Maribavir

LIVTENCITY Is the First and Only Post-Transplant Anti-CMV Treatment Approved in Japan That Targets/Inhibits UL97 Protein Kinase1 CMV Is One of the Most Common and Serious Post-transplant Infections and Can Lead to Secondary Infections and Serious Consequences, Including Loss of Transplanted Organ and Failure of Graft2,3 OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today announced that LIVTENCITY® (maribavir) has been approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) for post-transplant cytomegalovirus (CMV) infection/disease that is refractory to existing anti-CMV therapies.4 LIVTENCITY is the first and only post-transplant anti-CMV treatment approved in Japan that targets and inhibits pUL97 kinase and its natural substrates.1 “We are pleased by the approval of LIVTENCITY in Japan, which will provide the transplant community with a new option for treatment of post-transplant CMV infection in patients refractory to other therapies,” said Yasushi Kajii, Head, R&D Japan Region at Takeda. “A diagnosis of CMV infection can be particularly challenging for patients, and serious complications such as increased organ rejection and hospitalization rates can occur, when not successfully treated. We believe LIVTENCITY has the potential to help address the challenges faced by people with post-transplant CMV and transform the treatment landscape for patients in Japan.” The approval is primarily based on the results of the Phase 3 SOLSTICE trial (NCT02931539), which evaluated the safety and efficacy of LIVTENCITY versus alternative antiviral treatments for patients with CMV infection/disease refractory* to prior therapies who underwent hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT), and the Japanese Phase 3 open-label study in patients with CMV infection, including those with refractory* CMV infection who underwent HSCT or SOT (NCT05137717). In the SOLSTICE trial (maribavir n=235, alternative treatments n=117), maribavir showed statistically significant improvement when compared to alternative antiviral treatments at the end of Week 8 for the primary endpoint of confirmed CMV viremia clearancea in post-transplant (HSCT or SOT) adults with refractory* CMV infection.5 Of the 234 patients included in the safety evaluation, adverse reactions (related cases) were observed in 141 patients (60.3%).5 An open-label, multicenter, single-arm study was conducted to evaluate the efficacy and safety in Japanese patients in post-transplant (HSCT or SOT) adultsc (41 randomized, including 3 subjects with CMV infection refractory* to the most recently administered anti-CMV agent). The primary endpoint of CMV viremia clearanceb at the end of Study Week 8 was achieved in 33.3% of patients with refractory* CMV infection.4 Of 41 subjects included in the safety evaluation, adverse reactions (related events) were observed in 36.6% (15 subjects). 4 About LIVTENCITY LIVTENCITY (maribavir), an orally administered (tablet) anti-CMV compound, is the first and only antiviral agent that targets and inhibits the CMV-specific UL97 protein kinase and thus its natural substrates.1 As of June 2024, LIVTENCITY is approved in more than 30 countries for post-transplant CMV refractory* to prior therapies, including such major markets as Japan, the United States, Canada, Australia, the European Union and China. LIVTENCITY Product Overview in Japan Product Name LIVTENCITY 200 mg tablets. Generic Name Maribavir Indications The post-transplant cytomegalovirus (CMV) infection/disease that is refractory to existing anti-CMV therapies. Precautions concerning indications This drug should be administered to post-transplant patients with CMV infection/disease who have responded inadequately to other therapies. Efficacy and safety have not been studied in patients with CMV infection of the central nervous system and CMV retinitis. Based on nonclinical studies, this drug is