This Phase 3 study will evaluate the safety and efficacy of plozasiran injection (ARO-APOC3) in adult participants with severe hypertriglyceridemia (SHTG). After providing informed consent eligible participants will be randomized to receive 4 doses (once every 3 months) of plozasiran or placebo, and be evaluated for efficacy and safety. After Month 12, eligible participants will be offered an opportunity to continue in an optional open-label extension under a separate protocol.

开始日期2024-07-23

申办/合作机构

Arrowhead Pharmaceuticals, Inc.

NCT06347003 / Recruiting临床3期

Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Plozasiran in Adults With Severe Hypertriglyceridemia

This Phase 3 study will evaluate the safety and efficacy of plozasiran injection (ARO-APOC3) in adult participants with severe hypertriglyceridemia (SHTG). After providing informed consent eligible participants will be randomized to receive 4 doses (once every 3 months) of plozasiran or placebo, and be evaluated for efficacy and safety. After month 12, eligible participants will be offered an opportunity to continue in an optional open-label extension under a separate protocol.

开始日期2024-07-22

申办/合作机构

Arrowhead Pharmaceuticals, Inc.

NCT06347133 / Recruiting临床3期

Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Plozasiran in Adults With Hypertriglyceridemia

This Phase 3 study will evaluate the safety and efficacy of plozasiran injection (ARO-APOC3) in adult participants with hypertriglyceridemia (HTG). After providing informed consent eligible participants will be randomized to receive 4 doses (once every 3 months) of plozasiran or placebo and be evaluated for efficacy and safety.

开始日期2024-05-21

申办/合作机构

Arrowhead Pharmaceuticals, Inc.

100 项与 APOC3 相关的临床结果

登录后查看更多信息

100 项与 APOC3 相关的转化医学

登录后查看更多信息

0 项与 APOC3 相关的专利（医药）

登录后查看更多信息

3,210

项与 APOC3 相关的文献（医药）

2024-12-01·Clinical proteomics

Closing the gaps in patient management of dyslipidemia: stepping into cardiovascular precision diagnostics with apolipoprotein profiling

Review

作者: Cobbaert, Christa M ; Ruhaak, L Renee ; Reijnders, Esther ; van der Laarse, Arnoud

Abstract:

In persons with dyslipidemia, a high residual risk of cardiovascular disease remains despite lipid lowering therapy. Current cardiovascular risk prediction mainly focuses on low-density lipoprotein cholesterol (LDL-c) levels, neglecting other contributing risk factors. Moreover, the efficacy of LDL-c lowering by statins resulting in reduced cardiovascular risk is only partially effective. Secondly, from a metrological viewpoint LDL-c falls short as a reliable measurand. Both direct and calculated LDL-c tests produce inaccurate test results at the low end under aggressive lipid lowering therapy. As LDL-c tests underperform both clinically and metrologically, there is an urging need for molecularly defined biomarkers. Over the years, apolipoproteins have emerged as promising biomarkers in the context of cardiovascular disease as they are the functional workhorses in lipid metabolism. Among these, apolipoprotein B (ApoB), present on all atherogenic lipoprotein particles, has demonstrated to clinically outperform LDL-c. Other apolipoproteins, such as Apo(a) - the characteristic apolipoprotein of the emerging risk factor lipoprotein(a) -, and ApoC-III - an inhibitor of triglyceride-rich lipoprotein clearance -, have attracted attention as well. To support personalized medicine, we need to move to molecularly defined risk markers, like the apolipoproteins. Molecularly defined diagnosis and molecularly targeted therapy require molecularly measured biomarkers. This review provides a summary of the scientific validity and (patho)physiological role of nine serum apolipoproteins, Apo(a), ApoB, ApoC-I, ApoC-II, ApoC-III, ApoE and its phenotypes, ApoA-I, ApoA-II, and ApoA-IV, in lipid metabolism, their association with cardiovascular disease, and their potential as cardiovascular risk markers when measured in a multiplex apolipoprotein panel.

2024-11-01·GENE

Multiple genetic polymorphisms are associated with the risk of metabolic syndrome, fatty liver, and airflow limitation: A Taiwan Biobank study

Article

作者: Yang, Hwai-I ; Huang, Chia-Chang ; Pan, Mei-Hung ; Lee, Kuei-Chuan ; Huang, Chih-Jen ; Shen, Hsiao-Chin ; Lin, Yi-Hsuan ; Yang, Ying-Ying ; Hou, Ming-Chih ; Yeh, Hsiao-Yun

BACKGROUND:

Links have been reported between the airflow limitation and both metabolic syndrome (MetS) and fatty liver (FL). Additionally, associations between genetic factors and risks of MetS, FL, and airflow limitation have been identified separately in different studies. Our study aims to simultaneously explore the association between specific single nucleotide polymorphisms (SNPs) of certain genes and the risk of the three associated diseases.

