Evinacumab-dgnb

如果你觉得降脂药的江湖还是他汀、依折麦布、PCSK9抑制剂“三足鼎立”，那今天这篇《European Heart Journal》可能要让你重新认识什么叫“降维打击”——一款名叫Solbinsiran的“基因沉默师”，用每季度一针的方式，把甘油三酯砍掉50.3%、非HDL-C砍掉25.5%、apoB砍掉14.3%，还顺手把肝脏脂肪减了27.6%。更神奇的是，它干的活儿，是同时降低所有含apoB的坏粒子，不管你是LDL、VLDL还是残粒，统统“一网打尽”。 🧬 第一幕：ANGPTL3——脂代谢的“双控开关”先来认识一下Solbinsiran的“靶标”——ANGPTL3（血管生成素样蛋白3）。这家伙是肝脏分泌的一种蛋白质，干的事儿很“缺德”：它同时抑制脂蛋白脂酶（LPL）和内皮脂酶（EL），相当于给脂肪代谢踩了两脚刹车。结果呢？· 甘油三酯：清不掉，堆积成VLDL· LDL-C：也受影响（因为VLDL是LDL的前体）· 残粒胆固醇：更是“冤大头”，比LDL颗粒的胆固醇含量高10-40倍但天无绝人之路。人群中有一部分人天生携带ANGPTL3的“功能丧失型”突变，这些人甘油三酯、LDL-C、HDL-C都低，心血管风险也低。这就给药物研发指了一条明路：抑制ANGPTL3，能不能模拟这种“天选之人”的保护效果？🔬 第二幕：Solbinsiran——RNA干扰的“定向拆弹”Solbinsiran的设计堪称“分子界的精确制导导弹”：· 弹头：siRNA（小干扰RNA），专门靶向ANGPTL3的mRNA，让肝细胞“闭嘴”不生产ANGPTL3· 导航：GalNAc（N-乙酰半乳糖胺），这是肝细胞表面“唾液酸糖蛋白受体”的“专属钥匙”，确保药物几乎只进肝细胞，不伤无辜这比第一代ANGPTL3抑制剂（如vaponarsen，因肝毒性被砍）聪明得多，也比evina-cumab（每月静脉输注的单抗）方便得多——每季度皮下注射一次，患者依从性直接拉满。📊 第三幕：PROLONG-ANG3试验，数据说话试验设计：II期、随机、安慰剂对照，纳入已用中/高强度他汀的混合型血脂异常患者，分四组：安慰剂、Solbinsiran 100mg、400mg、800mg（每季度一次）。核心结果：1. 主要终点：apoB降幅 · 400mg组：降14.3%（达到主要终点） · 800mg组：没达到（原因？安慰剂组apoB莫名其妙降了11.6%，把基线拉低了——这在降脂试验里极其罕见，可能是试验设计或人群选择的“乌龙”）2. 次要终点：全面开花 · 甘油三酯：降50.3%（400mg组） · 非HDL-C：降25.5% · VLDL-C：降50.1% · HDL-C：降16.8%（HDL-C降了是“副作用”，但整体心血管净获益仍为正）3. 探索性终点：肝脏脂肪 · 肝脂肪分数：降27.6%（而且不依赖体重下降或CRP变化） · 这提示Solbinsiran可能在MASH（代谢相关脂肪性肝炎） 领域也有用武之地4. 安全性： · 不良事件与安慰剂组相当 · 注射部位反应发生率低 · 无死亡事件💡 第四幕：临床意义——填补“残余风险”的空白为什么这药重要？因为现有的降脂药有个“盲区”：· 他汀：降LDL-C一流，但对甘油三酯和残粒胆固醇的“打击力”有限· PCSK9抑制剂：降LDL-C超强，但主要针对LDL颗粒· 贝特类/鱼油：降甘油三酯，但PROMINENT试验证明，光降甘油三酯而不降apoB，心血管获益不明确而Solbinsiran的特点是：同时降低所有含apoB的颗粒，无论你是大VLDL、小LDL，还是“坏蛋中的坏蛋”残粒胆固醇。这种“全覆盖”式的打击，理论上能更全面地覆盖“残余风险”。此外，每季度一针的给药频率，比PCSK9抑制剂的每两周/每月一针更方便，比evinacumab的静脉输注更友好。对于需要长期用药的患者，依从性就是王道。🤔 第五幕：后续思考——还有哪些坑要填？1. 剂量-反应关系的“谜之曲线”400mg有效，800mg反而没达到主要终点——这“倒挂”的剂量-反应关系，让统计学家的头发又少了几根。最可能的解释是安慰剂组的“异常波动”（apoB降了11.6%）。但这也提醒我们：II期试验样本量小，偶然性大，III期才是“照妖镜”。2. HDL-C降低，要不要担心？Solbinsiran让HDL-C降了16.8%。按传统观念，HDL-C是“好胆固醇”，降了似乎不妙。但孟德尔随机化研究早就告诉我们：HDL-C的因果关系很弱，真正决定心血管风险的是HDL颗粒的功能，不是它的数量。而且，Solbinsiran带来的整体心血管获益（甘油三酯、残粒胆固醇、apoB全面下降）大概率能“抵消”HDL-C下降的“心理不适”。3. 心血管结局试验，何时来？目前只有II期，还没做CVOT。降脂药能不能用，最终还得看能不能降低心梗、卒中、心血管死亡。PCSK9抑制剂当年也是靠FOURIER和ODYSSEY OUTCOMES才封神。Solbinsiran的CVOT，应该已经在路上了。4. 与现有药物的“排兵布阵”如果Solbinsiran上市，它会是“一线”还是“二线”？目前看，它最适合的人群可能是：· 他汀治疗后甘油三酯仍高、非HDL-C仍高的患者· 合并MASH（肝脂肪）的血脂异常患者· PCSK9抑制剂不耐受或依从性差的患者但它和PCSK9抑制剂是“替代”还是“补充”？目前还不清楚。理论上，两者靶点不同（PCSK9在LDL受体回收，ANGPTL3在VLDL代谢），联合使用可能有叠加效果，但需要临床试验验证。5. 成本与可及性siRNA药物的生产成本高，定价通常不便宜。但“每季度一针”的给药频率，能减少注射次数，可能间接降低医疗系统负担。至于患者能不能用得起，还得看医保谈判的结果。🎬 彩蛋：Angptl3抑制剂的“前世今生”Solbinsiran并不是第一个靶向ANGPTL3的药物。它的“前辈”包括：· vaponarsen（IONIS-ANGPTL3-LRx）：反义寡核苷酸，因剂量依赖性肝毒性被砍· evinacumab（再生元/赛诺菲）：单抗，每月静脉输注，已获批用于纯合子家族性高胆固醇血症（HoFH），但需要静脉输注，不方便Solbinsiran的“后发优势”在于：GalNAc-siRNA技术，让肝靶向更精准，副作用更少，给药更方便。如果III期成功，它有望成为ANGPTL3靶点的“最终答案”。🔚 结语：降脂的“第四次革命”如果说他汀是降脂的“第一次革命”，PCSK9抑制剂是“第二次革命”，小分子口服药（如贝派地酸）是“第三次革命”，那siRNA类药物可能就是“第四次革命”。它们不需要频繁注射，不需要口服吸收，只需要每季度一次皮下注射，就能让肝脏“闭嘴”几个月。这种“基因沉默”的思路，正在从罕见病走向常见病，从高胆固醇走向混合型血脂异常。Solbinsiran的PROLONG-ANG3试验，只是这场革命的“第一声炮响”。未来，我们可能会看到更多“一针管一季”的降脂药，让患者从“每天吃药”变成“每季度打针”，从“被动治疗”变成“主动管理”。一句话总结：Solbinsiran用一针管一季的“基因沉默术”，把甘油三酯砍了50%，非HDL-C砍了25%，还给肝脏减了27.6%的脂肪——这波操作，堪称降脂界的“三杀”。🔥🚀

Approval in moderate-to-severe patients was based on pivotal trial results showing over four times more Dupixent patients experienced sustained disease remission through Week 36 compared with placebo BP is a chronic, relapsing skin disease with underlying type 2 inflammation characterized by intense itch alongside painful blisters and other lesions BP is the seventh approved indication for Dupixent in Japan March 24, 2026 (GLOBE NEWSWIRE) -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi today announced that the Ministry of Health, Labour and Welfare (MHLW) in Japan has approved Dupixent® (dupilumab) for the treatment of adults