COX-2

关注并星标CPHI制药在线       皮肤是机体最大的器官，具有屏障、吸收、感觉、体温调节、代谢、免疫等多种生理功能。大面积皮肤烧伤、皮肤良恶性肿瘤、皮肤色素性疾病等引起的皮肤损伤严重影响患者健康。其中，皮肤烧伤不仅破坏皮肤的屏障功能，还改变皮肤的痛觉、温觉、触觉等。研制含皮肤附属器的功能性组织工程全层皮肤是解决大面积皮损的有效途径，具有重要的研究价值。近年来，随着组织工程学的飞速发展，发现间充质干细胞（MSCs）是构建全层皮肤的理想种子细胞，在治疗皮肤创伤方面展现了良好的应用前景。       1、皮肤愈合的过程和机制       皮肤损伤修复需要经过皮肤细胞严密的编排、整合及分化、迁移、增殖和凋亡过程，才能实现皮肤多层结构的再生。皮肤损伤的修复可以概括为以下 4 个时期：①血液凝固期：损伤初期血小板和凝血因子被激活，启动内、外源性凝血途径实现凝血；②炎症反应期：中性粒细胞、单核细胞和巨噬细胞增多，通过吞噬异物和调节炎症因子的释放调控炎症反应；③细胞增殖期：包括通过成纤维细胞增殖介导肉芽组织形成、通过角质细胞介导再上皮化和通过内皮细胞增殖介导血管生成等过程；④组织重塑期：随着细胞外基质（extracellular matrix，ECM）的分泌和肉芽组织的增生，成纤维细胞分裂合成大量胶原纤维，新生血管增多。后期在基质金属蛋白酶（matrix metalloproteinase，MMPs）作用下，降解 ECM，胶原蛋白发生新陈代谢，最终导致瘢痕的形成。       2、MSCs促进创伤愈合、抑制瘢痕形成机制       ①免疫调节作用。在组织损伤发生后，伤口处炎症环境会直接刺激MSCs发挥其特有的免疫调节作用，包括增强环氧合酶2的活性，上调前列腺素E2（prostaglandin E2，PGE2）等。在PGE2的影响作用下，T 细胞和巨噬细胞开始重新编程并开始表达高浓度的IL-10，而研究发现IL-10 对无瘢痕修复必不可少，其过量表达能明显抑制瘢痕的形成。MSCs 抑制中性粒细胞侵入到伤口处，以防止嗜中性粒细胞释放的活性氧（reactive oxygen species，ROS），进一步引起机体组织氧化损伤；IL-10 也可通过直接下调巨噬细胞和T细胞中TGF-β1 的表达、重新编码成纤维细胞、上调基质金属蛋白酶（matrix metalloproteinases，MMPs）的表达、下调胶原的表达促进细胞外基质的重塑以达到抗纤维化的目的。此外，IL-10 还能通过减少促炎因子IL-6 及IL-8 的表达来达到抑制胶原过度沉积。       ②分泌一氧化氮中和活性氧。MSCs 可以促进氧化氮合酶的产生，通过改变 ROS/RNS 的平衡来有效地抑制纤维化组织的形成。在创伤开始的炎症期，中性粒细胞分泌胶原过度沉积的增强剂如超氧化物、过氧化氢以及烷基过氧化物等大量的ROS。ROS的主要作用是对膜磷脂产生氧化作用以及通过对TGF-β1的诱导而促进纤维化的发生。MSCs可促使ROS 转变为活性氮分子（reactive nitrogen species，RNS），如过氧硝酸盐等，减缓对DNA和膜磷脂的损伤，从而抑制纤维化的发生。       ③分泌具有抗纤维化生长因子。研究表明，MSCs可分泌各种细胞因子和生长因子，一些因子具有抗纤维化的作用，如肝细胞 生长因子（hepatocyte growth factor，HGF）、IL-10 以及肾上腺髓质素等。HGF 在减轻纤维化以及抑制皮肤瘢痕形成的机制主要包括：一是对成纤维细胞功能的调节，在HGF的存在情况下，HGF 受体通过绑定中和TGF-β/Smad 信号通路的下游信号级联反应，抑制SMAD3 蛋白的促炎基因的转录因子作用，成纤维细胞下调 TGF-β1、Ⅰ型和Ⅲ型胶原的表达，还可以刺激成纤维细胞 MMP 家族 MMP-1、MMP-3及MMP-13 表达的上调，促使ECM发生逆转。二是HGF通过促进角化细胞的迁移增殖，并上调血管内皮 生长因子A（vascular endothelial growth factor-A，VEGF-A）的表达，促使创伤处生成高质量的并且血运丰富的肉芽组织，促进伤口的上皮化的形成。三是HGF可抑制各种来源的肌成纤维细胞的分化，HGF可以抑制创伤处的成纤维细胞向肌成纤维细胞分化。       ④调节皮肤成纤维细胞的数量及功能。MSCs可作用于损伤处的成纤维细胞来调控细胞外基质的产生，使损伤皮肤的修复更接近于正常皮肤。在创伤修复过程中，皮肤恢复其完整性必须要有成纤维细胞的参与，但是这些成纤维细胞会产生过多的 ECM，从而导致瘢痕的产生。在创伤处的MSCs 通过分泌的生物活性分子包括HGF、PGE2 等可以抑制血管内皮细胞 EMT，也可以抑制肌成纤维细胞的分化。另外，在修复过程中，MSCs 还可通过旁分泌分泌生物活性因子促进成纤维细胞的功能。       ⑤促进组织的血管再生及血管稳定。创伤修复过程中的炎症阶段、上皮形成期、成熟期等都必须依靠新生的毛细血管和结缔组织即肉芽组织的增殖和修补来完成，在增殖阶段，血管再生可为肉芽组织形成提供营养。在血管系统重塑的过程中，除巨噬细胞及成纤维细胞外，MSCs也会分泌促进血管化的细胞因子包括成纤维细胞生长因子、VEGF-A等，促进微血管内皮细胞的增殖、迁移以及分化。另外，MSCs 还可通过旁分泌（如分泌肾上腺髓质素等）来促进血管的稳定保护脉管系统。       ⑥可分化为各种皮肤细胞。MSCs都具有典型的成骨、成脂及成软骨的分化能力，这也类似于在创伤部位各种来源的成纤维细胞向肌成纤维细胞转化一样，是一个表型的转化。研究表明，MSCs 可分化为各种皮肤细胞，包括表皮细胞、角化细胞、小血管内皮细胞等，直接参与到表皮和真皮结构再生过程，达到促进皮肤创伤愈合的目的。       3、提高MSCs修复皮肤损伤效率的有效途径       目前应用MSCs促进皮肤损伤修复的方法主要是局部注射和静脉注射。局部注射一般是将MSCs注射至创面的周围，但由于注射的面积和深度难以控制，并不能让MSCs直接、均匀地分布在创面上。静脉注射则不能保证所有MSCs都参与皮肤修复，且MSCs分泌的外泌体在体内很快会被清除，难以维持较高浓度状态，需多次给药。此外，注射的方法还会对皮肤造成二次伤害，给治疗带来一定的困难。