Patupilone

本文参考2022年发表在Journal of Hematology & Oncology的一篇药物综述文章《Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021》，介绍1991-2021年FDA批准的24种乳腺癌治疗新药（这是该文作者统计的，不一定涵盖全）。背景乳腺癌在女性中很常见（男性约占乳腺癌患者的1%）。仅乳腺癌就占女性癌症病例的24.5%和癌症相关死亡的15.5%，并在2020年超过肺癌成为最常诊断的癌症之一 。1991-2021年，FDA 批准了24种乳腺癌治疗药物（包括18种小分子、三种单抗和三种ADC，这是该文作者统计的，不一定涵盖全），比任何其他类型的实体瘤都多。1）激素受体 (HR) 阳性乳腺癌，包括雌激素受体 (ER) 和/或孕激素受体 (PR) 阳性乳腺癌，占所有乳腺癌病例的70%以上，并导致约50%的乳腺癌死亡。2）HER2阳性乳腺癌占所有乳腺癌病例的13~15%，并且与侵袭性和转移行为相关 。3）在超过5%的乳腺癌病例中观察到BRCA1/2突变。BRCA1/2突变通常表明通过同源重组修复DNA DSB的缺陷 ，并使患者易患乳腺癌、卵巢癌和其他癌症。4）三阴性乳腺癌（TNBC）被定义为缺乏ER、PR和HER2表达的乳腺癌，占所有乳腺癌病例的10~15%，是乳腺癌中预后最差的亚型。下面分a-m分别介绍具体的药物。a）1991-2021年FDA批准上市的乳腺癌治疗药物情况b）微管抑制剂在细胞毒性药物中，多西紫杉醇（docetaxel）可能是最著名的微管抑制剂之一。多西紫杉醇与其类似物紫杉醇共享相同的β-微管蛋白紫杉烷结合位点，但显示出更有效的抗肿瘤活性。它通过与游离β-微管蛋白结合并诱导微管聚合来发挥其活性，从而导致细胞周期停滞和死亡。伊沙匹隆（ixabepilone）是埃博霉素B的β-内酰胺类似物，以与紫杉醇类似但不完全相同的方式结合微管蛋白，并在含有P-糖蛋白表达或突变微管蛋白的紫杉醇抗性细胞中表现出强大的细胞毒活性。相比之下，艾日布林（eribulin）是一种微管去稳定剂，主要通过结合β-微管蛋白上的长春花结构域来终止原丝伸长，从而导致微管灾难。c）抗代谢物卡培他滨是5-氟尿嘧啶 (5-FU) 的前体药物，首先在肝脏中被羧酸酯酶和胞苷脱氨酶代谢为 5'-脱氧-5-氟尿苷 (5'DFUR)。5'DFUR通过胸苷磷酸化酶 (TP) 和/或尿苷磷酸化酶 (UP) 转化为5-FU。鉴于肿瘤组织中TP和UP的浓度明显高于正常组织 ，5-FU的形成和随后产生的活性代谢物优先出现在肿瘤组织中。 这些代谢物最终通过减弱胸苷酸合酶活性（通过FdUMP）并将碱基类似物掺入 RNA（通过FUTP）和DNA（通过FdUTP）而导致细胞损伤。d）DNA拓扑异构酶抑制剂表柔比星是蒽环类抗生素多柔比星的 4'-差向异构体，至少表现出等效的细胞毒性，但骨髓毒性低于多柔比星。它与拓扑异构酶‍ IIα (TOP2A) 结合，后者会干扰解旋酶活性和 TOP2A- DNA可裂解复合物的形成，导致不可逆的 DNA 双链断裂 (DSB) 和基因转录抑制。e）芳香化酶抑制剂在绝经前妇女中，雌激素主要在卵巢中合成。然而，在绝经后妇女中，雌激素是在脂肪组织、乳房和皮肤中合成的，而这个过程是由芳香酶介导的。芳香酶将卵巢和肾上腺释放的雄烯二酮和睾酮分别转化为雌酮 (E1) 和 E2。 基于此开发了三种第三代芳香化酶抑制剂，用于患有ER阳性乳腺癌的绝经后妇女 。可逆性非甾体芳香酶抑制剂阿那曲唑（anastrozole）和来曲唑（letrozole）是三唑衍生物，通过与芳香酶的血红素辅基结合发挥临床疗效。相反，不可逆的芳香酶灭活剂依西美坦（exemestane）与芳香酶的底物结合袋结合，导致其降解。f）ER抑制剂托瑞米芬是一种结构类似于他莫昔芬的 SERM，仅与一个氯原子不同 。与他莫昔芬一样，托瑞米芬通过竞争性抑制雌二醇 (E2) 与 ER 的结合发挥药理活性。因此，由于相似的药理学机制，它不能用作他莫昔芬失败后的二线治疗。相比之下，氟维司群是一种完整的 ER 拮抗剂，被批准为 SERD，可克服他莫昔芬和托瑞米芬的激动作用。然而，由于其较差的理化特性，氟维司群必须每月肌肉注射一次，限制了其临床应用。g）CDK4/6抑制剂细胞周期蛋白D-细胞周期蛋白依赖性激酶 4/6 (CDK4/6) 和CDK4/6诱导的视网膜母细胞瘤 (RB) 磷酸化的形成是细胞周期中G1-S期转变的核心事件。抑制CDK4/6可诱导RB低磷酸化和再激活，从而导致稳定的细胞周期停滞在G1期。三款CDK4/6抑制剂（palbociclib、ribociclib和abemaciclib）已获准与非甾体芳香酶抑制剂联合用于HR+、HER2-乳腺癌患者的一线治疗。尽管三种CDK4/6抑制剂有多种相似之处，但它们各自都存在独特的特征。Palbociclib主要针对CDK4单体而不是内源性CDK4三聚体复合物或CDK6，但会促进无活性CDK2复合物的形成。Palbociclib和ribociclib对CDK4/6的选择性高于abemaciclib，这可能是由于前者具有更高的亲脂性和更大的结合位点侧链，从而降低与脱靶激酶ATP结合口袋的相互作用。h）靶向HER2的单抗曲妥珠单抗（trastuzumab）在与HER2的胞外结构域 IV 的C末端部分结合，并通过ADCC、HER2脱落的抑制和配体非依赖性下游级联破坏等多种机制发挥其功能。然而，曲妥珠单抗不足以阻断配体诱导的HER2/HER3二聚化。相比之下，帕妥珠单抗（pertuzumab）结合HER2的胞外结构域 II 并阻断配体依赖性和配体非依赖性HER2/HER3二聚化和激活。与不含pertuzumab的方案相比，在trastuzumab加多西他赛的组合中加入pertuzumab可显著改善PFS和OS。Margetuximab作为最新批准的HER2单抗，提高了HER2-low肿瘤的 ADCC效应，增强了靶向活性并克服了trastuzumab耐药性。与trastuzumab联合化疗相比，margetuximab联合化疗可显著改善既往接受过两次或两次以上抗HER2治疗的HER2阳性患者的PFS。Trastuzumab可显著改善HER2阳性乳腺癌患者的临床结果。然而，在转移情况下，大多数接受trastuzumab治疗的患者在一年内会出现耐药和疾病进展。Trastuzumab耐药的一般机制是指trastuzumab与HER2相互作用发生障碍、HER2下游信号通路的重新激活、旁路信号通路的启动以及未能触发免疫介导的机制。i）靶向HER2的ADCKadcyla（TDM-1，2013年上市）由trastuzumab和细胞毒素DM1组成，通过不可切割的硫醚linker（SMCC，MCC）连接。DM1是从各种Maytenus物种中分离出来的美登素衍生物，通过破坏微管的稳定性发挥抗肿瘤活性。TDM-1保留了trastuzumab的所有抗肿瘤功效，并且对拉帕替尼耐药的乳腺癌细胞和拉帕替尼不敏感的肿瘤具有活性。TDM-1显示出比拉帕替尼加卡培他滨、曲妥珠单抗加多西紫杉醇更显著的临床优势。尽管取得了这些治疗进展，但大多数接受TDM-1治疗的患者最终都会出现疾病进展。