METHODS:

In this retrospective cross-sectional nationwide study, 150,709 participants from the Taiwan Biobank (TWB) were enrolled. We conducted a genotype-phenotype association analysis of nine SNPs on seven genes (ApoE-rs429358, MBOAT7-rs641738, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, TM6SF2-rs58542926, and IFNL4-rs368234815) using data from the TWB1.0 and TWB2.0 genotype dataset. Participants underwent a series of assessments including questionnaires, blood examinations, abdominal ultrasounds, and spirometry examinations.

RESULTS:

MetS was associated with FL and airflow limitation. ApoE-rs429358, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, and TM6SF2-rs58542926 were significantly associated with the risk of MetS. The cumulative impact of T alleles of ApoE-rs429358 and TM6SF2-rs58542926 on the risk of FL was observed (p-value for trend < 0.001). Individuals without MetS and airflow limitation carrying LEPR-rs1805096 G_G genotype exhibited a reduction in the forced expiratory volume in 1 s percentage prediction (Coefficient -35, 95 % confidence interval (CI) -69.7- -0.4), low forced vital capacity percentage prediction (Coefficient -41.6, 95 % CI -82.6- -0.6), and low vital capacity percentage prediction (Coefficient -42.2, 95 % CI -84.2- -0.1).

CONCLUSIONS:

MetS significantly correlated with FL and airflow limitation. Multiple SNPs were notably associated with MetS. Specifically, T alleles of ApoE-rs429358 and TM6SF2-rs58542926 cumulatively increased the risk of FL. LEPR-rs1805096 shows a trend-wise association with pulmonary function, which is significant in patients without MetS or airflow limitation.

2024-11-01·PHYTOMEDICINE

Chaiqin chengqi decoction treatment mitigates hypertriglyceridemia-associated acute pancreatitis by modulating liver-mediated glycerophospholipid metabolism

Article

作者: Sutton, Robert ; Wen, Yongjian ; Wang, Qiqi ; Mukherjee, Rajarshi ; Zhong, Shaoqi ; Phillips, Anthony R ; Xia, Qing ; Sun, Xin ; Windsor, John A. ; Luo, Wenjuan ; Li, Fei ; Jin, Tao ; Yao, Linbo ; Liu, Tingting ; Wang, Wen ; Li, Yuying ; Cai, Wenhao ; Phillips, Anthony R. ; Yang, Xinmin ; Huang, Wei ; Deng, Dan ; Windsor, John A ; Hong, Jiwon ; Xue, Jing ; Huang, Lijia

BACKGROUND:

The incidence of hypertriglyceridemia-associated acute pancreatitis (HTG-AP) is increasing globally and more so in China. The characteristics of liver-mediated metabolites and related key enzymes are rarely reported in HTG-AP. Chaiqin chengqi decoction (CQCQD) has been shown to protect against AP including HTG-AP in both patients and rodent models, but the underlying mechanisms in HTG-AP remain unexplored.

PURPOSE:

To assess the characteristics of liver-mediated metabolism and the therapeutic mechanisms of CQCQD in HTG-AP.

METHODS:

Male human apolipoprotein C3 transgenic (hApoC3-Tg; leading to HTG) mice or wild-type littermates received 7 intraperitoneal injections of cerulein (100 μg/kg) to establish HTG-AP and CER-AP, respectively. In HTG-AP, some mice received CQCQD (5.5 g/kg) gavage at 1, 5 or 9 h after disease induction. AP severity and related liver injury were determined by serological and histological parameters; and underlying mechanisms were identified by lipidomics and molecular biology. Molecular docking was used to identify key interactions between CQCQD compounds and metabolic enzymes, and subsequently validated in vitro in hepatocytes.

RESULTS:

HTG-AP was associated with increased disease severity indices including augmented liver injury compared to CER-AP. CQCQD treatment reduced severity and liver injury of HTG-AP. Glycerophospholipid (GPL) metabolism was the most disturbed pathway in HTG-AP in comparison to HTG alone. In HTG-AP, the mRNA level of GPL enzymes involved in phosphocholine (PC) and phosphatidylethanolamine (PE) synthesis (Pcyt1a, Pcyt2, Pemt, and Lpcat) were markedly upregulated in the liver. Of the GPL metabolites, lysophosphatidylethanolamine LPE(16:0) in serum of HTG-AP was significantly elevated and positively correlated with the pancreas histopathology score (r = 0.65). In vitro, supernatant from Pcyt2-overexpressing hepatocytes co-incubated with LPE(16:0) or phospholipase A2 (a PC- and PE-hydrolyzing enzyme) alone induced pancreatic acinar cell death. CQCQD treatment downregulated PCYT1a and PCYT2 enzyme levels in the liver. Hesperidin and narirutin were identified top two CQCQD compounds with highest affinity docking to PCYT1a and PCYT2. Both hesperidin and narirutin reduced the level of some GPL metabolites in hepatocytes.

