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更新于：2025-03-20
Tiopronin
硫普罗宁
更新于：2025-03-20
概要
基本信息
非在研机构- |
最高研发阶段批准上市 |
首次获批日期 日本 (1970-03-30), |
最高研发阶段(中国)批准上市 |
特殊审评孤儿药 (日本) |
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结构/序列
分子式C5H9NO3S |
InChIKeyYTGJWQPHMWSCST-UHFFFAOYSA-N |
CAS号1953-02-2 |
关联
2
项与 硫普罗宁 相关的临床试验NCT03663855
Effect of Increasing Doses of Tiopronin on Cystine Capacity in Patients With Cystinuria
The purpose of this study is to determine the minimum effective dose of the cysteine binding thiol drug (CBTD) Tiopronin on urine cystine capacity, which is a measure of cystine solubility in the urine, in patients with cystinuria to evaluate the effect of escalating doses of cystine binding thiol drugs on the cystine capacity of the urine. The overall goal will be to help guide therapy and ultimately minimize unnecessary side effects caused by larger dosages.
Cystinuria is a rare genetic disease that can lead to significant morbidity in affected patients due to the recurrent nature of the disease. This study will follow the levels of urine cystine capacity in order to help guide treatment and to use lower than usually prescribed Tiopronin doses to decrease the potential side effects while maintaining therapeutic benefit. This will increase adherence with the medications by decreasing the burden of the large number of pills that need to be taken daily.
Cystinuria is a rare genetic disease that can lead to significant morbidity in affected patients due to the recurrent nature of the disease. This study will follow the levels of urine cystine capacity in order to help guide treatment and to use lower than usually prescribed Tiopronin doses to decrease the potential side effects while maintaining therapeutic benefit. This will increase adherence with the medications by decreasing the burden of the large number of pills that need to be taken daily.
开始日期2018-11-01 |
申办/合作机构 |
NCT01095731
Phase II Study of the Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage
The purpose of this phase II study is to further assess the safety of tiopronin in aneurysmal subarachnoid hemorrhage(aSAH) patients in order to obtain preliminary data on the efficacy of tiopronin versus placebo in reducing serum and cerebrospinal fluid (CSF) 3AP levels in this patient population.
Funding Source - FDA Office of Orphan Products Development
Funding Source - FDA Office of Orphan Products Development
开始日期2010-04-01 |
申办/合作机构  Columbia University [+3] |
100 项与 硫普罗宁 相关的临床结果
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100 项与 硫普罗宁 相关的转化医学
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100 项与 硫普罗宁 相关的专利（医药）
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王多伟
中国药科大学特聘副研究员，硕士生导师，药理学博士，曾于 2018 年赴美国医学院Albert Einstein College of Medical 从事博士后研究工作。目前已在国际重要学术期刊 PNAS、Gut、Cell Rep、Hepatology、Cancer Lett 等发表 SCI 论文 10 余篇。主持国家自然科学基金面上项目及青年项目各 1 项。主要研究方向为肝癌治疗靶标的发现和确证，抗体及新抗原疫苗等肝癌治疗产品的研发。
肝纤维化发生机制及相关治疗药物研究进展PPS
郭飞宇，王多伟 *
（中国药科大学多靶标天然药物全国重点实验室，江苏 南京 211198）
[摘要] 肝损伤引起的肝细胞死亡会导致肌成纤维细胞激活，进而分泌大量细胞外基质，造成肝纤维化。肝纤维化是慢性肝病向肝硬化发展过程中的关键步骤，但目前临床上公认有效的肝纤维化治疗药物较少。因此，深入了解肝纤维化的发生机制并寻找其新的治疗靶点十分重要。对肝纤维化发生机制以及临床治疗药物研究进展进行综述，以期为肝纤维化的预防和治疗提供参考。
1
引言
肝脏疾病每年导致全球近 200 万人死亡，对人类健康造成严重威胁 [1]。肝纤维化是病毒性肝炎、酒精性肝病、代谢功能障碍相关的脂肪性肝炎（metabolic dysfunction-associated steatohepatitis，MASH）、胆汁淤积性肝病等晚期慢性肝病的共同病理特征 [2]。肝损伤引起肝细胞大量死亡后，细胞外基质蛋白和纤维结缔组织会在肝脏中过度沉积，造成纤维化 [3-4]。随后，肝纤维化产生的过量纤维进一步改变肝脏结构，形成瘢痕和再生结节，从而导致肝功能异常和肝脏血流阻力增加 [5]。目前，临床有效的肝纤维化治疗药物较少，且局限于控制病因的药物和中药。因此，深入了解肝纤维化发生发展机制，寻找新的肝纤维化治疗靶点，对于解决肝纤维化治疗难题至关重要。本文对肝纤维化发生机制及临床治疗药物研究进展进行综述，旨在为肝纤维化的预防和治疗提供参考。
2
肝纤维化的发生机制
肝纤维化发生机制涉及多种复杂因素，主要包括肝细胞损伤、炎症反应、肝星状细胞（hepatic stellate cell，HSC）激活和细胞外基质沉积。其中肝损伤是肝纤维化发生的基础，当肝脏受到酒精、药物、病毒或代谢异常等刺激时，肝细胞遭受损伤，主要表现为细胞膜流动性降低和通透性增加以及线粒体受损。随后肝损伤引起白细胞介素（interleukin，IL）-1β 等炎症因子释放，诱导 HSC 活化。激活的HSC 转化为肌成纤维细胞，迁移至损伤部位，加速增殖并分泌细胞外基质，导致纤维化的形成 [5]。以下将从慢性肝炎病毒感染、酒精性肝损伤、代谢功能障碍相关肝损伤和胆汁淤积性肝损伤 4 个方面介绍肝纤维化的发生机制。
2.1 慢性肝炎病毒感染
慢性肝炎病毒感染是影响全球数亿人的重要健康问题，其中慢性乙型肝炎患者数量超过 2.57 亿，慢性丙型肝炎患者数量超过 1.5 亿 [6]。慢性肝炎病毒感染可以进一步发展为肝纤维化，其机制主要涉及炎症反应和 HSC 的激活。
肝炎病毒感染可损伤肝细胞并直接引起炎症反应。乙型肝炎病毒（hepatitis B virus，HBV）感染肝细胞后，病毒的 X 蛋白通过髓样分化初级应答蛋白88（myeloid differentiation primary response protein 88，MyD88）途径促进 IL-6 的分泌，加剧肝脏炎症 [7]。而丙型肝炎病毒（hepatitis C virus，HCV）的核心蛋白和 NS3 蛋白通过 Toll 样受体 2（Toll like receptor 2，TLR2），激活 IL-1 受体相关激酶（IL-1 receptor-associated kinase，IRAK）和激活蛋白-1（activator protein-1，AP-1），引起炎症反应 [8]。同时，肝细胞被 HCV 感染后还可以分泌 C-C 基序趋化因子配体（C-C motif chemokine ligand，CCL）2 和 CCL21 等趋化因子，招募淋巴细胞，加剧肝脏炎症 [9]。慢性肝炎病毒除了通过感染并损伤肝细胞来引起炎症反应，还可以通过 HSC 加剧肝脏炎症，研究表明，在乙型肝炎肝纤维化晚期患者中，HSC通过前列腺素 E2（prostaglandin E2，PGE2）/前列腺素 E 受体 2（prostaglandin E receptor 2，EP2）途径以及 PEG2/EP4 途径增加肝组织中辅助性 T 细胞17（T helper cell 17，Th17）的数量 [10]，而 Th17 通过分泌IL-6、IL-17和IL-23等炎症因子，引发炎症[11]。此外，HSC 与 HCV 感染的肝细胞共培养时，HSC可通过分泌 IL-1α 上调肝细胞中 CCAAT/增强子结合蛋白 β（CCAAT/enhancer binding protein β，C/EBP β）的表达，促进肝细胞分泌 IL-6 等炎症因子，加剧肝脏炎症 [12]。以上研究表明，HBV 和 HCV 不仅可以直接损伤肝细胞、造成炎症，还可以通过HSC 间接作用于肝细胞，进而加剧肝脏炎症，最终促进肝纤维化进程 [13-15]。
HSC 的活化是肝纤维化形成的关键因素，激活的 HSC 转化为肌成纤维细胞 [16]，分泌细胞外基质，导致肝纤维化的形成。HBV 和 HCV 感染通过激活HSC 促进肝纤维化进程。HBV 的 X 蛋白通过 c-Jun氨基末端激酶（c-Jun N-terminal kinase，JNK）和细胞外信号调节激酶（extracellular signal-regulated kinase，ERK）信号通路，促进肝细胞分泌结缔组织生长因子（connective tissue growth factor，CTGF）等促纤维化因子，激活 HSC[17]，同时 HBV 感染的肝细胞还会通过分泌含有 miRNA-222 的外泌体激活 HSC[18]。感染 HCV 的肝细胞通过分泌转化生长因子-β（transforming growth factor-β，TGF-β）和血小板衍生生长因子（platelet-derived growth factor，PDGF），诱导 HSC 活化，同时通过抑制自然杀伤细胞分泌 γ 干扰素（interferon-γ，IFN-γ）， 抑制HSC 的凋亡 [19]，从而促进肝纤维化进程。慢性肝炎病毒感染引起肝纤维化的过程复杂，其机制涉及多条信号通路的激活，相关信号通路及其激活机制与作用如表 1 所示。
2.2 酒精性肝损伤
全球每年约有 300 万人因有害使用酒精死亡，占总死亡人数的 5.3%。酒精可通过其代谢物乙醛、氧化应激反应、线粒体功能障碍、脂肪积聚和肠道微生物紊乱造成肝损伤，导致肝脏炎症并进一步发展为肝纤维化 [25]。
乙醇在肝脏中代谢产生乙醛，乙醛与肝细胞的蛋白质、核酸和脂质形成加合物，进而引起内质网应激反应与未折叠蛋白反应（unfolded protein response，UPR），造成肝细胞损伤 [26]。此外，长期饮酒会诱导细胞色素 P450 2E1（cytochrome P450 2E1，CYP2E1）表达增加，其产生 ROS，从而引起氧化应激反应，造成肝细胞损伤 [9]。乙醇摄入还会导致线粒体功能障碍，主要表现为线粒体去极化和线粒体自噬 [27]，线粒体功能障碍造成的能量代谢异常可促进 ROS 产生，引起氧化应激并损伤肝细胞。乙醇还可以通过激活固醇调节元件结合蛋白（sterol regulatory element binding protein，SREBP）1 或SREBP2，促进脂肪酸和胆固醇的合成，导致肝细胞积聚脂滴、小叶中心气球样病变和Mallory小体形成，引起肝损伤 [9]。有研究表明，乙醇及其代谢产物会导致微生物合成饱和长链脂肪酸减少，介导肠道微生物群紊乱，造成肝损伤 [28]。研究发现，粪肠球菌在酒精性肝炎患者粪便中显著增加，其分泌的溶细胞素会造成肝细胞损伤，且溶细胞素阳性的粪肠球菌数量与肝病的严重程度及患者死亡率呈显著正相关 [29]，以上研究表明肠道微生物失调在酒精性肝损伤中也扮演了重要角色。
