The purpose of this study is to evaluate the long-term safety and efficacy of donidalorsen in people with HAE and the effects of donidalorsen on the number of HAE attacks and their impact on quality of life (QoL).

开始日期2022-07-13

申办/合作机构

Ionis Pharmaceuticals, Inc.

NCT05139810

/ Completed临床3期

A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients With Hereditary Angioedema (HAE)

The purpose of this study is to evaluate the safety and efficacy of donidalorsen in participants with HAE and effect of donidalorsen on the quality and pattern of HAE attacks and their impact on quality of life (QoL).

开始日期2021-12-03

申办/合作机构

Ionis Pharmaceuticals, Inc.

NCT04549922

/ Completed临床2期IIT

Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19: A Phase II Randomized Controlled Trial

Up to 1/3 of all patients infected with COVID-19 can develop complications that require hospitalization. Severe pneumonia associated with acute respiratory distress syndrome (ARDS) is the most threatening and feared complication of COVID-19 infection, with mortality rates close to 50% in some groups.
Autopsies between these severe cases reveal severe capillary involvement, with signs of intense inflammatory changes, microvascular thrombosis, endothelial injury and abnormal tissue repair. The available evidence suggests that abnormal activation or imbalance in the counter-regulation of the kallikrein-kinin system may play a central role in a positive feedback cycle, leading to consequent diffuse microangiopathy. Blockade of the kallikrein-kinin system can therefore prevent deterioration of lung function by reducing inflammation, edema and microthrombosis.
The objective of this phase IIb study is to assess the preliminary effects on the oxygenation parameters of an antisense oligonucleotide that inhibits pre-kallikrein synthesis in patients with moderate to severe COVID-19.

开始日期2020-10-19

申办/合作机构

Hospital do Coração

[+2]

100 项与 Donidalorsen 相关的临床结果

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100 项与 Donidalorsen 相关的转化医学

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100 项与 Donidalorsen 相关的专利（医药）

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项与 Donidalorsen 相关的文献（医药）

2024-12-01·JOURNAL OF CRITICAL CARE

Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial

Article

作者: Buchele, Gustavo ; Gomes, Samara P C ; Santos, Maria Adelaide Dos ; Negrelli, Karina L ; Dal-Pizzol, Felipe ; Falavigna, Maicon ; de Freitas, Flávio Geraldo ; Miranda, Tamiris A ; Germano, Almir ; Gebara, Otávio ; Rosa, Regis G ; Santucci, Eliana Vieira ; Santos, Renato H N ; Zampieri, Fernando G ; Gomes, Jackeline O ; Valeis, Nanci ; Ishihara, Luciana M ; Azevedo, Luciano C P ; Cavalcanti, Alexandre B ; Berti, Isabele Ribeiro ; Machado, Flávia R ; Schettini, Daniel Almeida ; Westphal, Glauco Adrieno ; Janiszewski, Mariano ; Cohn, Danny M ; de Matos Soeiro, Alexandre ; Laranjeira, Ligia N ; Veiga, Viviane C ; de Souza Dantas, Vicente Cés ; Damiani, Lucas P

PURPOSE:

To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients.

MATERIAL AND METHODS:

Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life.

RESULTS:

From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference - 0.65, 95% confidence intervals from -2.95 to 1.36, p = 0.520).

CONCLUSION:

Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020.

CLINICALTRIALS:

GOV IDENTIFIER:

NCT04549922.

2024-07-04·NEW ENGLAND JOURNAL OF MEDICINE

Efficacy and Safety of Donidalorsen for Hereditary Angioedema

Article

作者: Tachdjian, Raffi ; Wang, Sophie ; Manning, Michael E ; Treadwell, Sabrina ; Reshef, Avner ; Lumry, William R ; Craig, Timothy ; Newman, Kenneth B ; Stobiecki, Marcin ; Yarlas, Aaron ; Gelincik, Asli ; Bordone, Laura ; Riedl, Marc A ; Cohn, Danny M ; Jacobs, Joshua S ; Gokmen, Nihal M ; Karakaya, Gül ; Gompels, Mark M

BACKGROUND:

Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression.

METHODS:

In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25.

RESULTS:

A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity.

CONCLUSIONS:

Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).

2024-04-01·The journal of allergy and clinical immunology. In practice

Clinical Progress in Hepatic Targeting for Novel Prophylactic Therapies in Hereditary Angioedema

Article

作者: Riedl, Marc A ; Newman, Kenneth B ; Bordone, Laura ; Revenko, Alexey ; Cohn, Danny M

Hereditary angioedema (HAE) is typically caused by a deficiency of the protease inhibitor C1 inhibitor (C1INH). The absence of C1INH activity on plasma kallikrein and factor XIIa leads to overproduction of the vasoactive peptide bradykinin, with resulting angioedema. As the primary site of C1INH and prekallikrein production, the liver is recognized as an important therapeutic target in HAE, leading to the development of hepatic-focused treatment strategies such as GalNAc-conjugated antisense technology and gene modification. This report reviews currently available data on hepatic-focused interventions for HAE that have advanced into human trials. Donidalorsen is an investigational GalNAc₃-conjugated antisense oligonucleotide that binds to prekallikrein mRNA in the liver and reduces the expression of prekallikrein. Phase 2 data with subcutaneous donidalorsen demonstrated a significant reduction in HAE attack rate compared with placebo. Phase 3 trials are underway. ADX-324 is a GalNAc₃-conjugated short-interfering RNA being investigated in HAE. BMN 331 is an investigational AAV5-based gene therapy vector that expresses wild-type human C1INH and is targeted to hepatocytes. A single intravenous dose of BMN 331 is intended to replace the defective SERPING1 gene and enable patients to produce functional C1INH. A first-in-human phase 1/2 study is ongoing with BMN 331. NTLA-2002 is an investigational in vivo clustered regularly interspaced short palindromic repeats/Cas9-based therapy designed to knock out the prekallikrein-coding KLKB1 gene in hepatocytes; a phase 1/2 study is ongoing. Findings from these and other ongoing studies are highly anticipated with the expectation of expanding the array of treatment options in HAE.

