Netupitant

关于NK1R神经激肽受体 1 (Neurokinin 1 receptor, NK1R), 又被称为速激肽受体 1 (tachykinin receptor 1, TACR1) 或物质P受体 (substance P receptor, SPR), 隶属于 GPCR 家族，主要存在于中枢神经系统和周围神经系统中，其内源性配体是 P 物质，它对其他一些速激肽也有一定的亲和力。物质 P (一种神经肽) 通过激活 NK1R，对突触神经传递进行持久调节。例如，物质 P 在神经系统中的作用对疼痛、情绪、呼吸和恶心有重要影响，其次，物质 P 在其他组织中的作用与炎症或平滑肌收缩有关。大量研究表明，NK1R 拮抗剂对物质 P 活性的抑制可能会导致对疼痛、炎症和情绪失调的有效治疗。根据智慧芽新药情报库统计，到目前为止，靶向 NK1R 的拮抗剂开发主要用于临床治疗化疗引起的恶心和呕吐。全球获批的 NK1R 拮抗剂一共5款，包括 Fosnetupitant, Rolapitant，Netupitant (与5-HT3R 拮抗剂 Palonosetron 的复方制剂)，Fosaprepitant，Aprepitant 等；在中国获批上市的主要是后三者。5款靶向 NK1R 的拮抗剂药物Aprepitant 是全球首款获批上市的 NK1R 受体拮抗剂产品，由 Merck 公司原研并进行临床适应症开发。Aprepitant 可与其他止吐药联合使用，用于预防与高致吐性癌症化疗初始疗程和重复疗程相关的急性和迟发性恶心和呕吐。Aprepitant (L-754030, MK-869) 是一种选择性高亲和力人源 NK1R 受体拮抗剂，它对5-羟色胺（5-HT3）、多巴胺和皮质类固醇受体几乎没有亲和力，而这些受体也是现有化疗引起的恶心和呕吐疗法的靶点。1999 年，《新英格兰医学杂志》首次发表了一项使用选择性神经激肽-1 受体拮抗剂 (Aprepitant, L-754030) 对接受抗癌化疗的患者的止吐效果。结果显示，在化疗病人的急性呕吐期，每日服用 L-754,030 (第 1 组) 和单次服用 (第 2 组) 中 93% 的患者没有呕吐，而对照组 (第 3 组) 中 67% 的患者没有呕吐。在迟发性呕吐期，第 1 组有 82% 的患者没有呕吐，第 2 组有 78% 的患者没有呕吐，第 3 组有 33% 的患者没有呕吐。整体而言，每日服用 L-754,030 在迟发性呕吐阶段的恶心评分中位数明显低于对照组。L-754,030 治疗未引发严重不良事件。随后的临床研究，进一步表明，每日口服一次 NK1R 受体拮抗剂 MK-869 可有效减少大剂量化疗治疗后的延迟性呕吐和恶心。与此同时，MK-869 与 5HT3R 受体拮抗剂和 dexamethasone 的三联疗法对急性呕吐的控制效果最佳，这进一步扩展NK1R 与 3-HT3R 双靶点联用治疗的可能性。2003 年，多项相继公布的临床研究证据，验证了 Aprepitant 对于化疗引起的恶心和呕吐的安全性和疗效。Aprepitant 于 03 年 3 月被美国 FDA 批准上市。Fosaprepitant (L-758,298, MK-0517) 是由 Merck 公司开发上市的全球第二款 NK1R 受体拮抗剂，首批适应症依然为化疗引起的恶心和呕吐。L-758,298 是 L-754,030 的一种水溶性静脉注射原药，它是一种强效、选择性的NK1受体拮抗剂。根据 2001 年公布的一项双盲、随机、对照临床研究试验结果，评估了预防化疗治疗后急性（0-24 h）和延迟（第 2-7 天）呕吐的效果。在急性期，L-758,298 组和 5-HT3R 拮抗剂 ondansetron 组无呕吐的患者比例分别为 37% 和 52%（组间无显著差异）。在延迟期，L-758,298治疗组和 L-754,030 治疗组无呕吐的患者比例分别为72%和30%。与 ondansetron 组相比，L-758,298治疗组在延迟期的平均恶心评分分布较低。2007 年，Merck 团队进一步研究了 Fosaprepitant 在健康受试者中的耐受性以及与 Aprepitant 的生物等效性。72 小时的血浆浓度检测结果显示，静脉注射制剂 115 mg Fosaprepitant 与 125 mg Aprepitant 生物等效。2008 年后，Fosaprepitant 在多个国家和地区获批上市后。Netupitant/Palonosetron 是由瑞士Helsinn 医疗公司开发的一款 NK1R 受体拮抗剂Netupitant 与 5-HT3R 拮抗剂 Palonosetron 组成的复方制剂，首批适应症为化疗引起的恶心和呕吐。2019年后，多项 Netupitant/Palonosetron 复方制剂的临床研究成果先后发表。国内市场方面，2017年，Helsinn 医疗公司与诺思格（北京）医药科技提交上市申请。2019年8月，奈妥匹坦帕洛诺司琼胶囊 (奥康泽, Netupitant/Palonosetron) 在中国成功获批，用于成人患者预防高度致吐性化疗引起的急性恶心呕吐和延迟性恶心呕吐，预防中度致吐性化疗引起的急性恶心呕吐和延迟性恶心呕吐。2021 年 10 月，上海复星医药从 Helsinn 医疗公司共同宣布，双方签署独家许可和分销协议，Helsinn 授权复星医药在中国内地和港澳地区独家分销、推广和销售奥康泽。2023年01月，《国家基本医疗保险、工伤保险和生育保险药品目录（2022年）》正式公布，复星医药的止吐药物奈妥匹坦帕洛诺司琼胶囊成功进入国家医保目录。另外，多个药企也陆续启动奈妥匹坦帕洛诺司琼胶囊的仿制药研究，其中，四川科伦和齐鲁药业的等效性临床研究已完成。2023年4月，四川科伦药业递交的奈妥匹坦帕洛诺司琼胶囊仿制药上市申请获受理，国内首家报产的本土药企。Fosnetupitant 是 Helsinn 医疗公司开发的一款 NK1R 受体拮抗剂，是 Netupitant 的原药。2018 年，美国 FDA 批准 Fosnetupitant 与 Palonosetron 固定剂量复方制剂的静脉注射剂型合用，该复方制剂在欧盟和加拿大也被批准用于临床治疗呕吐用途。据研究，患者或健康受试者单次静脉注射 235 mg Fosnetupitant 和 0.25 mg Palonosetron 后，Fosnetupitant 的最大浓度在 30 分钟输注结束时达到。每种动物的口服生物利用度差异很大，大鼠、狗和猴子的生物利用度分别为42-105%、34-83%和37-62%。Rolapitant (SCH-619734) 是由先灵葆雅公司（Schering Plough Corporation）原研开发的一款高选择性 NK1R 受体拮抗剂。2009 年全球经济危机，默沙东以411亿美元收购先灵葆雅。收购时“被赠送”的 K 药，后来成为可默沙东王牌产品。也是 2009 年，OPKO Health 公司从先灵葆雅收购了 Rolapitant 和其他神经激肽-1 资产，并于 2010 年将 Rolapitant 的开发、生产和商业化独家授权给专注于肿瘤的生物制药公司 TESARO 公司。根据2009年发表的一篇研究论文，Rolapitant 是一种具有选择性、生物可利用性、中枢神经系统穿透性的神经激肽 NK1R 受体拮抗剂，可在呕吐动物模型中显示出行为效应。体外研究表明，Rolapitant 对人类 NK1R 受体的亲和力为 0.66 nM，对人类 NK2R 和 NK3R 亚型的选择性大于 1000 倍。（来源于，DOI: 10.1016/j.pbb.2012.03.021）在静脉注射和口服最低有效剂量为 0.1 mg/kg的情况下，Rolapitant 可逆转 NK1R 激动剂诱发的沙鼠足部叩击长达 24 小时。Rolapitant 在雪貂急性和延迟性呕吐模型中的活性剂量分别为 0.1 mg/kg 和 1 mg/kg，这与其他 NK1 拮抗剂的临床数据一致。止吐药的临床疗效与雪貂致呕吐模型的疗效高度相关，这表明 Rolapitant 是这一适应症的可行临床候选药物。2015 年，TESARO 公司团队在《柳叶刀-肿瘤学》杂志发表了两项临床3期研究成果，分别研究了 Rolapitant 预防癌症患者接受中度致吐化疗或蒽环类和环磷酰胺方案、接受顺铂为基础的高致吐性化疗后化疗引起的恶心和呕吐的安全性和有效性。同年7月，恒瑞医药发布公告称，公司与美国 Tesaro 公司达成协议，引进 Tesaro 公司用于肿瘤辅助治疗的止吐专利药 Rolapitant，恒瑞将被授权负责该药在中国的临床开发、注册和市场销售。目前该药处于申请上市阶段。以上文章来源于GPCR drug diacovery，作者段思研本文仅作信息交流之目的，文中观点不代表相关疾病治疗立场，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。