TDM-1的耐药机制与trastuzumab部分重叠，还包括P-糖蛋白过表达和受体介导的内吞作用缺陷。2019年，第三代ADC药物Enhertu（T-DXd，大名鼎鼎的DS-8201）获批上市，DS-8201由曲妥珠单抗和TOP1抑制剂有效载荷（Dxd，一种exatecan衍生物）组成，通过蛋白酶可切割的马来酰亚胺四肽linker连接。DS-8201在先前接受过TDM-1治疗的患者中表现出持久的抗肿瘤活性。j）HER2小分子抑制剂三种HER2抑制剂拉帕替尼（lapatinib）、来那替尼（neratinib）和图卡替尼（tucatinib）被批准作为与曲妥珠单抗和/或卡培他滨联合治疗HER2阳性乳腺癌的三线方案。与HER2单抗相反，HER2抑制剂结合细胞质酪氨酸激酶结构域而不是HER2的胞外区。拉帕替尼是EGFR和HER2双重抑制剂，通过可逆地结合EGFR和HER2的细胞质ATP位点发挥抗肿瘤活性。有趣的是，拉帕替尼还通过直接减弱其转运活性来逆转P-糖蛋白和ABCG2介导的多药耐药性 (MDR) 。k）PARP小分子抑制剂PARP和BRCA是主要的DNA修复蛋白，当同时抑制这两个蛋白时会导致细胞死亡，而单独抑制其中一个则不会，这个现象被称为“合成致死”（synthetic le‍thality）。PARP抑制剂通过合成致死机制导致BRCA1/2突变癌细胞死亡。Olaparib（奥拉帕尼）、rucaparib、niraparib和talazoparib是FDA批准的四款PARP抑制剂，它们的IC50值分别为1.94、1.98、3.8和0.57 nM 。‍l）PI3K-α小分子抑制剂在大约40%的HR+、HER2-乳腺癌中观察到磷脂酰肌醇3-激酶催化亚基A (PIK3CA)基因突变。Alpelisib是PI3K-α抑制剂，与PI3K-α结合在ATP口袋处，从而抑制PI3K-α的酶活性和PI3K-α介导的下游通路。Alpelisib与氟维司群或来曲唑联合治疗HR+、HER2-乳腺癌，在PIK3CA患者中表现出可耐受的安全性和良好的临床疗效。m）靶向Trop-2的ADC滋养层细胞表面抗原-2（Trop-2，也称为EGP-1）是一种跨膜糖蛋白，在 83%的乳腺癌病例和85%的TNBC中过表达。它被认为是人类癌症的关键驱动因素，使其成为TNBC治疗的一个热门靶标 。2020年上市的Trodelvy是一款以Trop-2 ADC，由sacituzumab和SN-38组成，通过可水解的CL2A linker共价连接。Safituzumab是从鼠RS7-3G11开发的人源化Trop-2单抗，SN-38是TOP1抑制剂伊立替康的活性代谢物。与标准化疗相比，Trodelvy在接受重度治疗的转移性TNBC患者中表现出持久的客观反应和显著优势。然而，Trodelvy的临床益处高度依赖于Trop-2的表达，在低Trop-2表达亚组中很难得出明确的结论。参考文献：[1] Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021. Journal of Hematology & Oncology 2022.

LA JOLLA, Calif., Sept. 14, 2022 (GLOBE NEWSWIRE) -- MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), today announced that it has received an Issue Notification from the U.S. Patent and Trademark Office for a new patent which covers MN-166 (ibudilast) for the treatment of glioblastoma. This new patent is expected to expire no earlier than February 2039. The allowed claims cover a method of treating a patient diagnosed with glioblastoma or recurrent glioblastoma, wherein the patient expresses unmethylated MGMT, using MN-166 (ibudilast) in combination with one or more other therapeutic agents including temozolomide (TMZ), carmustine, bevacizumab, procarbazine, hydroxyurea, irinotecan, lomustine, nimotuzumab, sirolimus, mipsagargin, cabozantinib, onartuzumab, patupilone (epothilone B), and recombinant oncolytic poliovirus (PVS-RIPO). The allowed claims cover a wide range of doses of MN-166 (ibudilast) as well as the other therapeutic agents. The allowed claims also cover different types of glioblastoma including classical glioblastoma, proneural glioblastoma, mesenchymal glioblastoma, and neural glioblastoma. Kazuko Matsuda, MD, PhD, MPH, Chief Medical Officer of MediciNova, Inc. commented, “We are very pleased to receive the issue notification for this new patent as it offers additional coverage compared to our other two patents covering glioblastoma. We have an ongoing clinical trial of MN-166 in combination with temozolomide for the treatment of recurrent glioblastoma at the Dana-Farber Cancer Institute, Harvard Medical School. Results of our glioblastoma animal model study showed that median survival was longer in the group that received combination treatment