CONCLUSION:

Liver-mediated GPL metabolism is excessively activated in HTG-AP with serum LPE(16:0) level correlating with disease severity. CQCQD reduces HTG-AP severity partially via modulating key enzymes in GPL metabolism pathway.

136

项与 APOC3 相关的新闻（医药）

2024-09-12

·研发客

信立泰为何10亿元引进一款未有成功先例的临床前药物？| 第一现场

// • 信立泰表示，“如果依从性较差的患者比例较高，合理定价的碱基编辑疗法进入医保的可能性也会更高。” • 全球首款PCSK9碱基编辑药物开发过程坎坷； • YOLT-101预计明年进入1期临床； • 在现有药物疗效可满足需求的前提下，更便利、患者更容易接受的疗法是慢病的未来方向。 8月27日，信立泰以总交易金额近10.35亿元，引进尧唐生物PCSK9碱基编辑药物YOLT-101的中国权益。该产品尚处于临床前阶段，并于今年4月完成一项IIT研究中的首例受试者给药。信立泰已有一款PCSK9单抗SAL003进入高脂血症3期临床，为何还要引进同靶点的碱基编辑药物？迄今全球尚未有PCSK9碱基编辑疗法成功的案例。 “从新一代PCSK9疗法来看，CRISPR基因编辑需要切断DNA双链，安全性风险较高；而从表观遗传层面调控PCSK9蛋白的研究还处于早期阶段，调控效果尚不稳定，理论上疗效无法终生持续，这与小核酸药物相比优势并不明显。所以‘下手过重或者过轻’似乎都不行，单碱基编辑疗法则正好处于适度范围。”信立泰投资部副总经理杨睿解释。在他看来，“碱基编辑技术已出现苗头信号”。拓展阅读对话吴宇轩：CRISPR体内基因编辑下一个突破在哪里 “中国降血脂市场足够大。单抗是为了满足现有人群延长给药周期的需求，当大家普遍接受基因编辑的概念时，我们又可以将其切换为更长周期甚至‘一生一次’的碱基编辑药物。这是分步的过程，我们提前布局，两者并不冲突。” 杨睿说。 “不刻意追求速度” PCSK9是降低低密度脂蛋白胆固醇（LDL-C）的热门靶点，多款抑制其活性的创新疗法已经过临床验证并获得监管批准，其中就包括诺华的小核酸药物英克司兰钠。PCSK9碱基编辑药物通过使编码PCSK9的DNA遗传序列发生单一的A到G的改变，从而达到永久抑制PCSK9的效果。不过开发碱基编辑药物并不容易。以全球首款PCSK9碱基编辑药物VERVE-101为例，其开发过程可谓坎坷，导致Verve Therapeutics的股价多次暴跌。早在2022年11月，该产品的IND就遭到FDA搁置，直到一年后才取消。2023年11月，VERVE-101在家族性高胆固醇血症（HeFH）早期试验中显示，一次治疗可将患者LDL-C水平降低55%，并持续长达180天以上。虽然疗效令人充满幻想，但试验中的严重不良事件也引发安全担忧，10名受试者中2名出现心脏病，其中一名死亡。今年4月，在1名受试者经历严重的药物相关不良事件后，VERVE-101治疗HeFH的早期研究被暂停。据BioSpace报道，Verve首席执行官Sekar Kathiresan曾在一份声明中表示，VERVE-101的安全性问题“可归因于LNP给药系统”，但该公司对PCSK9碱基编辑的作用机制仍充满信心。随后，该公司将目光转向VERVE-102，它与VERVE-101使用相同的PCSK9靶向碱基编辑器，主要区别在于使用了新的递送技术，能够更有效地介导基因编辑系统被肝脏吸收。 “我们在选择项目标的时做了大量研究，并与Verve第二代产品VERVE-102直接对标。