A Phase 4 Safety Study Assessing the Adverse Events Occurring Within One Day of TEGSEDI Administration in Patients With Polyneuropathy of Hereditary Transthyretin-mediated Amyloidosis (hATTR-PN)

The objective of the study was to characterize adverse events (AEs) occurring within one day of TEGSEDI administration to adult participants with hATTR-PN overall and in individual participants with respect to time course of AE onset, vital sign changes, preventive measures, treatment required, risk factors, and subsequent adverse outcomes.

开始日期2021-01-21

申办/合作机构

Akcea Therapeutics, Inc.

NCT04270058

/ RecruitingN/A

Pregnancy Surveillance Program of Women and Infants Exposed to TEGSEDI During Pregnancy

This is a worldwide safety surveillance study of pregnancy outcomes in women with hATTR-PN who may have been exposed or were not exposed to TEGSEDI prior to or during the pregnancy and of pediatric outcomes up to 1 year of age.

开始日期2020-01-15

申办/合作机构

Akcea Therapeutics, Inc.

NCT03702829

/ Unknown status临床2期IIT

24 Month Open Label Study of the Tolerability and Efficacy of an Antisense Oligonucleotide (Inotersen) in Patients With Transthyretin (TTR) Amyloid Cardiomyopathy

Transthyretin is a protein produced in the liver that transports thyroid hormone and vitamin A. A single substitution of an amino acid in the structure of TTR can result in a relatively unstable protein, the breakdown products of which (predominantly monomers) aggregate abnormally and produce proteinaceous deposits in nerves and the heart. These deposits are known as amyloid and produce progressive nerve and heart damage. Amyloidosis due to a mutant TTR is usually an autosomal dominant and hence is a familial condition. Wild-type TTR is also capable of producing amyloid deposits which predominantly involves the heart (rather than the nervous system) resulting in a progressive decrease in cardiac function with increasing signs of heart failure. This study aims to determine whether subcutaneous injection of an antisense oligonucleotide drug, known as inotersen, that has been specifically designed to reduce production of the protein transthyretin by the liver, can slow or stop the progression of TTR amyloid cardiomyopathy as compared to historical controls, using advanced echocardiography and cardiac MRI. The study also aims to determine the tolerability and safety of this drug when administered over a 24-month period to patients with TTR amyloid cardiomyopathy.

开始日期2019-02-28

申办/合作机构

The Brigham & Women's Hospital, Inc.

100 项与 Inotersen sodium 相关的临床结果

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100 项与 Inotersen sodium 相关的转化医学

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100 项与 Inotersen sodium 相关的专利（医药）

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119

项与 Inotersen sodium 相关的文献（医药）

2025-07-11·Kardiologia Polska

Transthyretin-related amyloid cardiomyopathy: A single-center experience in southern Poland, an endemic area.

Article

作者: Stępień-Wroniecka, Agnieszka ; Kostkiewicz, Magdalena ; Boczar, Krzysztof ; Podolec, Piotr ; Dziewięcka, Ewa ; Ząbek, Andrzej ; Mróz, Krystian ; Holcman, Katarzyna ; Rubiś, Paweł ; Ostrowska, Monika ; Winiarczyk, Mateusz ; Ćmiel, Bogdan ; Graczyk, Katarzyna ; Kurek, Maria

BACKGROUND:

Transthyretin amyloid cardiomyopathy (ATTR CA) is a rare, fatal disease characterised by the deposition of amyloid fibrils derived from misfolded transthyretin (TTR) protein. This single-center study investigated the clinical characteristics, genetic profile, and geographic distribution of ATTR CA patients in southern Poland, a suspected endemic area.

MATERIAL AND METHODS:

This prospective study was conducted between 2020 and 2025 involving 100 adults, including a cohort of consecutive index patients with confirmed ATTR CA. Furthermore, all consenting first-degree relatives were invited to undergo targeted assessment through a familial cascade screening approach. The study incorporated clinical data, echocardiography, scintigraphy, genetic testing, and prospective follow-up for five years to assess all-cause mortality.

RESULTS:

Among 100 participants (27 index patients and 73 relatives), 6 relatives were diagnosed with ATTR CA and 15 were identified as carriers of a pathogenic TTR variant. The most frequently identified TTR variant was Phe53Leu, suggesting a high regional prevalence in southern Poland, alongside Glu109Lys, Glu122Lys, and Glu82Lys. The presence of hereditary ATTR CA was significantly associated with increased risk of all-cause mortality (HR, 7.67; 95% CI, 2.33-25.26; P < 0.001). All 33 patients with ATTR CA were eligible for tafamidis; moreover, two patients in this cohort with polyneuropathy were treated with inotersen, representing the first applications of these therapies in Poland.

CONCLUSION:

A comprehensive diagnostic approach is crucial for timely initiation of disease-modifying therapies. Our study suggests that, in this region, there is a high rate of the Phe53Leu TTR variant; however, further research is needed to validate these findings (NCT05814380).

