸药物有siRNA和miRNA，其中siRNA是一类长度为20~25个核苷酸的双链RNA分子，miRNA是内源性生成的单链RNA分子，长度通常为21~23个核苷酸[3]。saRNA是一种双链RNA分子，能够在转录水平上激活基因表达，而sgRNA则是单链RNA分子，在CRISPR/Cas9系统中起到导航作用，引导Cas9核酸酶到特定的基因位点进行编辑。适配体是一类具有特定三级结构的单链短核苷酸分子，与其他小核酸药物不同，适配体不通过碱基配对，而是类似于抗体，依靠其三维结构特异性结合配体。此外，AOCs和POCs将小核酸药物与抗体或多肽结合，提高小核酸药物的靶向性和递送效率[4]。自20世纪90年代初以来，小核酸药物领域经历了多次重大突破。1993年，Ambros和Ruvkun在秀丽隐杆线虫中首次发现miRNA，揭示了其在转录后基因调控中的重要作用[5]。1998年，Mello和Fire进一步阐明了RNAi的机制，为小核酸药物的发展奠定了理论基础，并于2006年荣获诺贝尔生理学或医学奖[6]。2023年，Karikó和Weissman因在核苷碱基修饰方面的贡献获得诺贝尔生理学或医学奖，其发现极大推动了mRNA疫苗和疗法的发展[7]。2024年，诺贝尔生理学或医学奖再次授予Ambros和Ruvkun，以表彰其在miRNA发现及miRNA在转录后基因调控中的作用方面作出的开创性贡献[8]。这些重要科学发现推动了小核酸药物的发展，国内外各大制药企业纷纷通过自主研发或合作引进管线等方式布局[9]。本研究使用科睿唯安公司的药物早期研发情报数据库(Cortellis Drug Discovery Intelligence，CDDI)检索上市及临床在研的小核酸药物，分析其分类、研发国家及机构、靶点、适应证和递送系统等信息，总结小核酸药物研发现状，探索其未来发展方向。资料与方法1 数据来源以科睿唯安公司CDDI数据库为检索来源，利用CDDI数据库检索“药物和生物制剂(Drugs&Bi ologics)”，在“药物分类(Product Category)”字段，限定“Antisense Therapy和Oligonucleotides，siRNA，mi croRNA，aptamer，saRNA，sgRNA，AOC，POC”，在“最高研发状态(Highest Phase)”字段，限定“Launched，Pre-Registered，PhaseⅢ，PhaseⅡ/Ⅲ，PhaseⅡ，PhaseⅠ/Ⅱ，PhaseⅠ”，共检索到17个已上市的小核酸药物和192个研发活跃(12~18个月内有进展的小核酸管线，去掉暂停/停止/未报告进展/非积极的项目)并处于临床研究阶段的小核酸药物，检索时间为2024年9月18日。2 数据处理数据处理阶段，对每种药物进行详细的临床试验匹配。利用CDDI数据库，针对研究范围内的192个小核酸药物，逐一访问其“临床试验(Clinical&Studies)”模块，并通过查阅和对比，实现了药物与相应临床试验的精确关联。文章内容由凡默谷小编查阅文献选取，排版与编辑为原创。如转载，请尊重劳动成果，注明【来源：凡默谷公众号】。结果1 已上市药物情况截至2024年9月18日，全球共有17款小核酸药物获批上市，见表1。1998年，首款ASO药物福米韦生获美国FDA批准上市，用于治疗获得性免疫缺陷综合征患者并发的由巨细胞病毒(cytomegalov irus，CMV)引起的视网膜炎。随着高效抗逆转录病毒治疗(highly active antiretroviral therapy，HAART)的发展，CMV感染病例显著减少，导致福米韦生的市场需求和销售额大幅下滑，该药于2002年在欧洲退市[10]。TTＲ: 转甲状腺素蛋白， transthyretin; SOD1: 超氧化物歧化酶1， superoxide dismutase 1; DMD: 抗肌萎缩蛋白基因; APOC3: 载脂蛋白C3， apolipoprotein C3; SMN2: 运动神经元存活基因2， survival of motor neuron 2; LDHA: 乳酸脱氢酶A， lactate dehydrogenase A; PCSK9: 前蛋白转化酶枯草溶菌素9， proprotein convertase subtilisin /kexin type 9; HAO1: 羟基酸氧化酶1， hydroxyacid oxidase 1; ALAS1: 5-氨基乙酰丙酸合酶1，5 -aminolevulinate synthase 1; LNP: 脂质纳米颗粒， lipid nanoparticle; PS: 硫代磷酸酯; 2＇-O-MOE: 2＇-O-甲氧基乙基; 2＇-O-Me: 2＇-O-甲氧基; 2＇-F: 2＇-氟; 5mC: 5-甲基胞苷; PMO: 磷酰二氨基吗啉代寡核苷酸， phosphorodiamidate morpholino oligomer2006年，RNAi机制获得诺贝尔生理学或医学奖，极大推动了该领域的研究与开发。