肝细胞损伤后会释放损伤相关的分子模式（damage associated molecular pattern，DAMP），并通过 TLR4 造成肝脏炎症 [30]。另外，长期饮酒会引起肠道通透性增加和细菌过度繁殖，促进脂多糖（lipopolysaccharide，LPS）从肠道入血 [31]。LPS 作为一种内毒素，在肝脏中激活巨噬细胞的 TLR4，并通过 MyD88 依赖途径和 MyD88 非依赖途径，引起炎症反应 [32]。其中 MyD88 依赖途径通过激活巨噬细胞的 NF-κB 信号通路，诱导巨噬细胞分泌肿瘤坏死因子 -α（tumor necrosis factor-α，TNF-α）等炎症因子，导致炎症反应 [33]。在 MyD88 非依赖途径中，能诱导产生 β 干扰素的含 TIR 结构域的衔 接 蛋 白（TIR domain-containing adaptor inducing interferon-β，TRIF）和 TRIF 相关接头分子（TRIFrelatedadaptor molecule，TRAM） 形成复合物，导致 κB 抑制因子激酶（inhibitor of κB kinase，IKK）的募集，诱导干扰素调节因子 3（interferon regulatory factor 3，IRF3）的磷酸化，从而诱导巨噬细胞分泌 IFN-β 等炎症因子 [34]，导致炎症反应。而 TNF-α 等炎症因子可以招募中性粒细胞和骨髓来源巨噬细胞（bone marrow-derived macrophage，BMDM），并促使其释放 ROS 和炎症因子，进一步加剧肝脏炎症。另外，这些炎症因子还会激活肌成纤维细胞，促进其分泌细胞外基质和 TGF-β 等促纤维化因子，促进肝纤维化进程 [35-36]（见图 1）。
2.3 代谢功能障碍相关肝损伤
代谢功能障碍相关的脂肪性肝病（metabolic dysfunction-associated steatotic liver disease，MASLD）是常见的慢性肝脏疾病，全球患病率约为25%[37]，其主要病理特征为脂肪积累。肝细胞的脂肪积累可进一步导致肝细胞线粒体功能障碍、内质网应激和氧化应激，引起肝细胞损伤 [38]。MASLD中脂肪积累由脂肪酸转运蛋白（fatty acid transport protein，FATP）表达增加、过氧化物酶体增殖物激活受体 γ（peroxisome proliferator activated receptor γ，PPARγ）激活和蛋氨酸胆碱缺乏（methioninecholine-deficient，MCD）饮食引起。FATP主要负责促进脂肪酸的吸收，其在 MASLD 发展过程中表达增加。研究发现，敲除 FATP 可显著减轻高脂小鼠肝脏中脂肪积累，提示 FATP 在 MASLD 中发挥重要作用 [39]。PPARγ 是关键的脂肪生成调节因子，在MASLD 中被脂肪酸、二十烷酸和氧化磷脂激活 [40]，促进脂肪生成并导致脂肪积累。蛋氨酸和胆碱对磷脂和极低密度脂蛋白（very low density lipoprotein，VLDL）的合成十分重要，使用 MCD 饲料喂养动物，可以限制动物摄入蛋氨酸和胆碱，导致其肝细胞无法有效合成磷脂和分泌 VLDL，从而引起脂肪积累和肝脏损伤 [41]，表明蛋氨酸和胆碱是维持正常肝脏功能和脂肪代谢的重要营养素，MCD 通过抑制磷脂合成和 VLDL 分泌，引起脂肪积累。
MASH 由 MASLD 进展而来，全球患病率约为 3% ~ 5% [42]。与 MASLD 单纯的脂肪积累不同，MASH 的病理特征还包括炎症和纤维化，这与其过程中的炎症反应和 HSC 激活密切相关。
研究表明，MASH 通过内质网应激增加Caspase-2 表达，后者通过激活 SREBP，引起肝细胞中胆固醇与甘油三酯的过量积累，从而增加脂毒性，加剧肝脏炎症 [43]。研究表明，白细胞分化抗原36（cluster of differentiation 36，CD36） 在 MASH患者肝细胞质膜上表达增加。CD36 是一种脂肪酸转移酶，其棕榈酰化可以调节自身分布与功能，抑制 CD36 棕榈酰化不仅可以改善脂肪酸代谢紊乱，还能减轻炎症反应，为 MASH 提供了新的治疗策略 [44]。临床上，MASH 患者常出现肠道通透性增加，这导致 LPS 可以通过门静脉进入肝脏，LPS 的入侵进一步激活 Kupffer 细胞，促使其产生 IL-1β、TNF-β、IL-6 等促炎因子，并招募单核细胞，最终加剧肝脏炎症 [45]。
MASH 中的炎症状态诱导免疫细胞释放PDGF、TGF-β、TNF-α、IL-1 等细胞因子，并通过诱导 HSC 的活化与增殖促进肝纤维化进程。研究显示，用脂肪酸处理的 HepG2 细胞，在缺氧诱导因子 -1α（hypoxia inducible factor-1α，HIF-1α）的稳定剂氯化钴的化学诱导下发生缺氧后，可以分泌细胞外囊泡（extracellular vesicle，EV），激活 LX-2细胞，这表明 MASH 中局部的缺氧环境可能通过促进肝细胞分泌 EV 激活 HSC，从而促进肝纤维化进程 [46]。同时，研究发现 MASH 患者中骨形态发生蛋白 8B（bone morphogenetic protein 8B，BMP8B）表达增 加，BMP8B 属于 TGF-β 超家族，其可通过SMAD2/3 和 SMAD1/5/9 途径激活 HSC，造成肝纤维化。鉴于健康肝脏中 BMP8B 表达较低，抑制 BMP8B 可能成为 MASH 的潜在治疗方法 [47]。此外，高脂高糖饮食引起的肠道菌群失调通过促进病原体相关分子模式（pathogen-associated molecular pattern，PAMP）释放，激活 TLR 信号通路，诱导HSC 活化，促进肝纤维化进程 [48]。
2.4 胆汁淤积性肝损伤
胆汁淤积性肝病是由胆汁淤积、胆管进行性破坏和持续肝内炎症引起的一类慢性肝病，可进一步发展为肝纤维化和胆汁性肝硬化 [49]。此类疾病包括原发性胆汁性肝硬化（primary biliary cirrhosis，PBC）和原发性硬化性胆管炎（primary sclerosing cholangitis，PSC），其主要病理特征为胆汁分泌异常和胆管阻塞 [50]。在不同地区，PBC 的患病率为 1.91/100 000 ~ 40.2/100 000，而 PSC 的患病率为 0 ~ 31.7/100 000[51]。胆汁淤积性肝损伤引起肝纤维化的机制主要涉及胆汁酸淤积和胆管反应。
胆汁酸淤积是肝纤维化发展过程中的关键起始因素，由胆管阻塞或胆汁分泌异常引起，可以诱导线粒体产生氧化应激，从而引起线粒体受损和细胞死亡。胆汁酸转运蛋白在维持胆汁酸稳态方面起重要作用，可以避免肝脏中的胆汁酸淤积 [9]，但在胆汁淤积性肝损伤中，维生素 D 受体（vitamin D receptor，VDR）可通过抑制胆盐输出泵（bile salt export pump，BSEP）的表达，引起胆汁酸淤积，加剧肝脏炎症 [52]。
胆汁酸淤积还会引起胆管反应，并促进肌成纤维细胞的活化和增殖 [53]，胆管反应以胆管细胞增殖、基质变化和炎症细胞浸润为主要病理特征。胆汁淤积引起的炎症反应会促进骨髓来源的IBA1+CD16lowCD163low 巨噬细胞浸润至肝脏非实质区，激活胆管反应 [54]。胆管反应可以促进胆管上皮细胞分泌 TGF-β、CTGF、血小板衍生生长因子B 亚基（platelet-derived growth factor-BB，PDGFBB）和内皮素-1（endothelin-1，ET-1），形成复杂的细胞因子网络，诱导 HSC 转化为肌成纤维细胞，并促进肌成纤维细胞增殖 [55]。此外，研究表明，胆汁来源的 NF-κB 诱导激酶（NF-κB-inducing kinase，NIK）在胆管反应中起调节作用，通过 IL1β、IL-4、IL-6、诱导型一氧化氮合酶（induciblenitric oxide synthase，iNOS）、TNF-α、CCL2 和TGF-β 等细胞因子激活巨噬细胞与 HSC，发挥促炎促纤维化作用 [56]。
3
肝纤维化治疗药物相关研究
当前，肝纤维化的治疗药物主要通过对致病因素（如病毒、乙醇、代谢功能障碍）的根除，以及对肝纤维化病灶的治疗和对疾病发展过程的遏制与逆转，保护肝脏结构与功能。以下根据肝纤维化药物的作用靶点，从抗病毒、抗酒精性肝损伤、代谢调节及抗纤维化 4 个方面对已经批准上市和处于临床研究阶段的肝纤维化治疗药物进行总结。肝纤维化因其病因复杂以及治疗难度大，目前临床上有效的治疗药物较少，仅有一种药物 [ 瑞司美替罗（resmetirom）] 上市，而 selonsertib、emricasan、irbesartan、cenicriviroc 等临床候选药物已被陆续宣告其临床研究的失败 [49]，因此，肝纤维化治疗药物的研发仍是重点及难点。
3.1 抗病毒药物
对于由病毒性肝炎引起的肝纤维化，抗病毒治疗是首选方法。有效的抗病毒治疗可以减少病毒复制，从而减轻肝脏的炎症和纤维化。目前，抗 HBV药物聚乙二醇干扰素 α-2a[57] 和抗 HCV 药物利巴韦林 [58] 已获批上市。此外，Cai 等 [59] 报道了抗肝纤维化新药羟尼酮（hydronidone）用于治疗乙型肝炎肝纤维化患者的Ⅱ期临床研究结果。该研究采用随机、双盲、对照试验方案，将恩替卡韦（entecavir）作为基础治疗药物，3 种不同剂量的羟尼酮作为联合治疗药物。结果显示，使用中剂量（270 mg · d-1）的羟尼酮进行联合治疗取得了 56.1% 的肝纤维化逆转率，因此，羟尼酮针对乙型肝炎纤维化的治疗极具前景。目前该药的临床研究已推进至Ⅲ期。
3.2 抗酒精性肝损伤药物
过量饮酒是肝病发生的主要原因之一 [60]，酗酒会导致一系列肝损伤，其被统称为酒精相关肝病。近年来，酒精性肝损伤发展至肝纤维化的发病率呈上升趋势。
目前，已有治疗酒精性肝病的药物上市，包括美他多辛（metadoxine）、还原型谷胱甘肽钠（reduced glutathione sodium）和硫普罗宁（tiopronin）。研究表明，美他多辛可以通过激活乙醛脱氢酶，促进乙醇和乙醛的代谢，从而减少乙醇和乙醛毒性作用时间，治疗酒精性肝损伤 [61]。其也可以发挥抗氧化作用，进而预防由乙醇和乙醛引起的谷胱甘肽耗竭，维持胞内的氧化还原平衡，并降低 TNF-α 水平，从而治疗酒精性肝损伤 [62]。硫普罗宁可通过促进乙醇代谢，抑制甘油三酯在肝脏中的积聚，维持肝细胞谷胱甘肽浓度以及抑制过氧化物的产生，从而治疗酒精性肝损伤 [63]。
坎地沙坦（candesartan）作为一种抗肾素药物，可以阻断血管紧张素Ⅱ 1 型受体（angiotensin II type 1 receptor，AT1-R）。有研究选取了 85 例经肝活检确诊的酒精性肝损伤相关的中度肝纤维化患者并随机分组，进行坎地沙坦和熊去氧胆酸联合治疗或单独给予熊去氧胆酸治疗。采用 Laennec 组织病理学分级系统进行评估，坎地沙坦组在肝纤维化的组织学改善方面显著优于对照组（33.3% vs 11.6%，P = 0.020）；此 外，采 用 NAS 评分系统进行分析，结果显示坎地沙坦组的纤维化评分从治疗前的（3.4±1.4）降至（3.1±1.5）（P = 0.005），而 对照组无显著变化 [64]。上述结果表明坎地沙坦对酒精性肝纤维化患者具有治疗作用。
瑞沙托维（resatorvid）作为 TLR4 的抑制剂，可以与 TLR4 胞内区域结合，从而抑制 LPS 引起的炎症反应与肝细胞损伤，并减少 TNF-α 和 IL-6 等炎症因子产生，进而减少肝细胞死亡 [65]。此外，瑞沙托维还可以抑制成纤维细胞的分化与胶原合成 [66]，提示该药对肝纤维化有潜在的治疗效果。已有研究表明，瑞沙托维可抑制小鼠的肝纤维化进程 [67]。目前，该候选药物正处于治疗酒精性肝病的Ⅱ期临床研究阶段。
3.3 代谢调节剂
MASLD 和 MASH 是由代谢性疾病引起的进行性慢性肝脏疾病，可导致肝脏炎症和纤维化，最终演变为肝硬化和肝细胞癌。甲状腺激素在调节肝脏脂代谢中起关键作用，β 型甲状腺激素抵抗（resistance to thyroid hormone β，RTHβ）综合征患者由于 THR 基因突变，导致肝脏对甲状腺激素的敏感性降低。研究表明 RTHβ 患者循环中的游离脂肪酸浓度升高，肝脏中出现脂肪变性，该研究结果提示甲状腺激素对肝脏脂质代谢具有重要作用，并为针对甲状腺激素受体-β（thyroid hormone receptor-β，THR-β） 的选择性激动剂的开发提供了依据 [68]。研究表明，甲状腺功能减退症可能是 MASH 发病的驱动因素 [69]。生理条件下，甲状腺释放的四碘甲状腺原氨酸（T4）被碘甲状腺原氨酸脱碘酶 1（deiodinase，DIO1）脱碘为肝脏中代谢活跃的游离三碘甲状腺原氨酸（T3）。游离 T3 可以和 THR-β 结合，并促进其与类视黄醇 X 受体（retinoid X receptor，RXR）形成异二聚体，从而改变肉碱棕榈酰转移酶1（carnitine palmitoyltransferase 1，CPT1）的转录。而 CPT1 可通过调节线粒体脂肪酸氧化以及抑制固醇调节元件结合转录因子 1（sterol regulatory element binding transcription factor 1，Srebf1）活性，减少脂肪生成。而在 MASH 和晚期纤维化患者中，肝内甲状腺激素信号传导受损，这会抑制 DIO1 将游离 T4 转化为游离 T3，并促进 DIO3 将游离 T4 转化为无活性反向T3（rT3），从而导致脂毒性物质的进一步积累 [69-70]。瑞司美替罗是一种靶向肝脏、小分子口服的 THR-β选择性激动剂，其摄取过程由肝脏特异性的有机阴离子转运多肽1B1（organic anion transporting polypeptide 1B1，OATP1B1）介导，可以模拟甲状腺激素对 THR-β 的激动作用，降低肝脏脂质含量，缓解肝脏炎症和纤维化 [69-70]。
