Hereditary Angioedema Types I and II

- TAKHZYRO® is the First Routine Prevention Treatment of HAE Approved in the EU for Patients Under the Age of Six. - The therapeutical indication for TAKHZYRO® has been extended to patients aged 2 years and older .1 - O ffers a New Preventative Treatment Option for young HAE patients with high unmet need ZURICH, Nov. 17, 2023 /PRNewswire/ -- Takeda (TSE:4502/NYSE:TAK) today announced the European Commission has approved TAKHZYRO® (lanadelumab) for the routine prevention of recurrent attacks of Hereditary Angioedema (HAE) in patients aged 2 years and older1, expanding its initial approved use and making it the first long-term prophylactic treatment of HAE available in European Economic Area for patients under the age of six.2,3,4 The recently approved extension of the indication in paediatric patients was paired with an additional strength of 150 mg for Lanadelumab solution for injection in pre-filled syringe. TAKHZYRO® 150mg should be used in patients aged 2 years and older and weighing less than 40 kg to prevent angioedema attacks in patients with Hereditary Angioedema (HAE).1 Previously indicated for the routine prevention of recurrent attacks of HAE in patients aged 12 years and older in the EEA5, the update is supported by clinical data from Phase 3 Study SHP643-3016, in combination with extrapolation of data from the pivotal Adult and Adolescent Study DX-2930-037, and by quality data supporting the new 150 mg pre-filled syringe formulation8. Overall, the safety and efficacy of TAKHZYRO® in preventing Hereditary Angioedema (HAE) attacks in paediatric patients aged 2 and above was demonstrated and the benefit risk-balance was considered positive. The EMA is the second Agency recommending approval in paediatric population 2 years of age and older, following the U.S. Food and Drug Administration's (FDA) approval of the supplemental Biologics License Application (sBLA) in February this year, for the same expanded use of TAKHZYRO® (lanadelumab-flyo).9 "Potentially fatal upper airway angioedema has been reported in patients as young as 3 years old10, presenting an acute unmet need in some of the most vulnerable of HAE patients." said Didier Relin, Head of International Regulatory at Takeda. "With this expanded label, TAKHZYRO® offers a welcomed new preventative treatment option for the paediatric HAE patient population, and one that can be administered at home with the support of a trained caregiver." Notes to editors: European Commission Decision number: EMEA/H/C/004806/X/0034/G About HAE Hereditary angioedema (HAE) is a rare genetic disorder that results in recurring attacks of oedema – swelling – in various parts of the body, including the abdomen, face, feet, genitals, hands and throat. The swelling can be debilitating and painful.11 Attacks that obstruct the airways can cause asphyxiation and are