这些问题使得间充质干细胞的最终治疗潜力受到限制，达不到其应有的修复效果。因此，人们也对如何提高 MSCs 的修复效率做了许多探索，取得了较为丰富的研究进展。       ①生物支架。生物支架具有良好的生物相容性和生物降解性，可将干细胞输送到伤口处。常见的用于促进皮肤损伤修复药物递送的生物支架材料分为天然支架和合成支架。天然支架的材料成分包括透明质酸、壳聚糖、胶原蛋白、海藻酸盐等，合成支架材料成分包括聚乙二醇、聚乳酸-羟基乙酸等。目前，对于皮肤损伤应用最多的支架形式为水凝胶支架，它可以使外泌体在皮肤局部应用后浓度更加稳定，以延迟外泌体的释放并增强其伤口愈合能力。水凝胶是一种稳定的亲水性网络结构，通过物理、化学和生物酶法交联而成，具有良好的生物相容性、可降解性和保水性等，已被证实是最友好、经济并容易获得的材料，在临床医学中显现出极大的应用潜力。水凝胶负载间充质干细胞来源的外泌体（MSC-EXOs）既可解决静脉注射法造成的外泌体在体内被快速清除的问题，又可以将含有外泌体的水凝胶直接放置于目标部位或其附近，能够保证外泌体的作用剂量更加集中，同时发挥外泌体和水凝胶促进伤口修复的作用。       ②预处理。通过某些预处理可以改善 MSCs 的生化和生物物理特性，从而增强其修复功能。研究发现内皮细胞培养基预处理的脂肪MSCs 在体外和糖尿病小鼠创伤模型中均显示出血管生成能力、增殖能力和向内皮分化能力的增强。MSCs 还可以经过一些化学物质的预处理提高修复皮肤损伤的能力。如使用卵磷脂乳化的鸸鹋油和丁基羟基甲苯处理脂肪 MSCs，显著提高了其再生潜力。此外，也有人尝试用生物玻璃材料激活尿液来源的MSCs，通过刺激 MSCs 与受体细胞之间以及成纤维细胞与内皮细胞之间的旁分泌效应来提高小鼠皮肤的愈合能力。       ③低氧环境。研究表明，缺氧可以提高 MSCs 的皮肤创伤愈合能力。在小鼠伤口愈合模型中植入人羊膜MSCs，发现与正常条件下培养的 MSCs 相比，缺氧条件下培养的 MSCs 具有更高的生存能力和增殖能力，并增加了血管内皮 生长因子的表达。这些MSCs 还提高了人真皮成纤维细胞的活力和迁移率，增加了细胞外基质的表达，加速了伤口愈合。此外有研究人员发现低氧环境下，小鼠的骨髓 MSCs在体外分泌了更多的碱性纤维母细胞生长因子、血管内皮 生长因子 A 和白细胞介素-6。在体内实验也发现移植的骨髓 MSCs 在低氧环境下能使皮肤伤口收缩明显加快，体内细胞增殖、新生血管形成速度明显提升。       ④基因重组。对 MSCs 进行基因重组，将 MSCs 既用作种子细胞又用作将目的基因传递到伤口部位的载体，也是一种很有前景的治疗皮肤损伤的手段。有研究针对 MSCs 进行基因改造，通过改变其活性来增强其修复皮肤损伤的能力。例如，过表达转化生长因子-β3的骨髓 MSCs 不仅改善了家兔耳部伤口愈合过程，而且减少了瘢痕组织的形成。研究人员使用重组慢病毒载体修饰人羊膜 MSCs 过表达白细胞介素-10，发现其在加速小鼠伤口愈合、促进血管生成、调节炎症、调节 ECM 重构、促进创面愈合和提高愈合质量方面等方面明显强于未修饰的 MSCs。       ⑤细胞膜片技术。细胞膜片是一种无支架的细胞密集组织。由于细胞密度是提高细胞移植治疗效果的重要因素之一，与单细胞片相比，移植构建的分层细胞片可以更好地促进组织功能的恢复和组织再生。研究报道，以血卟啉包合聚酮膜为材料，将骨髓MSCs 接种到膜上后敷在小鼠伤口上，这种三层细胞片移植和堆叠的方法促进了小鼠创面血管生成和皮肤再生，增强了受损皮肤组织的修复。       尽管 MSCs 的应用无法复制胚胎式的创伤修复，而使成人的创伤修复达到无瘢痕的完美修复，但它仍然可存在巨大的治疗潜能。在皮肤创面修复愈合过程中，通过抑制皮肤瘢痕的形成达到提高创面愈合质量已成为当前皮肤再生修复研究的新目标，此时，MSCs 巨大的治疗潜能则成为抑制皮肤瘢痕形成的新策略，为创面修复提供一种新的视角和治疗手段。       参考资料       [1]张立,王强.间充质干细胞在皮肤损伤修复中的作用研究[J].中国临床医学,2015,22(04):571-574.   [2]武艳,张哲,杨岚等.间充质干细胞在创伤愈合过程中抑制瘢痕形成的作用机制[J].中国医药导报,2016,13(09):47-50.       [3]程延思危,宋关斌.间充质干细胞与皮肤的损伤修复[J].生物医学工程学杂志,2021,38(02):387-392.       作者简介：小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。【智药研习社近期课程预告】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~

DUBLIN, March 26, 2024 /PRNewswire/ -- Endo International plc (OTC: ENDPQ) announced today that one of its operating companies, Par Pharmaceutical, Inc., launched ibuprofen-famotidine 800 mg/26.6 mg tablets, a generic version of Amgen's (formerly Horizon Therapeutics) DUEXIS®. "We're proud to provide affordable choices to healthcare providers and their appropriate patients while strengthening our reputation as a reliable, quality supplier," said Scott Sims, Senior Vice President and General Manager, Injectable Solutions & Generics at Endo. The combination medication is used to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis while decreasing the risk of developing ulcers of the stomach and upper intestines people may experience from ibuprofen alone. According to IQVIA™, ibuprofen-famotidine tablet sales were approximately $49 million for the 12 months ended December 31, 2023. DUEXIS® is a registered trademark of Horizon Therapeutics USA, Inc. CONTRAINDICATIONS: Ibuprofen and famotidine tablets are contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to ibuprofen or famotidine or any components of the drug product. History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients. In the setting of coronary artery bypass graft (CABG) surgery. Ibuprofen and famotidine tablets should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists. Cross sensitivity with other H2-receptor antagonists has been observed. WARNINGS AND PRECAUTIONS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG. Post-MI Patients Avoid the use of ibuprofen and famotidine in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ibuprofen and famotidine is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including ibuprofen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDS. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue ibuprofen and famotidine until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding. Active Bleeding When active and clinically significant bleeding from any source occurs in patients receiving ibuprofen and famotidine, the treatment should be withdrawn. Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue ibuprofen and famotidine immediately, and perform a clinical evaluation of the patient. Hypertension NSAIDs, including ibuprofen and famotidine, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema Fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]). Avoid the use of ibuprofen and famotidine in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ibuprofen and famotidine is used in patients with severe heart failure, monitor patients for signs and symptoms of worsening heart failure. Renal Toxicity and Hyperkalemia Renal Toxicity Avoid the use of ibuprofen and famotidine in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal failure. If ibuprofen and famotidine is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Anaphylactic Reactions Ibuprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma. Seek emergency help if an anaphylactic reaction occurs. Seizures Central nervous system (CNS) adverse effects including seizures, delirium, and coma have been reported with famotidine in patients with moderate (creatinine clearance <50 mL/min) and severe renal insufficiency (creatinine