Antithrombin III(Grifols SA)

关注并星标CPHI制药在线 家族性乳糜微粒血症综合征(FCS)，也被称为Ⅰ型原发性高脂蛋白血症(T1HLP)或脂蛋白脂肪酶缺乏症(LPLD)，是一种罕见的常染色体隐性遗传疾病。FCS通常由多种单基因（如LPL、GPIHBP1、APOC2、APOA5或LMF1）的功能缺失突变或复合/双重杂合突变引起，从而使LPL的活性下降或功能缺失，导致血浆中乳糜微粒(CM)浓度升高和高三酰甘油血症(HTG)。乳糜微粒是肠细胞在吸收后状态下合成和分泌的富含TG的脂蛋白。 FCS多始于儿童期、青少年期或成年早期，主要临床特征包括急性发作性腹痛、乏力、皮肤黄色瘤、肝脾肿大、视网膜脂质症、反复发作急性胰腺炎(AP)及神经症状，如易怒、记忆丧失和抑郁，严重者影响患者的生活质量。 FCS治疗现状 FCS治疗目的包括降低发生胰腺炎的风险、减轻因血浆TG水平升高相关的短期临床症状。由于FCS患者缺乏分解代谢脂肪的能力，对标准降脂药物反应不佳。 目前，全球获批治疗FCS的药物有限，仅有Glybera(alipogene tiparvovec) 和Waylivra（volanesorsen）。其中Glybera（alipogene tiparvovec）是UniQure公司开发的一款AAV基因疗法，其以AAV为载体将治疗基因LPL转导入肌细胞，从而使相应的细胞能够产生一定数量的脂蛋白脂酶，起到缓解疾病的作用。2012年11月，Glybera在欧盟被批准用于治疗严格限制脂肪饮食却仍然发生严重或反复胰腺炎发作的FCS。但由于定价太高、市场需求受限等因素，2017年Glybera退市。 Waylivra是Akcea和Ionis公司联合开发的一款反义寡核苷酸（ASO）药物，旨在减少ApoC-III的产生（ApoC-III是载脂蛋白C家族中含量最丰富的一类，主要在肝脏中合成，是血清TG的关键调节因子），2019年5月在欧盟被批准辅助饮食控制，用于治疗对饮食控制和降甘油三酯疗法一直控制不佳、存在胰腺炎高风险的成人FCS。 已公布的Waylivra针对FCS的3期临床试验APPROACH（NCT02211209）数据显示：与安慰剂相比，volanesorsen能显著降低FCS患者的甘油三酯（TG）水平（76.5% Vs 17.6%）。 除了获批治疗FCS，Waylivra在巴西还被批准用于治疗家族性部分脂肪营养不良(FPL)，成为全球首个获批治疗FPL的药物。不过，Waylivra在美国进展不顺，FDA处于安全性考虑，曾拒绝批准其治疗FCS。 在研FCS药物研究进展 据不完全统计，目前全球还有几款在研FCS新疗法，详见下表。这几款药物均作用于apoC-III，且部分药物进入临床后期。        全球部分在研FCS疗法        资料来源：公开资料 Olezarsen：3期临床成功，即将申请上市 Olezarsen是一种新型N-乙酰半乳糖胺（GalNAc）结合的反义寡核苷酸，靶向肝脏APOC III mRNA，选择性地抑制APOC III的合成。2023年1月，该药被FDA授予治疗FCS的快速通道资格。 2023年9月，Ionis公司宣布Olezarsen治疗FCS的3期临床试验Balance取得积极结果，达到主要疗效终点，能够显著改善患者的甘油三酯水平，同时展现出良好的安全性和耐受性。Balance试验是一项全球、多中心、随机、双盲、安慰剂对照研究，共入组66例成人FCS患者，研究中患者按1:1:1比例随机皮下注射50、80mg Olezarsen或者安慰剂，每4周1次，持续53周。 研究数据显示：6个月时，80mg Olezarsen治疗组患者的甘油三酯水平较安慰剂组显著降低（p=0.0009）；12个月时，80mg Olezarsen治疗组患者的甘油三酯水平持续改善。而且，与安慰剂相比，80mg Olezarsen治疗组患者急性胰腺炎事件减少了100%（Olezarsen组0例，安慰剂组11例）。接受Olezarsen 80mg治疗后，apoC-III也减少75%以上。不过，50mg Olezarsen治疗组在降低甘油三酯的主要终点方面并未达到统计学显著性。 基于该研究结果，Ionis公司计划于2024年向FDA以及欧盟提交Olezarsen 治疗FCS的新药申请。 ARO-APOC3：获FDA通道资格，可3个月给药一次 ARO-APOC3是一种皮下给药、靶向ApoC-III的小干扰RNA（siRNA）药物，通过特异性靶向和沉默APOC-III mRNA，减少肝脏内apoC-III的生成，使VLDL和乳糜微粒残留物更好地清除。2019年7月，ARO-APOC3被FDA授予治疗FCS的孤儿药资格。2023年3月，该疗法又被FDA授予快速通道资格，用于降低FCS成年患者的甘油三酯。 2021年AHA（美国心脏协会）上公布的1/2期临床试验数据显示：在FCS患者中，ARO-APOC3可将甘油三酯水平降低91%。目前，该药针对FCS的3期临床试验PALISADE正在进行，关键数据今年上半年有望读出。此外，该药还有一个很大优势，给药间隔比较长，只需每3个月或6个月打一针，就可以有效控制血脂。 VSA001：中国3期临床试验完成入组 VSA001是靶向ApoC-III的siRNA药物，2023年9月被CDE纳入突破性治疗品种，用于降低FCS成人患者的甘油三酯水平。2024年1月，维亚臻宣布VSA001已顺利完成中国FCS 3期临床试验超过36例全部患者入组，并计划于2025年第一季度完成该临床试验的全部终点评价，以支持后续的新药注册上市申请。 不过考虑到维亚臻是由Arrowhead与维梧资本联合创立，且与Arrowhead建立了长期合作关系。笔者推测VSA001可能就是从Arrowhead引进的ARO-APOC3。 RBD5044：我国药企研发，1期试验已启动 RBD5044基于瑞博生物RIBO-GalSTAR? 肝靶向递送技术开发的一款旨在治疗高甘油三酯血症的GalNAc缀合siRNA药物，可以抑制肝细胞ApoC-III表达，上调脂蛋白脂肪酶和肝细胞受体介导的残余颗粒摄取，促进富甘油三酯脂蛋白（TRLs）上甘油三酯（TGs）的水解，实现降低血液中TG水平的目标。 非临床安全性和有效性研究数据显示，RBD5044具有潜在同类领先的有效性和较长药效持续时间。2022年11月，RBD5044在澳大利亚的首次人体临床试验启动。 总结 作为一种罕见病，家族性乳糜微粒血症综合征(FCS)治疗领域几近空白，曾获批的Glybera因定价高等因素撤市，Waylivra仅在部分国家和地区获批上市。FDA因Waylivra在临床试验中存在血小板减少和出血相关的安全性，拒绝批准其上市申请。不过，罕见病虽然患者群体相对较小，但药企并未放弃FCS领域新药的研发。 在研FCS药物几乎均作用于ApoC-III靶点，其中Olezarsen进展最快，3期临床已取得积极结果，预计今年将申请上市。此外，罕见病药物大多定价太高，如何惠及更多罕见病患者也是药企和监管部门需要考虑的点。 【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~

Researchers say they have uncovered insights as to why lupus symptoms and severity present differently in individuals with the autoimmune condition, which affects up to 1.5 million Americans. The team says this is a crucial step forward in understanding biological mechanisms behind lupus, and may also lead to shifts in how clinicians treat patients with the condition. In a new study, researchers from Johns Hopkins Medicine say they have uncovered insights as to why lupus symptoms and severity present differently in individuals with the autoimmune condition, which affects up to 1.5 million Americans. The team says this is a crucial step forward in understanding biological mechanisms behind lupus, and may also lead to shifts in how clinicians treat patients with the condition. The full report, published in Cell Reports Medicine on May 13, concludes that specific combinations and elevated levels of immune system proteins, known as interferons, are associated