with MN-166 plus temozolomide compared to the group that received the standard treatment of temozolomide alone, and this data was presented at the American Society of Clinical Oncology (ASCO) annual meeting. Encouragingly, the FDA granted orphan-drug designation to MN-166 as adjunctive therapy to temozolomide for the treatment of glioblastoma based on this data.” About Glioblastoma According to the American Association of Neurological Surgeons, glioblastoma is an aggressive brain cancer that often results in death during the first 15 months after diagnosis. Glioblastoma develops from glial cells (astrocytes and oligodendrocytes), grows rapidly, and commonly spreads into nearby brain tissue. Glioblastoma is classified as Grade IV, the highest grade, in the World Health Organization (WHO) brain tumor grading system. The American Brain Tumor Association reports that glioblastoma represents about 15% of all primary brain tumors and approximately 10,000 cases of glioblastoma are diagnosed each year in the U.S. Despite decades of advancements in neuroimaging, neurosurgery, chemotherapy and radiation therapy, only modest improvements have been achieved and the prognosis has not improved for individuals diagnosed with glioblastoma. Median survival is about 11-15 months for adults with more aggressive glioblastoma (IDH-wildtype) who receive standard treatment of surgery, temozolomide, and radiation therapy. About MN-166 (ibudilast) MN-166 (ibudilast) is a small molecule compound that inhibits phosphodiesterase type-4 (PDE4) and inflammatory cytokines, including macrophage migration inhibitory factor (MIF). It is in late-stage clinical development for the treatment of neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis), progressive MS (multiple sclerosis), and DCM (degenerative cervical myelopathy); and is also in development for glioblastoma, CIPN (chemotherapy-induced peripheral neuropathy), and substance use disorder. In addition, MN-166 (ibudilast) was evaluated in patients that are at risk for developing acute respiratory distress syndrome (ARDS). About MediciNova MediciNova, Inc. is a clinical-stage biopharmaceutical company developing a broad late-stage pipeline of novel small molecule therapies for inflammatory, fibrotic, and neurodegenerative diseases. Based on two compounds, MN-166 (ibudilast) and MN-001 (tipelukast), with multiple mechanisms of action and strong safety profiles, MediciNova has 11 programs in clinical development. MediciNova’s lead asset, MN-166 (ibudilast), is currently in Phase 3 for amyotrophic lateral sclerosis (ALS) and degenerative cervical myelopathy (DCM) and is Phase 3-ready for progressive multiple sclerosis (MS). MN-166 (ibudilast) is also being evaluated in Phase 2 trials in glioblastoma and substance dependence. MN-001 (tipelukast) was evaluated in a Phase 2 trial in idiopathic pulmonary fibrosis (IPF) and a second Phase 2 trial in non-alcoholic fatty liver disease (NAFLD) is ongoing. MediciNova has a strong track record of securing investigator-sponsored