clearance <10 mL/min), and the dosage of the famotidine component in ibuprofen and famotidine is fixed. Therefore, ibuprofen and famotidine is not recommended in patients with creatinine clearance < 50 mL/min. Exacerbation of Asthma Related to Aspirin Sensitivity Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, ibuprofen and famotidine is contraindicated in patients with this form of aspirin sensitivity. When ibuprofen and famotidine is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Serious Skin Reactions NSAIDs, including ibuprofen, which is a component of ibuprofen and famotidine tablets, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of ibuprofen and famotidine at the first appearance of skin rash or any other sign of hypersensitivity. Ibuprofen and famotidine is contraindicated in patients with previous serious skin reactions to NSAIDs. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ibuprofen and famotidine. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. If such signs or symptoms are present, discontinue ibuprofen and famotidine and evaluate the patient immediately. Fetal Toxicity Limit use of NSAIDs, including ibuprofen and famotidine, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. Masking of Inflammation and Fever The pharmacological activity of ibuprofen and famotidine in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and chemistry profile periodically. Concomitant NSAID Use Ibuprofen and famotidine tablets contain ibuprofen as one of its active ingredients. It should not be used with other ibuprofen-containing products. The concomitant use of NSAIDs, including aspirin, with ibuprofen and famotidine may increase the risk of adverse reactions. Aseptic Meningitis If signs or symptoms of meningitis develop in a patient on ibuprofen and famotidine, the possibility of its being related to ibuprofen should be considered. Ophthalmological Effects Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a patient develops such complaints while receiving ibuprofen and famotidine, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing. ADVERSE EVENTS Most common adverse reactions (>1% and greater than ibuprofen alone) are nausea, diarrhea, constipation, upper abdominal pain, and headache. INDICATION AND USAGE Ibuprofen and famotidine tablets, a combination of the NSAID ibuprofen and the histamine H2-receptor antagonist famotidine, is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers, which in the clinical trials was defined as a gastric and/or duodenal ulcer, in patients who are taking ibuprofen for those indications. The clinical trials primarily enrolled patients