Vorasidenib

CAMBRIDGE, Mass., Sept. 11, 2024 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and PK activation pioneering therapies for rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to the company’s novel pyruvate kinase (PK) activator tebapivat (AG-946) for the treatment of myelodysplastic syndromes (MDS). “Receiving orphan drug designation for tebapivat in MDS underscores the importance of bringing new oral treatment options to patients suffering from this rare disease,” said Sarah Gheuens, M.D., Ph.D., chief medical officer and head R&D at Agios. “We aim to deliver the first oral therapy that addresses anemia due to ineffective erythropoiesis in lower-risk MDS, which affects approximately 75,000-80,000 patients in the U.S. and EU5 and accounts for approximately 70% of MDS cases.” Agios completed a Phase 2a study of tebapivat in lower-risk MDS late last year and is currently initiating a Phase 2b study of tebapivat in lower-risk MDS. The FDA’s Office of Orphan Drug Products grants orphan drug designation to support the development of medicines for rare disorders that affect fewer than 200,000 people in the U.S. Under the Orphan Drug Act, orphan drug designation qualifies a company for incentives, including tax credits, exemptions from certain FDA fees for clinical trials, and the potential for seven years of market exclusivity following drug approval. Mitapivat, the company’s lead PK activator, was previously granted FDA orphan drug designation for the treatment of PK deficiency, thalassemia, and sickle cell disease. Tebapivat is not approved for use by any regulatory authority. About AgiosAgios is the pioneering leader in PK activation and is dedicated to developing and delivering transformative therapies for patients living with rare diseases. In the U.S., Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company's deep scientific expertise in classical hematology and leadership in the field of cellular metabolism and rare hematologic diseases, Agios is advancing a robust clinical pipeline of investigational medicines with programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency, MDS-associated anemia and phenylketonuria (PKU). In addition to its clinical pipeline, Agios is advancing a preclinical TMPRSS6 siRNA as a potential treatment for polycythemia vera. For more information, please visit the company’s website at www.agios.