potentially life threatening.12 HAE affects an estimated 1 in 50,000 people worldwide.13 It is often under recognised, under diagnosed and under treated.11 HAE, like so many other rare diseases, is highly complex, and patients, their families and caregivers often undergo years of strain trying to understand their disease, get a definitive diagnosis and gain access to the medicines they need. At Takeda we are a committed champion for the patients we serve. Every individual living with HAE is unique and by listening and reacting to their needs, we translate the insights we gain into innovative solutions – from diagnosis to ongoing management. Advancing the science is crucial to the way we operate and we are bold in our mission to accelerate diagnosis and develop treatments that will make a difference to the lives of HAE patients, their support networks and those medical professionals who care for them. About Lanadelumab (TAKHZYRO®) Lanadelumab is a fully human monoclonal antibody that specifically binds and decreases plasma kallikrein and is indicated for routine prevention of recurrent attacks of HAE in patients aged 2 years and older. It was studied in one of the largest prevention studies in HAE with the longest active treatment duration, and Lanadelumab consistently demonstrated HAE attack reduction. Lanadelumab is formulated for subcutaneous administration and has a half-life of approximately two weeks. Lanadelumab is intended for self-administration or administration by a caregiver once trained by a healthcare professional.5 About Study SHP643-301 (SPRING Study) SHP643-301 is A Multicenter, Open-Label Phase 3 Study to Evaluate Safety, PK, Pharmacodynamics, And Clinical Activity/Outcomes of TAKHZYRO® (lanadelumab) for Prevention Against Acute Attacks of HAE in Pediatric Patients 2 To <12 Years of Age. The safety profile was consistent with that seen in the clinical program for patients 12 years of age and older; there were no serious adverse events and no dropouts due to adverse events. The study also successfully reached the secondary objective evaluating the clinical activity/outcome of TAKHZYRO in preventing hereditary angioedema (HAE) attacks as well as characterizing the pharmacodynamics of TAKHZYRO in paediatric patients 2 to <12 years of age.6 About Takeda Pharmaceutical Company Takeda is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people's lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions. 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 briefings 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. 1 (23)01019-X/pdf#:~:text=How%20does%20this%20study%20impact,prophylaxis%20in%20this%20age%20group. 2 HAEGARDA® (C1 Esterase Inhibitor Subcutaneous [Human]). Product Characteristics. 3 CINRYZE® (C1 esterase inhibitor [human]). Product Characteristics. 