This is a study to determine if a certain drug, called telotristat ethyl (Xermelo®), can help reduce the chance of blood pressure and heart rate variations (known as carcinoid crisis) in individuals who have neuroendocrine tumors (also called carcinoid tumors). These complications can be life-threatening for patients who already have to experience challenging surgeries to remove their tumors. To determine if telotristat ethyl (Xermelo®) will help reduce these complications during surgery, researchers will give the drug to study participants before surgery.

开始日期2022-01-01

申办/合作机构

The University of Chicago

NCT04543955 / Terminated临床2期IIT

Study of Telotristat (Xermelo) in Combination With Luetetium Lu177 Dotatate (Lutathera) in Well-Differentiated Neuroendocrine Tumors

This trial will test the hypothesis that Telotristat treatment increases the antitumor efficacy of Lutetium Lu 177 Dotatate therapy in neuroendocrine tumors (NETs).

开始日期2021-09-13

申办/合作机构

University of Kentucky

[+1]

NCT04810091 / Recruiting临床3期IIT

TELEHEART: Telotristat Ethyl in a Heart Biomarker Study

This phase III trial compares the effect of telotristat ethyl and the current standard of care somatostatin analog therapy or somatostatin analog therapy alone in treating patients with neuroendocrine tumor that has spread to other places in the body (metastatic). Telotristat ethyl and somatostatin analog therapy may help to control carcinoid syndrome and carcinoid heart disease.

开始日期2021-05-18

申办/合作机构

The University of Texas MD Anderson Cancer Center

100 项与特罗司他乙酯相关的临床结果

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100 项与特罗司他乙酯相关的转化医学

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100 项与特罗司他乙酯相关的专利（医药）

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项与特罗司他乙酯相关的文献（医药）

2024-02-07·International journal of molecular sciences

Does Telotristat Have a Role in Preventing Carcinoid Heart Disease?

Article

作者: Aura D Herrera-Martínez ; Antonio C Fuentes-Fayos ; Rafael Sanchez-Sanchez ; Antonio J Montero ; André Sarmento-Cabral ; María A Gálvez-Moreno ; Manuel D Gahete ; Raúl M Luque

Carcinoid heart disease (CHD) is a frequent and life-threatening complication in patients with carcinoid tumors. Its clinical management is challenging is some cases since serotonin-induced valve fibrosis leads to heart failure. Telotristat is an inhibitor of tryptophan-hydroxylase (TPH), a key enzyme in serotonin production. Telotristat use in patients with carcinoid syndrome and uncontrollable diarrhea under somatostatin analogs is approved, but its specific role in patients with CHD is still not clear. IN this context, we aimed to explore the effect of telotristat in heart fibrosis using a mouse model of serotonin-secreting metastasized neuroendocrine neoplasm (NEN). To this aim, four treatment groups (n = 10/group) were evaluated: control, monthly octreotide, telotristat alone, and telotristat combined with octreotide. Plasma serotonin and NT-proBNP levels were determined. Heart fibrosis was histologically evaluated after 6 weeks of treatment or when an individual mouse's condition was close to being terminal. Heart fibrosis was observed in all groups. Non-significant reductions in primary tumor growth were observed in all of the treated groups. Feces volume was increased in all groups. A non-significant decrease in feces volume was observed in the octreotide or telotristat-treated groups, while it was significantly reduced with the combined treatment at the end of the study compared with octreotide (52 g reduction; p < 0.01) and the control (44.5 g reduction; p = 0.05). Additionally, plasma NT-proBNP decreased in a non-significant, but clinically relevant, manner in the octreotide (28.2% reduction), telotristat (45.9% reduction), and the octreotide + telotristat (54.1% reduction) treatment groups. No significant changes were observed in plasma serotonin levels. A similar non-significant decrease in heart valve fibrosis was observed in the three treated groups. In conclusion, Telotristat alone and especially in combination with octreotide decreases NT-proBNP levels in a mouse model of serotonin-secreting metastasized NEN, when compared with the control and octreotide, but its effect on heart valve fibrosis (alone and in combination) was not superior to octreotide in monotherapy.

2024-01-01·Endocrinology, diabetes & metabolism case reports

Use of perioperative telotristat in a patient with carcinoid heart disease.

Article

作者: Maria Flynn ; Christopher Noss ; Robert Miller ; Corey Adams ; Dean Ruether ; Denise Chan ; Janice Pasieka ; Kirstie Lithgow

Summary:

Carcinoid heart disease is a rare complication of carcinoid syndrome, resulting in right-sided valvular heart disease and subsequent heart failure due to long-term exposure to vasoactive substances. The management of this condition is complex, often requiring surgical intervention. Current perioperative regimens entail the use of prophylactic somatostatin analogs to prevent carcinoid crisis; however, regimens vary widely among practitioners and evidence supporting their efficacy in this clinical setting is mixed. This case report describes the perioperative management of a 65-year-old man with carcinoid heart disease requiring tricuspid and pulmonary valve replacement surgery. As an adjunct to somatostatin analog therapy, the novel tyrosine hydroxylase inhibitor, telotristat, was initiated preoperatively. This combination resulted in normalization of preoperative urinary 5-HIAA levels. The patient successfully underwent tricuspid and pulmonic valve replacement without evidence of carcinoid crisis. This clinical case is the first published documenting the use of telotristat in the perioperative period in a patient with carcinoid syndrome and carcinoid heart disease and was associated with a good long-term outcome despite the high-risk nature of the case.