3.4 抗纤维化药物
抗纤维化药物针对肝纤维化的病灶及发展过程进行遏制与逆转，从而保护肝脏结构与功能，该类药物包括奥贝胆酸（obeticholic acid）和氟非尼酮（fluorofenidone）。
氟非尼酮是一种小分子吡啶类药物，具有广谱抗纤维化和抗炎作用。其可作用于活化的 HSC，靶向 TGF-β1 介导的细胞信号通路，减轻肝纤维化。同时，氟非尼酮对肝纤维化大鼠有显著的治疗作用，能明显减轻其肝损伤及纤维化程度，减轻肝小叶的结构破坏及汇管区纤维组织的异常增生 [71]。
Intercept Pharmaceuticals 公司已提交将奥贝胆酸用于治疗肝纤维化的上市申请。奥贝胆酸是鹅去氧胆酸（chenodiol，CDCA）的类似物，具有胆汁酸样特性，因此可以通过肠肝循环在肝脏和胃中激活法尼醇X 受体（farnesoid X receptor，FXR），从而治疗肝脂肪变性、炎症和纤维化并提高胰岛素敏感性 [72]。
此外，利福昔明-α 是一种不可吸收的抗生素，目前已成为酒精性肝纤维化的一种潜在治疗药物 [73]。其主要通过减少酒精性肝损伤中肠道菌群的促纤维化作用，抑制 LPS 对 TLR4 的激活，进而减少 HSC和内皮细胞产生纤连蛋白 [74]，由此治疗酒精性肝损伤相关的肝纤维化。目前已开展该药治疗酒精性肝损伤相关的肝纤维化的Ⅱ期临床试验 [75]。
3.5 小结
随着对肝纤维化发生发展机制认识的不断加深，针对该疾病领域的药物研发也呈现出蓬勃发展的态势。表 2 总结了当前处于Ⅱ、Ⅲ期临床阶段及已上市的常见肝纤维化治疗药物的相关信息，包括其药物类型、作用机制、适应证和研发阶段（见表2）。
4
结语与展望
肝纤维化是慢性肝病进程中的关键步骤，其导致肝脏结构和功能异常，严重影响患者的生存率和生活质量。肝损伤是肝纤维化发展的基础，本文从慢性肝炎病毒感染、酒精性肝损伤、代谢功能障碍相关肝损伤和胆汁淤积性肝损伤 4 个角度系统地介绍了肝纤维化的发生机制。在肝纤维化治疗方面，目前临床有效药物较少，大部分处于研究阶段。本文根据肝纤维化药物的作用靶点，从抗病毒药物、抗酒精性肝损伤药物、代谢调节剂及抗纤维化药物4 个方面总结了目前已上市以及处于临床研究阶段的肝纤维化治疗药物。
肝纤维化常出现在外界因素刺激引起的肝细胞损伤之后，因此预防和治疗肝纤维化的首要策略是祛除引起肝脏慢性损伤的病因，例如治疗慢性肝炎病毒感染、酒精性肝损伤和非酒精性肝损伤。HSC的活化和增殖是肝纤维化过程中的重要环节，因此可以通过靶向 HSC 活化，研发抗纤维化药物。另外，已有大量实验及临床研究表明，肝纤维化具有可逆性，因此该疾病的治疗或可通过调节肝纤维化的逆转来实现。
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临床研究疫苗
2024-10-31
FILSPARI® (sparsentan) received full FDA approval as the only non-immunosuppressive treatment that significantly slows kidney function decline in IgAN Type C meeting scheduled with FDA to discuss potential sNDA submission for FILSPARI in FSGS sNDA requesting modification of liver monitoring for FILSPARI submitted to FDA Net product sales of FILSPARI totaled $35.6 million for the third quarter of 2024; 505 new PSFs received in the period Total revenue for the third quarter of 2024 was $62.9 million, including net product sales of $61.0 million SAN DIEGO, Oct. 31, 2024 (GLOBE NEWSWIRE) -- Travere Therapeutics, Inc., (NASDAQ: TVTX) today reported its third quarter 2024 financial results and provided a corporate update. “Our performance in the third quarter was exceptional. FILSPARI received full approval as the only medicine that can provide superior preservation of kidney function and replace current standard of care in IgAN, and our commercial team delivered strong growth in sales of FILSPARI in the U.S. Additionally, I am pleased to report that in the weeks since full approval we have seen a meaningful increase in demand, supporting our expectation that the broader label granted upon full approval coupled with the recent draft KDIGO guidelines will strengthen FILSPARI’s growth,” said Eric Dube, Ph.D., president and chief executive officer of Travere Therapeutics. “As we look ahead, we are very well-positioned to further accelerate our growth with FILSPARI. At ASN Kidney Week, we illustrated the potential benefits of using FILSPARI as a first-line treatment, and presented data in combination with other therapies. Our European partner CSL Vifor has launched FILSPARI commercially in the first EU countries. And following the recent PARASOL group recommendation of a proteinuria-based clinical trial endpoint for FSGS, we have scheduled a meeting with the FDA to discuss a potential path forward for FILSPARI in FSGS.” Financial Results for Continuing Operations for the Quarter Ended September 30, 2024 The following financial results discussion compares Travere’s continuing operations. All periods unless otherwise specified have been adjusted to exclude discontinued operations related to the divestiture of the bile acid product portfolio completed on August 31, 2023. Net product sales for the third quarter of 2024 were $61.0 million, compared to $33.9 million for the same period in 2023. The increase is attributable to sales from the ongoing commercial launch of FILSPARI. Research and development (R&D) expenses for the third quarter of 2024 were $51.7 million, compared to $60.6 million for the same period in 2023. For the nine months ended September 30, 2024, R&D expenses were $155.4 million, compared to $185.2 million for the same period in 2023. The decrease is largely attributable to previously announced restructuring initiatives and a decline in costs associated with the development of sparsentan as the Phase 3 programs advance towards completion. On a non-GAAP adjusted basis, R&D expenses were $48.4 million for the third quarter of 2024, compared to $53.8 million for the same period in 2023. Selling, general, and administrative (SG&A) expenses for the third quarter of 2024 were $65.6 million, compared to $67.8 million for the same period in 2023. For the nine months ended September 30, 2024, SG&A expenses were $194.6 million, compared to $202.0 million for the same period in 2023. The decrease is primarily driven by the previously announced restructuring and other cost saving initiatives. On a non-GAAP adjusted basis, SG&A expenses were $49.7 million for the third quarter of 2024, compared to $51.8 million for the same period in 2023. Total other income, net, for the third quarter of 2024 was $1.3 million, compared to total other income, net, of $3.4 million for the same period in 2023. The difference is largely attributable to a decrease in interest income during the period. Net loss including discontinued operations for the third quarter of 2024 was $54.8 million, or $0.70 per basic share, compared to a net income of $150.7 million, or $1.97 per basic share for the same period in 2023. For the nine months ended September 30, 2024, net loss including discontinued operations was $261.3 million, compared to $21.2 million for the same period in 2023. On a non-GAAP