MAK-683

最近，诺华公司决定将心血管、血液学、实体瘤、免疫学和神经科学五个治疗领域以及一小部分技术平台作为其研发活动的重点。为了增强对这五个核心治疗领域的关注，诺华公司（Novartis）对其管线进行了大规模削减，放弃了10%的研发项目。诺华首席执行官、医学博士Vas Narasimhan在凌晨与媒体的电话会议上表示：“我们将管线规模减少了约10%。这主要是因为我们削减了这五个核心治疗领域之外的资产，如果不符合该框架，我们要么停止这些项目，要么撤资。”Narasimhan在随后与分析师的通话中进一步阐述了这一决定，他解释说，“管道“清理”是将诺华公司的研发与其他大型制药公司进行比较的结果，我们的项目比同行多，这导致我们每个项目的投资比同行少。”诺华公司正在筹备的项目数量从150个下降到134个。实体瘤是一个持续关注的领域，受到的削减程度最大，在两次更新之间，活跃项目的数量从42个下降到32个。诺华放弃的研发管线们下面概述了诺华公司在季度管线更新中删除的项目。1、司他利珠单抗spartalizumab（临床Ⅲ期）但在罗列项目之前，司他利珠单抗spartalizumab值得着重交代。在2022年第四季度，诺华公司列出了六项涉及司他利珠单抗spartalizumab的研究。司他利单抗是一种抗PD-1检查点抑制剂，在2020年的黑色素瘤3期试验中失败。如今，诺华停止了几乎所有PD-1单抗spartalizumab的研究，转而支持百济神州的tislelizumab。目前Spartalizumab在管线图中只有一条，作为与CD73拮抗剂NZV930联合的1期药物的一部分。 2、ADPT06(临床II期)ADPT06是诺华公司在自免疫药物的2期临床试验中测试的平台化认知障碍候选药物。在这项针对阿尔茨海默病引起的轻度认知障碍患者的试验中，据悉诺华公司测试了卡纳单抗canakinumab（Ilaris）。卡纳单抗是一种高选择性，全人源化，抗白介素-1β的单体。其在2009年6月被美国FDA批准用于治疗4岁以上儿童和成人的Cryopyrin蛋白相关性周期综合征患者4年后，即2013年，Canakinumab被欧盟批准用于急性痛风性关节炎。2016年，Canakinumab在美同天斩获3种罕见病适应症：肿瘤坏死因子受体相关周期热综合征(TRAPS)、高免疫球蛋白D综合征(HIDS)/甲羟戊酸激酶缺乏(MKD)、家族性地中海热(FMF)。2020年，Canakinumab在美被批准用于治疗活动性斯蒂尔氏病。现在它作为阿兹海默症候选药物之路已经正式停止。 3、HSY244 (临床II期)HSY244是诺华公司于2020年进入二期临床的一种心房颤动候选药物。根据欧洲数据库，诺华“提前结束”了这项研究，但ClinicalTrials.gov仍将其列为招募患者中。诺华的 CRM（心血管、肾科和代谢）领域针对临床上高度未满足需求，拥有强大的中后期管线。同公司的兄弟竞品PCSK9 siRNA 药物 Inclisiran（Leqvio®）是其中最受瞩目的产品，针对高血脂适应症的 BLA 已经在多个国家和地区获批，另有 3 个适应症也已经进展至 3 期临床。其他将要进展至临床 3 期的还包括沙库巴曲缬沙坦（Entresto®）的慢性心衰适应症、反义核苷酸（ASO）药物 Pelacarsen、HSY244，以及 Iptacopan。其中HSY244药物在此次管线缩减中被砍。4、Ensovibep (临床II期)Ensovibep是诺华去年年初以1.5亿瑞士法郎（1.68亿美元）购买的新冠肺炎抗病毒药物。几个月内，由于美国食品药品监督管理局没有批准该药物的紧急使用授权（EUA），要求提供第三阶段临床的数据，诺华公司将该分子短期内推向市场的计划宣告失败，因此管线被裁撤。Ensovibep是设计的锚蛋白重复序列（DARPins）形式的蛋白药物，是一种拟抗体，串联多种功能抗体片段，具备多种抗体特性。2022年1月10日，诺华与合作伙伴Molecular Partners共同宣布，DARPins（设计的锚蛋白重复序列）形式的蛋白药物Ensovibep（开发代码：MP0420）临床2期试验（EMPATHY研究的A部分）顶线结果积极，达到主要终点及2个次要终点。诺华将行使项目选择权，向Molecular Partners支付1.5亿瑞郎（约1.65亿美元）里程碑付款以获得Ensovibep相关权益，加速建设Ensovibep产能，并计划寻求全球药监机构的紧急授权，首要目标为获得FDA的紧急使用授权（EUA），如Ensovibep获批上市，Molecular Partners将有资格获得22%的销售分成。而如今，这个项目也被砍掉了。 5、LKA651 (临床II期)LKA651是诺华公司在糖尿病视网膜病变研究与MorphoSys合作的EPO抑制剂。去年夏天，诺华公司完成了该候选药物的2期临床试验。被裁撤的原因可能是同类产品的竞争。6、FIA586（临床I期）诺华的研发管线中有6款肝病候选药物：ADTP02：非酒精性脂肪性肝炎（NASH），临床二期；iscalimab：肝移植（新适应症），临床二期；FIA586：非酒精性脂肪性肝炎（NASH），临床一期；tropifexor,cenicriviroc（定剂量组合）：非酒精性脂肪性肝炎（NASH），临床二期；tropifexor：非酒精性脂肪性肝炎（NASH），临床二期；lanalumab：自身免疫性肝炎（AIH）（新适应症），临床二期。其中FIA586将从管线中退出，诺华推倒了非酒精性脂肪性肝炎的多米诺骨牌。7、MHS552（临床I期）MHS552是诺华公司在一项狼疮1期试验中研究的一种自身免疫性疾病候选药物。该公司申请在1型糖尿病中测试该分子，但在招募任何患者之前撤回了这项研究。8、ADPT03（临床I期）ADPT03是针对镰状细胞病的BCL11A项目。Intellia透露，诺华公司已于今年早些时候停止了体外CRISPR编辑的细胞疗法的工作，该疗法旨在降低BCL11A的活性。基础研究表明，高水平的由α-和γ-珠蛋白组成的红细胞-胎儿血红蛋白（HbF）可通过减轻镰状血红蛋白聚合和红细胞镰状化来改善这些症状。BCL11A是成人红细胞中γ珠蛋白表达和HbF产生的抑制因子，它的下调是诱导HbF的有潜力的治疗策略。9、JEZ567（临床I期）JEZ567（CD123 CART）是一种CART细胞疗法，对患者T细胞进行工程化以识别和消除表达CD123的肿瘤细胞，适应症为急性髓系白血病。