Learning points:

Carcinoid crisis is a life-threatening complication of carcinoid syndrome, resulting in hemodynamic instability, bronchospasm, and arrhythmia. Cardiac surgical patients with carcinoid syndrome present a unique challenge as they are subject to physiologic conditions and medications which can potentiate intraoperative carcinoid crisis. Perioperative management of patients with carcinoid syndrome currently entails the use of prophylactic somatostatin analogs; however, these agents do not prevent carcinoid crisis in all cases. Telotristat, a tryptophan hydroxylase inhibitor, shows promise as an adjunctive therapy to somatostatin analogs to reduce the risk of intraoperative carcinoid crisis.

2023-05-20·The oncologist

Carcinoid Heart Disease Management: A Multi-Disciplinary Collaboration.

Article

作者: Satya Das ; Shannon S Stockton ; Saamir A Hassan

Carcinoid heart disease (CaHD) is an important complication among patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS). CS patients (25%-65%) eventually develop CaHD; these patients face a significantly increased risk of morbidity and mortality. Guidance papers (eg, clinical practice guidelines, consensus guidelines, and expert statements) have been established by major organizations across the disciplines of cardiology and oncology; however, these recommendations are not routinely implemented. The aim of this article is to encourage the integration of current recommendations from national societies into clinical practice. Early screening upon recognition of CS and prior to the development of CaHD symptoms is paramount, as no existing therapies are approved to reverse the fibrotic damage to the heart once it occurs. Valvular replacement is the only definitive treatment for CaHD once it has developed. When patients are noted to have urinary 5-hydroxyindoleacetic acid (5-HIAA) levels ≥300 µmol/24 h and/or serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels >260 pg/mL, echocardiography is recommended. Systemic approaches to control tumor growth and hormonal secretion include somatostatin analogs (SSAs), followed by options including peptide receptor radiotherapy (PRRT), everolimus and liver embolization. Telotristat is the primary choice for control of diarrhea refractory to SSA. Diuretics are the mainstay of heart failure symptom management for patients who develop CaHD. Considerations for future research are discussed, including the ongoing TELEHEART (TELotristat Ethyl in a HEART biomarker study) trial involving telotristat and not yet activated CHARRT (Carcinoid Heart disease And peptide Receptor Radiotargetted Therapy) study involving PRRT with lutetium 177 (177Lu) dotatate.