项与 Donidalorsen 相关的新闻（医药）

2025-01-20

·药明康德

官宣！FDA正式发布2024年新药年度报告（附全文链接）

▎药明康德内容团队编辑近日，美国FDA药物评价和研究中心（CDER）发布了2024年度的新药获批报告。FDA旗下CDER在2024年共计批准50款创新疗法，超过过去10年的平均水平（47款）。其中，用于治疗罕见疾病和罕见癌症的新药占比超过50%，展现了FDA致力于解决罕见病相关未竟医疗需求方面的努力。在今天的文章中，药明康德内容团队将结合公开资料，回顾2024年FDA批准疗法的亮点，并展望2025年有望获批的潜在“first-in-class”疗法。 ▲2015-2024年CDER批准的创新药物数量（图片来源：参考资料[1]）从创新角度来看，CDER在2024年批准的50款新药中，24款被认定为“first-in-class”新药。这些新药采用了与已有疗法不同的作用机制。FDA的报告中着重介绍了下面几款“first-in-class”创新药物。 Anktiva（nogapendekin alfa inbakicept）是一款白细胞介素-15（IL-15）超级激动剂。它获得批准与卡介苗（BCG）联合使用，用于治疗对BCG无应答且伴有原位癌（CIS）的非肌层浸润性膀胱癌（NMIBC）成年患者，这些患者伴或不伴有乳头状肿瘤。在2/3期临床试验中，接受治疗的患者完全缓解率达62%。 Cobenfy（xanomeline和trospium chloride）获得FDA批准治疗精神分裂症成人患者。它是靶向胆碱能受体的首个抗精神病药物（antipsychotic drug），长期以来精神分裂症的标准疗法靶向多巴胺受体。该疗法也标志着过去数十年来首个治疗精神分裂症的新机制药物。 Nemluvio（nemolizumab）是一款靶向白介素-31（IL-31）受体的单克隆抗体，获得FDA批准用于成人结节性痒疹（prurigo nodularis）患者。它是首款获得FDA批准用以抑制IL-31信号的单克隆抗体。 Revuforj（revumenib）是一种针对menin-KMT2A相互作用的强效、选择性小分子抑制剂。它获得FDA批准治疗携带KMT2A易位的复发或难治性（R/R）急性白血病成人和1岁以上儿童患者。Revuforj是首款获批的menin抑制剂。 Rezdiffra（resmetirom）是一款每日一次、口服甲状腺激素受体（THR）-β选择性激动剂，获得FDA加速批准治疗患有中重度肝纤维化（F2至F3期）的非肝硬化非酒精性脂肪性肝炎（NASH）/代谢功能障碍相关脂肪性肝炎（MASH）成人患者。这是获得FDA批准的首款NASH疗法，标志着该领域的一项重要里程碑。 Tryvio（aprocitentan）是一款靶向双重内皮素（endothelin）受体的口服拮抗剂。它获得批准与其他抗高血压药物联合，用以治疗使用其他药物无法充分控制血压的成年高血压患者。这款药物是30年来首个获批基于新机制的降血压药物。 FDA加速罕见病药物的开发与审评 2024年，CDER批准的50款新药中有26款（52%）获得孤儿药资格，这些药物专门针对罕见疾病——即患者总数不足20万人的疾病。对于这些罕见疾病患者来说，他们通常面临着极其有限或完全缺乏有效治疗选择的困境。 ▲2024年CDER批准的获得孤儿药资格的罕见病疗法（数据来源：公开资料，药明康德内容团队制图） FDA采用多种方式促进和加快新药审评在2024年，CDER采用了多种监管策略来加快药品的审评流程。在2024年获批的50款新药中，有22款（44%）获得快速通道资格，18款（36%）获得突破性疗法认定，28款（56%）获得优先审评资格（不包括使用优先审评券递交监管申请的药物），7款药物（14%）获得加速批准，33种新药（66%）使用了一个或多个加快审评过程的资格认定。加速批准旨在以比传统审评路径更快的速度，推动解决未满足医疗需求的某些药物上市。对于符合加速批准路径的药物，其安全性和有效性评估将不基于直接临床获益的指标，而是基于可能预测临床获益的替代终点或中间临床终点。2024年，CDER利用这一渠道批准了7款创新药。 ▲2024年CDER加速批准的创新药（数据来源：公开资料，药明康德内容团队制图） 2025年，哪些潜在“first-in-class”疗法值得期待？疗法：Donidalorsen 公司：Ionis Pharmaceuticals 目标适应症：遗传性血管性水肿 Donidalorsen是一款反义寡核苷酸配体偶联（LICA）药物，旨在精确沉默前激肽释放酶（PKK）的表达，中断导致遗传性血管性水肿（HAE）发作的信号通路。在3期临床试验OASIS-HAE中，接受每四周一次donidalorsen（80毫克）治疗的患者与安慰剂相比，在第1至第25周内将患者月均HAE发作率降低81%（p<0.001）。疗法：Fitusiran 公司：赛诺菲，Alnylam Pharmaceuticals 目标适应症：血友病A和血友病B Fitusiran是一款RNAi疗法，旨在作为体内产生/未产生凝血因子抑制物的血友病A或血友病B患者的预防性治疗。Fitusiran可降低抗凝血酶水平，从而促进凝血酶生成，重新平衡止血功能并预防出血。在两项3期临床研究中，与对照组相比，每月一次皮下注射fitusiran预防治疗组患者的年化出血率降低了90%。