Glasdegib Maleate

This article will continue to review the antitumor targets of the GPCR family and the therapeutic drugs that have been marketed. 05 SMOThe Smoothened (SMO) receptor is a key signal transduction receptor in the Hedgehog signaling pathway and belongs to the GPCR family, featuring the classical seven-transmembrane domain structure. The SMO receptor plays a vital role in the activation of the Hedgehog signaling pathway. The discovery of the Hedgehog signaling pathway dates back to 1980 when Christiane Nüsslein-Volhard and Eric Wieschaus, during their research on the embryonic development of fruit flies, identified gene mutations affecting the segmental development of the Drosophila larvae through genetic screening. These genes were later named Hedgehog genes because their mutant flies' embryos had a spiky appearance reminiscent of hedgehogs. The Hedgehog signaling pathway is highly conserved evolutionarily, playing significant roles not only in fruit flies but also in vertebrates, including in processes such as cell differentiation, cell proliferation, cellular senescence, tumorigenesis, malignant transformation, and tumor resistance. With further research, scientists have identified that the Hedgehog pathway involves a series of proteins, particularly core components that include two membrane proteins, Patched and Smoothened (SMO), along with three transcription factors (Gli1/2/3). The activity of the Hedgehog signaling pathway is regulated by multiple mechanisms, and abnormal pathway activity is associated with various diseases, including birth defects and tumors. In the absence of a Hedgehog ligand, the SMO receptor is inhibited by the Patched (PTCH) receptor, which acts as a tumor suppressor protein that restricts SMO activity and prevents signal transduction. When Hedgehog ligands such as Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), or Desert Hedgehog (Dhh) bind to the PTCH receptor, this inhibition is released, leading to the accumulation and activation of SMO within the cell. Activation of SMO further triggers downstream signaling pathways, particularly the activation of the GLI (Glioma-associated oncogene) family of transcription factors. These transcription factors exist in a repressive form when the signaling pathway is inactive, and upon SMO activation, they are dephosphorylated and converted into an active form, which then enters the nucleus to activate the expression of Hedgesten target genes. Vismodegib (brand name Erivedge™), an oral SMO receptor antagonist, was developed by Genentech and approved by the FDA in January 2012 in the United States. It is primarily used for the treatment of locally advanced or metastatic basal cell carcinoma, especially in patients who are not suitable for surgery or radiation therapy. In 2009, Genentech first disclosed the early drug discovery data of the SMO receptor antagonist candidate drug GDC-0449. Researchers used mouse embryonic fibroblasts harboring a luciferase reporter gene plasmid and performed high-throughput screening downstream of Gli