2025-04-21·Expert Review of Pharmacoeconomics & Outcomes Research

A retrospective observational analysis of the real-world care pathway of people with hereditary transthyretin amyloidosis with polyneuropathy in Italy

Article

作者: D’Amelio, Marco ; Martini, Nello ; Ronconi, Giulia ; Dondi, Letizia ; Piccinni, Carlo ; Esposito, Immacolata ; Addesi, Alice ; Gnesi, Marco ; Calabria, Silvia ; Dondi, Leonardo ; Cosentino, Nicola ; Dell’Anno, Irene ; Maggioni, Aldo Pietro

BACKGROUND:

This retrospective observational study described the epidemiology and the burden on the Italian healthcare service (SSN) of patients with polyneuropathy (PN) associated with hereditary transthyretin amyloidosis (ATTRv).

RESEARCH DESIGN AND METHODS:

From the Fondazione ReS (Ricerca e Salute) administrative healthcare database (~5.5 million inhabitants in 2021), patients were identified as having ATTRv-PN in 2021 if they had received treatments for ATTRv-PN under SSN reimbursement (i.e. tafamidis, patisiran, or inotersen) from 1 January 2014 to 31 December 2021 (index date in 2021). Demographics and comorbidities at the baseline, healthcare resource consumption, and related direct costs reimbursed by the SSN throughout the one-year follow-up were described.

RESULTS:

In 2021, 36 patients with ATTRv-PN (prevalence: 7.4/1,000,000) were identified (males were 83.3%; patients with ≥2 comorbidities were 61.1%; the mean age was 73 ± 8 years). During follow-up, of patients, 91.7% received drugs for ATTRv-PN; >50% received antiepileptics and acid suppressants; 22.2% were admitted to overnight hospitalizations; 30.6% accessed the emergency department; 97.2% received local outpatient specialist care. The per patient mean annual cost was € 122,017; drugs for ATTRv-PN accounted for 94.7% of the total expenditure.

CONCLUSIONS:

This study of real-world patients with ATTRv-PN showed a high rate of comorbidities, and substantial direct healthcare and economic burdens on the SSN.

2025-03-01·JOURNAL OF NEUROLOGY

Patisiran in ATTRv amyloidosis with polyneuropathy: “PatisiranItaly” multicenter observational study

Article

作者: Guaraldi, Pietro ; Turri, Mara ; Gemelli, Chiara ; Vitali, Francesca ; Luigetti, Marco ; Manganelli, Fiore ; Salvalaggio, Alessandro ; Briani, Chiara ; Antonini, Giovanni ; Novo, Giuseppina ; Sciarrone, Maria Ausilia ; Filosto, Massimiliano ; Goglia, Mariangela ; Russo, Massimo ; Palumbo, Giovanni ; Petrelli, Cristina ; Mazzeo, Anna ; Falzone, Yuri ; Tozza, Stefano ; Barilaro, Alessandro ; Poli, Loris ; Leonardi, Luca ; Pradotto, Luca Guglielmo ; Carlini, Giulia ; Brighina, Filippo ; Cortelli, Pietro ; Di Stefano, Vincenzo ; Gentile, Luca ; Ceccanti, Marco ; Burattini, Marco ; Lotti, Antonio ; Fenu, Silvia ; Di Muzio, Antonio ; Currò Dossi, Marco ; Di Lisi, Daniela ; Gasverde, Sabrina ; Cianci, Vittoria ; Tagliapietra, Matteo ; Cani, Ilaria ; Milella, Giammarco ; Romano, Angela ; Longhi, Simone ; Verriello, Lorenzo ; Sellitti, Luigi

Abstract:

Background:

Hereditary amyloid transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare, inherited, multisystemic, progressive adult-onset disease, affecting sensorimotor nerves, and various organs. It is caused by mutations in the TTR gene, leading to misfolded monomers that aggregate, forming amyloid fibrils. Patisiran is a small, double-stranded interfering RNA encapsulated in a lipid nanoparticle, designed to enter hepatocytes and selectively target TTR mRNA to reduce both variant TTR and wild-type TTR (wt). This study presents a multicenter, real-life experience of patisiran’s effectiveness and safety in ATTRv-PN.

Methods:

We enrolled genetically confirmed ATTRv-PN patients from 29 specialized Italian centers. All subjects underwent neurological assessments, including familial amyloid polyneuropathy (FAP) staging, the Neuropathy Impairment Score (NIS), quality-of-life assessment using the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire, and the Compound Autonomic Dysfunction Test (CADT). Additional assessments included baseline and follow-up measures of serum NT-proBNP and interventricular septal thickness.

Results:

A total of 181 ATTRv patients (69% male) were enrolled. Neurological onset was reported in 60.2% of cases. At baseline, 83.4% of patients exhibited multisystemic involvement, while only 16.6% presented isolated polyneuropathy. For approximately 70% of patients, patisiran was the first treatment; the remainder transitioned from tafamidis or inotersen. Following treatment, most patients demonstrated stabilization of neuropathy progression, regardless of baseline disease severity or genotype. The treatment was well-tolerated, with 90% of patients reporting no adverse events.

Conclusion:

Patisiran can be considered a valid therapeutic option for the management of patients with ATTRv amyloidosis. Considering its mechanism of action, similar outcomes could also be expected with the wider utilization of newly approved gene silencers for ATTRv therapy, such as vutrisiran.