疗法：Mirdametinib 公司：SpringWorks Therapeutics 目标适应症：神经纤维瘤病1型相关的丛状神经纤维瘤 Mirdametinib是一种口服别构小分子MEK抑制剂，靶向MEK1和MEK2。美国FDA已接受SpringWorks递交的新药申请并授予其优先审评资格。关键性2b期临床试验ReNeu数据显示，接受mirdametinib治疗的儿童患者客观缓解率为52%，成人患者为41%。ReNeu试验中的儿童和成人患者的疼痛、生活质量和身体功能较基线有统计学上显著的改善。疗法：Plozasiran 公司：Arrowhead Pharmaceuticals 目标适应症：家族性乳糜微粒血症综合征 Plozasiran是一款靶向APOC3基因的潜在“first-in-class”RNAi疗法。APOC3是富含甘油三酯脂蛋白（TRL）的组成部分，也是甘油三酯代谢的关键调节因子。APOC3通过抑制脂蛋白脂肪酶分解TRL以及肝脏受体吸收TRL残留物来增加血液中的甘油三酯水平。Plozasiran治疗目标是通过下调APOC3降低甘油三酯水平。Arrowhead Pharmaceuticals日前宣布，FDA已接受为plozasiran递交的新药申请，用于治疗家族性乳糜微粒血症综合征。疗法：Suzetrigine 公司：Vertex Pharmaceuticals 目标适应症：中重度急性疼痛 Suzetrigine是一种口服选择性NaV1.8抑制剂，与其它NaV离子通道相比，它对NaV1.8具有高度选择性。NaV1.8是在外周神经系统的痛觉信号传导中起到关键性作用的电压门控钠通道。它是经过遗传学验证的疼痛治疗靶点。Vertex的策略是通过选择性抑制NaV1.8，开发新的药物类型。与阿片类药物相比，它们可能在提供更好镇痛效果的同时，避免上瘾等副作用。2024年7月，美国FDA接受了Vertex为该疗法递交的NDA，并授予其优先审评资格，预计在2025年1月30日之前完成审评。疗法：Telisotuzumab vedotin 公司：艾伯维目标适应症：c-Met蛋白过度表达的经治局部晚期或转移性非鳞状非小细胞肺癌（NSCLC） Telisotuzumab vedotin是一款靶向c-Met的抗体偶联药物，以微管蛋白抑制剂MMAE作为毒性有效载荷。艾伯维已经向美国FDA提交了telisotuzumab vedotin的生物制品许可申请，寻求加速批准，用于治疗c-Met蛋白过度表达的经治局部晚期或转移性非鳞状NSCLC成人患者，这些患者肿瘤的表皮生长因子受体（EGFR）为野生型。此前公布的2期临床试验数据显示，肿瘤c-Met高度表达和中度表达患者的总缓解率分别为35%和23%。疗法：UGN-102 公司：UroGen Pharma 目标适应症：低级别中等风险非肌层浸润性膀胱癌 UGN-102膀胱灌注液是一种创新的丝裂霉素（mitomycin）药物。该疗法利用UroGen专有的RTGel技术，这种基于水凝胶的持续释放制剂可使膀胱组织能够更长时间地暴露于丝裂霉素之下，从而通过非手术手段治疗肿瘤。在3期临床试验中，接受UGN-102治疗患者在首次灌注后三个月的完全缓解率为79.6%（95% CI：73.9-84.5）。FDA预计在今年6月13日之前公布审评结果。疗法：UX111 公司：Ultragenyx Pharmaceutical 目标适应症：IIIA型黏多糖贮积症 UX111是一种用于治疗IIIA型黏多糖贮积症的新型体内基因疗法。它旨在通过一次性静脉输注完成给药，使用AAV9载体将表达N-磺基葡萄糖胺磺基水解酶（SGSH）的转基因递送至细胞中。Ultragenyx Pharmaceutical公司已向美国FDA提交了生物制品许可申请，寻求加速批准UX111。关键性Transpher A研究的数据显示，接受UX111治疗后，患者脑脊液中的硫酸乙酰肝素（HS）水平迅速且持续降低，且这一生物标志物的持续降低与长期认知发育的改善相关。除了上述内容，CDER的报告还详细概述了2024年关于新药批准的PDUFA目标日期的准时达成情况、药物适用范围的扩展批准，以及对生物类似药的审评情况。欲了解更多详情，可点击文末“阅读全文/Read more”下载报告全文。展望2025年，我们期待更多创新疗法的批准，为全球患者带来新的治疗选择。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] Advancing Health Through Innovation: New Drug Therapy Approvals 2024. Retrieved January 20, 2025, from https://www.fda.gov/media/184967/download?attachment [2] Ten first-in-class drugs on track for FDA approval in 2025. Retrieved January 20, 2025, from https://www.labiotech.eu/best-biotech/first-in-class-drugs-to-watch-2025/ 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