adjusted basis, net loss including discontinued operations for the third quarter of 2024 was $35.6 million, or $0.46 per basic share, compared to a net income of $173.5 million, or $2.27 per basic share for the same period in 2023. As of September 30, 2024, the Company had cash, cash equivalents, and marketable securities of $277.4 million. Program Updates FILSPARI® (sparsentan) – IgA Nephropathy (IgAN) On September 5, 2024, the U.S. Food and Drug Administration (FDA) granted full approval to FILSPARI to slow kidney function decline in adults with primary IgAN who are at risk of disease progression. The expanded indication made FILSPARI available to patients with IgAN at risk of progression and the updated label includes data showing superior long-term durable benefit on proteinuria and kidney function preservation that accrued over two years when compared to 300 mg of the active comparator irbesartan.Commercial progress in the ongoing launch has resulted in: 505 new patient start forms (PSFs) received in the third quarter of 2024; a total of 2,989 PSFs have been received since launch in February of 2023.Net product sales of $35.6 million for the third quarter; year-to-date FILSPARI net product sales total $82.6 million. The Company has submitted a supplemental New Drug Application (sNDA) requesting a modification to the frequency of liver monitoring for FILSPARI.In connection with full approval and an expanded indication, the FDA granted an additional term of Orphan Drug Exclusivity for FILSPARI in IgAN expiring in September 2031.In August 2024, Kidney Disease Improving Global Outcomes (KDIGO) published its draft guidelines for IgAN, recommending FILSPARI as a foundational kidney-targeted therapy and lowering the targeted proteinuria level for all IgAN patients to under 0.5 g/day or ideally complete remission (under 0.3 g/day).At ASN Kidney Week (October 23 – 27), the Company presented 9 abstracts on FILSPARI in IgAN, including: An analysis from the PROTECT Study examining the clinical benefit of FILSPARI in IgAN regardless of participants’ baseline proteinuria demonstrating that treatment with FILSPARI reduced proteinuria and preserved kidney function in patients with lower ranges of proteinuria (<1.0 g/g); and patient-reported outcomes from PROTECT suggesting that patients receiving FILSPARI had less burden of kidney disease over time and trend toward improved health-related quality of life compared with maximally dosed irbesartan.Data from a pre-specified interim analysis of the SPARTAN Study demonstrating that as a first-line treatment in patients newly diagnosed with IgAN, FILSPARI delivered a rapid and sustained reduction in proteinuria of approximately 70% from baseline over 24 weeks and was generally well tolerated. In addition, nearly 60% of patients achieved complete remission at any point of time during the treatment period. Throughout the 24 weeks, estimated glomerular filtration rate was stable.Interim data from the SPARTACUS Study demonstrating that FILSPARI when added to stable SGLT2 inhibitors was generally well tolerated and at 24 weeks approximately one-third of patients had their proteinuria reduced by at least 50% after the addition of FILSPARI. The Company also presented new combination data from the ongoing PROTECT open label extension, and real-world clinical experience of FILSPARI in IgAN demonstrating FILSPARI induced further proteinuria reduction and showed favorable safety and additive efficacy results when used in combination with SGLT2 inhibitors or steroids. In the third quarter, the Company’s commercial partner CSL Vifor launched FILSPARI in Germany and Austria, and recently received temporary marketing approval in Switzerland. Sparsentan – Focal Segmental Glomerulosclerosis (FSGS) The Company has scheduled a Type C meeting with FDA to discuss a potential regulatory pathway for a sparsentan FSGS indication. The Company expects to provide an update on the FSGS program by its fourth quarter 2024 earnings call.At ASN Kidney Week 2024, the Company presented two abstracts illustrating the potential benefit of sparsentan in patients with FSGS. A late-breaking presentation in patients with genetic FSGS, a small subgroup of patients that are often resistant to treatment, with results that demonstrated a rapid and sustained proteinuria reduction, including some patients who achieved complete remission and long-term kidney health benefits.Patient-reported outcomes from the DUPLEX Study suggesting health-related quality of life with sparsentan was stable over the two-year treatment period. Pegtibatinase (TVT-058) – Classical Homocystinuria (HCU) In September 2024, the Company announced a voluntary pause of enrollment in the Phase 3 HARMONY Study of pegtibatinase to allow for necessary process improvements in manufacturing scale-up to support commercial scale manufacturing as well as full enrollment in the HARMONY Study.Currently enrolled patients will be able to continue uninterrupted on study medication for the duration of the trials they are participating in.The Company expects to further evaluate the necessary commercial process improvements to enable the continuation of the Phase 3 program and anticipates the earliest date to restart enrollment in the Phase 3 HARMONY Study will be in 2026. Conference Call Information Travere Therapeutics will host a conference call and webcast today, October 31, 2024, at 8:30 a.m. ET to discuss company updates as well as third quarter 2024 financial results. To participate in the conference call, dial +1 (888) 394 8218 (U.S.) or +1 (323) 994-2093 (International), confirmation code 1616163 shortly before 8:30 a.m. ET. The webcast can be accessed on the Investor page of Travere’s website at ir.travere.com/events-presentations. Following the live webcast, an archived version of the call will be available for 30 days on the Company’s website. Use