binding sites. When the Hedgehog signaling pathway in these cells was stimulated, the activity of luciferase could be measured optically. Hedgehog pathway antagonists reduce the strength of this signal, leading researchers to obtain lead compounds. Subsequent SAR (Structure-Activity Relationship) studies yielded the candidate drug GDC-0449. At a low dose of 12.5 mg/kg, GDC-0449 was able to completely regress tumors in an orthotopic xenograft mouse model of medulloblastoma that entirely depended on the Hedgehog signaling pathway. Between 2009 and 2012, the Genentech team published two clinical research papers consecutively in the New England Journal of Medicine, reporting the efficacy and safety of Vismodegib in treating advanced basal cell carcinoma. The results showed that among 33 patients with metastatic basal cell carcinoma, the independently assessed response rate was 30%. Among 63 patients with locally advanced basal cell carcinoma, the independently assessed response rate was 43%, with 13 patients (21%) achieving a complete response. The median duration of response for both groups was 7.6 months. In terms of safety, over 30% of patients experienced adverse reactions such as muscle spasms, hair loss, taste disturbances, weight loss, and fatigue. It was reported that 25% of patients experienced severe adverse reactions; 7 patients died due to adverse reactions. Sonidegib (NVP-LDE225), developed by the Novartis team, is a SMO receptor antagonist also used for the treatment of locally advanced, recurrent basal cell carcinoma post-surgery and radiation, or in cases unsuitable for surgery and radiation. Sonidegib works by inhibiting a mechanism known as SMO activation, thereby blocking the Hh signaling pathway and exhibiting antitumor activity across various animal models. In a transgenic mouse pancreatic tumor model, tumors in mice treated with Sonidegib were reduced by 95% compared to untreated mice. In 2014 and 2015, the Novartis team published clinical research papers detailing trial data for Sonidegib used in patients with advanced or metastatic basal cell carcinoma. In the primary efficacy analysis cohort, 20 out of 55 patients (36%) receiving 200 mg of Sonidegib achieved an objective response, and 39 out of 116 patients (34%) receiving 800 mg of Sonidegib achieved an objective response. Among the 200 mg Sonidegib group, 18 of 42 patients (43%) with locally advanced basal cell carcinoma achieved an objective response via central review, and 2 out of 13 patients (15%) with metastatic disease also achieved an objective response. In the 800 mg Sonidegib group, 35 out of 93 locally advanced patients (38%) obtained an objective response through central review, and 4 out of 23 metastatic disease patients (17%) also achieved an objective response. Compared to the 800 mg group, the 200 mg group experienced fewer adverse events leading to dose reduction or treatment discontinuation. The most common grade 3-4 adverse events were elevated creatine kinase and increased lipase levels. In the 200 mg group of 79 patients, 11 (14%) experienced severe adverse events; in the 800 mg group of 150 patients, 45 (30%) experienced severe adverse events. Overall, the benefit-risk ratio of 200 mg Sonidegib provides a new treatment option for patients with advanced basal cell carcinoma. In June 2015, the U.S. FDA approved Sonidegib for the treatment of adult basal cell carcinoma. In 2021, Sonidegib was approved for market in Mainland China, becoming the first SMO receptor antagonist approved in China. Following the market entries of Genentech's Vismodegib and Novartis's Sonidegib Phosphate, Pfizer's SMO antagonist drug, Glasdegib Maleate, was approved in 2018 for the treatment of patients with acute myeloid leukemia. The representative molecular formula for SMO antagonists is as follows: 06 TSHRThe Thyroid-Stimulating Hormone Receptor (TSHR) is a gene that encodes a GPCR controlling the metabolism of thyroid cells. This protein acts as a receptor for thyroid-stimulating hormone (TSH) and thyroxine. In addition to the thyroid, TSHR expression has also been confirmed in various tissues including the brain, bone marrow, peripheral blood, and bones. Thyroid-stimulating hormone (TSH) is a pituitary hormone that stimulates the production of thyroid hormones by the thyroid gland. TSH is primarily synthesized in the thyrotroph cells of the anterior and nodular portions of the pituitary gland. Additionally, hematopoietic cells in the bone marrow, particularly monocyte/macrophage precursors, have also been shown to be a source of TSH. TSH binds to TSHR in the thyroid, stimulating the production and release of thyroid hormones. TSH is a non-covalently linked heterodimeric glycoprotein composed of alpha and beta subunits. The alpha subunit is common with other glycoprotein hormones, such as luteinizing hormone and follicle-stimulating hormone, while the beta subunit is unique to each hormone. TSH signaling can stimulate the secretion of vascular endothelial growth factor (VEGF), leading to angiogenesis and accelerating genomic instability in thyroid cancer. The tumorigenic role of TSH in thyroid cancer has been established. Many patients with differentiated thyroid cancer undergo radioactive iodine ablation postoperatively to remove residual normal thyroid tissue. Several non-randomized studies suggest that radioactive iodine ablation can reduce mortality and recurrence rates. Thyrotropin alfa is a recombinant form of thyroid-stimulating hormone, developed by Genzyme, and was initially approved by the U.S. FDA in 1998 as a diagnostic tool for managing patients undergoing recurrence monitoring of well-differentiated thyroid cancer. This product helps to enhance the sensitivity of tests while allowing patients to avoid potential debilitating symptoms associated with thyroid hormone withdrawal. In 2008, the FDA approved a new supplementary indication for Thyrotropin Alfa for use in conjunction with radioactive iodine to ablate or destroy residual thyroid tissue in patients who have undergone thyroidectomy for cancer. A study published in the New England Journal of