Lugano, Switzerland, June, 12, 2023 - Helsinn Group (“Helsinn”), a fully integrated global biopharma company with a track record of over forty years of commercial execution and a strong focus in oncology and rare diseases, announces the publication of real-world evidence of AKYNZEO® (fosnetupitant with palonosetron) injection/for injection in the journal Advances in Therapy. The article, “Real-world Treatment Outcomes, Healthcare Resource Use, and Costs Associatedwith Antiemetics Among Cancer Patients on Cisplatin-based Chemotherapy”, evaluates the effect of AKYNZEO® on rates of chemotherapy-induced nausea and vomiting (CINV) events, inpatient and outpatient visits, as well as treatment costs. AKYNZEO® was compared to fosaprepitant/palonosetron (APPA) combination among patients who received cisplatin-based chemotherapy in the US. The study analyzed a medical and pharmacy claims data source which was created using the all-payer claims databases (APCD) compiled and maintained by the Agency for Healthcare Research and Quality. The dataset provides insight to nearly 80% of the US healthcare system, with patient-level data from all provider types. Referring to the details of the publication below, these real-world data showed that healthcare resource utilization, such as CINV-related visits were significantly lower after AKYNZEO® compared to fosaprepitant/palonosetron (APPA). CINV-related healthcare costs were also statistically and/or numerically lower for patients receiving AKYZNEO® compared to APPA. The study findings suggest that the downstream resource use and cost impact of AKYNZEO® and APPA is not equivalent. As clinicians are making therapeutic decisions on CINV prevention, the use of real-world data can contribute to thoughtful selection of therapy to result in better resource use and cost outcomes. Dr. Rudolph Navari, MD, PhD, FACP, Hematologist Oncologist and Lead Author commented: “Despite many available antiemetic options, CINV control remains suboptimal, which carries a substantial economic and quality of care burden. There remains a gap between expected and actual patient outcomes as clinicians translate trial data and clinical guidelines into practice. Real-world studies like ours generate evidence based on day-to-day clinical experiences and can enable practical improvements in oncology practices.” Details of the publication: Title: Real-world Treatment Outcomes, Healthcare Resource Use, and Costs Associated with Antiemetics Among Cancer Patients on Cisplatin-based ChemotherapyAuthors: Rudolph M. Navari, Winnie W. Nelson, Sofia Shoaib, Risho Singh, Weiping Zhang, William L. BaileyLink: https://link-springer-com.libproxy1.nus.edu.sg/article/10.1007/s12325-023-02537-7 The study retrospectively analyzed claims data from 15,696 patients (421 AKYNZEO® and 