136

项与 Inotersen sodium 相关的新闻（医药）

2025-07-03

·行舟Drug

全球小核酸药物的上市及临床研究现状分析

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

寡核苷酸信使RNA核酸药物siRNA上市批准

2025-06-05

·CPHI制药在线

收藏 | 现有管线与上市RNA疗法汇总

关注并星标CPHI制药在线RNA疗法正迅速成为现代医学中最具变革性的治疗策略之一。从反义寡核苷酸（ASO）和小干扰RNA（siRNA）等精准调控基因表达的工具，到mRNA疫苗和肿瘤免疫疗法等前沿应用，RNA技术已在多个疾病领域展现出巨大潜力。近年来，随着递送系统、生物偶联技术和修饰化学的不断进步，RNA疗法的临床管线迅速扩展，涵盖了罕见病、神经系统疾病、代谢性疾病以及肿瘤等多个领域。目前，RNA疗法的临床开发全景涵盖了ASO、siRNA、mRNA、核酸适体（aptamer）等主要技术路径，在不同适应症中布局广泛，关键企业的研发动态频繁，已获批上市的代表性药物不断涌现。本文总结了现有管线和上市的 RNA疗法，将这一新兴领域的开发全景呈现出来。1. ASO类 RNA资产梳理 1.1 I期ASO资产 • Praxis ASO资产：Elsunersen（PRAX-222）靶点：SCN2A基因适应症：由SCN2A基因的功能获得性突变引起的早发性SCN2A发育性和癫痫性脑病。 • PYC Therapeutics ASO资产：VP-001 靶点：PRPF31基因适应症：由PRPF31基因突变引起的视网膜色素变性11型 ASO资产：PYC-001 靶点：OPA1基因适应症：由OPA1基因突变引起的常染色体显性视神经萎缩（ADOA） ASO资产：PYC-003 靶点：PKD1基因适应症：常染色体显性多囊肾病（ADPKD） • Bio-Path Holdings ASO资产：BP1002（Liposomal Grb2 ASO）适应症：急性髓性白血病（AML）、B细胞淋巴瘤（B-cell lymphoma）技术特点：使用独特的中性脂质体递送系统（DNAbilize® Platform）递送ASO。1.2 II期ASO资产 • Stoke Therapeutics ASO资产：Zorevunersen（STK-001）靶点：SCN1A基因适应症：Dravet综合征（一种严重癫痫） ASO资产：STK-002 靶点：OPA1基因适应症：常染色体显性视神经萎缩（ADOA） • Entrada Therapeutics ASO资产：ENTR-601-44 适应症：Duchenne肌营养不良（DMD）靶点：DMD中的Exon 44跳跃技术特点：使用Entrada独有的分子穿透技术（Endosomal Escape Vehicle, EEV）提高细胞内递送效率。 ASO资产：ENTR-601-45 靶点：DMD基因的外显子45（Exon 45）适应症：适用于外显子45跳跃的杜氏肌营养不良症（DMD）患者 • Dyne Therapeutics ASO资产：DYNE-251 适应症：Duchenne肌营养不良（DMD），针对DMD中的Exon 51跳跃。技术特点：使用抗体-寡核苷酸结合平台（FORCE platform）进行肌肉组织特异性递送。 ASO资产：DYNE-101 适应症：肌强直性营养不良症1型（DM1）靶点：DMPK基因的异常CTG重复序列 • Ribomic ASO资产：Umedaptanib Pegol（原RBM-007，严格来说是核酸适体aptamer，而不是典型ASO) 靶点：FGF2（成纤维细胞生长因子2）。适应症：湿性年龄相关性黄斑变性（wAMD），软骨发育不全症 • Wave Life Sciences ASO资产： WVE-N531：DMD（杜氏肌营养不良症）治疗，靶向Exon 53跳跃 WVE-003：亨廷顿舞蹈症（Huntington's Disease, HD），靶向HTT基因突变 • PepGen ASO资产：PGN-EDO51 适应症：Duchenne肌营养不良（DMD）技术特点：结合增强型细胞穿透肽（Enhanced Delivery Oligonucleotide, EDO）技术，提高ASO进入肌肉细胞的效率。 