加速审批

2025-01-17

·同写意

2025：10款有望获批的FIC药物

First-in-class（FIC）药物是一类采用全新作用机制、攻克疑难病症的疗法。2024年，FDA共批准了50种新分子实体，其中24种被认定为FIC。例如，Cobenfy是近三十年来获批的首款新型精神分裂症药物，由Karuna Therapeutics研发，后被BMS收购，通过毒蕈碱受体作用于胆碱能系统，区别于传统的基于多巴胺的治疗方法。另一个例子是Rezdiffra——首个获批用于治疗MASH的疗法。展望2025年，多款FIC疗法有望问世。 Labiotech预测了2025年即将获批的10款FIC药物，写意君据此进行了整理。 1 Donidalorsen 研发公司：Ionis Pharmaceuticals 适应症：遗传性血管性水肿（HAE）技术：反义寡核苷酸 HAE是一种罕见的遗传性疾病，会导致身体各个部位反复出现严重肿胀（血管性水肿）。这些发作难以预测，伴有疼痛，如果影响到气道则可能会危及生命。 Donidalorsen采用的技术为反义寡核苷酸，通过特异性地靶向并降解肝细胞中负责生成激肽释放酶原（PKK）的mRNA，降低PKK水平，从而减少HAE发作的频率和严重程度。相比当前HAE的治疗方法（如C1酯酶抑制剂、激肽释放酶抑制剂等），Donidalorsen可以降低用药频率提供更持久保护，且副作用可能更少，患者依从性更高。在临床研究中，Donidalorsen在为期两年的治疗期间，持续且稳定地为患者提供了防护。 2024年11月，FDA已受理Donidalorsen的NDA，PDUFA日期定为 2025年8月21日。 2 Fitusiran 研发公司：赛诺菲/Alnylam 适应症：A型和B型血友病技术：siRNA Fitusiran是一款靶向抗凝血酶的siRNA，通过与表达抗凝血酶的RNA相结合，降低抗凝血酶的产生，从而恢复凝血因子和抗凝血因子之间的平衡，达到降低血友病患者出血事件的作用。这款创新疗法只需每个月皮下注射一次，与常规预防性凝血因子注射相比，为患者控制出血风险提供了很多便利。由于安全性原因，Fitusiran曾多次被搁置：2017年开展II期研究中，一名A型血友病患者死于血栓事件或血栓，FDA停止了Fitusiran的研发。2022年11月，由于在临床试验中发现了新的副作用，赛诺菲在“发现新的不良事件”后主动搁置全球研究，但尚未公布不良事件的细节。直到2023年2月，全球研究继续。 III期临床研究显示：Fitusiran皆表现出良好的活性，并展示了具有统计学意义的针对出血减少疗效。结果皆显示，使用Fitusiran的亚组中位年出血率为0。传统的血友病治疗方法包括定期静脉输注凝血因子浓缩物，以补充缺失或不足的凝血因子。由于给药频率高，且可能会产生使因子替代治疗效果降低的抑制剂，这些治疗方法可能会给患者带来负担。 3 Ivonescimab 研发公司：康方生物/Summit Therapeutics 适应症：肿瘤学技术：双特异性抗体康方和Summit在全球开展的临床研究，覆盖一线二线NSCLC、胰腺癌、乳腺癌、卵巢癌等。Ivonescimab是一种人源化双特异性抗体，同时靶向PD-1和VEGF。 PD-1和VEGF的双重作用机制同时增强了抗肿瘤免疫力，并抑制肿瘤血管生成。传统的癌症疗法通常只针对单一路径，由于肿瘤生物学的复杂性，这可能会限制其疗效。与仅抑制PD-1或VEGF单一途径的疗法相比，Ivonescimab有可能产生更强的抗肿瘤效果。在临床研究中，Ivonescimab在晚期实体瘤患者中显示出有前景的抗肿瘤活性，且安全性可控，该产品已在中国获批。根据2025年JPM大会上披露的信息，Ivonescimab完成了全球III期的入组。 HARMONi-2研究结果显示，中位PFS方面Ivonescimab比K药提高5.3个月，进展和死亡风险降低49%；Ivonescimab鳞状和非鳞状的NSCLC和K药对比均获益，进展或死亡风险降低50%左右。安全性方面，Ivonescimab严重的TRAE略高于K药，总体安全可控。 4 Mirdametinib 研发公司：SpringWorks Therapeutics 适应症：1型神经纤维瘤病相关丛状神经纤维瘤（NF1-PN）技术：选择性抑制剂丛状神经纤维瘤（PNs）是一种特定类型的肿瘤，发生在患有1型神经纤维瘤病的患者身上。它们沿着周围神经生长，由异常神经组织和结缔组织构成的复杂网络组成。尽管它们是非癌性的，但可能会大量生长并引发严重的并发症。 Mirdametinib是一种口服变构小分子MEK抑制剂，主要作用于 MEK1和MEK2，这两种蛋白在MAPK信号通路中占据关键位置。MAPK通路是一个关键的信号网络，调节细胞生长和存活，当该通路失调时，在多种癌症和罕见疾病中起着核心作用。