of Non-GAAP Financial Measures To supplement Travere’s financial results and guidance presented in accordance with U.S. generally accepted accounting principles (GAAP), the Company uses certain non-GAAP adjusted financial measures in this press release and the accompanying tables. The Company believes that these non-GAAP financial measures are helpful in understanding its past financial performance and potential future results. They are not meant to be considered in isolation or as a substitute for comparable GAAP measures and should be read in conjunction with the consolidated financial statements prepared in accordance with GAAP. Travere’s management regularly uses these supplemental non-GAAP financial measures internally to understand, manage and evaluate its business and make operating decisions. In addition, Travere believes that the use of these non-GAAP measures enhances the ability of investors to compare its results from period to period and allows for greater transparency with respect to key financial metrics the Company uses in making operating decisions. Investors should note that these non-GAAP financial measures are not prepared under any comprehensive set of accounting rules or principles and do not reflect all of the amounts associated with the Company’s results of operations as determined in accordance with GAAP. Investors should also note that these non-GAAP financial measures have no standardized meaning prescribed by GAAP and, therefore, have limits in their usefulness to investors. In addition, from time to time in the future the Company may exclude other items, or cease to exclude items that it has historically excluded, for purposes of its non-GAAP financial measures; because of the non-standardized definitions, the non-GAAP financial measures as used by the Company in this press release and the accompanying tables may be calculated differently from, and therefore may not be directly comparable to, similarly titled measures used by the Company’s competitors and other companies. As used in this press release, (i) the historical non-GAAP net loss measures exclude from GAAP net loss, as applicable, stock-based compensation expense, amortization and depreciation expense, and income tax; (ii) the historical non-GAAP SG&A expense measures exclude from GAAP SG&A expenses, as applicable, stock-based compensation expense, and amortization and depreciation expense; (iii) the historical non-GAAP R&D expense measures exclude from GAAP R&D expenses, as applicable, stock-based compensation expense, and amortization and depreciation expense. About Travere Therapeutics At Travere Therapeutics, we are in rare for life. We are a biopharmaceutical company that comes together every day to help patients, families and caregivers of all backgrounds as they navigate life with a rare disease. On this path, we know the need for treatment options is urgent – that is why our global team works with the rare disease community to identify, develop and deliver life-changing therapies. In pursuit of this mission, we continuously seek to understand the diverse perspectives of rare patients and to courageously forge new paths to make a difference in their lives and provide hope – today and tomorrow. For more information, visit travere.com. FILSPARI® (sparsentan) U.S. Indication FILSPARI (sparsentan) is indicated to slow kidney function decline in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression. IMPORTANT SAFETY INFORMATION BOXED WARNING: HEPATOTOXICITY AND EMBRYO-FETAL TOXICITY Because of the risks of hepatotoxicity and birth defects, FILSPARI is available only through a restricted program called the FILSPARI REMS. Under the FILSPARI REMS, prescribers, patients and pharmacies must enroll in the program. Hepatotoxicity Some Endothelin Receptor Antagonists (ERAs) have caused elevations of aminotransferases, hepatotoxicity, and liver failure. In clinical studies, elevations in aminotransferases (ALT or AST) of at least 3-times the Upper Limit of Normal (ULN) have been observed in up to 3.5% of FILSPARI-treated patients, including cases confirmed with rechallenge. Measure transaminases and bilirubin before initiating treatment and monthly for the first 12 months, and then every 3 months during treatment. Interrupt treatment and closely monitor patients who develop aminotransferase elevations more than 3x ULN. FILSPARI should generally be avoided in patients with elevated aminotransferases (>3x ULN) at baseline because monitoring for hepatotoxicity may be more difficult and these patients may be at increased risk for serious hepatotoxicity. Embryo-Fetal Toxicity FILSPARI can cause major birth defects if used by pregnant patients based on animal data. Therefore, pregnancy testing is required before the initiation of treatment, during treatment and one month after discontinuation of treatment with FILSPARI. Patients who can become pregnant must use effective contraception before the initiation of treatment, during treatment, and for one month after discontinuation of treatment with FILSPARI. Contraindications FILSPARI is contraindicated in patients who are pregnant. Do not coadminister FILSPARI with angiotensin receptor blockers (ARBs), ERAs, or aliskiren. Warnings and Precautions Hepatotoxicity: Elevations in ALT or AST of at least 3-fold ULN have been observed in up to 3.5% of FILSPARI-treated patients, including cases confirmed with rechallenge. While no concurrent elevations in bilirubin >2-times ULN or cases of liver failure were observed in FILSPARI-treated patients, some ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. To reduce the risk of potential serious hepatotoxicity, measure serum aminotransferase levels and total bilirubin prior to initiation of treatment and monthly for the first 12 months, then every 3 months during treatment. Advise patients with symptoms suggesting hepatotoxicity (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) to immediately stop treatment with FILSPARI and seek medical attention. If aminotransferase levels are abnormal at any time during treatment, interrupt FILSPARI and monitor as recommended. Consider re-initiation of FILSPARI only when hepatic enzyme levels and bilirubin return to pretreatment values and only in patients who have not experienced clinical symptoms of hepatotoxicity. Avoid initiation of FILSPARI in patients with elevated aminotransferases (>3x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult and these patients may be at increased risk for serious hepatotoxicity. Embryo-Fetal Toxicity: FILSPARI can cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. Advise patients who can become pregnant of the potential risk to a fetus. Obtain a pregnancy test prior to initiation of treatment with FILSPARI, monthly during treatment, and one month after discontinuation of treatment. Advise patients who can become pregnant to use effective contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with FILSPARI.FILSPARI REMS: Due to the risk of hepatotoxicity and embryo-fetal toxicity, FILSPARI is available only through a restricted program called the FILSPARI REMS. Prescribers, patients, and pharmacies must be enrolled in the REMS program and comply with all requirements (www.filsparirems.com).Hypotension: Hypotension has been observed in patients treated with ARBs and ERAs. There was a greater incidence of hypotension-associated adverse events, some serious, including dizziness, in patients treated with FILSPARI compared to irbesartan. In patients at risk for hypotension, consider eliminating or adjusting other antihypertensive medications and maintaining appropriate volume status. If hypotension develops, despite elimination or reduction of other antihypertensive medications, consider a dose reduction or dose interruption of FILSPARI. A transient hypotensive response is not a contraindication to further dosing of FILSPARI, which can be given once blood pressure has stabilized.Acute Kidney Injury: Monitor kidney function periodically. Drugs that inhibit the renin-angiotensin system (RAS) can cause kidney injury. Patients whose kidney function may depend in part on the activity of the RAS (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute kidney injury on FILSPARI. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in kidney function while on FILSPARI.Hyperkalemia: Monitor serum potassium periodically and treat appropriately. Patients with advanced kidney disease, taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics), or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia. Dosage reduction or discontinuation of FILSPARI may be required.Fluid Retention: Fluid retention may occur with ERAs, and has been observed in clinical studies with FILSPARI. FILSPARI has not been evaluated in patients with heart failure. If clinically significant fluid retention develops, evaluate the patient to determine the cause and the potential need to initiate or modify the dose of diuretic treatment then consider modifying the dose of FILSPARI. Most common adverse reactions The most common adverse reactions (≥5%) are hyperkalemia, hypotension (including orthostatic hypotension), peripheral edema, dizziness, anemia, and acute kidney injury. Drug interactions Renin-Angiotensin System (RAS) Inhibitors and ERAs: Do not coadminister FILSPARI with ARBs, ERAs, or aliskiren due to increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure).Strong and Moderate CYP3A Inhibitors: Avoid concomitant use of FILSPARI with strong CYP3A inhibitors. If a strong CYP3A inhibitor cannot be avoided, interrupt FILSPARI treatment. When resuming treatment with FILSPARI, consider dose titration. Monitor blood pressure, serum potassium, edema, and kidney function regularly when used concomitantly with moderate CYP3A inhibitors. Concomitant use with a strong CYP3A inhibitor increases sparsentan exposure which may increase the risk of FILSPARI adverse reactions.Strong CYP3A Inducers: Avoid concomitant use with a strong CYP3A inducer. Concomitant use with a strong CYP3A inducer decreases sparsentan exposure which may reduce FILSPARI efficacy.Antacids and Acid Reducing Agents: Administer FILSPARI 2 hours before or after administration of antacids. Avoid concomitant use of acid reducing agents (histamine H2 receptor antagonist and PPI proton pump inhibitor) with FILSPARI. Sparsentan exhibits pH-dependent solubility. Antacids or acid reducing agents may decrease sparsentan exposure which may reduce FILSPARI efficacy.Non-Steroidal Anti-Inflammatory Agents (NSAIDs), Including Selective Cyclooxygenase-2 (COX-2) Inhibitors: Monitor for signs of worsening renal function with concomitant use with NSAIDs (including selective COX-2 inhibitors). In patients with volume depletion (including those on diuretic therapy) or with impaired kidney function, concomitant use of NSAIDs (including selective COX-2 inhibitors) with drugs that antagonize the angiotensin II receptor may result in deterioration of kidney function, including possible kidney failure.CYP2B6, 2C9, and 2C19 Substrates: Monitor for efficacy of concurrently administered CYP2B6, 2C9, and 2C19 substrates and consider dosage adjustment in accordance with the Prescribing Information. Sparsentan decreases exposure of these substrates, which may reduce efficacy related to these substrates.P-gp and BCRP Substrates: Avoid concomitant use of sensitive substrates of P-gp and BCRP with FILSPARI. Sparsentan may increase exposure of these transporter substrates, which may increase the risk of adverse reactions related to these substrates.Agents Increasing Serum Potassium: Monitor serum potassium frequently in patients treated with FILSPARI and other agents that increase serum potassium. Concomitant use of FILSPARI