ASO资产：PGN-EDODM1 靶点：DMPK基因的异常CUG重复序列适应症：肌强直性营养不良症1型（DM1） • 罗氏 ASO资产：Tominersen（RG6042）靶点：Huntingtin（HTT）基因适应症：亨廷顿病（Huntington's Disease, HD） ASO资产：IONIS-FB-LRx（RO7434656 / RG6299）靶点：补体因子B（Factor B）适应症：IgA肾病（IgAN） • Ultragenyx ASO资产：GTX-102 靶点：UBE3A-AS（UBE3A反义转录本）适应症：天使综合征（Angelman Syndrome）1.3 ASO类3期资产 • Oncotelic Therapeutics ASO资产：OT-101（也叫Trabedersen）靶点：转化生长因子β2（TGF-β2）适应症：胶质母细胞瘤（GBM）、胰腺癌、恶性黑色素瘤机制：抑制TGF-β2，有望减轻肿瘤免疫抑制，增强抗肿瘤免疫反应 • 阿斯利康 ASO资产：ION449（亦称AZD8233），与Ionis合作开发的ASO疗法靶点：PCSK9（一种影响低密度脂蛋白胆固醇LDL-C水平的蛋白质）适应症：高胆固醇血症（hypercholesterolemia）备注：主要竞争对手包括小分子抑制剂和PCSK9单抗（如Repatha、Praluent） • GSK ASO资产：bepirovirsen 靶点：乙型肝炎病毒（HBV）的前基因组RNA和mRNA 适应症：慢性乙型肝炎（chronic hepatitis B, CHB），通过抑制HBV基因表达，帮助病毒清除或实现功能性治愈（functional cure）。 • 诺华 ASO资产：Pelacarsen 靶点：LPA基因（编码脂蛋白(a)）作用机制：Pelacarsen通过抑制LPA基因的mRNA，降低血液中脂蛋白(a)(Lp(a))水平，从而降低心血管疾病风险。Lp(a)是目前被认为的重要但尚无针对性治疗手段的心血管风险因子。适应症：主要用于治疗动脉粥样硬化性心血管疾病高危患者中，血脂异常（特别是Lp(a)升高）的情况。临床阶段：正在进行III期临床试验（Lp(a)HORIZON）。Pelacarsen可能成为首个专门针对Lp(a)升高治疗获批的药物。1.4 ASO类上市药物 • 渤健 Spinraza（nusinersen）靶点：SMN2前体mRNA（促进功能性SMN蛋白表达）适应症：脊髓性肌萎缩症（SMA）获批时间：2016年12月（美国FDA批准）备注：全球首个获批的SMA治疗药物。由Ionis开发，Biogen负责商业化。 • Sarepta Therapeutics Exondys 51（eteplirsen）靶点：DMD基因的Exon 51 适应症：Duchenne肌营养不良（DMD）获批时间：2016年9月（FDA加速批准） Vyondys 53（golodirsen）靶点：DMD基因的Exon 53 适应症：DMD 获批时间：2019年12月 Amondys 45（casimersen）靶点：DMD基因的Exon 45 适应症：DMD 获批时间：2021年2月（FDA加速批准） • Ionis Pharmaceuticals Tegsedi（inotersen）靶点：TTR（转甲状腺素蛋白）适应症：遗传性转甲状腺素蛋白淀粉样变性多发性神经病（hATTR-PN）获批时间：2018年10月（FDA，EMA批准） Waylivra（volanesorsen）靶点：APOC3（载脂蛋白C-III）适应症：家族性乳糜微粒血症综合征（FCS）获批时间：2019年5月（欧洲EMA批准；未获美国FDA批准） • NS Pharma Viltepso（viltolarsen）靶点：DMD基因的Exon 53 适应症：Duchenne肌营养不良（DMD）获批时间：2020年8月（FDA加速批准）2.RNAi类 RNA资产2.1 I期RNAi资产 • Aligos Therapeutics RNAi资产：ALG-125755 靶点：乙型肝炎病毒（HBV）RNA 适应症：慢性乙型肝炎（CHB） • Regulus Therapeutics RNAi资产：RGLS8429 靶点：microRNA-17（miR-17家族）适应症：常染色体显性多囊肾病（ADPKD） • Phio Pharmaceuticals RNAi资产：PH-762 靶点：程序性死亡受体1（PD-1）适应症：癌症免疫疗法（通过下调T细胞表面PD-1，增强免疫杀伤）技术特点：采用其自有的INTASYL✓平台，优化了siRNA的稳定性和局部递送。 • TransCode Therapeutics RNAi资产：VIR-2218 TTX-MC138 靶点：microRNA-10b（miR-10b）适应症：针对转移性实体肿瘤（如乳腺癌、胰腺癌、脑肿瘤等）技术特点：使用纳米颗粒系统高效递送siRNA药物，特别适合针对深部转移灶。2.2 II期RNAi资产 • Arbutus Biopharma RNAi资产：AB-729 靶点：乙型肝炎病毒（HBV）表面抗原（HBsAg）适应症：慢性乙型肝炎（CHB）备注：AB-729是Arbutus当前最重要的核心资产之一。 • OliX Pharmaceuticals RNAi资产：OLX703A 靶点：HBV病毒相关RNA 适应症：慢性乙型肝炎（CHB）机制：抑制HBV病毒蛋白表达 • Silence Therapeutics RNAi资产：SLN360 靶点：LPA基因（编码脂蛋白Lp(a)）适应症：高脂蛋白(a)血症（Lp(a)过高相关的心血管疾病）机制：通过降低血液中Lp(a)水平，减少动脉粥样硬化风险。备注：SLN360是Silence在心血管RNA疗法领域的主力项目。 • Sirnaomics RNAi资产：STP705 靶点：双靶点siRNA药物，靶向TGF-β1和COX-2。适应症：瘢痕治疗（皮肤纤维化）、非黑色素瘤皮肤癌（如基底细胞癌、鳞状细胞癌）机制：抑制纤维化、降低肿瘤微环境免疫抑制。备注：Sirnaomics的特点是双靶点siRNA联合递送。 • GSK RNAi资产：GSK4532990 靶点：靶向HSD17B13基因适应症：代谢功能障碍相关脂肪性肝炎（MASH） • 礼来 RNAi项目：LY3561774 靶点：SERPINA1基因适应症：α1-抗胰蛋白酶缺乏症（AATD）机制：降低异常α1-抗胰蛋白酶（AAT）积聚 • VIR Biotechnology RNAi项目：VIR-2218 靶点： HBV RNA 适应症：慢性乙型肝炎（CHB）。机制：抑制HBV表面抗原表达 • 罗氏 RNAi资产：Zilebesiran 靶点：肝脏表达的血管紧张素原（AGT）基因。适应症：高血压，特别是高心血管风险患者。2.3 III期RNAi资产 • Arrowhead Pharmaceuticals RNAi资产：ARO-APOC3 靶点：APOC3（载脂蛋白C-III），适应症：高甘油三酯血症和罕见脂代谢异常 • 武田 RNAi资产：Fazirsiran 靶点：SERPINA1（编码α1-抗胰蛋白酶）适应症：α1-抗胰蛋白酶缺乏症（AATD）引起的肝病 • 安进 RNAi资产：Olpasiran 靶点：LPA基因（脂蛋白(a)）适应症：高脂蛋白(a)血症及其引发的心血管疾病风险备注：这是一款非常重磅的RNAi项目，对心血管领域意义重大。 • Avidity Biosciences RNAi资产：AOC 1001 靶点：DMPK基因（导致肌强直性营养不良症1型DM1）适应症：肌强直性营养不良症1型（DM1）技术特点：AOC（Antibody Oligonucleotide Conjugate，抗体-寡核苷酸偶联体），用于肌肉靶向递送siRNA。 • 赛诺菲 RNAi资产：Fitusiran 靶点：AT（抗凝血酶）适应症：血友病A或B患者的出血预防 • VIR Biotechnology RNAi资产：VIR-2218 靶点：HBV RNA 适应症：慢性乙型肝炎（CHB）2.4 上市RNAi资产 • Alnylam Pharmaceuticals Alnylam是全球RNAi疗法先锋，拥有最多已上市RNAi药物。 Onpattro（Patisiran）靶点：TTR 适应症：遗传性转甲状腺素蛋白淀粉样变性引起的多发性神经病（hATTR-PN）批准情况：2018年FDA/EMA批准 Givlaari（Givosiran）靶点：ALAS1 适应症：急性肝卟啉症（AHP）批准情况：2019年FDA/EMA批准 Oxlumo（Lumasiran）靶点：HAO1 适应症：原发性高草酸尿症1型（PH1）批准情况：2020年FDA/EMA批准 Amvuttra（Vutrisiran）靶点：TTR 适应症：遗传性转甲状腺素蛋白淀粉样变性引起的多发性神经病（hATTR-PN）（长效皮下注射版）批准情况：2022年FDA批准 • 诺华 RNAi资产：Leqvio（Inclisiran）靶点：PCSK9 适应症：高胆固醇血症，动脉粥样硬化性心血管疾病风险降低批准情况：2020年欧洲EMA批准；2021年底美国FDA批准 • 诺和诺德 RNAi资产：Rivfloza (nedosiran) 靶点：肝脏中乳酸脱氢酶（LDH）mRNA 适应症：治疗9岁及以上、肾功能相对良好的原发性高草酸尿症1型（PH1）患者。