Mirdametinib通过抑制MEK1和MEK2，阻断MAPK通路的过度激活，从而抑制肿瘤细胞的生长和增殖。 FDA和EC均授予mirdametinib治疗NF1的孤儿药资格。此外，FDA还授予了该药物快速通道资格，用于治疗2岁及以上的NF1-PN患者。2024年，该公司已向FDA递交了NDA，并且已被受理，且提供了优先审查的资格，预计的审批日期为2025年2月28日。 5 Plozasiran 研发公司：Arrowhead Pharmaceuticals 适应症：严重高甘油三酯血症（SHTG）和家族性乳糜微粒血症综合征（FCS）技术：RNAi Plozasiran是一种靶向载脂蛋白C-III（apoC-III）的RNAi疗法。ApoC-III是一种在肝脏中产生的蛋白质，会抑制脂蛋白脂肪酶的活性，从而影响甘油三酯的代谢。Plozasiran通过RNA干扰机制，特异性地降低肝脏中apoC-III的表达，从而增强脂蛋白脂肪酶的活性，促进甘油三酯的分解代谢，降低血液中甘油三酯的水平。 Plozasiran在III期试验中达到了主要终点和所有关键次要终点。25毫克和50毫克剂量在10个月内分别实现了80%和78%的甘油三酯中位数降低，而安慰剂组的降低率为17%。此外，接受Plozasiran治疗的患者发展为急性胰腺炎的风险比安慰剂组降低了83%，并显示出良好的安全性。目前针对SHTG和FCS的治疗选择有限，通常包括饮食限制和降脂药物，但这些可能无法充分控制甘油三酯水平。 6 RGX-121 研发公司：Regenxbio 适应症：II型粘多糖贮积症（MPS II）——亨特（Hunter）综合征技术：基因疗法 RGX-121是一种针对II型粘多糖贮积症（MPS II，也称为亨特综合征）的基因疗法，通过使用AAV9递送健康的基因拷贝，帮助患者改善发育迟缓、骨骼异常等症状。2024年2月，Regenxbio宣布RGX-121在关键试验中表现优异，显著降低了疾病标志物的水平，并改善了患者的神经发育。在正在进行的CAMPSIITE试验中，RGX-121已显示出有前景的结果。值得注意的是，接受关键剂量水平RGX-121治疗的患者，其脑脊液（CSF）中的硫酸乙酰肝素（HS）D2S6（一种脑疾病活动的关键生物标志物）水平中位数降低了85%，接近正常水平，并可持续长达两年。 1月14日，Regenxbio和Nippon Shinyaku（日本新药株式会社）宣布建立战略合作伙伴关系，开发和商业化RGX-121治疗MPS II。 Regenxbio已与FDA完成了BLA前的会议，为RGX-121的加速审批途径提供了支持。这可能意味着该首创药物有望在2025年获得FDA批准，成为首个获批用于治疗MPS II的基因疗法。 7 Suzetrigine 研发公司：Vertex Pharmaceuticals 适应症：中重度急性疼痛和周围神经性疼痛技术：非阿片类镇痛药 Suzetrigine是一种口服高选择性Nav1.8疼痛信号抑制剂，可作为周围神经系统中Nav1.8依赖性疼痛信号通路的选择性抑制剂。Nav1.8是一种主要表达于伤害感受神经元上的河豚毒素不敏感型钠通道，在外周神经系统的痛觉信号传导中起着关键性作用，该药物通过抑制Nav1.8通道，阻止疼痛信号的传递，从而发挥镇痛作用。 Vertex对Suzetrigine开展了两项II期研究和三项III期研究，包括NAVIGATE1和NAVIGATE2试验，这些试验分别研究了该候选药物对接受过拇囊炎切除术和腹部整形术的患者的镇痛效果。结果表明，Suzetrigine单一疗法可将腹部整形术后的疼痛评分改善48.4分，在接受拇囊炎切除术的患者中，suzetrigine使疼痛评分降低了29.3分，与安慰剂相比，两项试验治疗效果均具有统计学显著性。疼痛治疗通常依赖阿片类药物，而阿片类药物存在成瘾和其他不良反应的风险。如果Suzetrigine在2025年获批，将可能为疼痛管理提供一种非阿片类替代方案。 2024年7月30日，FDA已接受Suzetrigine的NDA，并授予其优先审查权，PDUFA日期为2025年1月30日。 8 Telisotuzumab vedotin 研发公司：艾伯维适应症：c-met蛋白过表达的NSCLC 技术：ADC Telisotuzumab vedotin（ABBV-399）是艾伯维开发的一款靶向c-Met的ADC产品，主要用于治疗NSCLC。 Teliso-V由人源化单克隆抗体ABT-700与单甲基澳瑞他汀E（MMAE）通过缬氨酸-瓜氨酸连接剂相连而成。它以特异性和高亲和力结合靶向表达c-Met的肿瘤细胞，并介导MMAE直接递送至肿瘤细胞。