然而，RNAi的不稳定性、潜在的免疫原性及递送系统的缺乏导致研发进展缓慢，大型制药企业削减投资，行业发展陷入停滞。2014年，N-乙酰半乳糖胺偶联物(N-acetylgalactosamine conjugate，GalNAc)作为一种小核酸偶合递送系统飞速发展，促进了小核酸药物研发的迅速复苏[11]。随着化学修饰和递送系统技术的进步，小核酸药物进入了稳健且快速发展的时代。2016年后多款重磅小核酸药物陆续上市，见图1。仅2023年全球共批准了4款小核酸药物，包括2款ASO药物、1款siRNA药物和1款适配体药物。全球17款获批小核酸药物中ASO药物数量最多(共10款)，其次为6款siRNA药物和1款适配体药物。国家药品监督管理局(National Medical Products Administration，NMPA)共批准了2款ASO药物和1款siRNA药物，分别是tofersen(2024年)、nusin-ersen(2019年)和inclisiran(2023年)。图1 2016—2023 年全球获批的小核酸药物数量分布遗传性疾病是目前获批最多的适应证类别，17种上市的小核酸药物中，有11种针对遗传性疾病(遗传性转甲状腺蛋白淀粉样变性、杜氏肌营养不良症、家族性乳糜微粒血症综合征、脊髓性肌萎缩、急性肝卟啉症)、1种用于眼科疾病(年龄相关性黄斑变性引起的地图样萎缩)、1种用于神经退行性疾病(肌萎缩侧索硬化症)、1种针对心血管疾病(高胆固醇血症)、1种用于血液肿瘤(骨髓增生异常综合征)、2种用于代谢疾病(1型原发性高草酸尿症)。2021年inclisiran作为饮食的辅助疗法获批，用于成人原发性高胆固醇血症或混合型血脂异常患者的治疗，该药适用于在接受最大耐受剂量的他汀类药物治疗仍无法达到低密度脂蛋白胆固醇(low-density lipoprotein cholesterol，LDL-C)目标水平的患者。inclisiran的获批标志着小核酸药物开始在慢性病管理中展现其独特的优势和潜力[12]。未经修饰的小核酸药物稳定性差且特异性低，容易引起脱靶毒性。化学修饰可以增强小核酸药物对核酸酶的抗性，减少免疫原性和脱靶效应，同时提高靶向性[13]。常见的化学修饰涉及对磷酸骨架、核糖和碱基的修饰，包括PS，2'-O-Me，2'-O-MOE，2'-F和5mC[14]。目前上市的11种ASO药物和6种siR NA药物均采用了骨架、核糖和碱基的化学修饰。PMO呈电中性，骨架中磷酸二酯键被磷酰二氨基键取代，核糖被吗啉环取代。PMO具有生物稳定性强、带中性电荷以及不依赖核糖核酸酶H(ribonuclease H，RNase H)的作用机制等优点[15-16]。基于PMO修饰的4种ASO药物eteplirsen，golodirsen，viltolarsen，casimersen获批用于杜氏肌营养不良症的治疗。核酸药物由于相对分子质量较大、容易降解和无法自由进入细胞等缺点，难以在体内发挥作用。递送系统可以保护核酸药物免于降解，确保其稳定性，并将其有效递送到靶组织。目前上市的小核酸药物采用了2种递送系统LNP和GalNAc，见图2。GalNAc是唾液酸受体(asialoglycoprotein receptor，ASGPR)的靶向配体，可以与肝脏实质细胞表面的ASGPR特异性结合，实现细胞的快速胞吞，该技术具有高度的肝靶向特异性[17]。在6种使用递送系统的siRNA药物中，5种采用了GalNAc偶联递送系统、1种使用了LNP递送系统。eplontersen是首个获批上市的GalNAc偶联ASO药物，是Ionis公司继inotersen之后的第2种遗传性转甲状腺蛋白淀粉样变性治疗药物，相比inotersen，eplontersen的给药剂量更小、给药频率更低[18]。2 临床研究阶段的药物研发情况截至2024年9月18日，全球共有192个研发活跃并处于临床研究阶段的小核酸药物，其中ASO药物86个，是临床研发数量最多的小核酸药物，约占45%; siRNA药物也是小核酸药物领域的研究热点之一，约占35%。此外，适配体、sgRNA、miRNA及saRNA的药物研发尚处于早期阶段，数量较少，见图3。