从设计角度来看，YOLT-101的LNP是在已被尧唐生物首发管线YOLT-201临床验证过的基础上，采用了升级的新版本，加上独特的引导RNA设计，其部位脱靶和序列脱靶的风险都大大降低。同时我们发现，该产品在NHP（非人灵长类动物）实验中以一半剂量就能获得比VERVE-102更好的降血脂效果，这提示其疗效和安全性可能更好。”杨睿说。在他来看，由于全球尚未有PCSK9碱基编辑疗法成功的案例，因此这类产品临床开发的难点和风险主要集中在两方面，一是疗效能否足够与现有药物竞争，二是安全性是否可接受，尤其在拓展至普通高血脂时。 “在YOLT-101的临床试验中，我们不刻意追求速度，希望对产品进行更为深入的研究、更为全面的观察。探索性项目在前期越早发现信号，对项目推进把握越大。当然，如果发现副作用较大，排除脱靶风险后，也不必追求一次性大剂量，一生两次或者三次给药仍具优势。”杨睿说。据悉，该产品的首个适应症将选择患者临床需求更为迫切的遗传性疾病——家族性高胆固醇血症（FH），后续会扩展至普通高血脂的治疗。“根据合同约定，合作方会在明年第一季度递交YOLT-101的IND申请。按照CDE临床试验默示许可制度，我们预计会在第二季度末或第三季度初拿到IND批件，随后开展1期临床。”杨睿说。未来降脂疗法的竞争点当下，中国高胆固醇血症的一线治疗方案为他汀类药物，这类产品价格便宜，但多达5%～30%的患者存在不同程度的他汀不耐受，且由于需每日服药，大约30%的患者使用他汀半年后会脱落。在这种背景下，PCSK9抑制剂以显著降低50%～70%的LDL-C水平和良好的安全性强势袭来，并一次次刷新用药周期。此前，安进的依洛尤单抗和赛诺菲的阿利西尤单抗均已在国内获批并进入医保，给药周期为两周一次或一月一次。2023年8月，信达最长可6周用药一次的托莱西单抗在中国获批，诺华半年一针的siRNA药物英克司兰紧随其后加入战局。据杨睿介绍：“在很多慢病领域，现有药物的疗效基本已经能够满足需求，开发疗效更好的药物并非目标，更便利、患者更容易接受的疗法才是未来的方向。所以，单抗和小核酸出来后许多企业跟进并布局，到现在很多大公司管线中都有基因疗法，这是药物开发的规律，也更符合患者具体的用药实践。” 此外，药品价格也不容忽视。从现有PCSK9抑制剂市场来看，依洛尤单抗和阿利西尤单抗年治疗费用大约7000元，托莱西单抗约为12000元，英克司兰约为2万元。那么未来，更加长效的碱基编辑疗法如何走好商业化之路？ “定价问题需综合考虑，如果碱基编辑疗法终生只是需一针，那么其定价不应该超过其他降脂疗法终身用药的总治疗费用。”杨睿进一步表示，“未来药物经济学的应用也可能促进这类疗法纳入医保。因为高血脂患者早期症状不明显，不吃药也没有任何不舒适，但一旦发现问题往往不可逆，这将给患者和社会造成极大医疗负担。如果依从性较差的患者比例较高，合理定价的碱基编辑疗法进入医保的可能性也会更高。” 据悉，碱基编辑疗法将来重点发展的目标人群主要分为两类：一类是对价格不敏感的高收入群体，他们有些难以接受频繁用药或无法坚持长期用药，愿意尝试新技术；另一类是基础用药较多的群体，比如已使用3种以上降压药的患者，此时再加一种药物容易导致身体负担过重。纵观全球降脂疗法研发管线，除了PCSK9，针对其它靶点的各种新型疗法也正在兴起，如Lp(a)、ANGPTL3、apoC-III等。对此杨睿表示，无论靶点和技术如何发展，未来降脂疗法的开发首先是围绕主战场——降低低密度脂蛋白，其次才是辅助战场——降低残余的心血管风险。 “从疾病角度来看，LDL-C升高始终是动脉粥样硬化性心血管疾病最重要的危险因素，因此新的治疗方法首先要解决LDL-C的问题，在这基础之上，再去开发降低残余的心血管风险的其他疗法，或者与前者联合用药。总体而言，行业会在解决主要矛盾的同时或之后，解决次要矛盾。”他说。编辑 | 姚嘉 yao.jia@PharmaDJ.com 总第2198期访问研发客网站，深度报道和每日新闻抢鲜看 www.PharmaDJ.com