Teliso-V与c-Met的结合导致ADC的内化和连接子蛋白水解后MMAE的细胞内释放，然后MMAE与微管蛋白结合，从而抑制有丝分裂并导致肿瘤细胞死亡。目前，尚无专门针对NSCLC中c-Met过表达的获批疗法。Telisotuzumab vedotin通过将细胞毒素直接递送至表达c-Met的肿瘤细胞，有望提高疗效，同时将对正常组织的损害降至最低。 2024年9月，艾伯维向FDA提交了Telisotuzumab vedotin用于既往治疗过的NSCLC的BLA。同年，CDE也正式将其纳入突破性治疗品种名单。 9 UGN-102 研发公司：UroGen Pharma 适应症：低级别中危非肌肉浸润性膀胱癌（LG-IR-NMIBC）技术：水凝胶基制剂 UGN-102是一种新型丝裂霉素药物，用于治疗低级别中等风险非肌层浸润性膀胱癌（LG-IR-NMIBC）。该产品采用了UroGen的专利技术RTGel®，这是一种缓释水凝胶，能够延长膀胱组织与丝裂霉素的接触时间，从而实现非手术治疗肿瘤的效果。这种制剂在较低温度下以液体形式直接注入膀胱。当在膀胱内达到体温时，它会转变为凝胶，使丝裂霉素与膀胱内壁能够长时间接触。这种延长的接触时间增强了药物有效消融癌细胞的能力。目前，LG-IR-NMIBC的标准治疗方法包括经尿道膀胱肿瘤切除术（TURBT），然而，TURBT存在出血、感染等风险，且复发率较高。UGN-102提供了一种非手术替代方案，可以在门诊进行给药，有可能减少重复手术的需求。在III期试验中，UGN-102首次使用三个月后的完全缓解率为79.6%。在达到完全缓解的患者中，82.3%的患者在12个月时仍维持缓解，表明其疗效持久。此外，试验表明，与单独使用TURBT相比，UGN-102无论是否联合TURBT，都能使复发、进展或死亡风险降低55%。如果在2025年获批，这款产品将成为FDA批准的首个用于LG-IR-NMIBC的非手术治疗方法。 10 UX111 研发公司：Ultragenyx Pharmaceuticals 适应症：A型Sanfilippo综合征（MPS IIIA）技术：基因疗法 A型Sanfilippo综合征，又称为IIIA型黏多糖贮积症（MPS IIIA），是一种常染色体隐性遗传病，由编码N-磺基葡萄糖胺磺基水解酶（SGSH）的基因发生突变所引起。SGSH酶可分解并回收HS，后者调控着一系列重要的生理过程，但是当编码SGSH的基因发生突变而导致酶失活时，HS会在器官中积聚并破坏器官的正常功能，特别是造成中枢神经系统的功能损伤，患者可能出现发育迟缓、行为障碍、癫痫发作等认知或生理异常状况。 UX111是一种用于治疗MPS IIIA的新型体内基因疗法，旨在通过一次性静脉输注完成给药，使用AAV9载体将功能性SGSH基因递送至细胞中。该疗法的设计目的是解决SGSH酶缺乏这一根本问题，该缺陷会导致脑内糖胺聚糖（如硫酸乙酰肝素）的异常积累，从而引发进行性细胞损伤和神经退行性病变。数据显示，接受UX111治疗后，患者的CSF HS水平迅速且持续降低，且CSF HS的持续降低与长期认知发育的改善相关，相较于自然病程数据中观察到的认知能力下降，治疗效果显著。迄今为止，最常见的治疗相关不良事件是肝酶升高，其中大多数事件为轻度（1级）或中度（2级）且均已恢复。 2024年12月，Ultragenyx Pharmaceutical宣布已向FDA提交了BLA，寻求加速批准其AAV基因疗法UX111，用于治疗MPS IIIA患者。FDA已同意将脑脊液中的硫酸乙酰肝素作为评估该疗法疗效的替代终点。 — 结语 — 根据Citeline旗下Biomedtracker预测，2025年FDA预计将批准近70种药物、新增适应症。在这70个潜在候选药物中，抗肿瘤产品一如既往地是占比最大的疾病领域。 FDA曾在2019年表示，到2025年，每年会批准10-20种CGT产品。如果说抗肿瘤是FDA批准药物的首要疾病领域，那么CGT在技术方面肯定处于领先地位。肥胖是过去几年一直备受关注的另一个重要话题，2025年仍将如此。如果几个月前撰写这篇文章，诺和诺德的肥胖药物CagriSema很可能会成为榜单上的有力候选药物。然而，临床试验结果令人失望，甚至导致该公司市值下跌1250亿美元。2025年对于CagriSema来说，似乎更多的会是开展新试验而非获批，也许2026年才是它的机会之年。随着2025年的推进，行业将密切关注这些FIC候选药物是否能发挥其潜力。对于患有像MPS II这类罕见疾病的患者，或者面临像NSCLC这样侵袭性癌症的患者来说，这些FIC疗法带来了更多希望，在某些情况下，甚至会成为首选。参考文章： 1、Ten first-in-class drugs on track for FDA approval in 2025；Labiotech 2、药明康德公众号同写意媒体矩阵，欢迎关注↓↓↓