expected to cross the blood-brain barrier but has low potential to enter the central nervous system. Dosage and Administration Usually, the recommended dosage for adultsc is 400 mg of maribavir to be administered orally twice daily. About Takeda’s SOLSTICE Trial The TAK-620-303 (SOLSTICE) trial (NCT02931539, EudraCT 2015-004725-13) was a Phase 3 global, multicenter, randomized, open-label, active-controlled trial to assess the efficacy and safety of maribavir treatment compared to investigator-assigned treatment (alternative antiviral therapies) in 352 HSCT and SOT recipients with CMV infections that were refractory* or resistant to one or a combination of the alternative antiviral therapies: ganciclovir, valganciclovir, foscarnet, or cidofovir. Adult patients underwent a 2-week screening period, followed by randomization 2:1 to maribavir (n=235) (400 mg, twice daily) or alternative antiviral treatments (n=117) (as dosed by the investigator) for up to 8 weeks. After completion of the treatment period, subjects entered a 12-week follow-up phase.5 The trial’s primary efficacy endpoint was confirmed CMV viremia clearance a at the end of Week 8. The key secondary endpoint was confirmed CMV viremia clearance and CMV infection symptom control† at the end of Study Week 8 with maintenance of this treatment effect through Study Week 16.5 About Cytomegalovirus (CMV) CMV is a beta herpesvirus that commonly infects humans; serologic evidence of prior infection can be found in 40-100% of various adult populations.6 CMV typically resides latent and asymptomatic in the body but may reactivate during periods of immunosuppression. Serious disease may occur in individuals with compromised immune systems, which includes patients who receive immunosuppressants associated with various types of transplants including HSCT or SOT.5,7 Out of the estimated 200,000 adult transplants per year globally, CMV is one of the most common viral infections experienced by transplant recipients, with an estimated incidence rate between 16-56% in SOT recipients and 30-80% in HSCT recipients.7,8 In transplant recipients, reactivation of CMV infection can lead to secondary infections and serious consequences, including graft loss and, in extreme cases, can be fatal.2,3,5 About Takeda Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit . LIVTENCITY Safety Information Contraindications Contraindications include Hypersensitivity to the active substance or to any of the excipients and co‑administration with ganciclovir or valganciclovir. Special warnings and precautions for use Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. CMV DNA levels should be monitored, and resistance mutations should be investigated in patients who do not respond to treatment. Treatment should be discontinued if maribavir resistance mutations are detected. LIVTENCITY is not expected to be effective in treating CMV CNS infections (e.g. meningo‑encephalitis). LIVTENCITY has the potential to increase the concentrations of immunosuppressants that are cytochrome P450 (CYP)3A/P-gp substrates with narrow therapeutic margins (including tacrolimus, cyclosporine, sirolimus and everolimus). The plasma levels of these immunosuppressants must be frequently monitored throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY, and doses should be adjusted, as needed. The concomitant use of LIVTENCITY and certain medicinal products may result in known or potentially significant medicinal product interactions, some of which may lead to: possible clinically significant adverse reactions from greater exposure of concomitant medicinal products. reduced therapeutic effect of LIVTENCITY. Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium‑free’. Pregnancy & Breast-feeding: LIVTENCITY is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast‑feeding should be discontinued during treatment with LIVTENCITY. Interactions Effect of other medicinal products on maribavir: Co-administration of maribavir with strong cytochrome P450 3A (CYP3A) inducers rifampicin, rifabutin or St. John’s wort is not recommended. If co-administration of maribavir with other strong or moderate CYP3A inducers (e.g., carbamazepine, efavirenz, phenobarbital and phenytoin) cannot be avoided, the maribavir dose should be increased to 1 200 mg twice daily. No dose adjustment is needed when maribavir is co‑administered with CYP3A inhibitors. Effect of maribavir on other medicinal products: If dose adjustments of concomitant medicinal products are made due to treatment with maribavir, doses should be readjusted after treatment with maribavir is completed. Co-administration of maribavir with valganciclovir and ganciclovir is contraindicated. Concomitant administration of maribavir and medicinal products that are sensitive substrates of CYP1A2 with a narrow therapeutic window (e.g., tizanidine and theophylline) should be avoided due to the risk for lack of efficacy of CYP1A2 substrates. When the immunosuppressants tacrolimus, cyclosporine, everolimus or sirolimus are co-administered with maribavir, immunosuppressant levels should be frequently monitored throughout treatment with maribavir, especially following initiation and after discontinuation of maribavir and dose adjusted, when needed. Caution should be exercised when maribavir and sensitive P-gp substrates (e.g., digoxin, dabigatran) are co‑administered. Serum digoxin concentrations should be monitored, and dose of digoxin may need to be reduced, as needed (see Table 1). Co‑administration of maribavir with sensitive BCRP substrates such as rosuvastatin, is expected to increase their exposure and lead to undesirable effects. Adverse Reactions Very common (≥1/10) Taste disturbance, Diarrhoea, Nausea, Vomiting, Fatigue Common (≥1/100 to <1/10) Headache, Abdominal pain upper, Decreased appetite, Immunosuppressant drug level increased, Weight decreased The most commonly reported serious adverse reactions were diarrhoea (2%) and nausea, weight decreased, fatigue, immunosuppressant drug level increased, and vomiting (all occurring at < 1%). Please consult the LIVTENCITY (maribavir) approved label before prescribing, particularly in relation to dosing and treatment monitoring. For Japan, please consult the LIVTENCITY Japan Package Insert. For the European Union, please consult the Summary of Products Characteristics (SmPC). For China, please consult the LIVTENCITY China Package Leaflet. For full U.S. Prescribing Information, including the approved indication and important safety information, please visit: Important Notice For the purposes of this notice, “press release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. 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Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results. Medical Information This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. * Including a subgroup with genotypic resistance to alternative antiviral treatments. a Defined as confirmed CMV DNA concentration below the lower limit of quantification (<LLOQ; i.e., <137 IU/mL) in two consecutive samples separated by at least five days. b Defined as confirmed CMV DNA concentration below the lower limit of quantification (<LLOQ; i.e., <34.5 IU/mL) in two consecutive samples separated by at least five days. c Defined as > 15 years old † CMV infection symptom control was defined as resolution or improvement of tissue-invasive disease or CMV syndrome for symptomatic patients at baseline, or no new symptoms for patients who were asymptomatic at baseline. References Avram S, et al. Novel drug targets in 2021. Nature Reviews Drug Discovery. 2022;21(5):328-328. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infection & Chemotherapy. 