项与特罗司他乙酯相关的新闻（医药）

2024-02-06

·药渡

前药及其活化策略在改善药物性质中的应用

前言前药（Prodrug）又称前体药物，一般是指一类本身没有活性或者活性很弱，在生物体内转化以后，生成具有药理活性或药理活性显著增强的代谢物或原药（Parent drug）的化合物。前药的设计和开发是药物筛选和先导化合物优化过程中比较常见和有效的策略，通常是在原药分子中最适宜的基团上进行修饰或通过共价键连接上新的基团或载体分子，以改善原药的理化特性，克服吸收、分布、代谢、排泄和毒性反应等不良性质。目前全球大约10%的上市药物可以被归类为前药，预计未来会有更多的前药进入药物市场。本文将根据以往的研究案例，重点总结前药及其活化策略在改善药物性质中的应用，主要从以下几个方面进行介绍：1. 不同类型的前药及相应的生物活化；2. 前药设计对药物理化特性及药代动力学性质的影响；3. 前药临床前研究需要重点关注的内容。表1. 由FDA批准上市的部分前药信息一览[1,2]注：虚线框内为载体基团大多数情况下，前药可根据已知的生物转化，在原药基础上经化学修饰或者衍生化进行相应的结构设计，经酶或非酶介导的活化作用释放原药发挥药效。根据前药结构及活化机制的不同，可以把前药分为两类：载体前药和生物前药，其概念示意图如下：图1. 载体前药和生物前药概念示意图[3]载体前药含有无毒的载体基团或前体基团，其载体基团通过共价键与原药分子连接。原药分子中一些常见的官能团包括羟基、氨基、羧基、巯基和醛基等，与载体基团连接以后形成酯键、碳酸盐、酰胺、磷酸盐和氨基甲酸酯等官能团结构（图2）。图2. 载体前药结构设计中常用的官能团[4]成酯是载体前药设计中最广泛的一类应用，酯类药物占据已上市前药的50%以上。酯键可以被血液、肝脏和其他器官或组织中广泛存在的酯酶所水解，将药物从其前体药物分子中释放出来。乙酯、芳基酯、二元醇酯、环碳酸酯和内酯等是比较常见的酯类前药。色氨酸羟化酶抑制剂特罗司他依替酯（Telotristat etiprate）就是酯类前药中的一种（图3），人体口服给药以后，其结构中乙酯官能团在体内羧酸酯酶作用下水解，快速转化为特罗司他（Telotristat）活性药物，体循环中仅发现极低的特罗司他前药暴露。图3. 酯类前药特罗司他依替酯水解活化[5]磷苯妥英的上市，使磷酸酯型前药获得广泛关注。磷苯妥英（Fosphenytoin）在胃肠道内被碱性磷酸酯酶水解，产生羟甲胺中间体和无机磷酸盐。该中间体不稳定，迅速分解为胺基原药（苯妥英）和等当量的甲醛，胺基原药穿过胃肠道粘膜，被吸收进入体循环（图4）。磷酸酯前药较多应用于胃肠外给药的药物，除了肠胃液以外，血浆和肝组织中也存在丰富的磷酸酯酶，可以将活性药物从磷酸酯前药中释放出来。图4. 磷酸酯前药磷苯妥英生物活化[6]虽然前药首选简单酯类，但某些简单烷基酯或芳基酯类的生物转化不能由酯酶介导或酯酶水解效率低，导致系统暴露量不足。此时，通过引入双酯基团，使前药分子通过第二个酯酶位点更容易被识别活化。（图5）双酯前药艾沙康唑硫酸酯（Isavuconazonium sulfate）静脉给药后，在肌氨酸酯键位点（红色标识）迅速被血浆酯酶完全水解，与此同时，游离出来的羟基进攻分子内另一个酯键位点（蓝色标识），发生分子内环化，生成活性药物艾沙康唑（Isavuconazole）、无活性的环状副产物（BAL8728）以及乙醛。在静脉输注1h后的0.25h内，血浆中基本检测不到前药，前体药物的暴露量小于活性药物的1%。艾沙康唑双酯前药策略显示出了极高的原药转化率。图5. 双酯前药艾沙康唑硫酸酯水解活化[1]相比于酯类前药，酰胺在体内具有一定的酶稳定性，不利于活性药物的完全释放，使得酰胺在前药应用中受到一定的限制，然而，酰胺可以被设计为增强口服吸收和靶向转运的前药，并被体内蛋白酶或肽酶水解释放活性药物。氨基酸前药LY544344（图6），利用分子内的丙氨酸基团与肠上皮细胞寡肽转运蛋白PepT1较高的亲和性，转运进入细胞，经肽酶水解成LY35470后被动扩散进入血液。对于胺官能团为特征的前药，还包括磺酰胺以及氨甲酸酯类，可被酯酶或酰胺酶水解，均为有效的前药。图6. 氨基酸类前药LY544344水解活化[7]除了酶介导活化以外，还存在一些特定生理条件下非酶介导活化的载体前药，例如腙（hydrozone）类前药和N-曼尼希碱（N-Mannich base）类前药等。腙类前药在系统循环正常pH值范围能够稳定存在，而在偏酸的组织环境或细胞隔室内发生裂解释放原药。抗癌药物阿霉素前药（Aldoxorubicin）肽偶联物，靶向肿瘤细胞以后，在酸性肿瘤细胞区室内体（pH 5.5-6.2）和溶酶体（pH 4.5-5.0）中裂解释放细胞毒素阿霉素。这种特殊微环境下的腙键裂解靶向释放原药，可以减少细胞毒素对正常细胞的损伤。而N-曼尼希碱在中性和碱性环境中分解，随着pH值升高触发原药释放，例如高水溶性的罗四环素（Rolitetracycline），在pH = 7.4下向原药四环素转化。图7. pH依赖的载体前药示例[2,6]与载体前药不同的是，生物前药不包含载体基团，仅在生物转化酶代谢以后（包括氧化、还原和二相结合等，图8）产生活性化合物，或者可以将生物前药理解为酶的底物，在体内代谢生成预期的活性产物，如抗炎药物舒林酸（Sulindac）在代谢酶作用下可逆还原为硫化物（图9a），其硫化物是活性物质；抗高血压药氯沙坦（Losartan）也可以认为是一种生物前药，在体内被氧化成羧酸活性代谢物发挥药效（图9b）。图8. 基于活化机制的生物前药分类[8]图9. 