作用机制：抑制LDH蛋白表达，减少草酸过度生成，缓解PH1疾病过程，减少肾脏损害风险。批准情况：2023年9月29日FDA正式批准Rivfloza上市。成为继Alnylam的Oxlumo（Lumasiran）之后，全球第二款获批用于PH1治疗的RNAi药物。3.mRNA类 RNA药物资产3.1 1期mRNA资产 • 赛诺菲 SP0237: 季节性流感 mRNA 疫苗适应症：针对 A/H3N2 毒株的季节性流感。 SP0256 – RSV mRNA 疫苗（老年人群）适应症：用于预防老年人群中的呼吸道合胞病毒（RSV）感染。 SP0268 – mRNA 痤疮疫苗适应症：针对痤疮（Acne）的 mRNA 疫苗。 SP0291 – 多价呼吸道病毒 mRNA 疫苗适应症：针对 RSV、人类偏肺病毒（hMPV）和副流感病毒 3 型（PIV3）的组合疫苗，主要用于老年人群。沙眼衣原体（Chlamydia）mRNA 疫苗候选适应症：预防沙眼衣原体感染，主要针对 18 至 29 岁的成人。 • Vertex mRNA资产：VX-522：用于囊性纤维化（CF）的mRNA疗法靶点：CFTR基因（囊性纤维化跨膜电导调节因子）。适应症：无法通过CFTR调节剂治疗的CF（囊性纤维化）患者，尤其是那些由于CFTR基因突变导致CFTR蛋白缺失的患者。作用机制：VX-522是一种mRNA疗法，通过脂质纳米颗粒（LNP）递送CFTR mRNA至肺部细胞，促使其合成功能性CFTR蛋白，从而恢复氯离子通道的功能。3.2 II期mRNA资产 • Gritstone Bio GRANITE（GRT-C901/GRT-R902）个体化肿瘤新抗原疫苗，采用腺病毒（ChAd68）和自扩增mRNA（samRNA）组成的异源prime-boost策略。适应症：用于治疗转移性微卫星稳定型结直肠癌（MSS-CRC）。 CORAL 基于自扩增mRNA（samRNA）的COVID-19疫苗，诱导广泛且持久的中和抗体和T细胞免疫反应。 • CureVac/GSK 季节性流感mRNA疫苗候选该疫苗候选基于CureVac的第二代mRNA平台，针对流感病毒株，包括A型和B型毒株。 COVID-19 mRNA疫苗候选CV0601和CV0701 CV0601为单价疫苗，编码Omicron BA.4/5变异株的刺突蛋白；CV0701为二价疫苗，编码Omicron BA.4/5变异株和原始SARS-CoV-2毒株的刺突蛋白。3.3 III期mRNA资产 • 第一三共 DS-5670a（原始毒株单价疫苗）适应症：Covid-19疫苗，作为加强针用于已完成初始疫苗接种的成人和老年人。 DS-5670a/b（原始毒株与Omicron BA.4/5二价疫苗）适应症：Covid-19疫苗，作为加强针用于12岁及以上已完成初始疫苗接种的人群。 DS-5670d（Omicron XBB.1.5单价疫苗）适应症：Covid-19疫苗，作为季节性加强针用于12岁及以上人群，包括未接种疫苗者。 • 默沙东 mRNA资产：V940（mRNA-4157）类型：肿瘤疫苗（个体化mRNA疫苗）适应症：手术切除后的高风险黑色素瘤患者辅助治疗靶点：个体化新抗原（根据患者肿瘤突变特异设计）3.4上市mRNA资产 • Arcturus Therapeutics mRNA资产：KOSTAIVE（ARCT-154 / Zapomeran）类型：自扩增mRNA（sa-mRNA）疫苗适应症：用于预防COVID-19，适用于18岁及以上人群靶点：SARS-CoV-2病毒刺突蛋白（Spike protein） • BioNTech/辉瑞 Comirnaty 类型：mRNA疫苗适应症：用于预防COVID-19，适用于6个月及以上人群靶点：SARS-CoV-2病毒刺突蛋白（Spike protein）获批时间：✓2020年12月获得FDA紧急使用授权，2021年8月获得美国FDA完全批准 • 莫德纳 Spikevax 类型：mRNA疫苗适应症：用于预防COVID-19，适用于6个月及以上人群靶点：SARS-CoV-2病毒刺突蛋白（Spike protein）获批时间：2020年12月18日，美国FDA授予紧急使用授权；2022年1月31日，获得FDA完全批准Ref. TD Cowen. Pharmaceuticals’ websitesEND【企业推荐】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床2期寡核苷酸上市批准信使RNA临床1期