2013;45(3):260 Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2017;10(4):233-238. doi:10.1016/j.hemonc.2017.05.001 LIVTENCITY Package Insert in Japan. Avery R, Alain S, Alexander BD, et al. SOLSTICE Trial Investigators. Maribavir for refractory cytomegalovirus infections with or without resistance post-transplant: results from a phase 3 randomized clinical trial. Clin Infect Dis. 2022;75(4):690–701. doi:10.1093/cid/ciab988 de la Hoz RE, Stephanie G, Sherlock C. Diagnosis and treatment approaches to CMV infections in adult patients. J Clin Virol. 2002;25(Suppl 1):S1-S12. doi:10.1016/s1386-6532(02)00091-4 Azevedo LS, Pierrotti LC, Abdala E, et al. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paolo). 2015;70(7):515-523. doi:10.6061/clinics/2015(07)09 Styczynski J. Who is the patient at risk of CMV recurrence: a review of the current scientific evidence with a focus on hematopoietic cell transplantation. Infect Dis Ther. 2018;(7):1-16. doi:10.1007/s40121-017-0180-z View source version on businesswire.com: Contacts International Media Rand Walton rand.walton@takeda.com Japan Media Shigeyuki Matsui shigeyuki.matsui@takeda.com Source: Takeda Pharmaceutical Company Limited View this news release online at:

2023年对于生物制药行业来说，是一个重要的里程碑。尽管行业面临着各种机遇和挑战，但对创新的热情依然高涨。近日，复旦大学邵黎明团队在《Nature Reviews Drug Discovery》杂志上发表了一篇名为《Approvals by the China NMPA in 2023》的文章，对我国在过去一年的新药审批情况进行了细致梳理。这份文章为我们更好地了解行业的发展提供了重要的参考。2023年，中国国家药品监督管理局（NMPA）共批准了191个新药申请（NDA），这一总数包括了化学药物1、2和5.1类、治疗性生物制品1、2、3.1和3.2类，以及根据2020年《药品注册规定》定义的传统中药1、2和3类，但不包括疫苗和诊断试剂。2023年批准的191个NDA中，有118个（62%）是化学药物，64个（34%）是治疗性生物制品，9个（5%）是中药（图1a）。根据NDA申请者的国别，进口药物仍然是中国NDA批准的主要来源（116个进口药物，75个国产药物）。进口化学药物的数量大大超过国内公司开发的数量（81个进口药物对比37个国产药物），但治疗性生物制品的相应数量相当（34个进口对比30个国产）。图1 2023年NMPA批准情况。a、按药物类别、来源和创新性批准。b、2023年按治疗领域批准。多个治疗领域的适应症在最常见的类别中仅计算一次。按药物创新程度分类，作为新的分子实体和生物制品获得批准的创新产品数量低于作为新适应症、新活性成分、新剂型或新组合获得批准的改良产品数量（74个对比117个）。在74个创新药物中，一半是进口药物，一半是国内公司开发的。癌症仍然是2023年批准的药物的主导治疗领域，共有65个NDA（34%）。第二大治疗领域是内分泌和代谢疾病（占NDA批准的13%），其次是神经系统疾病，占11%（图1b）。值得注意的是，进口药物涵盖的治疗领域范围比国产药物广泛。例如，所有经批准用于自身免疫性疾病、泌尿系统疾病和肌骨疾病的NDA都是进口药物。相比之下，国产药物的批准更集中在癌症治疗上（75种药物中的39种），占到了国产药物批准的一半以上。几乎四分之一的批准NDA（191个中的42个）通过优先审查和批准程序获得了NMPA的批准，包括29个进口药物和13个国产药物。其中，有11种儿童药物、14种具有突破性疗法指定的药物以及15种获得条件批准的药物（其中包括7种具有突破性疗法指定的药物）。此外，通过特殊的审查和批准程序，有4种新药获得了加速批准，以满足对COVID-19感染的治疗需求。创新药物NMPA批准的74种创新药物涵盖了广泛的已确认靶点，例如CSF3R、PCSK9、H/K ATPase、EGFR和HER2。大多数靶点要么是受体（53%），要么是酶（33%），而离子通道、转运蛋白和其他类型的靶点仅占14%。值得注意的是，NMPA在2023年批准了9种首创药物。其中包括索必恩公司的尼甲酮（4-HPPD抑制剂）和阿那奎拉（IL-1R拮抗剂），Recordati的卡格鲁酸（CPS1激动剂），赛诺菲的别博若莫司（ROCK2抑制剂），诺华的依纳米单抗（CALCRL单克隆抗体），辉瑞的利特西替尼（JAK3/TEC抑制剂），武汉海特克的阿泊内明（DR4/DR5激动剂），罗氏的法立西单抗（ANG2 × VEGF双特异性抗体）和武田的马立巴韦（UL97抑制剂）。其中只有阿泊内明是全球首次获批。一类创新药物代表了相对创新程度最高的水平。2023年，共有39种一类药物获得NMPA的批准，包括19种化学药物、15种治疗性生物制品和5种中药，如补充表2所示。药品注册规定的修订和COVID-19大流行对一类创新药物的批准产生了影响，导致2020年至2023年批准药物数量出现了显著波动（图2a）。图2 NMPA批准的创新药物和改良药物的特点。a、2020年至2023年NMPA批准的一级药物数量。2020年至2022年的数据来源于NMPA药品评价中心发布的药品审评年度报告。疫苗和诊断试剂被排除在外。b、2023年NMPA批准的改良药物类型。具有相同成分但不同比例的组合在中文通用名上有所不同，并且它们被单独计算。2023年，国内公司研发的37种创新药中，武汉海泰的阿泊诺显著突破，该药用于治疗经历了两种或两种以上系统疗法后仍出现复发或难治性多发性骨髓瘤的成年患者，是中国制药公司独立开发的唯一一种一类新药。此外，还有四种药物在癌症治疗方面获得了突破性疗法认定：海和的格鲁美替尼、迪扎的苏姆唯替尼、阿维斯通的维布雷替尼和和远的依那替昔细胞亚单位自体细胞。前三种药物获批用于非小细胞肺癌的治疗，而最后一种是专门用于治疗急性淋巴细胞白血病的首个CAR-T免疫疗法。此外，三诺制药获批了国内研发的第一种丙型肝炎病毒（HCV）NS5B聚合酶抑制剂阿瑞妥韦，用于治疗HCV感染，而信远获批了第一家国产PCSK9单克隆抗体陶妥昔单抗，用于治疗原发性高胆固醇血症和混合型血脂异常。在中国，治疗罕见病的创新药物一直是一个重要的优先事项。2023年，NMPA批准了19种罕见病药物，全部为进口药物，其中8种为创新药。例如，Recordati的卡古麦酸是首种可以替代N-乙酰谷氨酸，通过激活CPS1增强或恢复尿素循环从而治疗丙酸血症或丙酸甲酰血症引起的急性高氨血症的药物。它已经被欧洲药品管理局和美国食品和药物管理局批准用于这些适应症。Sobi的阿那肯肝素，已在其他地方获批，成为中国首个批准用于家族性地中海热和冷凝蛋白相关周期性综合征的IL-1受体抑制剂。Sobi研发的首个4-HPPD抑制剂尼提酮，获批用于遗传性酪氨酸代谢异常1型。改良药物2023年，NMPA批准了117种改良药物，包括38种国产药物和79种进口药物。其中大部分批准（117种中的70种）涉及已上市药物的新适应症。值得注意的是，超过一半的新适应症与癌症有关（70种中的37种）。29种药物获批用于新的剂型，如微球制剂、鼻喷剂和糖浆。值得注意的是，合适的剂型可以提高儿童的用药依从性，其中有18种儿童用新剂型中有12种是新剂型。例如，江苏恒瑞的右美托咪定盐酸盐鼻喷剂通过优先审评计划获批，显示出较高的黏膜吸收率和颇高的鼻腔使用后的生物利用度。与传统的静脉和口服剂型相比，鼻喷剂更容易给予儿童，减轻了麻醉前儿童的术前焦虑。总结2023年，NMPA批准的药物数量稳步增长。此外，NMPA对市场上重要的国外新药的审评和批准加速。改良新药继续占据新药批准的大部分比例，尤其是儿童用药的新剂型。参考文献doi: http://doi-org.ypl.ilibs.cn/10.1038/d41573-024-00034-2识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。