less than 65 years of age without a prior history of gastrointestinal ulcer. Controlled trials do not extend beyond 6 months. Click for Full Prescribing Information, including BOXED WARNING and Medication Guide. About Endo Endo (OTC: ENDPQ) is a specialty pharmaceutical company committed to helping everyone we serve live their best life through the delivery of quality, life-enhancing therapies. Our decades of proven success come from passionate team members around the globe collaborating to bring treatments forward. Together, we boldly transform insights into treatments benefiting those who need them, when they need them. Learn more at or connect with us on LinkedIn. Cautionary Note Regarding Forward-Looking Statements Certain information in this press release may be considered "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 and any applicable Canadian securities legislation including, but not limited to, the statements by Mr. Sims, any statements relating to product launch, quality, affordability, efficacy, reliability or sales, and any statements that refer to expected, estimated or anticipated future results or that do not relate solely to historical facts. Statements including words or phrases such as "believe," "expect," "anticipate," "intend," "estimate," "plan," "will," "may," "look forward," "intend," "guidance," "future," "potential" or similar expressions are forward-looking statements. All forward-looking statements in this communication reflect the Company's current views as of the date of this communication about its plans, intentions, expectations, strategies and prospects, which are based on the information currently available to it and on assumptions it has made. Actual results may differ materially and adversely from current expectations based on a number of factors, including, among other things, the outcome of the Company's contingency planning and restructuring activities; the timing, impact or results of any pending or future litigation, investigations, proceedings or claims, including opioid, tax and antitrust related matters; any actual or contingent liabilities; settlement discussions or negotiations; the Company's liquidity, financial performance, cash position and operations; the risks and uncertainties associated with chapter 11 proceedings; the time, terms and ability to complete a chapter 11 plan of reorganization or to pursuen an alternative emergence transaction; the risk that the Company's chapter 11 cases may be converted to cases under chapter 7 of the Bankruptcy Code; the adequacy of the capital resources of the Company's businesses and the difficulty in