15,275 APPA) who received cisplatin-based chemotherapy and the study antiemetic regimens between 1 January 2016 and 31 October 2020. Nausea and vomiting visit data were collected within 1 to 14 days after chemotherapy. A CINV-specific claim was defined as any post-chemotherapy claim during the 14-day follow-up period with nausea or vomiting in any position of the claim. In addition, all-cause and CINV-related HCRU for inpatient and outpatient settings were assessed, and costs were adjusted to 2021 US dollars. Logistic regression was used to evaluate the treatment outcomes in the follow-up period. Generalized linear models (GLM) were used to examine all-cause and CINV-related healthcare resource utilization and costs. Results from the study reported all-cause and CINV-related resource use and costs of AKYNZEO® and APPA: The mean number of all-cause inpatient visits per patient was lower among AKYNZEO® patients (4.83 vs. 5.41, p = 0.0195).The mean number of all-cause outpatient visits per patient was not statistically different between study groups (39.23 vs. 42.90; p = 0.0835).The mean number of CINV-related inpatient visits per patient was lower among AKYNZEO® patients (0.20 vs. 0.32, p<0.0001).The mean number of CINV-related outpatient visits per patient was lower among AKYNZEO® patients (1.32 vs. 2.49, p<0.0001).Mean all-cause inpatient costs per patient were not significantly different between study groups ($32,457 vs. $30,735; p = 0.0665).Mean all-cause outpatient costs per patient were significantly lower for AKYNZEO® ($83,070 vs. $126,263, p<0.0001).Mean CINV-related inpatient costs per patient were significantly lower for AKYNZEO® ($33 vs. $163, p<0.0001).Mean CINV-related outpatient costs per patient were not significantly different between study groups ($7,848 vs. $8,690, p = 0.4339). Limitations of this study include the potential errors in medical diagnostic coding in the insurance claims, the absence of clinical risk factors for nausea and vomiting in claims data, and the inability to track the use of low-cost medications such as olanzapine and dexamethasone. Lastly, statistical analyses for variables with a sample size less than 10 were not reported in accordance with the Agency for Healthcare Research and Quality's (AHRQ) data use agreement. About AKYNZEO® in the US INDICATION AKYNZEO® (netupitant 300mg/palonosetron 0.5mg) capsules was approved in October 2014 in the United States and is indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. AKYNZEO® (fosnetupitant 235mg/palonosetron 0.25) for injection was approved in April 2018 and AKYNZEO® injection was approved in May 2020 in the United States. Each is indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Limitations of Use: AKYNZEO® for injection and AKYNZEO® injection have not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy. AKYNZEO® is a combination of palonosetron, a serotonin-3 (5-HT3) receptor antagonist, and netupitant or fosnetupitant, substance P/neurokinin-1 (NK1) receptor antagonists: palonosetron prevents nausea and vomiting during the acute phase and netupitant/fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy. IMPORTANT SAFETY INFORMATION Warnings and Precautions: Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron, one of the components of AKYNZEO®, with or without known hypersensitivity to other 5-HT3 receptor antagonists. Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. Serotonin syndrome can be life threatening. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes, autonomic instability, neuromuscular symptoms, seizures, and gastrointestinal symptoms. Patients should be monitored for the emergence of serotonin syndrome, and if symptoms occur, discontinue AKYNZEO® and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if AKYNZEO® is used concomitantly with other serotonergic drugs. Adverse Reactions: Most common adverse reactions for AKYNZEO®: headache, asthenia, dyspepsia, fatigue, constipation and erythema. Drug-drug Interactions: Use with caution in patients receiving concomitant medications primarily metabolized by CYP3A4 isoenzyme. The plasma concentrations of CYP3A4 substrates can increase when co-administered with AKYNZEO®. The inhibitory effect on CYP3A4 can last for multiple days. Dexamethasone doses should be reduced when given with AKYNZEO®. A more than two-fold increase in the systemic exposure of dexamethasone was observed 4 days after a single dose of netupitant or a single infusion of fosnetupitant. Consider the potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) when administering with AKYNZEO®. When administered with netupitant, the systemic exposure to midazolam was significantly increased. Avoid concomitant use of AKYNZEO® in patients on chronic use of a strong CYP3A4 inducer such as rifampin as this may decrease the efficacy of AKYNZEO®. Use in Specific Populations: Avoid use of AKYNZEO® in patients with severe hepatic impairment, severe renal impairment, or end-stage renal disease. Avoid use in pregnancy, limited data is available, may cause fetal harm. For more information about AKYNZEO® please see the full US Prescribing Information About Helsinn Helsinn is a fully integrated global biopharma company headquartered in Lugano, Switzerland. It is focused on improving the lives of cancer patients all over the world with a leading position in cancer supportive care and a focus on cancer therapeutics and rare diseases. Helsinn is a third-generation family-owned company, that since 1976 has been focused on improving the lives of patients, guided by core values of respect, integrity and quality. Helsinn’s unique business model enables it to in-license or acquire assets at a late stage of development. It has a commercial presence in 190 countries either directly, with operating subsidiaries in the U.S. and China, or via its network of long-standing trusted partners. Helsinn also has a fully integrated supply chain and product development through its subsidiary in Ireland, Helsinn Birex Pharmaceuticals Ltd. Helsinn plays an active and central role in promoting social transformation in favor of people and the environment. Sustainability is at the heart of everything we do, which is reinforced in the company’s strategic plan by a commitment to sustainable growth. To learn more about Helsinn please visit: www.helsinn.com For more information: Helsinn Media Contact: Paola Bonvicini, Group Head of Communication Lugano, Switzerland Tel: +41 (0) 91 985 21 21 Email: Info-hhc@helsinn.com For more information, please visit www.helsinn.com and follow us on Twitter and LinkedIn