with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that raise serum potassium levels may result in hyperkalemia. Please see the full Prescribing Information, including BOXED WARNING, for additional Important Safety Information. Forward-Looking Statements This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, these statements are often identified by the words “on-track,” “positioned,” “look forward to,” “will,” “would,” “may,” “might,” “believes,” “anticipates,” “plans,” “expects,” “intends,” “potential,” or similar expressions. In addition, expressions of strategies, intentions or plans are also forward-looking statements. Such forward-looking statements include, but are not limited to, references to: statements regarding the potential for FILSPARI to replace current standard of care in IgAN and the potential to further accelerate growth with FILSPARI; statements relating to clinical studies, including but not limited to trial design, results and timing related thereto; statements regarding the continuing commercial launch of FILSPARI and trends related thereto; statements regarding the sNDA requesting a modification to the frequency of liver monitoring for FILSPARI and the expected outcome and timing thereof; statements regarding plans to meet with the FDA on a potential sNDA submission for FILSPARI in FSGS and the anticipated timing and outcome thereof; statements and expectations regarding the draft KDIGO guidelines; and statements regarding the voluntary pause of enrollment in the HARMONY Study, including expectations regarding process improvements and the potential timeline to restart enrollment. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among the factors that could cause actual results to differ materially from those indicated in the forward-looking statements are risks related to the timing and outcome of the studies described herein and uncertainties associated with the regulatory review and approval process, as well as risks and uncertainties associated with enrollment of clinical trials for rare diseases, and risks that ongoing or planned clinical trials may not succeed or may be delayed for safety, regulatory or other reasons. The Company also faces risks related to its business and finances in general, the success of its commercial products and risks and uncertainties associated with its preclinical and clinical stage pipeline. Specifically, the Company faces risks associated with the ongoing commercial launch of FILSPARI, market acceptance of its commercial products including efficacy, safety, price, reimbursement, and benefit over competing therapies, risks related to the challenges of manufacturing scale-up, as well as risks associated with the successful development and execution of commercial strategies for such products, including FILSPARI. The risks and uncertainties the Company faces with respect to its preclinical and clinical stage pipeline include risk that the Company’s clinical candidates will not be found to be safe or effective and that current or anticipated future clinical trials will not proceed as planned. There is no guarantee that regulators will grant approval of sparsentan for FSGS. The Company also faces the risk that it will be unable to raise additional funding that may be required to complete development of any or all of its product candidates, including as a result of macroeconomic conditions; risks relating to the Company’s dependence on contractors for clinical drug supply and commercial manufacturing; uncertainties relating to patent protection and exclusivity periods and intellectual property rights of third parties; risks associated with regulatory interactions; and risks and uncertainties relating to competitive products, including current and potential future generic competition with certain of the Company’s products, and technological changes that may limit demand for the Company’s products. The Company also faces additional risks associated with global and macroeconomic conditions, including health epidemics and pandemics, including risks related to potential disruptions to clinical trials, commercialization activity, supply chain, and manufacturing operations. You are cautioned not to place undue reliance on these forward-looking statements as there are important factors that could cause actual results to differ materially from those in forward-looking statements, many of which are beyond our control. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Investors are referred to the full discussion of risks and uncertainties, including under the heading “Risk Factors”, as included in the Company’s most recent Form 10-K, Form 10-Q and other filings with the Securities and Exchange Commission. TRAVERE THERAPEUTICS, INC.CONSOLIDATED BALANCE SHEETS(in thousands, except share amounts)
September 30, 2024 December 31, 2023Assets(unaudited) Current assets: Cash and cash equivalents$36,409 $58,176 Marketable debt securities, at fair value 241,030 508,675 Accounts receivable, net 25,170 21,179 Inventory 6,356 9,410 Prepaid expenses and other current assets 15,775 19,335 Total current assets 324,740 616,775
Long-term inventory 36,522 31,494 Property and equipment, net 6,162 7,479 Operating lease right of use assets 15,662 18,061 Intangible assets, net 104,205 104,443 Other assets 17,119 10,661 Total assets$504,410 $788,913
Liabilities and Stockholders' Equity Current liabilities: Accounts payable$23,195 $41,675 Accrued expenses 83,916 118,991 Convertible debt, current portion 68,599 — Deferred revenue, current portion 3,799 7,096 Operating lease liabilities, current portion 5,297 4,909 Other current liabilities 5,232 5,237 Total current liabilities 190,038 177,908 Convertible debt 309,957 377,263 Deferred revenue, less current portion — 1,835 Operating lease liabilities, less current portion 18,581 22,612 Other non-current liabilities 16,288 8,485 Total liabilities 534,864 588,103