siRNA并购临床结果临床2期引进/卖出

2025-01-13

·PRNewswire

Ionis enters new chapter in 2025 as commercial-stage biotech with multiple independent product launches anticipated and continued late-stage pipeline momentum

– Accelerating value creation with numerous commercial, regulatory and pipeline milestones – – Ionis outlines clear path to sustained positive cash flow – CARLSBAD, Calif., Jan. 13, 2025 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced highlights from the Company's 2024 achievements and previewed important milestones expected in 2025. Ionis will provide a business update at the 42nd Annual J.P. Morgan Healthcare Conference on Wednesday, January 15 at 10:30am PT; the presentation is available today on the Ionis website. "With last month's U.S. approval and launch of TRYNGOLZA™ (olezarsen) as the first-ever therapy for familial chylomicronemia syndrome and the potential approval of donidalorsen in hereditary angioedema later this year, Ionis has entered a new chapter as a fully integrated commercial-stage biotechnology company that independently brings our innovative medicines to patients," said Brett P. Monia, Ph.D., chief executive officer, Ionis. "TRYNGOLZA is the first of four independent Ionis product launches anticipated over the next three years. We also expect four key launches from important partnered programs within this timeframe. Collectively, these medicines stand to help millions of patients with serious diseases and create substantial value for all our stakeholders. To that end, we expect increasing product and royalty revenue to enable Ionis to achieve our goal of being cash flow positive." 2025 Anticipated Highlights Include: Launch TRYNGOLZA, Ionis' first independent product and the first-ever therapy for U.S. patients with familial chylomicronemia syndrome (FCS): U.S. Food and Drug Administration (FDA) Approval for FCS on December 19, 2024 Potential European Medicines Agency (EMA) approval for FCS Phase 3 results and U.S. regulatory submission for olezarsen in severe hypertriglyceridemia, a large patient population with high unmet need Phase 3 topline data for CORE, CORE 2 and ESSENCE Phase 3 trials expected in second half of 2025 Potential approval of donidalorsen, a first-in-class RNA-targeted medicine for hereditary angioedema and Ionis' second anticipated independent launch: U.S. FDA action date of August 21, 2025 U.S. commercial field team scale-up and launch Continue progress with WAINUA™ (eplontersen), Ionis' first U.S. co-commercialized medicine in collaboration with AstraZeneca: Continued positive performance in U.S. launch for polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) OUS approvals for ATTRv-PN Continuing the fully enrolled, landmark CARDIO-TTRansform trial in ATTR cardiomyopathy, with data expected in the second half of 2026 Advance the next wave of wholly owned medicines for serious neurological diseases, including seven clinical-stage therapies: Phase 3 trial start in first half of 2025 for ION582 for Angelman syndrome Phase 3 data for zilganersen in Alexander disease, a rare leukodystrophy with no approved disease-modifying therapies Phase 2 data for ION464 (SNCA) in multiple system atrophy Continue momentum with key partnered programs, including: Phase 3 data for pelacarsen, a potentially groundbreaking medicine for Lp(a)-driven cardiovascular disease (Novartis) Continue advancing next-generation technologies for RNA-targeted medicines Achieve clinical proof of concept for Mesyl Phosphoramidate (MsPA) backbone and siRNA platforms Advance first Bicycle-siRNA into clinical development Select first clinical candidate engineered to cross the blood brain barrier INDICATION for TRYNGOLZA™ (olezarsen) TRYNGOLZA™ (olezarsen) was approved by the U.S. Food and Drug Administration as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to TRYNGOLZA or any of the excipients in TRYNGOLZA. Hypersensitivity reactions requiring medical treatment have occurred. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills and myalgias) have been reported in patients treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. ADVERSE REACTIONS The most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count and arthralgia. Please see full Prescribing Information for TRYNGOLZA. INDICATION for WAINUA™ (eplontersen) WAINUA injection, for subcutaneous use, 45 mg is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. IMPORTANT SAFETY INFORMATION for WAINUA™ (eplontersen) WARNINGS AND PRECAUTIONS Reduced Serum Vitamin A Levels and Recommended Supplementation WAINUA leads to a decrease in serum vitamin A levels. Supplement with recommended daily allowance of vitamin A. Refer patient to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. ADVERSE REACTIONS Most common adverse reactions (≥9% in WAINUA-treated patients) were vitamin A decreased (15%) and vomiting (9%). Please see U.S. Full Prescribing Information for WAINUA. About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has six marketed medicines and a leading pipeline in neurology, cardiology, and other areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit Ionis.com and follow us on X (Twitter), LinkedIn and Instagram. Ionis Forward-Looking Statements This press release includes forward-looking statements regarding Ionis' business and the therapeutic and commercial potential of TRYNGOLZA, Ionis' technologies and other products in development. Any statement describing Ionis' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including but not limited to those related to our commercial products and the medicines in our pipeline, and particularly those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended Dec. 31, 2023, and most recent Form 10-Q, which are on file with the SEC. Copies of these and other documents are available at . Ionis Pharmaceuticals® and TRYNGOLZA™ are trademarks of Ionis Pharmaceuticals, Inc. WAINUA™ is a registered trademark of the AstraZeneca plc. Ionis Investor Contact: D. Wade Walke, Ph.D. [email protected] 760-603-2331 Ionis Media Contact: Hayley Soffer [email protected] 760-603-4679 SOURCE Ionis Pharmaceuticals, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

上市批准临床3期

100 项与 Donidalorsen 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
遗传性血管性水肿	申请上市	美国	Ionis Pharmaceuticals, Inc.	2024-11-04

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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