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the potential benefits of PYRUKYND® (mitapivat), tebapivat (AG-946), TMPRSS6 siRNA and AG-181, Agios’ PAH stabilizer; Agios’ plans, strategies and expectations for its preclinical, clinical and commercial advancement of its drug development, including PYRUKYND®, tebapivat and AG-181; Agios’ use of proceeds from the transaction with Royalty Pharma; potential U.S. net sales of vorasidenib and potential future royalty payments; Agios’ strategic vision and goals, including its key milestones for 2024; and the potential benefits of Agios’ strategic plans and focus. The words “anticipate,” “expect,” “goal,” “hope,” “milestone,” “plan,” “potential,” “possible,” “strategy,” “will,” “vision,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios’ product candidates will successfully continue. There can be no guarantee that any positive developments in Agios’ business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including, without limitation: risks and uncertainties related to the impact of pandemics or other public health emergencies to Agios’ business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products; Agios’ results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA, the EMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios’ ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Agios' ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios’ ability to establish and maintain key collaborations; uncertainty regarding any milestone or royalty payments related to the sale of its oncology business or its in-licensing of TMPRSS6 siRNA, and the uncertainty of the timing of any such payments; uncertainty of the results and effectiveness of the use of Agios’ cash and cash equivalents; and general economic and market conditions. These and other risks are described in greater detail under the caption "Risk Factors" included in Agios’ public filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Contacts: Investor ContactChris Taylor, VP, Investor Relations and Corporate CommunicationsAgios PharmaceuticalsIR@agios.com Media Contact Dan Budwick1AB dan@1abmedia.com

撰文 | 殷丹妮   //   • vorasidenib同时靶向IDH1、IDH2两个突变位点，通过双重抑制来解决胶质瘤的耐药； • 规避传统治疗10%概率出现的超突变进展至高级别胶质瘤； • 目前已启动一项一线治疗研究、两项联合用药研究； • 施维雅目标是在2030年实现肿瘤业务营收不低于30亿欧元。 首个针对IDH突变低级别胶质瘤的小分子靶向药物出现了。 2024年8月，FDA批准Voranigo®（vorasidenib）上市。这款可穿透血脑屏障、同时针对IDH1和IDH2突变的双重抑制剂，给IDH突变型低级别胶质瘤患者带来治疗新希望。 vorasidenib的获批是施维雅围绕IDH布局肿瘤业务的重要节点之一。进一步的规划，除了在IDH中拓展适应症的一线治疗、或是联合PD-1治疗高级别肿瘤，施维雅还借力AI技术、及外部合作持续开发创新靶点药物。结合已上市肿瘤产品的销售业绩，施维雅在肿瘤领域形成了早期创新发现、临床拓展以及持续商业化的完整布局。 面对中国市场，8月31日vorasidenib桥接研究在北京正式启动。该研究由江涛院士牵头，首都医科大学附属北京天坛医院担任组长单位,针对患有IDH1或IDH2突变的残留或复发2级胶质瘤的亚洲受试者进行3期、多中心、随机、双盲、安慰剂对照研究。 这项研究的启动，标志着中国在胶质瘤治疗领域的新进展，对于提升国内临床研究水平、推动新药研发具有重要意义。 全球首个IDH1/2抑制剂 vorasidenib会给IDH突变型低级别胶质瘤整体的未来治疗策略带来革命性变化，复旦大学附属华山医院吴劲松教授这样认为。 为什么如此评价，首先看疾病的未满足需求。脑胶质瘤是最常见的颅内恶性肿瘤，病死率极高，且缺乏有效的药物治疗。异柠檬酸脱氢酶（IDH）突变是脑胶质瘤中常见突变类型，通常发生在疾病早期。vorasidenib针对的就是早期、低级别胶质瘤中的IDH突变型患者，低级别脑胶质瘤约占脑胶质瘤的30%，其中近70%的低级别脑胶质瘤发生IDH突变，患者群体大。 该类患者目前的标准治疗是手术后采用放疗联合化疗方式。放化疗的副作用除了已知的急慢性相关毒性外，有文献报道，IDH突变低级别胶质瘤如果采用替莫唑胺化疗，可能诱发超突变进展至高级别胶质瘤，虽然概率只有10%。 