生物前药舒林酸（a）和氯沙坦（b）代谢活化[3]前药的设计思路是在原药分子结构的基础上进行基团修饰或引入新的官能团，以产生新的化学实体，这种新化学实体的产生常常会伴随药物性质的改变，特别是当原药存在药代动力学性质缺陷，如药物脂溶性或水溶性差引起的生物利用度低，代谢过快导致的药效不明显，再或是靶向性不足带来的药物毒性等。通过前药设计和优化可以很好的解决这些问题，并对药物的缺陷进行改善或规避。改善药物水溶性药物吸收的前提是要求它为溶解状态，水溶性差不利于药物在体内的吸收和转运。利用前药策略在药物结构中引入极性官能团如氨基酸酯、聚乙二醇、糖类或是磷酸酯等可以明显增加药物的溶解度。Degoey等设计了洛匹那韦（Lopinavir）磷酸盐前药，其水溶性比游离的洛匹那韦增加了700多倍，且药代动力学研究表明，经口给药以后，在血浆中由磷酸盐前药水解释放出来的活性药物浓度水平较高。Lobo等合成了双氯芬酸（Diclofenac）酯前体药物，在大鼠体外血浆实验中，可由酯酶迅速水解为双氯芬酸，其酯前体药物比游离的双氯芬酸有更好的溶解度和更好的透皮性能。图10. 洛匹那韦磷酸盐和双氯芬酸甘油酯[9]影响药物膜渗透性药物穿过细胞膜的能力和该药物的亲酯性以及膜蛋白上的转运蛋白识别有关。通过掩蔽极性基团或引入亲脂性基团增加药物脂溶性，或通过引入转运蛋白可识别的基团以改善药物穿透细胞膜的能力。神经氨酸酶抑制剂奥司他韦（Oseltamivir）是RO-64-0802的乙酯前药，酯官能团的引入掩盖了分子中极性羧酸基团。与RO-64-0802相比，奥司他韦脂溶性增加，其生物利用度也从5%增加到80%。对于另一种神经氨酸酶抑制剂扎那米韦（Zanamivir）（图11a），由于其极性结构，口服生物利用度非常低，而其氨基酸偶联酰氧基酯前药能够被肠腔细胞PepT1转运蛋白识别，表现出更好的肠道膜通透性和生物利用度。FDA批准的首款新冠肺炎治疗药物瑞德西韦（Remdesivir）（图11b），结构中采用了磷酰氨基酯前药设计，芳基酯、丙氨酸及烷氧基酯的引入使瑞德西韦具有较好的细胞膜穿透性，经细胞内代谢转化为三磷酸化产物（活性药物），在细胞内富集并干扰病毒RNA转录。图11. （a）扎那米韦的氨基酸偶联酰氧基酯前药在肠上皮细胞内转运过程[8];（b）磷酰胺基酯前药瑞德西韦细胞内代谢活化过程[2]改善药物代谢稳定性代谢不稳定大多归因于药物结构中存在易代谢位点，在肝脏或胃肠道等部位发生快速而广泛的代谢。这种不稳定性会降低进入体循环的活性药物总量，不利于药效发挥。利用前药策略通过修饰相应的官能团以掩蔽易代谢位点，可以提高药物代谢稳定性，保护活性药物免受系统前代谢的影响。支气管扩张剂班布特罗（Bambuterol）为特布他林（Terbutaline）的二甲氨基甲酸酯前药（图12），由于药物结构中易受代谢影响的酚羟基被保护，其首过代谢效应明显减弱。班布特罗主要通过非特异性丁酰胆碱酯酶缓慢代谢活化为特布他林。由于其释放较慢且作用时间较长，相比于特布他林每日三次给药，班布特罗可以实现每日一次给药，且具有较低的不良反应发生率。图12. 氨基甲酸酯前药班布特罗代谢活化[1]提高药物靶向性药物能否转运到靶器官是药物发挥药效的基础，对药物结构靶向性修饰以实现选择性组织递送，能提高药物的治疗活性并减少副作用。前药的靶向性设计往往通过将靶向组织或细胞的结构单元与细胞毒素分子偶联实现，例如肽-药物偶联的载体前药通过不同的连接子将肽共价连接到药物上形成靶向肿瘤细胞的多功能PDCs，可在肿瘤细胞中选择性蓄积，半衰期延长且疗效增强。抗体-药物偶联的载体前药利用单克隆抗体对肿瘤细胞表面抗原蛋白的高亲和性，通过受体介导的内吞，靶向肿瘤细胞释放活性药物。此外，利用叶酸或DNA适体链等与活性药物偶联的抗癌药设计也是前药靶向性应用中成功的案例。图13. 具有肿瘤细胞靶向递送功能的前药设计[10]前药在体内通过转化为原药的方式发挥治疗作用，其作为一个新的化学实体，不能简单的以原药的特性来推测前药的药效和药代。前药的研究需要对原药的理化性质和生物学性质有充分的理解，在此基础上优化原药的不足之处，同时又不会降低治疗作用。因此，对于前药的研究，同样需对其理化性质、药理作用、药代动力学性质和药效作用以及可能产生的毒性反应进行全面的评估[11]。前药稳定性考察：对于前药的设计，需要保证其能在适当的时间和适当的部位分解和释放原药，这就要求所设计的前药有合适的化学稳定性和酶稳定性，既不能在到达靶位点之前降解，也不能在进入靶位点后迟迟不降解而仍以前药形式存在，否则均无法发挥药效。根据给药途径及可能的转化途径，选择合适的体外转化实验考察前药的稳定性：1在不同pH条件下的体外转化实验，如进行人工肠液或胃液稳定性实验，测定不同pH条件下前药的转化速率和转化程度。2在不同酶条件下的体外转化实验，如酯酶或肽酶水解稳定性实验，测定前药水解成原药的转化速率和转化程度。3在不同生物基质条件下的转化实验，如肝匀浆、血浆、肝微粒体、肝细胞、肠微粒体和肠S9等稳定性实验，选用适当的基质测定前药的转化速率及可能的转化部位。与原药的比较：对于不同给药方式的前药，在整体动物水平上，尽可能同时进行血管内给予原药的实验，考察前药给药后体内原药的绝对生物利用度。此外，尽可能在等摩尔剂量给药条件下，提供原药对照组的药代动力学参数，与前药给药后原药在体内的相应参数进行比较，以考察前药对原药在药效或药代动力学性质等方面的优化效果。前药可能的毒性问题：前药在化学结构上有别于原药，这很可能为前药带来新的毒性。一方面，可能是前药在分解释放原药之前发生代谢作用，形成非预期代谢物；另一方面，可能是由于前药裂解产生的惰性载体转化为毒性代谢物，如甲醛和乙醛等。某些情况下，前药在其活化阶段可能消耗重要的细胞成分，如谷胱甘肽，从而导致毒性。对于前药可能带来的新的毒性，予以重点关注。