Multi-Centric Castleman's Disease

Sanofi’s Enjaymo, the only approved drug therapy for a rare and debilitating blood disorder, is being acquired by Recordati in a deal that helps the Italian company build its rare disease portfolio and expand its commercial reach in key markets. Recordati is paying $825 million up front for global rights to Enjaymo, a drug that is approved in the U.S., Japan, and Europe. If the drug achieves sales milestones, the company could pay out up to $275 million more, according to deal terms announced Friday. Sanofi and Recordati expect to complete the transaction by the end of this year. Enjaymo treats cold agglutinin disease, a condition in which the immune system attacks red blood cells and causes them to rupture. This process happens at cold temperatures, giving the disease its name. At these temperatures, antibodies that normally attack bacteria instead attach to red blood cells, causing them to bind together, or agglutinate. The red blood cells are destroyed by the immune system, leading to anemia. presented by Health Tech What’s Keeping Healthcare CIOs Up at Night: How to Improve Patient Satisfaction by Handling Calls More Efficiently Health systems have spent billions on portals while investments in modernizing the voice channel — the dominant preference of healthcare consumers — have taken a backseat. By Stephanie Baum The resulting anemia can be managed with blood transfusions. Enjaymo takes a different approach by interfering with the process that leads to red blood cell destruction in cold agglutin disease. The drug, an intravenously infused monoclonal antibody, is designed to selectively target and block a complement system protein called C1. This in turn stops immune system antibodies from attaching to immune cells. The FDA approved Enjaymo in 2022. Approvals in Japan and Europe soon followed. In these three markets, the companies estimate cold agglutin disease affects between 11,000 and 12,000 patients. Recordati, which is headquartered in Milan, is the latest stop in a long journey for Enjaymo. The drug was initially developed by True North Therapeutics, which itself was acquired by Bioverativ in 2017. In 2018, Sanofi paid $11.6 billion to buy Bioverativ. Enjaymo generated €72 million (about $79 million) in sales last year, a 240% increase over the product’s sales in 2022, according to Sanofi’s annual report. Sales for Enjaymo are continuing to grow, but it’s not on track to become a blockbuster seller. Recordati said that in the 12 months ending in August, the drug accounted for €100 million (about $109 million) in revenue. The company projects the product’s peak sales could reach €250 million to €300 million (about $274 million to $328 million). Recordati said its milestone payment to Sanofi is tied to the achievement of net sales at or above the top end of peak year sales expectations. Rare disease accounts for about 34% of Recordati’s more than €2 billion in annual revenue, according to a September investor presentation. Most of those rare disease sales are in the U.S. Much of the company’s rare disease portfolio is comprised of assets from its 2022 acquisition of EUSA Pharma, a developer of drugs for rare cancers. Sponsored Post Get Ready for HLTH 2024: A Preview Guide HLTH 2024, scheduled for October 20-23 at the Venetian Expo Center in Las Vegas, will highlight new programming, a physicians roundtable, generative