LDLR

作者｜dear&lin一直以来，日本小林制药公司（Kobayashi Pharmaceutical Co.，以下简称小林制药）的产品在访日游客中有着超高人气，甚至可以说是日本特产之一。然而有着日本“百年老字号”之称的小林制药，这次却在最重要的安全性问题上翻车了。近日，日本多人在服用日本小林制药生产的“红曲胆固醇颗粒”“纳豆激酶颗粒”以及“降胆固醇健康辅助颗粒”等保健产品后，导致肾脏疾病甚至死亡，截至目前，上述产品已导致5名日本消费者死亡，另有上百人住院接受治疗。3月22日，小林制药宣布对含有红曲成分的3款产品进行召回，并呼吁消费者立即停止服用这3款产品，据日媒报道，召回数量多达约30万份。然而，召回涉事产品，无法平息本次风波。根据日本帝国数据库公司一项最新调查结果显示，小林制药向225家企业提供红曲原料，这些原料有些被直接出售，有些经加工后二次出售，受波及企业恐达3.3万家，其中包括超过5000家食品和饮料零售商，购买上述问题红曲原料的企业所加工食品包括纳豆、面包、盒饭、咸鱼、腌菜和发酵食品等。帝国数据库公司指出，由于红曲原料用途广泛，要追溯使用问题原料的产品并非易事。2024年3月22日，小林制药株式会社社长小林明弘在大阪举行的新闻发布会上鞠躬致意。  01  曾经助力诺奖的红曲是本次事件的罪魁祸首吗？红曲是由曲霉科真菌-红曲霉的菌丝体寄生在粳米上而形成的，在我国已有2000余年使用历史，其对蛋白质具有很强的着色力，能用于改善菜肴或食品的外观色泽，并赋予独特的风味，不仅能作为天然食用色素使用，还能用于肉、鱼、豆类等各种食品的抗菌防腐。此外红曲还是酿酒酿醋的原料。1979年2月，他汀药之父、日本药学家远藤章在红色红曲霉中获得了一种对HMG-CoA还原酶具有优良抑制活性并能够发挥降血脂作用的化合物，这种化合物命名为 Monacolin K。这种物质可以抑制羟甲基戊二酰辅酶A还原酶。因为这种酶恰好是肝细胞合成胆固醇过程中的关键酶，如果没有这种酶参与，那么相关的代谢就会受阻，特别是胆固醇的合成就会减少。美国的迈克尔·布朗和约瑟夫·哥斯丁通过研究这种“Monacolin K” 发现了抑制胆固醇合成的作用机理。在1985年，诺贝尔生理学或医学奖被授予给了布朗和哥斯丁，以表彰他们关于胆固醇代谢调节机制的发现，特别是他们对低密度脂蛋白（LDL）受体的研究。布朗和哥斯丁揭示了细胞如何通过LDL受体从血液中摄取胆固醇，并且发现了一个关键调节系统，该系统控制着细胞内胆固醇的水平。他们的研究还发现，当LDL受体功能失常或数量不足时，血液中的胆固醇水平会升高，从而增加心脏病和中风的风险。这一发现对于发展降低血液胆固醇水平的治疗方法，包括降脂药物如他汀类药物的研发，具有极其重要的意义。自此红曲成为了世界关注的焦点，经过深入的研究和临床试验， Monacolin K得名洛伐他汀在1987年通过FDA审批，成为第一种上市的他汀类药物，商品名为美降脂 （Mevacor）。洛伐他汀凭着卓越的降胆固醇和降低低密度脂蛋白胆固醇作用，上市不久马上跻身世界十大畅销药行列，成为当时瞩目全球的“重磅炸弹式药物”。因此红曲中的主要有效成分红曲霉素实际上有着悠久的药用历史。但是如果不是红曲，那么引起问题的成分到底是什么呢？3月29日，小林制药公司向日本厚生劳动省报告，其红曲产品中导致问题的成分可能为“软毛青霉酸”。小林制药公司还表示，只有特定批次的产品中含有这种物质。软毛青霉酸是由青霉菌产生的一种天然化合物。那么实际上也就是说，制造红曲的原料被带入了污染物。  02  日本网红药问题频出作为日本著名的制药企业，小林制药的药妆品、保健品深受国人欢迎，在国人赴日旅游的购物清单上必不可少，中国多家电商平台都有小林制药官方店铺。本次保健品致死事件，让曾经号称“安全健康品质保障”的日本产品受到严重质疑。这并不是小林制药第一次翻车。早在2019年，小林制药的洗眼液，就被爆出在加拿大禁售，原因是其中含有处方药成分氨基己酸，副作用包括眼睛流泪、视力改变、头疼、头晕、恶心呕吐、肌肉无力及皮疹。不仅是小林制药，近年来，多家盛名在外的日本药企先后出现了问题。如：面包超人儿童感冒糖浆。这是一款池田模范堂旗下的“面包超人儿童感冒糖浆”，共有草莓、蜜桃等4种口味，小孩子容易服用，因而在日本本土和海外市场广受欢迎。2020年10月，池田模范堂宣布要大规模召回约775万瓶，召回原因是产品在出厂前，没有完成全部质检工序，在中间环节上有疏漏。大正感冒药。该药号称“一包就好，两包巩固，每家必备”，然而，浙大一院药学部专家在网络上查询药品配方后发现，大正感冒药里含有9种成分，在国内的感冒药处方中是基本见不到的。当发生感冒时，应根据症状选择相应的成分，而多余的成分对人体来说只有副作用。“白兔止痛片”。这是一款日本生产的非处方药，在我国并未批准上市，主要在网上代购销售。事实上，这种药起止疼作用的主要成分和国产常见药芬必得、布洛芬是一样的，都是布洛芬。 “白兔止痛片”里面，除了布洛芬之外，还用了丙戊酰脲和咖啡因这两种成分。调查发现，丙戊酰脲这一成分，在很多国家都已被淘汰。它在我国不能用作制药的成分、也不能作为药用，只能作为科研用的化学成分交易。    03  原因何在？政府监管方面的问题。日本人很喜欢服用保健品，2015年，安倍政权时代，为推动经济增长，将保健品当做商机，提出了“功能性标示（機能性表示）”食品制度，有此类标示的保健食品无需经过国家安全性和有效性审查，由厂家自主负责，申报后就可以上市销售。岸田文雄时代，该制度仍然沿用，因此为小林制药“爆雷”埋下了伏笔。历届日本政府急于推动经济增长，却忽视了安全监管的顶层设计方面的问题。小林制药危机反应迟缓。今年1月起，小林制药已陆续收到13名消费者身体不适的报告，其中有6人住院治疗，有的患者甚至还需要进行透析。小林制药在3月16日分析结果就已显示其中可能含有未知成分，但该公司直到22日才宣布召回，对此，小林制药社长承认决策迟缓。日本厚生劳动大臣武见敬三在新闻发布会上说，从最早出现健康问题报告到小林制药宣布召回产品间隔两个多月时间，在此期间小林制药公司未向政府提供相关信息，导致了危害扩大。  04  小林制药事件启示进口保健品应有审批程序。除了“日本网红药”，“泰国减肥药”、“澳洲保健品”……网络平台上各式各样的网红药因为“奇效”的“滤镜”被追捧。根据中国《食品安全法》规定，进口保健品应当到食品药品监督管理部门备案，戴上“蓝帽子”标志才可进入中国市场，未经依法审批进入中国国内销售的保健食品、药品或具有某种保健功能、医疗功效的普通食品，都不要购买。消费者在购买国外保健品应认准“蓝帽子”标志。保健品不能替代药品。消费者特别是中老年人、疾病患者，购买保健品时，除了包装正面，更应重视看背面的成分表，切勿片面听信商家或者所谓“网红”对保健食品的虚假广告和夸大宣传，更不要将保健食品用于疾病治疗。 主要参考文献 1.Another facility inspected amid supplement health scare of Japan's Kobayashi Pharma2.Japan drugmaker reports two more deaths in supplement scare3.What U.S. consumers should know about the health supplement linked to 5 deaths in Japan4.小林制药刚刚宣布：可退款！ 新闻晨报5.日本小林制药“红曲风波”发酵 中消协提示消费者应立即停止服用有关产品，CGTN 6.小林制药“红曲风波”的警示与启示，新华视点7.已致5人死亡！中消协：立即停止服用，中国新闻社8.大正感冒药、白兔止痛片……浙大一院药学部专家扒开“日本神药”真相，中国消费者报9.致死网红药，戳破了中产的日本神话 盐财经10.小林制药“问题原料”，恐波及日本3.3万家企业 澎湃新闻共建Biomedical创新生态圈！如何加入BiG会员？