CD123广泛表达于骨髓增生异常综合征以及血液恶性肿瘤患者的骨髓细胞，包括急性髓性白血病（AML）、B细胞急性淋巴细胞白血病（B-ALL）、毛细胞白血病（HCL）、BPDCN、慢性髓细胞白血病（CML）和霍奇金淋巴瘤（HL）。CD123表达于75%-89%的AML、超过90%的BPDCN患者中，因此是T细胞过继免疫治疗的一个非常有吸引力的靶点。现在，项目已经被停掉。 10、MAK683（临床I期）MAK683 是一种高效的PRC2抑制剂，可阻断癌细胞增殖，诺华公司自2016年以来在弥漫性大B细胞淋巴瘤患者中进行了研究。抑制正常或过度活跃的PRC2可以在几种类型的癌症中降低癌细胞存活率并抑制肿瘤生长。现在该项目已经停止。但是诺华公司在靶向EZH2的小分子抑制剂中已有药物经过FDA批准上市，Tazemetostat于2020年被美国FDA批准用于治疗晚期上皮样肉瘤和滤泡性淋巴瘤，标志着用于治疗人类癌症的EZH2抑制剂开发的一个重要里程碑。 11、WVT078（临床I期）WVT078是诺华公司在多发性骨髓瘤中研究的一种BCMAxCD3双特异性抗体。I期研究的初步临床数据表明，WVT078在人体中表现出强大的抗MM活性和良好的耐受性，且安全性和有效性良好。但许多其他BCMA候选药物在其他公司的存在，使WVT078不适合诺华公司专注于“对患者具有变革潜力的高价值药物”。参考出处&原作者：见下图

The number of projects in Novartis’ pipeline fell from 150 to 134. Novartis has undertaken an old-fashioned decimation of its pipeline. The Swiss drugmaker has decided to dump or out-license 10% of its R&D projects to narrow its sights on five core therapeutic areas and focus investment on its most promising programs within those spaces.  In recent quarters, Novartis has decided to make five therapeutic areas—cardiovascular, hematology, solid tumors, immunology and neuroscience—and a small clutch of technology platforms the focus of its R&D activities. More recently, disclosures about partnered programs that Novartis is dumping gave hints that an overhaul was underway. Now, Novartis has shared a full look at its slimmed-down pipeline. “We reduced our pipeline size by about 10%. And that's primarily as we prune assets that are outside of those five core therapeutic areas, or in the sixth area we call TAX which incubate certain therapeutic areas we're interested in,” Novartis CEO Vas Narasimhan, M.D., said on an early morning call with the media. “So we've taken the principal decision that if it doesn't fit within that framework, we are either going to stop the programs or divest them.”  Expanding on the decision in a later call with analysts, Narasimhan explained that part of the pipeline “cleanup” had been the result of benchmarking Novartis’ R&D against its fellow Big Pharmas. “We had more projects than our peers, which led us to have less investment per project versus the peer set,” the CEO explained. “We think that's important because in having strong investment in the early stage pre-clinically or in early clinical can also help us go faster, go broader into more lines of therapy, more indications.” As a result of the changes, the number of projects in Novartis’ pipeline has fallen from 150 to 134. Solid tumors, an ongoing area of focus, took the biggest hit, with the number of active projects falling from 42 to 32 between the two updates.  