with moderate-to-severe bullous pemphigoid (BP). The approval in Japan is based on data from the pivotal LIBERTY-BP-ADEPT Phase 2/3 trial, which evaluated Dupixent in adults with moderate-to-severe BP. Patients were randomized to receive Dupixent 300 mg (n=53) or placebo (n=53) added to standard-of-care oral corticosteroids (OCS). During treatment, all patients underwent a protocol-defined OCS tapering regimen if control of disease activity was maintained. For the primary endpoint, more than four times as many patients on Dupixent experienced sustained disease remission compared to placebo (18% vs. 4%; p=0.0250) at Week 36 in the companies’ core dataset used for the regulatory submission in Japan. Treatment-related adverse events (AEs) occurred in 26% of Dupixent patients and 15% of placebo patients. The treatment-related AE most commonly reported with Dupixent was conjunctivitis (4%). In addition to BP, Dupixent is approved in Japan in certain patients with atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), prurigo nodularis, chronic spontaneous urticaria (CSU) and chronic obstructive pulmonary disease (COPD). BP is a rare skin disease that primarily affects elderly patients, and is characterized by intense itch, painful blisters and lesions, as well as reddening of the skin. It can be chronic and relapsing with underlying type 2 inflammation. The blisters and rash can form over much of the body and cause the skin to bleed and break down, resulting in patients being more prone to infection and affecting their daily functioning. Available treatment options are limited and can add to overall disease burden by suppressing a patient’s immune system. ADEPT was a randomized, double-blind, placebo-controlled Phase 2/3 trial evaluating the efficacy and safety of Dupixent in 106 adults with moderate-to-severe BP for a 52-week treatment period. After randomization, patients received Dupixent or placebo every two weeks after an initial loading dose, along with OCS treatment. During treatment, OCS taper was initiated after patients experienced two weeks of sustained control of disease activity. OCS tapering could start between four to six weeks after randomization and was continued if disease control was maintained, with the intent of completion by Week 16. After OCS tapering, patients were only treated with Dupixent or placebo for the rest of the trial (rescue treatment could be used if required). The primary endpoint evaluated the proportion of patients achieving sustained disease remission at Week 36. Sustained disease remission was defined as complete clinical remission with completion of OCS taper by Week 16 without relapse after completion of the OCS taper and no rescue therapy use during the 36-week treatment period. Relapse was defined as appearance of ≥3 new lesions a month or ≥1 large lesion or urticarial plaque (>10 cm in diameter) that did not heal within a week. Rescue therapy could include treatment with high-potency topical corticosteroids, OCS (including increase of OCS dose during the taper or re-initiation of OCS after completion of the OCS taper) or systemic non-steroidal immunosuppressive medications or immunomodulating biologics. Dupixent is now available in Japan as a 300 mg pre-filled syringe or pre-filled pen for adults with bullous pemphigoid. Dupixent is intended for injection under the skin (subcutaneous injection) and is given every two weeks after an initial loading dose. It can be given in a clinic or at home by self-administration after training by a healthcare professional. Dupixent, which was invented using Regeneron’s proprietary VelocImmune® technology, is a fully human monoclonal antibody that