Following favorable FDA feedback for the treatment of liver disease, the company is preparing further pre-IND meetings with the FDA for the treatment of atherosclerosis and familial hypercholesterolemia SYRACUSE, NY / ACCESSWIRE / April 2, 2024 / Repair Biotechnologies, Inc. ( ) announced today that its lipid nanoparticle (LNP)/messenger RNA (mRNA) therapy has rapidly reversed the progression of atherosclerosis in mouse models applicable to both the rare genetic condition of familial hypercholesterolemia as well as atherosclerosis in the broader population. Repair Biotechnologies develops gene therapies based on the proprietary Cholesterol Degrading Platform (CDP) that safely break down excess free cholesterol inside cells. Excess free cholesterol is toxic to cells and contributes to the development of numerous conditions, including atherosclerosis and metabolic dysfunction-associated steatohepatitis (MASH). Established therapies that reduce LDL-cholesterol in the bloodstream have little effect on intracellular free cholesterol. "Unfortunately statins and PCSK9 inhibitors that reduce LDL-cholesterol in the blood exhibit little ability to reduce the size of established atherosclerotic lesions," said Mourad Topors, Chief Scientific Officer at Repair Biotechnologies. "Our studies in severely atherosclerotic mice demonstrate that LDL-cholesterol is the wrong target if the goal is the outright regression of plaque and dramatic reduction in risk of cardiovascular events. Instead, clearance of intracellular free cholesterol can potentially achieve these goals." Repair Biotechnologies scientists treated atherosclerotic APOE-null mice and LDLR-null mice over a period of six weeks with a CDP LNP-mRNA therapy, expressing therapeutic proteins that safely break down toxic free cholesterol in cells. APOE-null mice are a widely used, consensus model for atherosclerosis in the general population, while LDLR-null mice are the model for homozygous familial hypercholesterolemia, a genetic condition in which the LDLR gene suffers a loss of function mutation and which is characterized by greatly accelerated atherosclerosis. Both mouse models exhibited a dramatic reversal of atherosclerosis. Plaque in the aortic root of APOE-null mice exhibited a 19% drop in plaque lipids and a corresponding 23% increase in plaque collagen, indicating stabilization of soft, lipid-laden plaque that is prone to rupture. In LDLR-null mice, plaque obstruction of the aortic root was reduced by 17%, while treated mice exhibited a greatly improved capacity to run on a treadmill, a measure of cardiovascular health. "Our new results in atherosclerotic mice are as impressive as the results we achieved in mouse models of MASH," said Reason, co-founder and CEO of Repair Biotechnologies. "We are preparing for mid-2024 pre-IND meetings with the FDA for treatment of the rare genetic condition of homozygous familial hypercholesterolemia, as well as the treatment of atherosclerosis more generally. Our LNP-mRNA therapy is applicable in principle to the reversal of all forms of atherosclerosis." In high-fat diet mouse models of MASH, Repair Biotechnologies scientists have demonstrated as much as a 44% reduction in measures of liver fibrosis following eight weeks of CDP LNP-mRNA treatment. In March 2024, Repair Biotechnologies received favorable and comprehensive pre-IND feedback from the FDA. The company leadership looks forward to bringing this treatment to the clinic. Contact Information Reason CEO and Co-Founder press@repairbiotechnologies.com +1 315-299-2407 SOURCE: Repair Biotechnologies, Inc. View the original press release on newswire.com.