4 Farkas, H., Martinez–Saguer, I., Bork, K., Bowen, T., Craig, T., Frank, M., ... & Zuraw, B. (2017). International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency. Allergy, 72(2), 300-313. 5 European Medicines Agency, TAKHZYRO Summary of Product Characteristics. Available at: Last Accessed: November 2023. 6 Maurer M, Lumry WR, Li H, et al. Efficacy and Safety of Lanadelumab in Pediatric Patients Aged 2 to <12 years With Hereditary Angioedema: Results From the Open-Label, Multicenter Phase 3 SPRING Study. Abstract submitted to European Academy of Allergy and Clinical Immunology Hybrid Congress 2022. 7 8 . 9 TAKHZYRO®(lanadelumab-flyo) injection. U.S. Prescribing Information. 10 Bork, K., Hardt, J., Schicketanz, K. H., & Ressel, N. (2003). Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Archives of Internal Medicine, 163(10), 1229-1235. 11 Mau rer, M., Magerl, M., et al. (2022). The international WAO/EAACI guideline for the management of hereditary angioedema—The 2021 revision and update. Allergy, 77(7), 1961–1990. . 12 Banerji, A., Davis, K. H., Brown, T. M., Hollis, K., Hunter, S. M., Long, J., ... & Devercelli, G. (2020). Patient-reported burden of hereditary angioedema: findings from a patient survey in the United States. Annals of Allergy, Asthma & Immunology, 124(6), 600-607. 13 Longhurst, H. J., & Bork, K. (2019). Hereditary angioedema: an update on causes, manifestations and treatment. British Journal of Hospital Medicine, 80(7), 391-398. Logo -

前言肿瘤细胞采用各种策略来适应并抵抗免疫系统的攻击，这些机制统称为适应性免疫耐受(Adaptive Immune Resistance，AIR)。第一个AIR机制是在肿瘤中通过IFN-γ选择性诱导PDL1。抗PD治疗可以使部分晚期癌症患者缓解，特别是实体肿瘤患者。然而，许多临床试验联合抗PD治疗和其他抗肿瘤药物联合治疗，没有一个强有力的机制基础，未能确定协同或加性效应。此篇综述于2022年6月14日发表在Nature Reviews Drug Discovery上，这里讨论了理解AIR机制是未来指导药物开发的关键点，以及可以改善当前癌症治疗的方案。AIR的猜想众所周知，PD1在血液和肿瘤微环境（TME）中由活化的T表达，但是在T细胞激活前在TME中没有发现PDL1。并且，在一些表达PDL1的肿瘤中，没有明显的T细胞浸润（称为IV型肿瘤）。PD1-PDL1通路似乎是晚期癌症患者中占主导地位的AIR机制。AIR机制不同于一般的免疫抑制机制，如免疫检查点CTLA-4，因为在健康的个体中，CTLA-4是抑制自身反应所必须的，主要通过Treg调控。另一个是TGFβ，它可以抑制不必要的炎症和自身免疫，除了正常的稳态机制中有广泛的作用。除了PD1-PDL1通路，在TME中还存在其他的AIR机制。许多肿瘤在没有PDL1表达的情况下，可以被功能失调的肿瘤浸润淋巴细胞(TILs)浸润。此外，冷肿瘤没有明显的炎症和免疫反应，情况独特。总之，晚期癌症患者可以同时依靠多种AIR机制来逃避免疫攻击。AIR的分类据统计，实体瘤患者中25%的患者，和血液瘤中的40-60%患者对抗PD治疗有反应。不同肿瘤患者应答也有差异，在进行治疗前，准确判断哪些患者会有反应很重要。我们基于肿瘤免疫微环境(TIME)提出了四种不同类型的人类癌症（图1），以更好地定义免疫状态，预测肿瘤对抗PD治疗的反应和无反应或者耐药性。图1抗pd治疗的耐药性取决于肿瘤免疫微环境的类型2.1 Primary resistance我们将抗PD治疗的最初耐药定义为对II型肿瘤的抗PD治疗最初没有反应，II型肿瘤同时有PDL1表达和T细胞浸润(图1)。在黑色素瘤、肺癌和膀胱癌中，与PDL1−肿瘤相比，PDL1+肿瘤与抗PD治疗的更高应答率相关。然而，TILs的存在，尤其是CD8+ T细胞，还没有被用作预测生物标志物来选择患者。因为IV型肿瘤不存在T细胞浸润，抗PD治疗也不会产生反应，所以抗PD治疗的最初耐药不能仅根据PDL1阳性来确定。我们不知道抗PD治疗需要多少PDL1在TME中表达才能起作用。穿刺活检的肿瘤组织采样可能会漏掉PDL1+区域，但是可以通过对同一个肿瘤进行多次活检来避免。放射性同位素标记的PD1变异体或抗PDL1单抗在体内成像可能是评估PDL1在更大区域肿瘤表达的更好方法。总之，PDL1的表达可能是动态的，因为它在很大程度上是诱导的，这表明从活检开始到抗PD治疗开始，表达可能会有所不同。除了PDL1的表达，评估其他共抑制分子和共刺激分子的表达也很重要，以充分利用有效的免疫反应。这可能是抗PD治疗初期耐药性的关键。虽然TILs的存在似乎是必要的，但仍不清楚是哪些关键的细胞成分，以及TILs上的分子成分决定了初级耐药。CD8+和TME中的Th1细胞始终与较好的预后相关，这些细胞可能是预防原发性耐药的必要细胞成分。其他TIL成分包括CD4+ T细胞亚群、自然杀伤(NK)细胞、NKT细胞、B细胞、T reg细胞、γδ T细胞以及先天淋巴细胞，在TME中的作用尚不清楚。