而vorasidenib治疗能规避这10%的概率，且不会引发放化疗副作用。不仅如此，vorasidenib在IDH突变胶质瘤中还有两方面的治疗优势。 其一vorasidenib是全球首款同时针对IDH1、IDH2两个突变位点的抑制剂，几乎覆盖了所有IDH突变型低级别胶质瘤。且有数据表明，单一靶向IDH1或IDH2突变，两者突变易互相转化导致耐药，双重的抑制剂能解决耐药问题。 其二vorasidenib的分子设计使其可透过血脑屏障，其血脑屏障渗透率高于另一款IDH1抑制剂ivosidenib，增加了中枢神经系统的血药浓度，以及提高药物治疗有效性。 突破一线可能性 施维雅首席商务官Arjun H. Prasad认为，vorasidenib前所未有地改善了脑胶质瘤的疾病无进展生存期。从其3期关键研究INDIGO的结果看确实如此。 这项全球、随机、双盲、安慰剂对照研究，于2020年1月入组首例患者，对象为仅接受手术治疗且出现残留或复发的IDH1/2突变2级胶质瘤患者，共招募331例受试者。研究在2023年3月的第二阶段期中分析时成功达到了主要疗效终点及关键次要终点，共耗时约3年时间。 来源|medscape 具体数据看，vorasidenib的主要终点中位无进展生存期（PFS）达到27.7个月，而安慰剂组为11.1个月。关键次要终点至下一次干预时间（TTNI）具备统计学显著性，vorasidenib组的中位TTNI尚未达到，而安慰剂组为17.8个月。其他数据，vorasidenib组每6个月的肿瘤体积平均减少2.5%，而安慰剂组每6个月的肿瘤体积平均增加13.9%。 同时，施维雅正在进一步挖掘vorasidenib的潜力。 目前已启动一线治疗4级星形细胞瘤的2期临床、联合PD-1抑制剂pembrolizumab的1期临床、以及联合替莫唑胺治疗IDH1或IDH2突变脑胶质瘤的1b/2期临床研究。对vorasidenib的临床布局，可以看出施维雅对产品朝一线拓展以及联合用药方面的规划。 INDIGO研究针对的是低级别胶质瘤患者，而高级别（III/IV级）脑胶质瘤的治疗，才是真正的行业痛点，预后差的大多数是高级别患者。往一线的高级别患者拓展，也是vorasidenib自证疗效实力的方式之一。 与PD-1的联合治疗，吴劲松在解读时表示，IDH突变会造成肿瘤微环境的免疫抑制，免疫检查点抑制剂难以发挥疗效，而IDH抑制剂可以阻断这些效应，使微环境从“冷”变“热”，对肿瘤发挥协同免疫抑制作用。 同时，与pembrolizumab联合的1期研究已有部分结果公布，在7例复发或进展增强型IDH1突变的2/3级星形细胞瘤患者中，使用探索剂量是安全且可耐受。 从临床结果看，vorasidenib已在脑胶质瘤中达到了预期疗效结果，再结合疾病需求、分子设计，即印证了上述吴劲松的观点，vorasidenib将革新IDH突变型低级别胶质瘤的治疗策略，给该类患者带来治疗的新希望。 此外，针对vorasidenib的中国市场，施维雅也已开始布局。施维雅中国总经理Manuel RUIZ表示，vorasidenib在美国批准是一个重要里程碑，施维雅正在尽快将这一创新产品带入中国。 2024年6月，vorasidenib的3期临床试验方案在中国获得批准。同月，施维雅与艾德生物达成战略合作伙伴关系，艾德生物将开发vorasidenib的伴随诊断试剂，助力其在中国大陆的注册和商业化。 “同时面对中国脑胶质瘤患者对vorasidenib的迫切治疗需求，施维雅正积极与海南博鳌乐城、北京天竺、大湾区等具备优先准入的试点区域、或地方监管机构合作，尽可能在正式批准前，提早进入部分地区惠及有迫切需求的患者。” Manuel RUIZ说。 领跑全球IDH研发 在如今靶点内卷的时代，IDH抑制剂领域犹如一片蓝海。在这片蓝海赛道中，施维雅可谓遥遥领先，不仅拥有IDH1/2抑制剂Voranigo（vorasidenib），还有已上市的IDH1抑制剂Tibsovo（ivosidenib）、IDH2抑制剂Idhifa（enasidenib）。 疾病范畴覆盖胆管癌、脑胶质瘤等实体瘤，以及急性髓系白血病（AML）、骨髓增生异常综合征（MDS）等血液肿瘤，已获批6个适应症。 相比下，IDH赛道中其他产品，除了已上市的Rezlidhia（olutasidenib），仅有和黄医药的HMPL-306和正大天晴的TQB-3454处在3期临床阶段。可见未来施维雅在IDH赛道中，不论是双突变还是单突变，还将领跑相当长一段路程。 面对IDH这一蓝海，施维雅还在乘胜追击。 对于ivosidenib的临床拓展，施维雅在IDH1突变的胆管癌一线及二线、软骨肉瘤一线及二线、急性髓系白血病（AML）一线、以及骨髓增生异常综合征（MDS）的一线治疗中，均有临床试验正在进行中。 未来，施维雅将如何持续押注肿瘤，值得期待。目前，施维雅管线中的其他肿瘤在研产品覆盖到MET、TIM3、CD73、PD-L1/4-1BB、NKG2A、MAT2A等多个靶点，适应症拓展至非小细胞肺癌等实体瘤。 来源|施维雅官网 施维雅进军肿瘤领域是自2018年收购Shire肿瘤业务开始，后又通过收购Agios Pharmaceuticals、丹麦Symphogen公司持续公司在肿瘤领域的管线。其中vorasidenib是2020年收购Agios Pharmaceuticals所获得，也是施维雅专注肿瘤业务的标志性事件之一。 而后，施维雅不断通过外部合作模式拓展其早期临床管线，包括与GNS合作开发多发性骨髓瘤药物，与Oncodesign合作探索胰腺癌治疗新靶点、与Gustave Roussy签署肿瘤学合作框架协议。此外在MNC竞相拥抱AI的当下，施维雅也不例外，分别与人工智能公司Aqemia、Owkin合作开发创新靶点的小分子药物，并建立了自己的AI平台Patrimony，并利用平台开发出几个创新靶点药物。 已上市的肿瘤产品已给施维雅带来持续的销售业绩。2022~2023财报显示，公司的肿瘤药物收入突破10亿欧元，同比上涨26.7%。肿瘤收入占整个公司收入比例上升至20%，上一年的收入占比为17.4%。 施维雅曾在2022年发布2030集团发展目标，在2030年实现肿瘤业务营收不低于30亿欧元。相信随着vorasidenib的获批，以及围绕IDH展开的肿瘤业务，同时并借力AI技术不断开发创新肿瘤产品，施维雅在肿瘤领域的持续规划将助其实现目标。 编辑 | 姚嘉 yao.jia@PharmaDJ.com  总第2195期 访问研发客网站，深度报道和每日新闻抢鲜看 www.PharmaDJ.com