AI, the shifting landscapes of telemedicine, retail health, women's health, and lots more. By Stephanie Baum In a prepared statement, Recordati CEO Rob Koremans said Enjaymo is particularly complementary to one of those products, Sylvant. This drug, an antibody designed to block the inflammatory signaling protein IL-6, has approvals in more than 40 countries for treating idiopathic multicentric Castleman disease, a rare disorder characterized by abnormal growth of the lymph nodes. While this disease is not cancer, its progression is similar to that of lymphoma, a cancer of the lymph nodes. Last year, Recordati began exploring the development of Sylvant for other diseases driven by IL-6 signaling. “Enjaymo further expands our rare diseases footprint in the U.S., Japan and Europe, and will contribute positively to both our top and bottom lines,” Koremans said. “Most importantly, with a strong clinical profile and as the only product approved for the treatment of [cold agglutinin disease], Enjaymo addresses a serious unmet medical need for patients living with this debilitating disease.” Image by istocksdaily, via Getty Images

关注并星标CPHI制药在线 近日，FDA批准再生元（Regeneron Pharmaceuticals）和赛诺菲（Sanofi）共同开发的Kevzara（sarilumab），用于治疗体重63公斤或以上的活动性多关节型幼年特发性关节炎（pJIA）患者，这是一种同时影响多个关节的关节炎。 美国FDA批准该疗法用于治疗pJIA患者群体是基于充分且具有良好对照的试验结果、来自类风湿性关节炎成年患者的药代动力学数据，以及针对pJIA儿童患者的药代动力学、药效学、剂量探索和安全性研究。 Kevzara是再生元与赛诺菲共同开发的人源化单抗药物，它能结合白细胞介素-6（IL-6）受体，从而抑制由它介导的信号通路。在人体中，白细胞介素-6是一种在炎症反应中扮演了重要作用的细胞因子。当它的表达量长期高于正常水平时，就会造成一系列炎症反应，其中就包括了与类风湿性关节炎有关的炎症。除了pJIA，Kevzara目前已在25个国家或地区获批用于治疗中度至重度活动性类风湿性关节炎成人患者。Kevzara还获FDA批准用于治疗风湿性多肌痛（一种炎症性风湿性疾病），用于治疗对皮质类固醇反应不足或不能耐受皮质类固醇逐渐减量的成年患者。 IL-6简介及信号通路 IL-6属于白细胞介素的一种，是一种多功能细胞因子，参与多种细胞的生长、分化和功能调节，在免疫和炎症反应中具有重要作用，是机体重要的免疫-神经-内分泌调节因子。IL-6是小分子多肽，由四个α螺旋组成。分子量为19-28kD，具有184个氨基酸残基，通常情况下以单体形式存在，等电点为5.0，有糖基化位点，有两个二硫键。编码IL-6的基因位于染色体7p15-21，包括4个内含子与5个外显子。 IL-6的功能多样性主要在于和细胞表面多种IL-6受体的相互作用，然后经下游信号传导途径将多种生物信号传给不同的组织和细胞。IL-6分泌失调与多种疾病的病理生理过程密切相关。近年来研究发现，IL-6在许多炎症性疾病如类风湿性关节炎（RA）、系统性红斑狼疮（SLE）、克罗恩病（CD）等中高度表达，成骨细胞产生的IL-6能刺激破骨细胞的形成，并与多种细胞因子相联系参与炎症和发热反应，导致炎性疾病如类风湿性关节炎和强直性脊柱炎的发生。 IL-6作用模式主要包括经典信号途径（Classic Signaling）和转移信号途径（Trans-Signaling）。在经典途径中，IL-6与其膜结合受体mIL-6R、可溶性受体sIL-6R结合后，招募gp130（一种跨膜蛋白，细胞因子受体）结合形成IL-6-IL-6R-gp130六聚体，触发下游JAK-STAT、RAS-RAF等信号通路转导和基因表达。在转移信号途径中，IL-6-sIL-6R复合物与gp130结合，启动细胞内信号转导，促进细胞增殖、分化、氧化应激和免疫调节。        IL-6信号通路        图片来源：参考来源1 全球四款药物获批上市 目前，靶向IL-6通路的抗体药物已成为多种自身免疫病和癌症的创新疗法，并运用于细胞因子风暴等其他疾病。IL-6抑制剂可阻断IL-6与IL-6R结合，抑制IL-6的信号转导，从而减少病例炎症反应。据 Insight 数据库显示，目前全球已有四款IL-6/6R抑制剂获批，除了赛诺菲和再生元的Sarilumab外，还有罗氏的托珠单抗和萨特利珠单抗以及EUSA Pharma的司妥昔单抗。除Sarilumab外，其余三款目前均已在国内上市。        图片来源：肖恩记药 托珠单抗：托珠单抗最初由Chugai研发，后与罗氏共同开发和销售的可以结合sIL-6R和mIL-6R的单抗药物，先后于2005年、2009年、2010年和2013年在日本、欧盟、美国和中国获批上市，用于治疗类风湿关节炎（RA）、全身型幼年特发性关节炎(sJIA)和细胞因子释放综合征(CRS)等。目前，全球已有三款托珠单抗生物类似药获批上市，分别为Tyenne（Fresenius）、施瑞立（百奥泰/渤健）和安维泰（丽珠医药）。其中，施瑞立是唯一一款在中美均已获批上市的托珠单抗生物类似药。另外，还有三款托珠单抗生物类似药也已提交上市申请，分别为CT-P47（Celltrion）、CMAB806（迈博太科）和HS628（博锐生物）。 司妥昔单抗（Siltuximab）：司妥昔单抗是一款单克隆抗体，用于阻断在iMCD患者中检测到升高的多功能细胞因子白细胞介素-6（IL-6）的活动，最初由强生公司研发，后授权给EUSA Pharma公司。2020年1月，百济神州与EUSA Pharma达成合作，获得了在大中华地区开发和商业化包括司妥昔单抗在内两款药物的权利。多中心Castleman病是一种罕见、危及生命的衰竭性淋巴组织增生疾病，能够产生免疫细胞的异常增生，并在症状和组织学特征上与淋巴瘤有许多相似之处。患者有轻重不同的症状：有的只是单个淋巴结异常，伴有轻度流感一样的症状；严重的有全身许多淋巴结异常、血细胞数量异常、多个器官功能异常并危及生命。Sylvant也是FDA批准的首个MCD领域的药物。 萨特利珠单抗（Satralizumab）：萨特利珠单抗是罗氏开发的一款全人源化的白细胞介素-6（IL-6）单抗药物，可以抑制IL-6信号通路，并且抑制炎症的产生。2021年5月，该药首次在中国获批上市，用于治疗水通道蛋白4（AQP4）抗体阳性的视神经脊髓炎谱系疾病（NMOSD）的12岁及以上青少年及成人患者。