临床申请基因疗法临床3期核酸药物临床1期

2024-09-11

·Pharmaceutical Technology

FDA grants breakthrough therapy status to Arrowhead’s plozasiran

The designation is aimed at speeding up the development and review of drugs for serious conditions. Credit: skipper_sr/Shutterstock. The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to Arrowhead Pharmaceuticals ’ plozasiran, an investigational RNA interference (RNAi) therapeutic. Plozasiran is intended for use as an adjunct to diet to cut down triglycerides in adults with familial chylomicronemia syndrome (FCS), a rare genetic disease. The designation speeds up the development and review of drugs for serious conditions, where initial clinical evidence suggests significant improvement over existing treatments. Plozasiran reduces the production of apolipoprotein C-III (APOC3), a key regulator of triglyceride metabolism. High levels of APOC3 can lead to increased triglyceride levels in the blood, a characteristic of FCS. See Also: EASD 2024: Eli Lilly releases Phase III data for once-weekly insulin in diabetes In clinical studies, plozasiran has shown promising results by reducing triglycerides and other atherogenic lipoproteins in patients with FCS, severe hypertriglyceridemia (SHTG) and mixed hyperlipidaemia. The safety profile of plozasiran was also found to be favourable, with treatment-emergent adverse events generally reflecting the comorbidities and underlying conditions of the study populations. The SUMMIT programme, which includes multiple clinical studies such as the PALISADE Phase III study for FCS patients, the SHASTA studies for SHTG patients, and the MUIR and CAPITAN studies for mixed hyperlipidaemia patients, is investigating plozasiran. Arrowhead also plans to submit a new drug application for plozasiran to the FDA by the end of 2024 and will seek regulatory approval from additional global authorities thereafter. Plozasiran has also been granted orphan drug designation and fast track designation by the FDA and orphan drug designation by the European Medicines Agency. Arrowhead Pharmaceuticals’ president and CEO Chris Anzalone stated: “There are currently no FDA-approved therapies to specifically treat FCS, leaving physicians with very few options to help their patients. “Results from clinical studies of investigational plozasiran have been highly encouraging and strongly supportive of further development and commercialisation in multiple patient populations. Receiving FDA breakthrough therapy designation for plozasiran provides important benefits and the potential to expedite the process of getting plozasiran to the patients who need it.” The latest development comes after the company announced the advancement of two RNAi-based candidates to clinic obesity treatment.

孤儿药临床3期突破性疗法临床结果快速通道

2024-09-10

·药明康德

潜在“first-in-class”降血脂RNAi疗法获突破性疗法认定；礼来长效胰岛素登《柳叶刀》

▎药明康德内容团队编辑礼来每周一次长效胰岛素3期结果登《柳叶刀》礼来（Eli Lilly and Company）今天公布QWINT-5临床3期试验的详细结果。分析显示，其每周一次胰岛素efsitora alfa（efsitora）达到主要终点，与每日一次注射胰岛素相比，在试验26周时在降低1型糖尿病成人患者糖化血红蛋白（A1C）水平上展现非劣效性。Efsitora组患者的A1C降低了0.53个百分点，而活性对照组患者则降低了0.59个百分点，最终两组患者的A1C分别为7.37和7.32个百分点。详细数据同时发表于知名医学期刊《柳叶刀》当中。 Efsitora是一种每周一次皮下注射的基础胰岛素。Efsitora是一种融合蛋白，结合了新型单链胰岛素变体和人类IgG2 Fc结构域。由于其低的峰谷比，有望在整个周内提供患者更稳定的血糖水平（减少血糖波动）。潜在“first-in-class”降血脂RNAi疗法获美国FDA突破性疗法认定 Arrowhead Pharmaceuticals今天宣布，美国FDA授予其在研药物plozasiran突破性疗法认定，作为饮食控制的辅助疗法，用于减少患有家族性乳糜微粒血症综合征（FCS）成年患者的甘油三酯水平。FCS是一种严重且罕见的遗传性疾病，患者的甘油三酯水平极高，可能导致急性和潜在致命的胰腺炎。目前美国FDA尚未批准用以治疗FCS患者的治疗方案。 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剂。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，并将脂质恢复到更正常的水平。之前公布的PALISADE临床3期试验结果显示，plozasiran使经遗传学测试确认的FCS患者的甘油三酯水平相较基线降低了80%，并使患者发生急性胰腺炎的风险降低了83%。 ▲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] With once-a-week dosing, insulin efsitora alfa delivers similar A1C reduction compared to daily insulin in adults with type 1 diabetes. Retrieved September 10, 2024 from https://investor.lilly.com/news-releases/news-release-details/once-week-dosing-insulin-efsitora-alfa-delivers-similar-a1c [2] Arrowhead Pharmaceuticals Receives FDA Breakthrough Therapy Designation for Plozasiran. Retrieved September 10, 2024 from https://www.businesswire.com/news/home/20240910509591/en 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

临床3期突破性疗法临床结果