2025-05-06

·PRNewswire

PTC Therapeutics Provides Corporate Update and Reports First Quarter 2025 Financial Results

– Strong revenue performance of $190 million – – Positive CHMP opinion for Sephience™ (sepiapterin) received in April 2025, NDA review remains on track for July 29, 2025 PDUFA date – – Global Sephience launch activities progressing well – – Strong cash position of over $2.0 billion as of March 31, 2025 – WARREN, N.J., May 6, 2025 /PRNewswire/ -- PTC Therapeutics, Inc., (NASDAQ: PTCT) today announced a corporate update and financial results for the first quarter ended March 31, 2025. "Following a year of outstanding execution across every part of the Company, we have built on this positive momentum with solid revenue performance in the first quarter, allowing us to narrow our full-year revenue guidance," said Matthew B. Klein, M.D., Chief Executive Officer. "Our strong cash balance supports all of our planned commercial and R&D activities and provides the ability to reach cashflow breakeven without raising additional capital. The positive CHMP opinion for Sephience kickstarts our anticipated global launch for what we see as a significant revenue opportunity." Key Corporate Updates: First quarter 2025 total net product and royalty revenue of $190 million. First quarter 2025 revenue for the DMD franchise of $134 million, including net product revenue for Translarna™ of $86 million and for Emflaza® of $48 million. Key Clinical and Regulatory Milestones: Sephience Positive CHMP opinion on Sephience MAA for adult and pediatric PKU patients received on April 25, 2025; the opinion includes a broad label inclusive of all ages and disease severities. PTC expects the EC to adopt the opinion in approximately two months NDA currently under review by the FDA, with a target regulatory action date of July 29, 2025 Japan regulatory submission under review and a decision is expected in Q4 2025 Vatiquinone NDA for pediatric and adult patients with Friedreich's ataxia accepted and granted Priority Review by the FDA, with a target regulatory action date of August 19, 2025 Translarna NDA currently under review by the FDA PTC518 Phase 2 PIVOT-HD study results announced on May 5, 2025: Met primary endpoint of dose-dependent blood HTT lowering at Week 12 Dose-dependent trends of clinical benefit in Stage 2 patients at Month 12 Signals of dose-dependent clinical benefit relative to matched natural history cohort and dose-dependent lowering of NfL in Stage 2 subjects at Month 24 Continued favorable safety and tolerability with no treatment-related NfL spikes Plans to complete additional analyses and discuss next development and regulatory steps, including potential for accelerated approval First Quarter 2025 Financial Highlights: Total net product and royalty revenue was $189.9 million for the first quarter of 2025, compared to $208.8 million for the first quarter of 2024. Total revenue includes net product revenue across the commercial portfolio of $153.4 million for the first quarter of 2025, compared to $177.6 million for the first quarter of 2024. Total revenue also includes royalty, collaboration and license, and manufacturing revenue of $1,022.7 million for the first quarter of 2025, compared to $32.5 million for the first quarter of 2024. The first quarter of 2025 collaboration and license revenue includes $986.2 million, related to the PTC518 license and collaboration agreement with Novartis, which closed in January 2025. Translarna net product revenues were $86.2 million for the first quarter of 2025, compared to $103.6 million for the first quarter of 2024. Emflaza net product revenues were $47.8 million for the first quarter of 2025, compared to $57.5 million for the first quarter of 2024. Roche reported Evrysdi® full year 2025 sales of approximately 420 CHF million, resulting in royalty revenue of $36.4 million to PTC for first quarter 2025, as compared to $31.2 million for first quarter 2024. Based on U.S. GAAP (Generally Accepted Accounting Principles), GAAP R&D expenses were $109.0 million for the first quarter of 2025, compared to $116.1 million for the first quarter of 2024. Non-GAAP R&D expenses were $100.3 million for the first quarter of 2025, excluding $8.7 million in non-cash, stock-based compensation expense, compared to $107.2 million for the first quarter of 2024, excluding $9.0 million in non-cash, stock-based compensation expense. GAAP SG&A expenses were $81.0 million for the first quarter of 2025, compared to $73.3 million for the first quarter of 2024. Non-GAAP SG&A expenses were $71.6 million for the first quarter of 2025, excluding $9.4 million in non-cash, stock-based compensation expense, compared to $63.9 million for the first quarter of 2024, excluding $9.4 million in non-cash, stock-based compensation expense. Net income was $866.6 million for the first quarter of 2025, compared to net loss of $91.6 million for the first quarter of 2024. Cash, cash equivalents, and marketable securities were $2,027.2 million as of March 31, 2025, compared to $1,139.7 million as of December 31, 2024. Shares issued and outstanding as of March 31, 2025 were 79,225,276. PTC Updates Full-Year 2025 Financial Guidance: PTC now anticipates full-year 2025 revenue to be between $650 million and $800 million, which includes in-line products, potential new 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) CHMP: Committee for Medicinal Products for Human Use DMD: Duchenne Muscular Dystrophy EC: European Commission FDA: U.S. Food and Drug Administration GAAP: Generally Accepted Accounting Principles HD: Huntington's Disease HTT: Huntingtin protein MAA: Marketing Authorization Application NDA: New Drug Application NfL: Neurofilament light chain nmDMD: Nonsense mutation Duchenne muscular dystrophy PDUFA: Prescription Drug User Fee Act 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 focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to children and adults living with rare disorders. PTC's ability to globally commercialize products is the foundation that drives investment in a robust and diversified pipeline of transformative medicines and our mission to provide access to best-in-class treatments for patients who have an unmet medical need. The company's strategy is to leverage its strong scientific expertise and global commercial infrastructure to maximize value for its 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 Updates 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," 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 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 Translarna, Emflaza, Upstaza, Kebilidi, Evrysdi, Tegsedi, Waylivra, Sephience 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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临床结果财报引进/卖出申请上市临床2期

100 项与 Inotersen sodium 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10941	-	N07XX15	DB14713

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
淀粉样神经病	加拿大	Akcea Therapeutics, Inc.	2019-01-07
家族性淀粉样神经病	加拿大	Ionis Pharmaceuticals, Inc.	2018-10-03
遗传性转甲状腺素蛋白淀粉样变性	欧盟	Akcea Therapeutics Ireland Ltd.	2018-07-06
遗传性转甲状腺素蛋白淀粉样变性	冰岛	Akcea Therapeutics Ireland Ltd.	2018-07-06
遗传性转甲状腺素蛋白淀粉样变性	列支敦士登	Akcea Therapeutics Ireland Ltd.	2018-07-06
遗传性转甲状腺素蛋白淀粉样变性	挪威	Akcea Therapeutics Ireland Ltd.	2018-07-06
多发性神经病	欧盟	Akcea Therapeutics Ireland Ltd.	2018-07-06
多发性神经病	冰岛	Akcea Therapeutics Ireland Ltd.	2018-07-06
多发性神经病	列支敦士登	Akcea Therapeutics Ireland Ltd.	2018-07-06
多发性神经病	挪威	Akcea Therapeutics Ireland Ltd.	2018-07-06

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
老年性心脏淀粉样变性	临床2期	-	GSK Plc	2016-01-01
老年性心脏淀粉样变性	临床2期	-	Ionis Pharmaceuticals, Inc.	2016-01-01
肿瘤	临床前	瑞典	Immuneed AB	2025-04-30