结语前药方法是克服药学和药代动力学问题及优化活性药物分子治疗效果的成熟策略之一，是药物开发过程中筛选和优化化合物结构不可或缺的一部分。考虑到前药与原药结构不同，应把前药作为一个新的化学实体进行考察和评估，特别是对前药的理化性质、药物-药物相互作用及前药的在体内的吸收、分布、代谢和排泄情况等的研究。参考文献：[1].]Rautio J, Meanwell NA, Di L, Hageman MJ. The expanding role of prodrugs in contemporary drug design and development. Nat Rev Drug Discov. 2018 Aug; 17 (8):559-587. doi: 10.1038/nrd.2018.46.[2]Deb S, Reeves AA, Hopefl R, Bejusca R. ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential. Pharmaceuticals (Basel). 2021 Jul 8; 14 (7):655. doi: 10.3390/ph14070655.[3]Kokil GR, Rewatkar PV. Bioprecursor prodrugs: molecular modification of the active principle. Mini Rev Med Chem. 2010 Dec; 10 (14):1316-30. doi: 10.2174/138955710793564179.[4]Rautio J, Kumpulainen H, Heimbach T, Oliyai R, Oh D, Järvinen T, Savolainen J. Prodrugs: design and clinical applications. Nat Rev Drug Discov. 2008 Mar; 7 (3):255-70. doi: 10.1038/nrd2468.[5]Rautio J, Kärkkäinen J, Sloan KB. Prodrugs - Recent approvals and a glimpse of the pipeline. Eur J Pharm Sci. 2017 Nov 15; 109: 146-161. doi: 10.1016/j.ejps.2017.08.002.[6]Jana S, Mandlekar S, Marathe P. Prodrug design to improve pharmacokinetic and drug delivery properties: challenges to the discovery scientists. Curr Med Chem. 2010; 17 (32):3874-908. doi: 10.2174/092986710793205426.[7]Perkins EJ, Abraham T. Pharmacokinetics, metabolism, and excretion of the intestinal peptide transporter 1 (SLC15A1)-targeted prodrug (1S, 2S, 5R, 6S)-2-[(2'S)-(2-amino) propionyl] aminobicyclo [3.1.0.] hexen-2, 6-dicarboxylic acid (LY544344) in rats and dogs: assessment of first-pass bioactivation and dose linearity. Drug Metab Dispos. 2007 Oct; 35 (10):1903-9. doi: 10.1124/dmd.107.016154.[8]Abet V, Filace F, Recio J, Alvarez-Builla J, Burgos C. Prodrug approach: An overview of recent cases. Eur J Med Chem. 2017 Feb 15; 127: 810-827. doi: 10.1016/j.ejmech.2016.10.061.[9]Jornada DH, dos Santos Fernandes GF, Chiba DE, de Melo TR, dos Santos JL, Chung MC. The Prodrug Approach: A Successful Tool for Improving Drug Solubility. Molecules. 2015 Dec 29; 21 (1):42. doi: 10.3390/molecules21010042.[10]Mahato R, Tai W, Cheng K. Prodrugs for improving tumor target ability and efficiency. Adv Drug Deliv Rev. 2011 Jul 18; 63 (8):659-70. doi: 10.1016/j.addr.2011.02.002.[11]朱胤慈,孙建国,彭英等.前药的药代动力学研究进展[J].中国临床药理学与治疗学,2012,17(12):1433-1440. （下滑查看更多）作者：王慧娟，李瑞兴，曹卫群编辑：方健，钱卉娟设计：倪德伟，张莹莹免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！👇👇