小核酸药物的研发在全球多个国家和地区均有分布，其中美国、欧洲和中国是主要的研发基地。美国在小核酸药物的研发方面处于领先地位，目前有109个小核酸药物处于临床研究状态，远超其他国家。在欧洲，英国、瑞士、荷兰和德国的小核酸药物临床研究较为活跃。我国有25个小核酸药物处于临床研究状态，其中siRNA和sgRNA研发管线布局较多，ASO药物研发参与较少，见表2。全球范围内研发小核酸药物的企业中，Ionis公司和Alnylam公司布局最为广泛。Ionis公司专注于ASO药物研发，有32个临床在研的小核酸药物。Alnylam公司是RNAi领域的领军企业，有12个临床在研的小核酸药物。此外，Biogen公司、Arrow head公司、Lilly公司也较为活跃。我国小核酸药物发展呈现良好态势，多家企业积极布局小核酸药物的研发管线，瑞博生物公司、圣因生物公司、舶望制药公司和本导基因公司等企业都在积极推进多个项目的临床试验。全球临床在研的小核酸药物仅有9%的药物最高研发状态为预注册和Ⅲ期临床试验，大多数集中在Ⅰ期和Ⅱ期临床试验阶段。处于Ⅲ期临床试验的药物中以ASO和siRNA药物为主，适配体、sgRNA、miRNA、saRNA药物大多处于早期临床研究阶段，见图4。小核酸药物因其独特的机制和广泛的治疗潜力，能够针对多种疾病中的关键基因进行精准调控。与传统药物相比，小核酸药物能够作用于更广泛的靶点。目前，全球临床在研的小核酸药物中，针对HBV和DMD的靶点研究最为集中。此外，针对心血管疾病(如载脂蛋白和AGT)以及代谢性疾病[如PCSK9和patatin样磷脂酶结构域蛋白3(patatin-like phospholipase domain containing3，PNPLA3)]靶点也有多个药物正在进行临床研究，见表3。我国小核酸药物的靶点多集中于乙型肝炎和慢性病领域，较少涉及罕见病。全球小核酸药物的适应证分布广泛，涉及遗传性疾病、肿瘤、神经系统疾病、代谢疾病、感染、心血管系统疾病等多个疾病领域，见图5。目前上市的小核酸药物大多集中在遗传性疾病领域，如杜氏肌营养不良症、脊髓性肌萎缩症和遗传性转甲状腺蛋白淀粉样变性。然而，临床在研的小核酸药物适应证已逐渐从早期的遗传病拓展到肿瘤、心血管疾病、代谢疾病等慢性病领域。在这一趋势中，我国制药企业大多将布局重心放在慢性病领域，如信达生物公司的高血压治疗药物SGB-3908、圣因生物公司的高血脂治疗药物SGB-9768、舶望制药公司的高血脂治疗药物BW-01、瑞博生物公司的高血脂治疗药物RBD-7022。此外，乙型肝炎也是我国制药企业布局较为集中的领域，包括浩博医药公司、瑞博生物公司、恒瑞医药公司、舶望制药公司、星曜坤泽公司和正大天晴公司在内的多家企业均有相关药物在研。化学修饰和递送系统的进步推动了小核酸药物的发展和临床应用。目前已上市的ASO药物大多仅采用化学修饰，未使用特殊的递送系统。eplontersen是唯一获批上市的GalNAc-ASO偶联药物。多家制药公司如Ionis公司、CiVi Biopharma公司和Novartis公司正在积极开发GalNAc-ASO偶联药物。其中Ionis公司的临床进展最为迅速，已有2款产品进入预注册阶段、1款产品进入Ⅲ期临床试验，见表4。GalNAc是目前小核酸药物应用最广泛的递送系统，但仅能靶向肝脏细胞。为了实现肝外递送目的，多项临床研究开发了新型递送系统，包括AOCs、POCs、外泌体和聚合物基质等，见表5。AOCs将小核酸药物的靶点特异性与抗体的组织特异性相结合，协同发挥了这2种分子的优势[19-20]。Avidity Biosciences公司和Dyne Therapeutics公司在AOCs研发领域表现突出，其中Avidity Biosciences公司的强直性肌营养不良药物AOC-1001已进入Ⅲ期临床试验阶段。POCs将多肽与小核酸药物偶联，显著改善了小核酸药物的递送、细胞摄取和生物利用度。细胞穿透肽(cell-penetrating peptides，CPP)是一类能够有效穿过细胞膜的短肽序列，是POCs中研究最多的偶联物之一[21-22]。进展较快的POCs已进入Ⅱ期临床试验阶段。Sarepta Therapeutics公司的vesleteplirsen是已获批上市的eteplirsen与CPP偶联而成，用于治疗杜氏肌营养不良症。PepGen公司基于其增强递送寡核苷酸(enhanced delivery oligonucleotide，EDO)技术平台设计的PGN-EDO51也是一种多肽-寡核苷酸偶联物，用于治疗杜氏肌营养不良症[23]。