Stockholders' Equity: Preferred stock $0.0001 par value; 20,000,000 shares authorized; 0 issued and outstanding as of September 30, 2024 and December 31, 2023 — — Common stock $0.0001 par value; 200,000,000 shares authorized; 77,909,042, and 75,367,117 issued and outstanding as of September 30, 2024 and December 31, 2023, respectively 8 7 Additional paid-in capital 1,357,457 1,327,881 Accumulated deficit (1,386,903) (1,125,622)Accumulated other comprehensive loss (1,016) (1,456)Total stockholders' equity (30,454) 200,810 Total liabilities and stockholders' equity$504,410 $788,913 Note: Certain adjustments / reclassifications have been made to prior periods to conform to current year presentation. TRAVERE THERAPEUTICS, INC.CONSOLIDATED STATEMENTS OF OPERATIONS(in thousands, except share and per share data)(unaudited)
Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 (unaudited) Net product sales:
Tiopronin products$25,382 $25,888 $70,583 $73,112 FILSPARI 35,619 8,044 82,578 14,509 Total net product sales 61,001 33,932 153,161 87,621 License and collaboration revenue 1,897 3,163 5,227 12,558 Total revenue 62,898 37,095 158,388 100,179
Operating expenses:
Cost of goods sold 1,626 1,289 5,191 6,886 Research and development 51,679 60,590 155,429 185,244 Selling, general and administrative 65,619 67,801 194,618 201,954 In-process research and development — — 65,205 — Restructuring 123 — 1,035 — Total operating expenses 119,047 129,680 421,478 394,084
Operating loss (56,149) (92,585) (263,090) (293,905)
Other income, net:
Interest income 3,570 5,842 14,022 14,616 Interest expense (2,777) (2,821) (8,365) (8,513)Other income (expense), net 520 335 (2,737) 220 Total other income, net 1,313 3,356 2,920 6,323
Loss from continuing operations before income tax provision (54,836) (89,229) (260,170) (287,582)Income tax benefit (provision) on continuing operations 84 (12) (192) (155)
Loss from continuing operations, net of tax (54,752) (89,241) (260,362) (287,737)(Loss) income from discontinued operations, net of tax (59) 239,976 (919) 266,511 Net (loss) income$(54,811) $150,735 $(261,281) $(21,226)
Per share data:
Net (loss) income per common share$(0.70) $1.97 $(3.37) $(0.29)Weighted average common shares outstanding 77,779,379 76,305,603 77,473,161 73,523,620 Note: Certain adjustments / reclassifications have been made to prior periods to conform to current year presentation. TRAVERE THERAPEUTICS, INC.RECONCILIATION OF GAAP REPORTED TO NON-GAAP ADJUSTED INFORMATION(in thousands, except share and per share data)(unaudited)
Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 GAAP operating loss$(56,149) $(92,585) $(263,090) $(293,905)
R&D operating expense (51,679) (60,590) (155,429) (185,244)
Stock compensation 3,321 4,372 10,752 13,372 Amortization & depreciation — 2,447 — 7,261 Subtotal non-GAAP items 3,321 6,819 10,752 20,633 Non-GAAP R&D expense (48,358) (53,771) (144,677) (164,611)
SG&A operating expense (65,619) (67,801) (194,618) (201,954)
Stock compensation 4,700 6,949 16,946 22,730 Amortization & depreciation 11,242 9,032 31,462 21,785 Subtotal non-GAAP items 15,942 15,981 48,408 44,515 Non-GAAP SG&A expense (49,677) (51,820) (146,210) (157,439)
Subtotal non-GAAP items 19,263 22,800 59,160 65,148 Non-GAAP operating loss$(36,886) $(69,785) $(203,930) $(228,757)
GAAP net (loss) income$(54,811) $150,735 $(261,281) $(21,226)Non-GAAP operating loss adjustments 19,263 22,800 59,160 65,148 Income tax benefit (provision) (84) 12 192 155 Non-GAAP net (loss) income (1)$(35,632) $173,547 $(201,929) $44,077
Per share data:
Net (loss) income per common share$(0.46) $2.27 $(2.61) $0.60 Weighted average common shares outstanding 77,779,379 76,305,603 77,473,161 73,523,620
(1) Non-GAAP net income (loss) includes income from discontinued operations but excludes non-GAAP adjustments for the effect of discontinued operations. Note: Certain adjustments / reclassifications have been made to prior periods to conform to current year presentation. Contact: Investors:888-969-7879ir@travere.comMedia:888-969-7879mediarelations@travere.com
临床结果上市批准临床3期财报孤儿药
2024-08-30
转自：国家药监局 编辑：wangxinglai2004
2024年08月30日，国家药监局发布了第82批次仿制药一致性评价参比制剂目录，其中新增品种25个、变更及增加持证商品种9个。
通知原文
经国家药品监督管理局仿制药质量和疗效一致性评价专家委员会审核确定，现发布仿制药参比制剂目录（第八十二批）。
涉及品种：氟替美维吸入粉雾剂、阿瑞匹坦干混悬剂、环索奈德鼻喷雾剂、多奈哌齐透皮贴剂、唑尼沙胺片、甲氨蝶呤注射液、注射用盐酸伊达比星、氯化钾口服溶液、盐酸沙丙蝶呤散剂、苯巴那酯片、左甲状腺素钠口服溶液、曲美替尼片、糠酸氟替卡松维兰特罗吸入粉雾剂（II）、马利巴韦片、赖诺普利氢氯噻嗪片、硫普罗宁片、苯甲酸利扎曲普坦口腔崩解片、依折麦布瑞舒伐他汀钙片、恩那司他片/恩那度司他片等；
仿制药参比制剂目录
（第82批）
（点击阅读原文下载附件）
仿制药参比制剂目录（第82批）
一致性评价上市批准
100 项与 硫普罗宁 相关的药物交易
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研发状态
10 条最早获批的记录, 后查看更多信息
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| 适应症 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|
| 脂肪肝 | 中国 | 1998-01-01 | |
| 酒精性肝疾病 | 中国 | 1998-01-01 | |
| 慢性肝炎 | 中国 | 1995-01-01 | |
| 慢性肝炎 | 中国 | 1995-01-01 | |
| 胱氨酸尿症 | 美国 | 1988-08-11 | |
| 尿石症 | 美国 | 1988-08-11 | |
| 白内障 | 日本 | 1979-08-27 | |
| 汞中毒 | 日本 | 1979-08-27 | |
| 慢性肝病 | 日本 | 1970-03-30 |
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临床结果
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适应症
分期
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| 研究 | 分期 | 人群特征 | 评价人数 | 分组 | 结果 | 评价 | 发布日期 |
|---|
临床2期 | 10 | 鹹廠糧網選顧築窪憲餘(製遞遞鏇簾膚鬱衊艱淵) = 糧範獵淵襯艱範餘觸淵 膚壓襯鑰鹽獵簾積築鹹 (蓋觸窪範襯憲淵鹽醖製, 築鏇築網繭襯願積願鹹 ~ 醖製艱願構膚艱廠鬱夢) 更多 | - | 2021-12-17 | |||
N/A | - | 齋構獵範襯範範鏇簾壓(顧夢淵願鬱膚膚膚糧築) = 鏇壓選網淵齋艱網窪築 蓋遞襯觸夢憲鹽衊窪襯 (顧壓製積膚壓製構蓋夢 ) | 积极 | 2020-10-19 | |||
临床2期 | 60 | 遞顧餘膚廠糧顧遞製鏇(衊蓋鑰醖鏇壓積餘顧選) = 鏇鏇壓壓簾壓鹹鏇壓積 鹽顧構願衊膚築糧淵範 (膚夢願鹽選艱餘獵艱廠 ) | - | 2019-07-12 | |||
Placebo | 遞顧餘膚廠糧顧遞製鏇(衊蓋鑰醖鏇壓積餘顧選) = 夢廠鬱鹽齋淵簾醖憲膚 鹽顧構願衊膚築糧淵範 (膚夢願鹽選艱餘獵艱廠 ) | ||||||
N/A | 42 | (Bilateral cystine stone formers) | 艱範獵鏇蓋獵築糧獵鹹(糧願糧鏇蓋壓醖鹹齋壓) = 廠選壓積鹽遞醖餘齋簾 艱蓋壓淵襯鑰願蓋鹹構 (築獵鏇獵廠艱繭積壓製 ) | - | 2017-04-01 | ||
(Unilateral cystine stone formers) | 艱範獵鏇蓋獵築糧獵鹹(糧願糧鏇蓋壓醖鹹齋壓) = 構積鬱衊顧廠衊齋醖夢 艱蓋壓淵襯鑰願蓋鹹構 (築獵鏇獵廠艱繭積壓製 ) |
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