with certain lupus symptoms such as skin rashes, kidney inflammation and joint pain. Interferons normally help to fight infection or disease, but are overactive in lupus, causing widespread inflammation and damage. The study also shows that other common lupus-related symptoms cannot be explained by increased interferon levels. "For years, we have accumulated knowledge that interferons play a role in lupus," says corresponding author and rheumatologist Felipe Andrade, M.D., Ph.D., associate professor of medicine at the Johns Hopkins University School of Medicine. He says this research began with questions about why certain lupus treatments were ineffective for some patients. "We have seen instances where the patient surprisingly didn't improve -- we wondered if certain interferon groups were involved." Some lupus treatments are designed to suppress a specific group of interferons, known as interferon I. In clinical trials for these treatments, the team observed some patients failing to improve, despite genetic tests showing high interferon I levels before treatment, or what experts call a high interferon signature. The team believed that two other interferon groups, interferon II and interferon III, may be to blame for these poor treatment responses. To investigate, the team looked at how different combinations of interferon I, II or III, and their overactivity, may present in people with lupus. Researchers took 341 samples from 191 participants to determine the activity of the three interferon groups, and used human cell lines engineered to react to the presence of each specific interferon group to analyze the samples. Through this process, researchers determined that the majority of participants fell into four categories: those only with increased interferon I; those with a combination of increased interferons I, II and III; those with a combination of increased interferons II and III; or those with normal interferon levels. Researchers were able to use these findings to also make several associations between these interferon combinations and lupus symptoms. In those with elevated interferon I, lupus was mainly associated with symptoms affecting the skin, such as rashes or sores. Participants with elevated levels of interferon I, II and III exhibited the most severe presentations of lupus, often with significant damage to organ systems, such as the kidneys. Not every symptom found in lupus was associated with elevated interferons, though. The formation of blood clots and low platelet counts, which also affect clotting, did not have an association with increased levels of interferon groups I, II or III. Researchers say this indicates that both interferon-dependent and other biological mechanisms are involved in this complex disease. The study also found that genetic testing of genes associated with these interferon groups, or the interferon signature, did not always indicate elevated interferon levels. They plan to investigate this in future studies. "What we've seen in our study is that these interferon groups are not isolated; they work as a team in lupus and can give patients different presentations of the disease," says rheumatologist Eduardo Gómez-Bañuelos, M.D., Ph.D., assistant professor of medicine at the Johns Hopkins University School of Medicine and the study's first and additional corresponding author. Evaluating a patient's elevated interferon combinations allows for a better understanding of how they may react to treatments, and would allow clinicians to group them into clinical subtypes of lupus, Gómez-Bañuelos explains. Additional contributors to this work include Daniel Goldman, Victoria Andrade, Erika Darrah and Michelle Petri, affiliated with the Johns Hopkins University School of Medicine. Darrah is now also affiliated with AstraZeneca. Funding for this project includes National Institutes of Health grant numbers R21 AI147598, R21 AI169851, R21 AI176766 and R01 AR069572, as well as from the Jerome L. Greene Foundation.