外泌体是内源性的纳米级细胞外囊泡，具有免疫原性低、安全性高的特点[24]。Codiak BioSciences公司研发的exoASO-STAT6已进入Ⅰ期临床试验，该药物能够选择性递送ASO以破坏肿瘤相关巨噬细胞(tumor-associated macrophages，TAM)中的STAT6信号传导并诱导抗肿瘤免疫反应[25]。siG12D LODER是一种由可生物降解的聚合物基质包裹的针对KRAS G12D突变的siRNA，临床研究(NCT01676259)表明siG12D LODER联合化疗可延长KRAS G12D/V突变局部晚期胰腺癌患者总体生存期9.3个月[26]。讨论目前获批上市和处于临床研究状态的小核酸药物中，ASO药物因上市较早和成熟的商业化发展在小核酸药物研发中的占比较高，其次为siRNA药物。在靶点和适应证方面，上市的小核酸药物主要集中在罕见病领域，临床在研项目已开始向肿瘤、糖尿病、高血脂、乙型肝炎等领域拓展，但靶点已出现同质化现象，针对HBV、载脂蛋白、PCSK9的研究较为集中。临床分期方面，大多数小核酸药物仍处于早期研发阶段，而处于Ⅲ期临床试验的药物主要以ASO和siRNA药物为主。欧洲和美国在小核酸药物研发领域仍处于领先地位，以Ionis公司和Alnylam公司为代表的大型制药企业在行业发展初期主要聚焦于致病机制明确、缺乏有效治疗手段的遗传性罕见病，通过快速验证潜在治疗靶点的有效性，借助孤儿药(orphan)、快速通道(fast track)、加速审批(accelerated approval)、优先审评(priority review)和突破性疗法(break- through therapy)等多条特殊认定和审评途径，实现了药物的快速获批和上市[27]。在化学修饰和递送系统技术成熟后，逐步向心血管疾病及代谢疾病过渡。相比之下，我国对罕见病的研究相对较少，而更多集中在乙型肝炎和高血压、高血脂等慢性病领域，这可能与国内罕见病政策体系有待完善和罕见病药物研发成本较高有关[28]。尽管我国在小核酸药物研发方面起步较晚，但在政策扶持和科研投资增加的推动下，国内多家企业正积极布局临床开发。2024年瑞博生物公司和舶望制药公司先后完成了License-out授权，将企业的专利技术、药物候选物或研发平台授权给国际制药企业[29-30]，展现了国内制药企业在全球小核酸药物研发领域中的活跃参与和贡献，再次证明了我国核酸药物发展的良好态势。未来随着国内小核酸药物研发能力的不断提升，有望逐步进入突破型创新阶段。核酸药物具有其他药物所不具备的独特优势，但也面临诸多挑战。其在体内的稳定性较差、难以穿透细胞膜、靶向性不足，因而递送系统的开发一直是研发过程中需要解决的关键难题[31]。目前，Gal-NAc-siRNA递送系统已较为成熟，已上市的6种siRNA药物中有5种采用了GalNAc系统。但上市的ASO药物大多数仅采用了结构修饰，虽然在一定程度上解决了直接递送的难题，但大剂量给药可能会限制其临床应用以及增加用药风险。首款Gal NAc-ASO药物eplontersen的获批以及多项GalNAc ASO药物临床试验的推进标志着ASO药物开始进入“GalNAc递送系统”时代。GalNAc递送系统具有高效的肝脏靶向性，在治疗肝脏疾病方面表现出显著优势，但要实现对肝外组织/细胞的靶向递送并达到更安全、更稳定和更高效的递送效果，仍然面临巨大挑战。目前多项临床试验对肝外递送系统进行了研究，包括开发AOCs、POCs、外泌体、聚合物基质等，但同时也面临提高递送效率、降低毒性和免疫原性、减少研发成本等问题[4]。小核酸药物作为一种新型治疗方式，在罕见病和慢性病治疗领域已展现出显著潜力。为了充分释放其治疗潜力，需要克服一系列挑战，探索新的治疗靶点和拓展适应证、避免靶点同质化对于推动小核酸药物的发展至关重要。同时需要来自物理、生物、化学和工程学等多学科的科研人员共同努力，推动肝外递送系统的发展，以解决当前递送技术的局限性。此外，加强产学研的深度合作、促进基础研究与临床应用的紧密结合、加快药物的临床转化是实现小核酸药物广泛应用的重要途径[32]。未来，小核酸药物有望成为具有更大应用潜力的治疗手段，进一步丰富治疗药物的选择，为患者的健康和福祉作出更大的贡献。参考文献详见《中国新药杂志》 2025年 第34卷 第12期文章信息源于公众号凡默谷，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug每日更新 欢迎订阅+医药大数据|行业动态|政策解读