2.2 Acquired resistance四分之一到三分之一的转移性黑色素瘤患者最初对抗PD治疗有反应，但是会随着时间的推移复发。肺癌的治疗过程中也发现了这种情况。这些患者表现出对抗PD治疗的获得性耐药性。目前还没有明确的生物标志物或临床标准来预测复发，也没有大量收集病例来论证其共同机制的报道。临床观察为获得性耐药可能的潜在机制提供了一些线索。获得性耐药患者仍然可能是PDL1和PD1表达阳性。在某些情况下，复发的患者在停药一段时间或化疗后可以恢复对抗PD治疗的反应。在这些病例中，获得性耐药性不能用肿瘤抗原突变或丢失引起的肿瘤变异来解释。肿瘤细胞可能会发生内在变化，从而降低对免疫攻击的易感性。2.3 Target-missing resistance缺乏PD1或PDL1表达的肿瘤都被归为“靶缺失”。 因此，观察到I、III和IV型TIME（tumour immune microenvironment）患者对抗PD治疗的反应较差并不奇怪。在60-85%的实体肿瘤中出现靶缺失耐药(如表1)。这就是为什么只有一小部分患者对抗PD治疗有反应的主要原因。TIME type I和type IV的一个共同特征是缺乏TILs。检测肿瘤组织中的PD1和PDL1来制定纳入排除标准很重要。TIME型肿瘤有T细胞浸润，但缺乏PDL1表达。因此，与I型和IV型肿瘤不同，III型肿瘤可以招募T细胞，但这些细胞不能正常分化成完全成熟的细胞T细胞。在III型肿瘤中缺乏PDL1表达表明这种分化过程的缺乏，如缺乏IFNγ。这表明在抑制T细胞中存在非PD1 - PDL1 AIR机制。目前的联合治疗方案在晚期黑色素瘤患者中，抗PD治疗已被证明优于抗CTLA4治疗，因为其提高了总生存期也降低了毒性，因此在探索免疫治疗联合其他药物的临床试验中，抗PD治疗是最常见的方案。3.1 Combination with anti-CTLA4联合抗CTLA4治疗(ipilimumab)在转移性黑色素瘤患者中的单药活性在很大程度上得到了增强。这种序贯方法可能有助于降低显著毒性，同时保持疗效。事实上，对抗PD治疗有耐药性的患者对抗CTLA4治疗仍然有相当的反应率。3.2 Combination with chemotherapy众所周知，标准化疗对高增殖细胞有广泛的细胞毒性作用，特别是对造血和免疫系统。因此，全身化疗是免疫治疗的天敌。一些研究表明，某些化疗药物可以通过消除Treg细胞来促进T细胞免疫，以及增加肿瘤细胞死亡时抗原释放，从而能够刺激T细胞介导的免疫。效应T细胞可以分化为记忆细胞，这对长期免疫保护至关重要。目前，尚不清楚化疗是否会对长期记忆免疫细胞的产生产生不利影响，更好地了解化疗如何影响免疫系统对未来的临床试验至关重要3.3 Combination with targeted therapy靶向细胞内信号通路负责细胞的生长或生存与小分子已被证明在快速减少肿瘤体积有效。然而，许多这样的药物并没有持久的作用，主要是由于出现其他补偿途径。这一特点似乎是对抗PD治疗的补充，抗PD治疗可以产生长期效果，但通常需要数月的时间让免疫细胞在TME中繁殖和协调它们的功能。因此，靶向治疗既能抑制肿瘤生长，又不会对免疫系统造成不利影响，是与抗帕金森病治疗相结合的潜在选择。未来的联合治疗4.1 Altering the TME locally一项晚期黑色素瘤的Ib期临床试验结果表明，TLR9激动剂与抗PD治疗联合时显示出联合效应。然而，一项对实体肿瘤或淋巴瘤患者的试验的早期结果表明，STING激动剂在单药治疗中效果甚微，并且将其与抗PD治疗相结合的价值仍不确定。为了在临床中发挥作用，这些药物必须激活先天免疫，诱导成功的炎症反应，从而吸引免疫系统的适应性，如T细胞，最后诱导活化的T细胞分布到身体的其他部位，以抑制继发性肿瘤或转移。目前，尚不清楚这些因子是否触发了先天免疫，即使这些因子成功地刺激了先天免疫，也不能保证自发地产生适应性免疫，正如在许多冷肿瘤中所显示的那样，在这些肿瘤中，中性粒细胞甚至巨噬细胞仍然可能存在于TME中。4.1.1 Local radiation辐射会对组织和细胞产生深远的影响。除了破坏细胞外，它还触发先天免疫，随后在某些情况下促进免疫渗入肿瘤。理论上，放疗应该适合TIME  I型和IV型肿瘤患者产生新生炎症。但是，在TIME type II和III型肿瘤中不应考虑或应谨慎应用，因为辐射可能损害现有的TILs。4.1.2 Local administration of oncolytic viruses.最初使用溶瘤病毒治疗癌症的理由是，有些病毒只在癌细胞中复制，而不在正常细胞中复制。除了病毒固有的溶瘤特性外，一些产品的修饰已被应用于调节免疫反应，如插入细胞因子、重组抗体、T细胞接合配体和肿瘤抗原。4.1.3 Blockade of immunosuppression许多通用的免疫抑制机制在体内运行，以控制自身反应性免疫反应和/或过度反应性炎症反应。与AIR机制相反，这些机制并不一定是由癌症甚至炎症诱导或促进的，而是维持正常的内稳态所必需的。4.2 Enhancing T cell-mediated immunity4.2.1 Adoptive T cell therapy对于TIME I型和IV型肿瘤，CAR-T细胞和体外扩增的抗原特异性T细胞或TILs，是增加肿瘤部位T细胞浸润的一种有吸引力的方法。这种方法存在一些障碍，首先，转移的T细胞激活后应保持迁移到肿瘤组织的能力；其次，回输T细胞在TME中仍然可能遇到除PD途径外未知的AIR机制。这目前很难预测，也可能是T细胞治疗实体肿瘤的临床试验失败的主要原因。选择性地培养或对T细胞改造有望抵抗各种AIR机制。4.2.2 T cell co-stimulation与T细胞过继疗法相似，共刺激可以极大地促进T细胞的扩增和活化。CD80-CD28在肿瘤免疫的刺激中有望增加癌症患者免疫力。CD137能够促进T细胞扩增，和细胞毒性，还能够增加细胞因子效应。并且CD137与抗PD治疗的单药与联合治疗有很好的效果。OX40和OX40L激动剂单抗也在临床试验中。CD40和CD40L向树突状细胞传递强烈的信号，可以增强T细胞的启动和激活，也在进行临床试验。结语肿瘤诱导的AIR机制的发现和选择性阻断它们的治疗方法，已被证明对癌症患者有效，如抗PD治疗。通过对人类TME的解剖、分析和分类，我们发现了其他具有复杂性质和高度异质性的AIR机制的存在，我们很可能只是观察到冰山一角。尽管如此，仍有可能确定在TME中起作用的一些主要的AIR机制，从而使设计更具体的治疗方法成为可能。了解并针对这些新的AIR机制，将能在不久的将来有效治疗更多的癌症患者。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。