Medicine in 2012 demonstrated that low-dose radioactive iodine combined with thyrotropin alfa is as effective as high-dose radioactive iodine, with a lower incidence of adverse events. In the diagnosis and treatment of thyroid cancer, the use of Thyrotropin alfa enhances the uptake of radioactive iodine by these cells, thereby improving the effectiveness of radioactive iodine treatment or enhancing the clarity of imaging during radioactive iodine scans, helping physicians to more accurately assess the status of the disease. Outside of thyroid cancer, the incidence of prostate cancer, lung cancer, and colorectal cancer has been linked to low levels of TSH. For example, various mutations such as missense mutations, nonsense mutations, silent mutations, frameshift deletions, and in-frame deletions have been observed in cancers like colorectal cancer, skin cancer, and thyroid cancer. 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▎药明康德内容团队编辑编者按：世界范围内，癌症对公共健康和经济都造成了沉重的负担，据国际癌症研究机构（IARC）统计，仅2020年，全球因癌症去世的人数近1千万、新增癌症确诊人数更是高达1900余万。与此同时，癌症也是医药行业最为关注的领域之一，创新疗法在过去几年中层出不穷。为了及时分享全球最新的癌症疗法，药明康德内容团队也将做系列盘点，向读者介绍海外权威癌症协会的相关信息。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。‍‍急性髓系白血病（AML）是成年人中最常见的白血病类型之一，通常影响60岁及以上的人群，但也可能影响年轻人和儿童。根据美国癌症协会的统计，仅在2023年美国就有超过2万例新发AML病例，约占所有新发白血病病例数的34%。AML病情发展迅速，如果不接受治疗，患者将在几周到几个月内发展为重症并死亡。在正常情况下，骨髓会产生血液干细胞，随着时间的推移，这些细胞会变成成熟的血细胞。髓系干细胞可发育产生红细胞、粒细胞和血小板。在AML患者体内，髓系干细胞会转变为一种不成熟的白细胞（成髓细胞），无法执行健康白细胞的功能。此外，在AML中，过多的干细胞会变成异常的红细胞或血小板。这些异常的白细胞、红细胞或血小板会在骨髓和血液中积聚，使得健康的白细胞、红细胞和血小板的空间减少，导致患者发生感染、贫血或易出血。图片来源：123RF随着研究的深入，科学家们已经开始解析AML的分子机制，为我们开辟了治疗的新视角。除了传统的化/放疗手段之外，研究人员还开始尝试使用精准的靶向疗法来攻击白血病细胞。除此之外，他们还正在探索使用细胞疗法治疗AML的潜力。在今天的文章中，药明康德内容团队参考美国癌症协会的官方信息，整理了目前AML治疗的一部分常用靶向药，供读者参考。AML的靶向疗法有哪些?近年来，针对癌细胞特定组分的靶向药物崛起。靶向药物的作用机制与标准化疗药物不同，副作用也往往不同。有时，即使化疗无效，靶向药物也能发挥作用，或者与化疗一起使用，帮助化疗更好地发挥作用。其中一些靶向药物可用于治疗某些AML患者。FLT3抑制剂在一些AML患者中，白血病细胞的FLT3基因发生了突变。这种基因能帮助细胞制造一种有助于细胞生长的蛋白质。针对FLT3蛋白的药物可以帮助治疗一些白血病患者。在AML的临床治疗中，针对FLT3基因突变的靶向药主要包括midostaurin（商品名：Rydapt）、quizartinib（商品名：Vanflyta）以及吉瑞替尼（商品名：适加坦）。Midostaurin和quizartinib可与某些化疗药物一起用于治疗携带FLT3基因突变的新发白血病成人患者。吉瑞替尼可用于治疗携带FLT3基因突变、且在之前的治疗中没有好转或复发的AML成人患者。Midostaurin在2017年获得美国FDA的批准，结合标准阿糖胞苷、柔红霉素诱导和阿糖胞苷巩固化疗，以治疗FLT3突变阳性的AML成人患者。FDA在2018年批准吉瑞替尼用于治疗FLT3基因突变的复发/难治性AML。不久前，FDA也批准了quizartinib的上市申请，联合标准化疗以及作为巩固化疗后的维持性单药疗法，用于治疗FLT3-ITD突变阳性的新发AML成人患者。目前，除了吉瑞替尼获得了中国国家药品监督管理局（NMPA）的批准之外，其他两种药物在中国的上市申请仍在审批中。FLT3抑制剂的常见副作用包括发热、白细胞水平低（感染风险增加）、恶心、呕吐、腹泻、口腔发红或溃疡、肌肉或骨骼疼痛、头痛、肝脏检查异常和呼吸道感染。其他副作用也可能发生，具体取决于所用药物。图片来源：123RFIDH抑制剂在一些AML患者中，白血病细胞的IDH1或IDH2基因发生了突变从而导致功能异常，上述两种基因中任意一个基因的突变可以阻止血细胞正常成熟。IDH抑制剂可以阻断这些由突变IDH基因产生的异常IDH蛋白。这些药物的潜在机理是通过帮助白血病细胞成熟（分化）成更正常的细胞而起作用，因此它们有时也被称为分化剂。IDH抑制剂可以用来治疗IDH1或IDH2突变的AML，在接受治疗前，医生会先检测患者的血液或骨髓细胞，看是否携带上述基因突变。临床上常用的IDH抑制剂主要包括艾伏尼布（商品名：拓舒沃）、olutasidenib（商品名：Rezlidhia）、enasidenib（商品名：Idhifa）。图片来源：123RF艾伏尼布是一种IDH1抑制剂，可用于治疗IDH1突变的AML。它既可以作为老年AML患者或健康状况不足以耐受高强度化疗患者的一线疗法，也可以用于治疗复发或对其他治疗不再有反应的AML患者。艾伏尼布最初在2018年被FDA批准治疗IDH1突变的复发/难治性AML，并在2019年再次获批扩大其适应症，用于一线治疗IDH1突变的AML老年患者（≥75岁）或由于其他合并症无法接受高强度化疗的AML患者。2022年，FDA批准艾伏尼布与阿扎胞苷联合用药或作为单药治疗新发AML老年患者（≥75岁），或由于合并症无法接受强力诱导化疗的患者。Olutasidenib适用于治疗IDH1突变的AML患者，这些患者在治疗后复发或对其他治疗不再有反应。