clinical trials funded through government grants. Statements in this press release that are not historical in nature constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding the future development and efficacy of MN-166, MN-001, MN-221, and MN-029. These forward-looking statements may be preceded by, followed by or otherwise include the words "believes," "expects," "anticipates," "intends," "estimates," "projects," "can," "could," "may," "will," "would," “considering,” “planning” or similar expressions. These forward-looking statements involve a number of risks and uncertainties that may cause actual results or events to differ materially from those expressed or implied by such forward-looking statements. Factors that may cause actual results or events to differ materially from those expressed or implied by these forward-looking statements include, but are not limited to, risks of obtaining future partner or grant funding for development of MN-166, MN-001, MN-221, and MN-029 and risks of raising sufficient capital when needed to fund MediciNova's operations and contribution to clinical development, risks and uncertainties inherent in clinical trials, including the potential cost, expected timing and risks associated with clinical trials designed to meet FDA guidance and the viability of further development considering these factors, product development and commercialization risks, the uncertainty of whether the results of clinical trials will be predictive of results in later stages of product development, the risk of delays or failure to obtain or maintain regulatory approval, risks associated with the reliance on third parties to sponsor and fund clinical trials, risks regarding intellectual property rights in product candidates and the ability to defend and enforce such intellectual property rights, the risk of failure of the third parties upon whom MediciNova relies to conduct its clinical trials and manufacture its product candidates to perform as expected, the risk of increased cost and delays due to delays in the commencement, enrollment, completion or analysis of clinical trials or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials, and the timing of expected filings with the regulatory authorities, MediciNova's collaborations with third parties, the availability of funds to complete product development plans and MediciNova's ability to obtain third party funding for programs and raise sufficient capital when needed, and the other risks and uncertainties described in MediciNova's filings with the Securities and Exchange Commission, including its annual report on Form 10-K for the year ended December 31, 2021 and its subsequent periodic reports on Form 10-Q and current reports on Form 8-K. Undue reliance should not be placed on these forward-looking statements, which speak only as of the date hereof. MediciNova disclaims any intent or obligation to revise or update these forward-looking statements. INVESTOR CONTACT:Geoff O'BrienVice PresidentMediciNova, Inc.info@medicinova.com