除了NMOSD，罗氏还在探索萨特利珠单抗用于其他适应症，针对全身型重症肌无力、自身免疫性脑炎（AIE）、髓鞘少突胶质细胞糖蛋白抗体相关疾病（MOGAD）、甲状腺相关眼病（TED）处于临床3期，针对肺动脉高压、面肩肱型肌营养不良症处于临床2期。 IL-6/6R拮抗剂全球研发进展 除了上述上市的药物之外，目前全球约30个在研的IL-6/6R拮抗剂已进入临床或申报阶段，包括优时比的olokizumab、诺和诺德的ziltivekimab和罗氏的RG6179等已进入关键3期临床，其中olokizumab用于治疗RA疾病正在进行上市申请。国内方面伟德杰生物、嘉和生物也有相关产品进入临床阶段。从适应症布局来看，主要集中在类风湿关节炎（RA）、炎症性肠病(IBD)和系统性红斑狼疮（SLE）等常见的自身免疫性疾病，此外在眼科的糖尿病性黄斑水肿(DME)和心血管疾病动脉粥样硬化等领域也有涉及。        全球部分在研IL-6/6R拮抗剂        图片来源：写同意Biotech Olokizumab Olokizumab最初由优时比公司研发，是一款靶向IL-6的人源化单抗。后来在2013年转让给了俄罗斯药企R-Pharm，目前正在进行RA领域的上市申请。Josef等人在新英格兰医学杂志上报道了Olokizumab的一项为期24周的3期多中心安慰剂和阳性对照试验中（NCT02760407），该试验招募了1648名对甲氨蝶呤无反应的类风湿性关节炎志愿者，该队列被分成四组：每两周一次的olokizumab单抗，每四周一次的olokizumab单抗，每两周一次的阿达木单抗，或安慰剂。在所有措施中，24周后，与安慰剂相比，两种剂量水平的olokizumab都明显有效。尽管发现olokizumab单抗比阿达木单抗略微有效，但研究人员认为这种增加在统计学上并不显著，不足以认为它具有优势。但是，它至少与阿达木单抗同样有效的事实意味着它应该是对目前可用的治疗方法没有反应的患者的一个有希望的新选择。 Ziltivekimab Ziltivekimab是一款人白细胞介素6（IL-6）单克隆抗体，最初由Corvidia Therapeutics研发。2020年6月，诺和诺德以21亿美元收购Corvidia Therapeutics，获得了其主要候选药物ziltivekimab的开发工作。Ziltivekimab通过阻断IL-6通路来降低全身炎症，从而降低动脉粥样硬化性心血管疾病（ASCVD）和慢性肾脏病（CKD）患者的主要心血管不良事件风险。在II期临床研究中，结果显示，ziltivekimab显著降低了与动脉粥样硬化相关的炎症和血栓形成的生物标志物，包括高敏C反应蛋白（hsCRP）等。Ziltivekimab目前正在进行3期试验，以验证其在不同心血管疾病人群中的获益。 RG6179 罗氏的RG6179是一款专门为眼内使用的抗IL-6单克隆抗体，特别的优化让它很容易被系统清除。在治疗葡萄膜炎性黄斑水肿（uveitic macular edema）患者的1期临床试验中，所有剂量的RG6179均改善患者视力且并未导致视网膜积水。大约25-30%的患者在接受治疗12周后的视力可以从视力表上多读15个字母。基于这些结果，目前RG6179正在3期临床试验中接受检验。 结语 白细胞介素-6（IL-6）是一种功能广泛的多功能细胞因子，具有调节免疫应答、急性期反应及造血功能，并在机体的抗感染免疫反应中发挥重要作用。IL-6作为自免领域靶点取得了很大的成功，目前国内外还有多家药企布局在IL-6/IL-6R拮抗剂，开拓新的适应症。靶向IL-6疗法究竟还有多少潜力待挖掘呢？让我们拭目以待。 参考来源        1.Fernanda I Arnaldez,1 Steven J O'Day,2,3 Charles G Drake,4 Bernard A Fox,5 Bingqing Fu,6 Walter J Urba,5 Vincenzo Montesarchio,7 Jeffrey S Weber,8 Haiming Wei,6 Jon M Wigginton,9 Paolo Antonio Ascierto, The Society for Immunotherapy of Cancer perspective on regulation of interleukin-6 signaling in COVID-19- related systemic inflammatory response, J Immunother Cancer 2020;8:e000930. 2.Masashi Narazaki and Tadamitsu Kishimoto, The Two-Faced Cytokine IL-6 in Host Defense and Diseases, Int. J. Mol. Sci. 2018, 19, 3528. 3.Mansur Aliyu et.al, Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach, International Immunopharmacology 111 (2022) 109130 4.Josef S. Smolen et.al, Olokizumab versus Placebo or Adalimumab in Rheumatoid Arthritis, N Engl J Med 2022;387:715-26. 5.Paul M Ridker, Matt Devalaraja, Florian M M Baeres, Mads D M Engelmann, G Kees Hovingh, Milana Ivkovic, Larry Lo, Douglas Kling, Pablo Pergola, Dominic Raj, Peter Libby, Michael Davidson, IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial, Lancet 2021; 397: 2060–69 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

Researchers have developed a model of Kaposi sarcoma that could expedite the development of new drugs to treat the disease, which is the most common cancer in people living with HIV. Researchers at UNC Lineberger Comprehensive Cancer Center, after decades of research efforts, have developed a mouse model of Kaposi sarcoma that could be key to the development of new drugs to treat the disease. Kaposi sarcoma is a cancer that is the most common cancer in people living with HIV. The findings appeared in Cell Host & Microbe. "This is an important development as we have created the first animal model ever of Kaposi sarcoma. Animal models are essential to move new drugs from the laboratory bench into clinical trials," said UNC Lineberger's Dirk