医药出海

2022-12-07

·PRNewswire

TerSera® to sponsor "NET Cancer Health Storylines" digital platform to support patients suffering from Carcinoid Syndrome Diarrhea

DEERFIELD, Ill., Dec. 7, 2022 /PRNewswire/ -- TerSera Therapeutics announced today a new sponsorship with the Carcinoid Cancer Foundation (CCF) and Alira Health to expand and optimize a holistic patient journey digital platform for patients with Neuroendocrine Tumors and Carcinoid Syndrome. Carcinoid syndrome (CS) is a rare condition that occurs in patients living with metastatic neuroendocrine tumors (mNETs) and is characterized by frequent and debilitating diarrhea that often prevents patients from leading active, predictable lives. Other symptoms of CS include facial flushing, abdominal pain, fatigue and, over time, for some people, heart valve damage.1-3 To support patients in coping with the impact NETs have on their quality of life and collaborate with their care team on treatment decisions, Alira Health and the Carcinoid Cancer Foundation have collaborated since 2015 to build "NET Cancer Health Storylines," a customized version of the Health Storylines™ app that makes it easy for patients to record their symptoms, nutritional concerns, moods, medication and more. The NET Health Storylines app provides patients with resources developed by NET experts. Specific tools include a Stool Diary, NET Nutrition tool, Medication tracker, and additional educational resources. The app is available for download at the NET Cancer Health Storylines website or through the Apple App Store or Google Play. "We are grateful for this support from TerSera to continue to enhance the NET Health Storylines platform to distribute meaningful educational content to NETs patients. The resources available through this platform are important tools in supporting NET patients throughout their journey," said Keith Warner, Chief Executive Officer of the Carcinoid Cancer Foundation. TerSera Therapeutics is the manufacturer of Xermelo (telotristat ethyl), the only oral medication approved for the treatment of carcinoid syndrome diarrhea (CSD), in combination with somatostatin analog (SSA) therapy.4 "Collaborating with CCF and the NET Cancer Health Storylines platform is a fantastic opportunity for us to support patients with Carcinoid Syndrome Diarrhea beyond our existing clinical nurse educator program. We are also looking forward to learning from patients how we can continue to support them better on their journey," said Pamela Gaytan, Executive Director, Clinical Nurse Educators and Patient Advocacy of TerSera Therapeutics. About Carcinoid Syndrome and Carcinoid Syndrome Diarrhea Carcinoid syndrome (CS) is a rare condition which affects approximately 1 out of every 5 patients with neuroendocrine tumors (NETs).5 In CS, patients have NETs that overproduce certain hormones such as serotonin, bradykinin, and histamine.1 One key hormone that is overproduced in CS is serotonin. Elevated serotonin levels in patients with CS can cause carcinoid syndrome diarrhea (CSD) which is characterized by increased motility in the gastrointestinal (GI) tract and reduced absorption of water and nutrients.2 Patients with CSD can experience multiple, urgent, loose and watery stools several times a day. CSD can have a prominent effect on patients' quality of life. Patients with CSD may avoid social activities and have increased fatigue, anxiety, and weight loss.2,3 About Xermelo Xermelo is the first and only approved oral therapy for CSD.4 Xermelo targets tryptophan hydroxylase, an enzyme that mediates the excess serotonin production within metastatic neuroendocrine tumor (mNET) cells, providing an additional treatment option for patients suffering from CSD. Xermelo is approved in the United States, the European Union, and certain additional countries for the treatment of CSD in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. Patients and healthcare professionals with questions about Xermelo should call 1-844-334-4035 or visit . IMPORTANT SAFETY INFORMATION ABOUT XERMELO: Indication Xermelo is a tryptophan hydroxylase inhibitor indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. Contraindications: XERMELO is contraindicated in patients with a history of a hypersensitivity reaction to telotristat. Reactions have included angioedema, rash and pruritis. Warnings and Precautions: XERMELO may cause constipation, which can be serious. Serious complications of constipation have been reported during clinical trials and post marketing with individual reports of intestinal perforation, obstruction, and fecaloma. Monitor for signs and symptoms of constipation and/or severe, persistent, or worsening abdominal pain in patients taking XERMELO. Discontinue XERMELO if severe constipation or severe, persistent, or worsening abdominal pain develops. Adverse Reactions: In a clinical trial of patients with carcinoid syndrome diarrhea and 4-12 bowel movements per day, the most common adverse reactions (≥5%) include nausea, headache, increased gamma-glutamyl transferase, depression, flatulence, decreased appetite, peripheral edema, and pyrexia. In a second clinical trial of patients with carcinoid syndrome diarrhea and less than 4 bowel movements per day, additional adverse reactions of abdominal pain and constipation were reported in ≥5% of patients. Drug Interactions: If necessary, consider increasing the dose of concomitant CYP3A4 and CYP2B6 substrates, as XERMELO may decrease their systemic exposure. If combination treatment with XERMELO and short-acting octreotide is needed, administer short-acting octreotide at least 30 minutes after administering XERMELO. Use in Special Populations: Xermelo is not recommended in patients with moderate and severe hepatic impairment. For more information, please see the full Prescribing Information for Xermelo. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit , or call 1-800-FDA-1088. You can also contact TerSera Therapeutics at 1-844-334-4035 or [email protected]. About TerSera Therapeutics TerSera Therapeutics acquires, develops, and markets specialty pharmaceutical products with a focus on oncology and non-opioid pain. Its mission is to provide products which truly make a difference for patients. For more information about TerSera Therapeutics, please visit . About Carcinoid Cancer Foundation: The Carcinoid Cancer Foundation is the oldest nonprofit carcinoid and neuroendocrine cancer organization in the United States, founded in 1968. The mission of the foundation is to increase awareness and educate the general public and healthcare professionals regarding neuroendocrine tumors (NETs), to support NET cancer patients and their families, and to serve as patient advocates. Visit the CCF website for more information, . About Alira Health Alira Health is a global healthcare firm whose mission is to humanize healthcare and life sciences in partnership with patients. From development to medical care, we complement the expertise of our Pharma, Biotech, and MedTech clients with a full spectrum of services across their entire solutions lifecycle, including clinical operations, real-world evidence, and patient-centric technology offerings. Our integrated and multidisciplinary team of over 600 scientists, strategists, economists, clinicians, and biostatisticians collaborate across our North American, European, and Asian offices and advise 80% of the top 50 MedTech companies and 75% of the top 50 Pharma companies. More information may be obtained at . Media Contacts: References: Clement D, Ramage J, Srirajaskanthan R. Update on Pathophysiology, Treatment, and Complications of Carcinoid Syndrome. J Oncol. 2020 Jan 21;2020:8341426. Naraev BG, Halland M, Halperin DM, et al. Management of Diarrhea in Patients With Carcinoid Syndrome. Pancreas. 2019 Sep;48(8):961-972. Anthony L, Ervin C, Lapuerta P, Kulke MH, Kunz P, Bergsland E, Hörsch D, Metz DC, Pasieka J, Pavlakis N, Pavel M, Caplin M, et al. Understanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-controlled Study of Telotristat Ethyl. Clin Ther. 2017 Nov;39(11):2158-2168. XERMELO® (telotristat ethyl) Prescribing Information. TerSera Therapeutics LLC. Halperin DM, Shen C, Dasari A, Xu Y, et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol. 2017 Apr;18(4):525-534. Xermelo® is a registered trademark of TerSera Therapeutics LLC or its affiliates. ©2022 TerSera Therapeutics LLC. All rights reserved. SOURCE TerSera Therapeutics LLC

上市批准

2021-05-06

·GlobeNewswire

Lexicon Pharmaceuticals Reports First Quarter 2021 Financial Results and Provides Clinical Update