forecasting the liquidity requirements of the operations of the Company's businesses; the unpredictability of the Company's financial results; the Company's ability to discharge claims in chapter 11 proceedings; negotiations with the holders of the Company's indebtedness and its trade creditors and other significant creditors; the risks and uncertainties with performing under the terms of the restructuring support agreement and any other arrangement with lenders or creditors while in chapter 11 proceedings; the performance, including the approval, introduction, and consumer and physician acceptance of new products and the continuing acceptance of currently marketed products; and the Company's ability to obtain and successfully manufacture, maintain and distribute a sufficient supply of products to meet market demand in a timely manner. The Company expressly disclaims any intent or obligation to update these forward-looking statements, except as required to do so by law. Additional information concerning risk factors, including those referenced above, can be found in press releases issued by the Company, as well as the Company's public periodic filings with the U.S. Securities and Exchange Commission and with securities regulators in Canada, including the discussion under the heading "Risk Factors" in the Company's most recent Annual Report on Form 10-K and any subsequent Quarterly Reports on Form 10-Q or other filings with the U.S. Securities and Exchange Commission. SOURCE Endo International plc

ADC研发，早已内卷成了麻花。医药寒冬下，还有哪些研发机会？siRNA或是不错的突破方向。随着小核酸药物成为近年来研发热点之一，其类别ASO、siRNA、aptamer等研发方向开始发力，以品种数量来看，siRNA逐渐成为研发界新宠。01上市6款，临床≥II期数十款与传统小分子和抗体相比，siRNA关联独特的疾病靶点、开发成功率高、开发时间短、并可基于技术平台进行药物开发。目前，全球有100多家公司从事siRNA领域的研究，其中约30家专门从事siRNA药物的开发。截至2023年，已有6种siRNA药物获批上市，其中5款来自于Alnylam。据Alnylam官网介绍，成立于2002年的Alnylam开发了全球首个获批上市的RNAi治疗药物ONPATTRO®（patisiran），后相继开发了GIVLAARI®（givosiran）、OXLUMO®（lumasiran）、Leqvio®（inclisiran）、AMVUTTRA®（vutrisiran）等，该公司当前重点专注于遗传疾病、心脏代谢疾病、传染病、中枢神经系统和眼部疾病等适应症领域。图1 Alnylam公司公布的药物研发管线图片来源：https://www.alnylam.com/alnylam-rnai-pipeline另，有文献报道，截至到2023年8月，全球有15个正在研究的siRNA药物处于临床2期或以上阶段，适应症主要集中于遗传性疾病、罕见病、并向其他常见疾病拓展（如代谢性疾病、心血管疾病、乙型肝炎、癌症等）。如，ALN-AGT（NCT04936035，NCT05103332）目前正在开发用于治疗高血压，并已进入II期临床。Olpasiran（NCT05581303）旨在治疗动脉粥样硬化斑块，目前正在进行III期临床。SLN360（NCT05537571）是一种降脂siRNA，已进入II期。RBD1016（NCT05961098）是一种用于治疗乙型肝炎的N-乙酰半乳糖胺（GalNAc）偶联siRNA，将在欧洲开始II期临床试验。STP705和STP707由两种靶向转化生长因子-β1（TGF-β1）和环氧合酶-2（COX-2）的siRNA组成，并以肽纳米颗粒（PNPs）的形式开发；STP705局部给药于病变组织，用于治疗原位鳞状细胞癌（NCT04844983，2期）和基底细胞癌（NCT04669808，2期），而STP707（NCT05037149，1期）为静脉注射给药，用于治疗多种实体瘤和纤维化性肝脏疾病，如原发性硬化性胆管炎。