Pictured: Healthcare worker holding up a vial for an LDL-C test/iStock, Md Saiful Islam Khan Verve Therapeutics has suspended enrollment in the Phase Ib Heart-1 study evaluating its lead gene editing program VERVE-101 following a serious adverse event, the company announced Tuesday. A patient, who received a 0.45-mg/kg dose of VERVE-101, developed a grade 3 elevation in serum alanine aminotransferase levels, a key biomarker often used to assess liver damage. The patient also experienced grade 3 thrombocytopenia within four days after treatment. Both adverse events were deemed to be induced by VERVE-101. The laboratory abnormalities did not translate into clinical symptoms, such as bleeding, and were fully resolved within a few days, according to Verve. Still, an independent data and safety monitoring board recommended pausing enrollment in Heart-1 while Verve investigates the cause of the adverse events. The company has also reported these safety events to the FDA and other health regulatory authorities worldwide. VERVE-101’s Investigational New Drug application also remains active, according to the announcement. Verve’s stock price dropped 31% in premarket trading on Tuesday in response to the news, reported Seeking Alpha. Verve CEO Sekar Kathiresan in a statement said that the biotech believes these laboratory abnormalities “are attributable to the LNP [lipid nanoparticle] delivery system,” while adding that Heart-1 provides strong proof-of-concept evidence “for in vivo base editing of the PCSK9 gene in the liver, with a meaningful and durable lowering of LDL-C.” The company remains confident in this mechanism of action and will focus on the development of VERVE-102, another investigational gene editor that also targets the PCSK9 gene but uses a different LNP delivery technology. VERVE-102 uses an ionizable lipid that has already been shown to be well-tolerated in outside clinical trials. Verve is currently “prioritizing the initiation” of the open-label Phase Ib Heart-2 study, assessing VERVE-102 in patients with heterozygous familial hypercholesterolemia or premature coronary artery disease who need further LDL-C control, Kathiresan said. Heart-2, which will focus on the safety and tolerability of VERVE-102 with additional analyses for pharmacokinetics and PCSK9 and LDL-C concentrations, is set to start in the second quarter of 2024. Both VERVE-101 and VERVE-102 target the PCSK9 gene, which encodes a protein that regulates the amount of LDL receptors there are in the liver. Higher expression of PCSK9 has been shown to result in higher cholesterol levels. Both of Verve’s investigational gene editors carry messenger RNA and guide RNA, which let them target and permanently turn off the PCSK9 gene in the liver lowering the levels of disease-causing LDL-C in the blood. Results of the Heart-1 study validated this mechanism of action, demonstrating a mean, time-averaged 46% reduction in LDL-C, according to Verve. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.