Conference Call and Webcast at 5:00 pm Eastern Time THE WOODLANDS, Texas, May 06, 2021 (GLOBE NEWSWIRE) -- Lexicon Pharmaceuticals, Inc. (Nasdaq: LXRX), today reported financial results for the three months ended March 31, 2021 and provided an update on key milestones. “We continue to enroll patients in our two proof-of-concept Phase 2 clinical studies for LX9211 in neuropathic pain and look forward to results from these studies by the end of the year,” said Lonnel Coats, Lexicon’s president and chief executive officer. “We are also very pleased with the regulatory feedback received from the FDA on sotagliflozin in heart failure and we are moving expeditiously forward with a planned NDA filing in that indication this year.” First Quarter Highlights LX9211 Sotagliflozin 2021 Anticipated Milestones and Events First Quarter 2021 Financial Highlights Revenues: Revenues for the three months ended March 31, 2021 were negligible as compared to $8.0 million for the corresponding period in 2020, primarily due to the absence of product revenues as a result of the sale of XERMELO during the third quarter of 2020. Research and Development (R&D) Expenses: Research and development expenses for the three months ended March 31, 2021 decreased to $12.6 million from $55.2 million for the corresponding period in 2020, primarily due to decreases in external clinical development costs related to sotagliflozin resulting from the completion of clinical studies. Selling, General and Administrative (SG&A) Expenses: Selling, general and administrative expenses for the three months ended March 31, 2021 decreased to $8.3 million from $14.7 million for the corresponding period in 2020, primarily due to lower salaries and benefit costs as a result of reductions in personnel in September 2020 and lower marketing expenses. Net Loss: Net loss for the three months ended March 31, 2021 was $21.0 million, or $0.15 per share, as compared to a net loss of $66.6 million, or $0.63 per share, in the corresponding period in 2020. For the three months ended March 31, 2021 and 2020, net income included non-cash, stock-based compensation expense of $2.9 million and $4.4 million, respectively. Cash and Investments: As of March 31, 2021, Lexicon had $141.4 million in cash and investments, as compared to $152.3 million as of December 31, 2020. Conference Call and Webcast Information Lexicon management will hold a live conference call and webcast today at 5:00 pm ET / 4:00 pm CT to review its financial and operating results and to provide a general business update. The dial-in number for the conference call is 888-645-5785 (U.S./Canada) or 970-300-1531 (international). The conference ID for all callers is 8456671. The live webcast and replay may be accessed by visiting Lexicon’s website at . An archived version of the webcast will be available on the website for 14 days. About Lexicon Pharmaceuticals Lexicon is a biopharmaceutical company with a mission of pioneering medicines that transform patients’ lives. Through its Genome5000™ program, Lexicon scientists studied the role and function of nearly 5,000 genes and identified more than 100 protein targets with significant therapeutic potential in a range of diseases. Through the precise targeting of these proteins, Lexicon is pioneering the discovery and development of innovative medicines to safely and effectively treat disease. Lexicon advanced one of these medicines to market and has a pipeline of promising drug candidates in discovery and clinical and preclinical development in neuropathic pain, heart failure, diabetes and metabolism and other indications. For additional information, please visit . Safe Harbor Statement This press release contains “forward-looking statements,” including statements relating to Lexicon’s financial position and long-term outlook on its business, including the clinical development of, regulatory filings for, and potential therapeutic and commercial potential of LX9211, sotagliflozin and its other potential drug candidates. In addition, this press release also contains forward looking statements relating to Lexicon’s growth and future operating results, discovery and development of products, strategic alliances and intellectual property, as well as other matters that are not historical facts or information. All forward-looking statements are based on management’s current assumptions and expectations and involve risks, uncertainties and other important factors, specifically including Lexicon’s ability to meet its capital requirements, successfully conduct preclinical and clinical development and obtain necessary regulatory approvals of LX9211, sotagliflozin and its other potential drug candidates on its anticipated timelines, achieve its operational objectives, obtain patent protection for its discoveries and establish strategic alliances, as well as additional factors relating to manufacturing, intellectual property rights, and the therapeutic or commercial value of its drug candidates. Any of these risks, uncertainties and other factors may cause Lexicon’s actual results to be materially different from any future results expressed or implied by such forward-looking statements. Information identifying such important factors is contained under “Risk Factors” in Lexicon’s annual report on Form 10-K for the year ended December 31, 2020, as filed with the Securities and Exchange Commission. Lexicon undertakes no obligation to update or revise any such forward-looking statements, whether as a result of new information, future events or otherwise. Lexicon Pharmaceuticals, Inc. Selected Financial Data For Inquiries: Chas SchultzExecutive Director, Corporate Communications and Investor RelationsLexicon Pharmaceuticals(281) 863-3421cschultz@lexpharma.com

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100 项与特罗司他乙酯相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09975	特罗司他乙酯	A16A	DB12095

研发状态

适应症	最高研发状态	国家/地区	公司
恶性类癌综合征	批准上市	加拿大更多	SERB SAS 更多
神经内分泌肿瘤	临床2期	美国更多	Lexicon Pharmaceuticals, Inc. 更多
胆道肿瘤	临床2期	美国更多	Lexicon Pharmaceuticals, Inc. 更多
脂肪肉瘤	终止	美国更多	Lexicon Pharmaceuticals, Inc. 更多
结直肠癌	终止	美国更多	Lexicon Pharmaceuticals, Inc. 更多

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临床结果

适应症

分期

评价

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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