inhibits the signaling of the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways and is not an immunosuppressant. The Dupixent development program has shown significant clinical benefit and a decrease in type 2 inflammation in Phase 3 trials, establishing that IL-4 and IL-13 are two of the key and central drivers of the type 2 inflammation that plays a major role in multiple related and often co-morbid diseases. Dupixent has received regulatory approvals in more than 60 countries in one or more indications including certain patients with atopic dermatitis, asthma, CRSwNP, eosinophilic esophagitis (EoE), prurigo nodularis, CSU, COPD, BP and allergic fungal rhinosinusitis (AFRS) in different age populations. More than 1,400,000 patients are being treated with Dupixent globally.1 Regeneron's VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron's co-Founder, Board co-Chair, President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite® technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create a substantial proportion of all original, FDA-approved fully human monoclonal antibodies. This includes Dupixent® (dupilumab), Libtayo® (cemiplimab-rwlc), Praluent® (alirocumab), Kevzara® (sarilumab), vkeeza ® (evinacumab-dgnb), Inmazeb® (atoltivimab, maftivimab and odesivimab-ebgn) and Veopoz® (pozelimab-bbfg). In addition, REGEN-COV® (casirivimab and imdevimab) had been authorized by the FDA during the COVID-19 pandemic until 2024. Dupilumab is being jointly developed by Regeneron and Sanofi under a global collaboration agreement. To date, dupilumab has been studied across more than 60 clinical trials involving more than 12,000 patients with various chronic diseases driven in part by type 2 inflammation. In addition to the currently approved indications, Regeneron and Sanofi are studying dupilumab in a broad range of diseases driven by type 2 inflammation or other allergic processes in Phase 3 trials, including chronic pruritus of unknown origin and lichen simplex chronicus. These potential uses of dupilumab are currently under clinical investigation, and the safety and efficacy in these conditions have not been fully evaluated by any regulatory authority. Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to numerous approved treatments and product candidates in development, most of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, neurological diseases, hematologic conditions, infectious diseases, and rare diseases. Regeneron pushes the boundaries of scientific discovery and accelerates drug development using our proprietary technologies, such as VelociSuite, which produces optimized fully human antibodies and new classes of bispecific antibodies. We are shaping the next frontier of medicine with data-powered insights from the Regeneron Genetics Center® and pioneering genetic medicine platforms, enabling us to identify innovative targets and complementary approaches to potentially treat or cure diseases. Sanofi is an R&D driven, AI-powered biopharma company committed to improving people’s lives and delivering compelling growth. We apply our deep understanding of the immune system to invent medicines and vaccines that treat and protect millions of people around the world, with an innovative pipeline that could benefit millions more. Our team is guided by one purpose: we chase the miracles of science to improve people’s lives; this inspires us to drive progress and deliver positive impact for our people and the communities we serve, by addressing the most urgent healthcare, environmental, and societal challenges of our time. The content above comes from the network. if any infringement, please contact us to modify.