Olutasidenib在2022年获得FDA批准治疗携带敏感IDH1突变的复发或难治性AML成人患者。Enasidenib可用于治疗IDH2突变的AML。既可作为老年AML患者或健康状况不足以耐受强化疗的患者的一线疗法，也可用于治疗复发或对其他治疗不再有反应的AML患者。FDA在2017年批准其用于治疗IDH2突变的复发或难治性AML。图片来源：123RF上述3种IDH抑制剂中，目前只有艾伏尼布在中国上市，其余两种药物的上市申请目前正在审批中。IDH抑制剂治疗常见的副作用包括恶心、呕吐、腹泻、疲劳、关节疼痛、呼吸急促、胆红素水平升高和食欲不振。这类药物的一个潜在副作用是分化综合征，当白血病细胞向血液中释放某些化学物质时，可能会引发这种情况。分化综合征通常发生在开始治疗后不久，但有时也会发生在治疗几个月后。症状可能包括发烧、咳嗽或呼吸问题（由于肺部和心脏周围的液体堆积）、眩晕或头晕（由于低血压）、小便次数减少（由于肾脏损伤）以及身体其他部位的严重液体堆积。这种副作用通常可以通过停药一段时间并给予其他药物（如地塞米松或羟基脲）来治疗。CD33靶向药除了IDH蛋白，CD33也是白血病治疗中的一种常用靶点。CD33在大多数AML细胞中都存在，AML治疗中用到的CD33靶向药是抗体偶联药物gemtuzumab ozogamicin（商品名：Mylotarg），它由一种与化疗药物相连的单克隆抗体组成。一旦进入体内，抗体就会附着在CD33蛋白上，将化疗药物带到白血病细胞，并在它们试图分裂成新细胞时杀死它们。Mylotarg可以与化疗一起使用，作为CD33阳性的AML患者初始治疗的一部分。它也可以单独使用，既可以作为一线疗法（尤其是对那些健康状况无法承受强烈化疗的患者），也可以在其他治疗不再有效的情况下使用。美国FDA在2017年批准Mylotarg用于治疗新确诊的CD33阳性AML成人患者，以及复发/难治性CD33阳性AML儿童（2岁及以上）和成人患者。Mylotarg在中国的上市申请目前仍在审批中。Mylotarg治疗最常见的副作用是发烧、恶心和呕吐、血细胞水平低（感染、出血和疲劳的风险增加）、口腔肿胀和溃疡、便秘、皮疹和头痛。此外，其他不太常见但更严重的副作用还包括严重肝损伤（包括静脉闭塞性病）、输注过程中的不良反应、严重或危及生命的感染（特别是已经接受过干细胞移植的患者），以及心脏节律的变化。BCL-2抑制剂BCL-2是癌细胞中的一种蛋白质，可以帮助癌细胞活得更长。针对BCL-2的靶向药也可用于治疗AML，比如维奈克拉（商品名：唯可来）。维奈克拉可以和化疗一起用于治疗75岁或以上AML患者，或者健康状况不足以耐受高强度化疗的患者。维奈克拉在2018年获得FDA的批准，与阿扎胞苷/地西他滨、或低剂量阿糖胞苷联用，一线治疗老年（≥75岁）或者由于其他合并症不能接受高强度化疗的AML患者。中国NMPA已经批准了维奈克拉的上市申请，用于治疗AML。维奈克拉的副作用可能包括某些白细胞水平降低（嗜中性白血球减少症）、红细胞计数低（贫血）、腹泻、恶心、出血、血小板计数低（血小板减少症）和疲劳感。其他不太常见但更为严重的副作用可能包括肺炎和严重感染。此外，瘤溶解综合征（TLS）是这种药物的另一个潜在副作用。当治疗开始时，TLS在体内含有大量白血病细胞的患者中更常见。当白血病细胞被杀死时，它们会裂开并将其内容物释放到血液中。这会使肾脏不堪重负，从而导致血液中过多矿物质的积累，甚至肾衰竭。过量的矿物质也会导致心脏和神经系统的问题。为了防止这种情况发生，治疗一般从非常低的剂量开始，然后随着时间的推移慢慢增加。有时，在开始使用这种药物之前，可能会先使用其他药物来帮助将白细胞计数降低到一定水平以下。图片来源：123RFHedgehog信号通路抑制剂Hedgehog信号通路对胚胎和胎儿的发育至关重要，在一些成年细胞中也很重要，这一通路在白血病细胞中可能处于过度活跃状态。Glasdegib（商品名：Daurismo）是一种靶向Hedgehog通路蛋白的药物。它可以与化疗一起用于75岁或以上新发AML患者，或者健康程度不足以耐受高强度化疗的患者。在这个群体中，glasdegib治疗已经被证明可以延长患者的生存期。Glasdegib在2018年获得了FDA批准，联合低剂量阿糖胞苷治疗老年（≥75岁）或因其他合并症而不适合接受强化诱导化疗的新发AML成人患者。Glasdegib在中国的上市申请目前正在审批中。Glasdegib的副作用可能包括肌肉和骨骼疼痛、疲劳、白细胞计数低（嗜中性白血球减少症）、红细胞计数低（贫血）、出血、恶心、血小板计数低（血小板减少症）以及口腔发红或溃疡。当前，Glasdegib因为Hedgehog信号通路会影响胎儿发育，怀孕或准备怀孕的妇女不应服用这类药物。图片来源：123RF结语总之，近年来随着靶向疗法、免疫疗法等创新治疗模式的发展，AML的治疗取得了长足的进步。这些新的疗法为AML的个体化和精准医疗带来了新的希望，尽管在遗传学和生物学研究领域仍有许多挑战待克服。然而，通过持续的研究探索、跨学科的合作、并积极将科学研究成果应用于临床实践，我们有望将AML从一种致命性疾病转变为可控制、甚至可治愈的疾病。AML治疗的未来充满了希望，科学家们将继续推动该领域的进步，以便为患者带来更好的治疗结果。大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放‍参考资料：[1] Acute myelogenous leukemia，Retrieved July 24, 2023 from https://www.mayoclinic.org/diseases-conditions/acute-myelogenous-leukemia/symptoms-causes/syc-20369109[2] Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version，Retrieved July 24, 2023 from https://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq[3] Acute myeloid leukaemia，Retrieved July 24, 2023 from https://www.nhsinform.scot/illnesses-and-conditions/cancer/cancer-types-in-adults/acute-myeloid-leukaemia[4] Acute Myeloid Leukemia (AML)，Retrieved July 24, 2023 from https://my.clevelandclinic.org/health/diseases/6212-acute-myeloid-leukemia-aml[5] Targeted Therapy Drugs for Acute Myeloid Leukemia (AML)，Retrieved July 24, 2023 from 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