Dittmer, PhD, senior corresponding author, co-leader of the UNC Lineberger Virology Research Program and director of the UNC Viral Genomics Core. "Before this, only repurposed drugs from other cancers were used to treat Kaposi sarcoma, but now we can start investigating entirely new compounds to help treat what can be a lethal cancer." About 20% of all human cancers arise from viruses or require viral infection as an essential cofactor. The Kaposi sarcoma-associated herpes virus (KSHV) was discovered in 1994 and is associated with Kaposi's sarcoma as well as B-cell cancers. KSHV-associated diseases affect internal organs and are ultimately fatal. In the U.S., the diseases are found primarily in immunosuppressed people such as those who are HIV-positive or are transplant patients. Worldwide, an estimated 34,270 cases of Kaposi sarcoma were diagnosed, and 15,086 deaths reported in 2020, with twice as many cases and deaths occurring in men compared to women. Africa accounted for 73% of new cases and 86.6% of the deaths from Kaposi sarcoma worldwide. The disease is endemic, and not HIV-related, in some southern and eastern African countries. Aside from animal models, one way to study cancer is to look at tumor cells in the lab. But according to Dittmer, Kaposi sarcoma tumor cells are very finicky and dependent on signaling molecules and blood supply, which is why they don't survive in a laboratory culture dish. Therefore, researchers have been focusing on developing animal models that would mimic, as closely as possible, the disease in humans. One of the challenges the researchers faced in developing their model was the fact that two types of genes are transcribed into proteins in the Kaposi sarcoma mouse model. Normally when a virus infects a cell, the cell dies as the virus replicates, which is a process called cell lysis; the genes that are needed for the virus to propagate itself are lytic genes. Cancer viruses are different as they enter a quiet state, called latency, where only the genes that help the infected cell survive are expressed. The mouse model the researchers developed is complex as a bit of both types of genes were needed. Cervical cancer and its related virus, HPV (human papilloma virus), offers a good comparison for the challenge of developing a Kaposi sarcoma mouse model. The KSHV genome is 20 times larger than HPV. HPV has two cancer-causing genes, E6 and E7, so to mimic the disease in animals, researchers only needed to design two mice, one for each gene. KSHV may have as many as 10 cancer-causing genes that all work together so it would be way too difficult to develop that many mice, hence the virtue of their single model, Dittmer noted. "Another of the key virtues of our new mouse model is that it helps us understand angiogenesis, or new blood vessel formation. Without angiogenesis cancer cells are deprived of oxygen and die," Dittmer said. "In this mouse model, we can study angiogenesis blocking drugs better than ever before. If new drugs work against Kaposi sarcoma, they will also likely work against lesser-angiogenic tumors, which would be a major plus." For next steps, the researchers hope that others will pursue drug and vaccine development based on a new understanding of fundamental aspects of KSHV provided by their mouse model, including possible development of a much-needed primate model for human KSHV and Kaposi sarcoma.