图2 获批上市&临床≥II期siRNA疗法图片来源：Trends in Molecular Medicine,January 2024,Vol.30,No.1 https://doi.org/10.1016/j.molmed.2023.10.00502国内药企对siRNA的青睐据公开信息统计，国内药企在siRNA方向的产品布局，已有＞20款品种通过引进和自研的方式进行开发，最高临床阶段为临床II期。另，在刚刚过去的2023年，就有多个品种获得国内临床默示许可，具体如：君实生物与润佳医药共同研发的靶向血管生成素样蛋白3（ANGPTL3）siRNA药物JS401，拟用于治疗高脂血症。杭州舶临医药科技有限公司自主研发的siRNA新药BW-00163，拟用于治疗高血压；另一款siRNA新药BW-00112，拟用于治疗血脂异常；再一款siRNA新药BW-20805，拟用于治疗遗传性血管性水肿（HAE）。圣因生物自主研发的一款靶向肝细胞PCSK9的siRNA-GalNAc结合物SGB-3403，拟用于治疗高胆固醇血症、混合型血脂异常以及动脉粥样硬化性心血管疾病。正大天晴自主研发的一种靶向乙型肝炎病毒（HBV）的siRNA药物TQA3038，拟用于治疗慢性乙型肝炎。靖因药业开发的一款siRNA药物SRSD101，能特异性肝靶向PCSK9，临床拟用于治疗原发性高胆固醇血症；另一款siRNA药物SRSD107，临床拟用于预防或治疗血栓栓塞性疾病。石药集团自主研发的一款通过偶联GalNAc实现肝脏靶向递送的siRNA药物SYH2053，临床拟用于治疗成人原发性高胆固醇血症或混合型血脂异常。大睿生物自主研发的PCSK9靶向双链siRNA药物RN0191，临床拟用于治疗成人原发性高胆固醇血症（家族性和非家族性）或混合型血脂异常。03siRNA当前存在的技术痛点、解决方向尽管siRNA药物研究取得了重大进展，且国内药企对此青睐有加，但仍存在一些需要克服的关键挑战，有文献对此归纳为3个“E”挑战（进入-Entry、逃逸-Escape、疗效-Efficacy），并认为上述3点是限制siRNA临床开发的3个关键问题。➣进入挑战（有针对性的积累和细胞摄取）第一个挑战是在靶器官/组织中实现siRNA的有效富集和有效内化到目标靶细胞中。siRNA由于分子相对较大和阴离子电荷特性，未经修饰的裸siRNA表现出低生物利用度，且半衰期短至几分钟。同时，siRNA可以被存在于血浆、组织和细胞质中的核酸酶或磷酸酶迅速降解。尽管siRNA可以被动地在肝脏或肿瘤组织等多孔部位积累，但将这些治疗药物输送到优先吸收这些分子的器官以外的身体其他部位，以及BBB的有效跨膜，仍然面临着巨大的挑战。➣逃逸挑战（内体和溶酶体逃逸）第二个挑战是如何实现有效的内体和溶酶体逃逸。虽然siRNA可以通过内吞作用进入细胞，但只有不到1%的siRNA能够从内吞体逃逸，其中被动逃逸率小于0.01%。ASGPR（人去唾液酸糖蛋白受体）略不同，其肝细胞表达水平约为500000或更高，回收时间小于20分钟。治疗过程中，肝细胞细胞质中可以积累足够的GalNAc-siRNA偶联物，以达到治疗水平；但除了肝细胞外，对于其他类型的细胞，siRNA逃逸仍然是一个未解决的问题。➣疗效挑战（药物体内疗效）第三个挑战是需要良好的体内稳定性、持久的效果和安全性。利用病毒载体在体内传递核酸存在一定的毒副作用，化学合成的载体系统如阳离子脂质和大多数无机纳米颗粒也可能在体内诱导细胞凋亡和炎症。现，化学修饰已被广泛用于增强siRNA的稳定性，减少/消除脱靶效应和免疫原性，从而提高siRNA的“疗效”。通过复杂的修饰，siRNA已经成功实现了99%的基因沉默并在体内持续存在，可以实现低剂量的季度、半年甚至每年给药。然而，修饰诱导的稳定性和特异性增强可能会降低沉默活性或引起意想不到的不良反应。图3 限制siRNA临床开发的3个“E”挑战图片来源：Trends in Molecular Medicine,January 2024,Vol.30,No.1 https://doi.org/10.1016/j.molmed.2023.10.005针对上述3个挑战，业界也正在逐点进行问题的解决，如进一步的结构修饰，这包括开发新的化学修饰单体、修饰模式和RNAi触发结构。传统的siRNA修饰主要包括2'-OMe、2'-F、PS，而新的修饰单体和修饰模式的发展将进一步完善siRNA的药代动力学和安全性。如，新型单体如乙二醇核酸(GNA)、5'-(E)-乙烯基膦酸盐[5'-(E)-VP]，新型RNAi触发结构如sciRNAs，不对称siRNA和二价siRNA骨架等。同时，siRNA的设计和修饰正在通过AI算法来实现。再如，开发一些独特的递送系统。虽然各种纳米材料如LNPs、聚合物、无机纳米颗粒和外泌体已经被开发成siRNA载体，但它们的负载能力、稳定性、安全性和有效性仍然存在局限性。未来的基础研究大体还是侧重于优化这些载体的理化性质，如与配体共价连接，这些配体包括小分子、脂质、多肽、抗体、糖、非编码RNA等，并基于此进一步形成靶向。图4 规避三个“E”挑战的策略和方法图片来源：Trends in Molecular Medicine,January 2024,Vol.30,No.1 https://doi.org/10.1016/j.molmed.2023.10.00504结语siRNA自首款产品上市至今，较另一大类小核酸药物ASO，时间不长，相对具有更大的开发空间和潜力，国内药企也是纷纷将资源投入于此。但客观讲，基于该领域已形成的现有技术背景和现可以实现的技术特征如靶向、多途径给药、强效持久、低剂量、总体安全性等，国内企业目前大都处于跟进的状态，离“质”的突破尚需时间。同时，还需要注意其他类别小核酸药物的开发，防止形成技术方面总体被覆盖的可能性。参考来源：1.Trends in Molecular Medicine,January 2024,Vol.30,No.1.doi.org/10.1016/j.molmed.2023.10.0052.https://www.alnylam.com/声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 金银花转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信） 阅读原文，是昨天最受欢迎的文章哦