TELESTAR and TELECAST (Pubmed \| Med Lett Drugs Ther)	临床3期	恶性类癌综合征	-	Telotristat Ethyl	鏇繭鏇願顧觸構鏇遞壓(簾範壓壓餘構繭廠範願) = 築壓衊醖醖網艱蓋觸選遞觸構膚鏇獵鹹齋夢廠 (顧願網鹹齋遞顧衊願選 ) 更多	-	2021-10-01
NCT02026063 \| NCT01677910 \| NCT02063659 \| NCT01104415 \| NCT00853047 (ESMO2017) 人工标引	临床2/3期	恶性类癌综合征	239	Telotristat Ethyl	(鬱鹽鹹鹹構顧簾築醖鑰) = 1 death in Year 4 and no deaths in Years 5 and 6 鏇範顧網構夢鬱糧繭窪 (簾齋積鏇獵構夢製簾選 )	积极	2017-09-10
ASCO_GI2012	N/A	恶性类癌综合征	-	Telotristat etiprate	夢鏇願憲淵構糧壓窪醖(壓襯齋積夢範遞淵願鹹) = 鹹蓋鑰遞醖憲餘夢積淵膚齋壓淵壓餘蓋顧鬱遞 (淵淵膚繭鹽襯壓壓觸鬱 )	-	2012-02-01
NCT01677910 (TELESTAR, Pubmed \| Med Lett Drugs Ther)	临床3期	恶性类癌综合征	135	Placebo	(蓋構窪糧廠艱餘遞齋鬱) = 糧鏇鑰簾衊淵構範鑰網簾積鑰觸選製選蓋積餘 (衊遞顧顧願醖獵繭範構 ) 更多	-	2018-06-01
NCT01677910 (TELESTAR, Pubmed \| Med Lett Drugs Ther)	临床3期	恶性类癌综合征	135	Telotristat ethyl 250 mg	(蓋構窪糧廠艱餘遞齋鬱) = 積膚鏇蓋壓壓廠齋衊顧簾積鑰觸選製選蓋積餘 (衊遞顧顧願醖獵繭範構 ) 更多	-	2018-06-01
NCT04543955 (CTgov)	临床2期	神经内分泌肿瘤	1	Telotristat (Low-Dose) (Arm 1: Low-Dose Telotristat)	鹽遞繭製鬱齋夢製鏇淵(範膚醖襯遞壓積艱鹽襯) = 觸憲繭繭觸衊膚壓願鑰構夢窪餘網繭壓窪構衊 (夢範蓋願鹹蓋製鏇願淵, 鏇糧艱製淵鹽壓觸構鏇 ~ 簾願醖鏇築繭鹹網網築) 更多	-	2023-06-27
NCT04543955 (CTgov)	临床2期	神经内分泌肿瘤	1	Telotristat (High-Dose) (Arm 2: High-Dose Telotristat)	鹽遞繭製鬱齋夢製鏇淵(範膚醖襯遞壓積艱鹽襯) = 壓餘襯鹹鹹膚製遞壓築構夢窪餘網繭壓窪構衊 (夢範蓋願鹹蓋製鏇願淵, 築製餘膚簾築範選憲觸 ~ 壓築簾鬱顧範艱簾糧築) 更多	-	2023-06-27
ASCO2012	N/A	恶性类癌综合征	-	Telotristat etiprate	襯鏇積獵夢範憲選憲鹽(構遞製衊餘範夢餘選繭) = 構鹹繭遞鏇遞蓋蓋膚鬱窪齋築鹽淵窪窪蓋膚餘 (窪網鑰範廠齋衊願觸壓 )	-	2012-05-20
ASCO2022	N/A	APUD瘤	67	PRRT alone	(鑰鹽鬱醖獵構遞獵壓鏇) = 觸願襯蓋鏇憲鹽齋膚醖廠簾願範鹽鬱顧膚觸範 (顧範鏇積襯範網繭網廠 ) 更多	-	2022-06-02
ASCO2022	N/A	APUD瘤	67	PRRT with telotristatPRRT with telotristat	(鑰鹽鬱醖獵構遞獵壓鏇) = 鑰選簾鬱願糧築簾積觸廠簾願範鹽鬱顧膚觸範 (顧範鏇積襯範網繭網廠 ) 更多	-	2022-06-02
NCT01677910 (TELESTAR, ASCO2017)	临床3期	恶性类癌综合征	135	Telotristat ethyl 250 mg tid	網壓遞選醖憲糧鹹繭鹽(艱醖壓壓構蓋選鏇顧網) = Adverse events of cachexia were reported during the DBT period among those with weight loss but not those with weight gain 艱築憲願鑰鑰齋遞築襯 (衊鏇選餘廠齋衊膚選膚 ) 更多	积极	2017-05-30
NCT01677910 (TELESTAR, ASCO2017)	临床3期	恶性类癌综合征	135	Telotristat ethyl 500 mg tid		积极	2017-05-30
NCT01104415 (Pubmed \| J Clin Endocrinol Metab) 人工标引	临床2期	恶性类癌综合征	14	Telotristat	(膚憲遞範糧齋淵鹹淵夢) = abdominal pain, diarrhea, and gastroenteritis 窪選積構遞觸廠艱窪艱 (鏇網鹹窪獵襯鏇蓋築觸 ) 更多	积极	2015-04-01
TELEACE (ASCO_GI2021)	N/A	高分化胰腺内分泌肿瘤	-	Telotristat ethyl	鑰餘廠糧繭醖簾積廠鏇(遞顧鏇鑰醖蓋膚獵鬱鏇) = 齋醖糧襯憲願築觸鹽顧餘願憲壓蓋選繭積壓膚 (獵鹹願壓鬱積衊淵簾顧 )	积极	2021-01-22