Addressing the significant reduction in early-stage cancer assets, Narasimhan told analysts that Novartis had removed candidates with targets that “are no longer priority tumors for the company.” Below, we provide an overview of the programs that Novartis dropped from its pipeline in its quarterly pipeline update. But before getting to that, there is one candidate clinging on that is nonetheless worth discussing. In the fourth quarter, Novartis listed six studies involving spartalizumab, an anti-PD-1 checkpoint inhibitor that failed a phase 3 melanoma trial in 2020. Today, only one study remains.  Phase 2 ADPT06: A cognitive impairment candidate that Novartis tested in a phase 2 platform clinical trial of various anti-inflammatory agents. The mechanism of action is unknown. Novartis tested canakinumab, sold in other indications as Ilaris, in the same trial of patients with mild cognitive impairment due to Alzheimer's disease. HSY244: An atrial fibrillation candidate that Novartis took into phase 2 in 2020. Novartis “prematurely ended” the study, per the European database, but ClinicalTrials.gov still lists it as recruiting patients. Ensovibep: The COVID-19 antiviral that Novartis bought at the start of last year for 150 million Swiss francs ($168 million). Within months, Novartis’ plan to bring the molecule to market unraveled as the FDA requested phase 3 data. Novartis licensed the asset from Molecular Partners. LKA651: A MorphoSys-partnered EPO inhibitor that Novartis studied in diabetic macular edema. Novartis completed a phase 2 clinical trial of the drug candidate last summer. Phase 1 FIA586: The final domino to fall in Novartis’ exit from nonalcoholic steatohepatitis (NASH). The Swiss drugmaker wrapped up an early-phase trial of the candidate in mild and moderate hepatic impairment last summer. MHS552: An autoimmune disease candidate that Novartis was studying in a phase 1 lupus trial when it decided to pull the plug. The company filed to test the molecule in type 1 diabetes but withdrew the study before enrolling any patients.  ADPT03: A BCL11A program targeting sickle cell disease. Intellia disclosed that Novartis had stopped work on an ex vivo, CRISPR-edited cell therapy designed to reduce the activity of BCL11A earlier this year. JEZ567: A anti-CD123 CAR-T cell therapy that Novartis was developing in acute myeloid leukemia. MAK683: An inhibitor of embryonic ectoderm development protein that Novartis has studied in people with diffuse large B-cell lymphoma since 2016. WVT078: A BCMAxCD3 bispecific antibody that Novartis studied in multiple myeloma. The presence of many other BCMA candidates at other companies makes WVT078 a poor fit for Novartis’ focus on “high value medicines with transformative potential for patients.”