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04306510 (CTgov)	临床4期	遗传性转甲状腺素蛋白淀粉样变性	8	TEGSEDI	淵鹽夢鹽餘觸蓋憲製簾 = 鏇糧網齋鑰膚衊壓鑰鬱觸艱鹽蓋壓膚鹹艱觸鹹 (遞鑰夢憲窪衊網繭糧糧, 壓選選觸鏇鹹膚膚獵衊 ~ 艱製網鹹衊範觸壓淵選) 更多	-	2025-04-10
NCT02175004 (NEURO-TTR \| OLE, CTgov)	临床3期	家族性淀粉样神经病	135	Inotersen (Previous Placebo-Inotersen 300 mg)	鏇鬱鹹遞繭齋餘齋鹽膚 = 製醖廠簾壓襯觸遞獵膚獵觸遞蓋夢膚鹹壓顧鹽 (願艱構齋鹽醖範製網構, 願構遞網廠壓鹹糧簾鏇 ~ 鏇願製淵糧糧淵壓遞廠) 更多	-	2023-02-09
				Inotersen (Previous Inotersen-Inotersen 300 mg)	鏇鬱鹹遞繭齋餘齋鹽膚 = 遞鏇鑰範網製齋繭觸構獵觸遞蓋夢膚鹹壓顧鹽 (願艱構齋鹽醖範製網構, 鹹獵齋觸鏇獵鹽獵廠鏇 ~ 窪網選製餘餘淵網簾製) 更多
NCT02175004 (OLE, Pubmed \| J Neurol) 人工标引	临床3期	遗传性转甲状腺素蛋白淀粉样变性	109	inotersen (inotersen-inotersen)	製廠鑰窪構願獵齋壓夢(範構窪襯鑰範願夢遞觸) = 醖築網窪壓獵鹽餘鹽齋顧鬱積網淵餘醖艱獵膚 (鬱鏇鹹壓網遞衊鹹衊願 )	积极	2022-07-31
				inotersen (placebo-inotersen)	製廠鑰窪構願獵齋壓夢(範構窪襯鑰範願夢遞觸) = 選觸構醖淵鹹鹽鬱醖觸顧鬱積網淵餘醖艱獵膚 (鬱鏇鹹壓網遞衊鹹衊願 )
NCT01737398 (Pubmed \| Nucleic Acid Ther)	临床2/3期	家族性淀粉样神经病	173	Inotersen	鏇廠製膚簾淵壓鑰網鑰(築蓋願築鬱壓遞鬱鹹構) = 獵鹽糧淵憲構蓋築鹽製選顧醖憲淵鹽簾齋遞醖 (鹽繭壓願鹽醖繭糧廠襯 )	-	2020-10-01
NCT02175004 (OLE, Pubmed \| Eur J Neurol) 人工标引	临床3期	遗传性转甲状腺素蛋白淀粉样变性	135	inotersen (received inotersen in NEURO-TTR)	衊夢構鑰顧壓鏇齋鬱繭(醖構遞繭選餘廠鬱獵範) = 廠構壓鹽廠簾憲範廠範構壓蓋膚夢鏇遞積鹹選 (窪醖積範遞鹽願選襯廠 ) 更多	积极	2020-08-01
				inotersen (received placebo in NEURO-TTR)	衊夢構鑰顧壓鏇齋鬱繭(醖構遞繭選餘廠鬱獵範) = 膚鹽築範遞鹽網獵積襯構壓蓋膚夢鏇遞積鹹選 (窪醖積範遞鹽願選襯廠 ) 更多
NCT02175004 \| NCT01737398 (NEURO-TTR, AAN2020)	临床3期	家族性淀粉样神经病	135	Inotersen	鑰繭廠簾鏇艱壓簾獵範(夢襯廠廠構齋艱鹹壓簾) = 鬱獵網艱廠鏇製簾範膚觸選憲廠壓網築膚蓋憲 (餘鏇鏇顧壓網淵鹽餘選 ) 更多	积极	2020-04-14
				Placebo	鑰繭廠簾鏇艱壓簾獵範(夢襯廠廠構齋艱鹹壓簾) = 鹹窪衊衊淵夢夢獵廠鹹觸選憲廠壓網築膚蓋憲 (餘鏇鏇顧壓網淵鹽餘選 ) 更多
NCT01737398 (NEURO-TTR, CTgov)	临床2/3期	家族性淀粉样神经病	173	Inotersen (Inotersen)	襯網鬱遞窪簾膚鬱夢衊(膚壓廠選網範襯獵糧襯) = 憲壓鬱鏇鹹鑰襯壓繭壓齋餘醖壓觸獵獵鏇獵襯 (鑰膚獵憲壓膚蓋蓋餘網, 15.672) 更多	-	2019-01-23
				Placebo (Placebo)	襯網鬱遞窪簾膚鬱夢衊(膚壓廠選網範襯獵糧襯) = 憲餘遞鬱鏇願窪簾廠選齋餘醖壓觸獵獵鏇獵襯 (鑰膚獵憲壓膚蓋蓋餘網, 24.190) 更多
NCT01737398 (Pubmed \| Br Dent J \| N Engl J Med) 人工标引	临床3期	遗传性转甲状腺素蛋白淀粉样变性	172	Inotersen	醖餘憲蓋築範鑰醖積膚(構窪鹹築衊蓋鹹網齋艱): difference = -11.7 (95% CI, -18.3 ~ -5.1), P-Value = <0.001 更多	积极	2018-07-05
				Placebo