NCT04307381 (Corporate Publications) 人工标引	临床2期	遗传性血管性水肿	17	DonidalorsenDonidalorsen 80 mg SC Q4W	窪製艱繭衊衊遞顧鏇網(獵簾鬱構鹹鬱觸窪窪顧) = 獵鏇鹹淵鏇積願遞廠鏇襯製顧壓艱衊築製簾獵 (衊選衊窪積窪壓顧簾憲, 7.81)	积极	2024-10-30
				Donidalorsen 80 mg SC Q8WDonidalorsen 80 mg SC Q8W	衊選醖選獵廠網壓選淵(簾製築齋壓製願壓顧鏇) = 鏇鹽遞衊鹽鏇構繭觸襯醖鹹願壓築膚選鬱淵選 (鑰齋廠網醖憲壓餘糧觸 ) 更多
NCT04307381 (Phase 2 OPEN-LABEL EXTENSION OF DONIDALORSEN, ACAAI2024)	临床2期	遗传性血管性水肿 plasma prekallikrein	17	Donidalorsen 80 mg Q4W	窪蓋願衊鏇憲醖窪醖淵(積廠鹹顧壓遞遞鏇構積) = 艱窪積鹹簾壓獵鬱選觸衊糧築膚顧鬱觸夢獵積 (觸簾夢淵願醖觸積膚艱, 0.02 ~ 0.09) 更多	积极	2024-10-24
				Donidalorsen 80 mg Q8W	顧齋廠網鏇觸夢顧構選(鏇蓋淵選襯範鏇襯淵鹽) = 壓獵網窪獵鬱膚願蓋蓋觸築壓鹹衊鏇簾鹹壓憲 (醖鏇艱鹹鏇願鏇膚夢夢 )
NCT05392114 (OASISplus, ACAAI2024)	临床3期	遗传性血管性水肿 kallikrein-kinin system dysregulation	83	Donidalorsen 80 mg Q4W	鏇網膚醖繭構願顧築窪(築醖觸憲艱糧醖觸鹽醖) = Patients previously on placebo also reported improvements in AE-QoL total scores (24 points from OASIS-HAE baseline) 範鬱鹹壓憲構製窪願糧 (齋簾蓋鑰鑰鑰窪廠顧範 ) 更多	积极	2024-10-24
				Donidalorsen 80 mg Q8W
NCT05392114 (OASISplus, ACAAI2024)	临床3期	遗传性血管性水肿 kallikrein-kinin system dysregulation	64	Donidalorsen 80 mg every-4-weeks	繭築築窪齋齋窪簾醖簾(膚構繭淵餘顧餘鹽鏇遞) = The percentage of patients with well-controlled symptoms (AECT ≥10) increased from 67% (baseline) to 93% (Week 17) 壓觸繭餘鹽艱鬱齋範顧 (夢鑰鬱淵構鏇網簾醖築 ) 更多	积极	2024-10-24
NCT05139810 (OASIS-HAE, Pubmed) 人工标引	临床3期	遗传性血管性水肿	90	Donidalorsen 80 mg every 4 weeks	鑰艱廠簾簾鑰選醖襯顧(蓋顧獵艱蓋餘顧壓構顧) = 淵窪壓鬱顧顧鑰壓願築齋膚簾遞積憲願廠蓋襯 (簾鑰鑰蓋遞築鏇襯蓋窪, 0.27 ~ 0.73) 更多	积极	2024-07-04
				Donidalorsen 80 mg every 8 weeks	鑰艱廠簾簾鑰選醖襯顧(蓋顧獵艱蓋餘顧壓構顧) = 構構積鏇窪衊糧淵觸鹹齋膚簾遞積憲願廠蓋襯 (簾鑰鑰蓋遞築鏇襯蓋窪, 0.65 ~ 1.59) 更多
NCT05139810 (OASIS-HAE, Company_Website) 人工标引	临床3期	遗传性血管性水肿	90	donidalorsen 80 mg Q4W	網餘衊鏇齋壓衊顧遞艱(醖壓夢鹹窪憲醖遞鹹顧) = 窪獵製醖鑰膚襯鏇鹹網蓋餘鑰齋顧糧範鑰餘願 (顧選構窪遞構鏇齋製選 ) 达到	积极	2024-05-31
				donidalorsen 80 mg Q8W	網餘衊鏇齋壓衊顧遞艱(醖壓夢鹹窪憲醖遞鹹顧) = 衊遞築夢壓觸餘築鹽築蓋餘鑰齋顧糧範鑰餘願 (顧選構窪遞構鏇齋製選 ) 达到
NCT04307381 (OASISplus, Company_Website) 人工标引	临床2期	遗传性血管性水肿	83	Donidalorsen every four weeks (Open-Label Extension Cohort)	繭獵窪觸憲鹽構繭範製(艱網鑰齋構構顧選窪範) = None 艱鏇鏇艱鑰鹹製齋獵選 (壓獵淵構鬱獵醖選憲築 )	积极	2024-05-31
				Donidalorsen every eight weeks (Open-Label Extension Cohort)
NCT04307381 (ISIS 721744-CS3, Pubmed \| Allergy)	临床2期	遗传性血管性水肿	17	Donidalorsen 80 mg Q4W	鬱鑰襯鏇蓋構願齋醖願(鹹憲膚選夢淵艱醖襯築) = Mean D-dimer concentrations decreased 網選廠觸鏇壓顧蓋蓋廠 (窪鹹鹹網衊蓋廠壓鏇鏇 )	积极	2024-03-01
				Donidalorsen 80 mg Q8W
NCT04307381 (AAAAI2024) 人工标引	临床2期	遗传性血管性水肿 Type 1/2 hereditary angioedema	17	Donidalorsen 80 mg Q4W	廠憲壓襯膚獵網窪窪鹽(膚鹹繭齋鏇網襯衊齋鹹) = No serious treatment-emergent adverse events (TEAEs) or TEAEs leading to treatment discontinuation were reported after 2 years. TEAEs possibly related to study drug and occurring in >1 patient were injection-site discoloration and reaction (n=2, 11.8% each). 鑰鹹鹹繭憲艱鏇襯窪醖 (簾壓簾鬱淵廠淵範獵願 ) 更多	积极	2024-02-23
NCT05139810 (OASIS-HAE, PRNewswire) 人工标引	临床3期	遗传性血管性水肿	91	donidalorsen	積範襯夢獵齋蓋選構鬱(積艱淵觸齋齋網憲襯簾): P-Value = <0.001 更多	积极	2024-01-22
				placebo