Vorasidenib

– U.S. Regulatory Filing Under Active Review for Approval of PYRUKYND® (mitapivat) in Thalassemia, with PDUFA Goal Date of September 7, 2025 – – Phase 3 RISE UP Study of Mitapivat in Sickle Cell Disease On Track, with Topline Results Expected in Late 2025; Potential U.S. Commercial Launch in 2026 – – Tebapivat Advancing in Clinical Trials for Lower-Risk Myelodysplastic Syndromes (LR-MDS) and Sickle Cell Disease – – PYRUKYND Net Revenue of $8.7 Million in Q1; Cash, Cash Equivalents and Marketable Securities of $1.4 Billion as of March 31, 2025 – CAMBRIDGE, Mass. , May 01, 2025 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and pyruvate kinase (PK) activation pioneering therapies for rare diseases, today reported business highlights and financial results for the first quarter ended March 31, 2025 . “We are pleased with our strong start to 2025, highlighted by the acceptance of our sNDA for thalassemia with a PDUFA goal date of September 7, 2025 . Our engagement with the FDA is progressing as expected, and we are committed to bringing PYRUKYND to thalassemia patients, irrespective of genotype or transfusion needs,” said Brian Goff , chief executive officer at Agios. “Looking ahead, our focus is also on delivering the topline results from the Phase 3 RISE UP study in sickle cell disease, which remains on track for year-end, and continuing to advance our early and mid-stage clinical programs. Supported by our strong financial position and highly experienced team, we are driving forward PYRUKYND’s multi-billion-dollar potential while building a pipeline designed for lasting impact, with the goal of creating significant value for shareholders and delivering transformative therapies for patients.” First Quarter 2025 and Recent Highlights PYRUKYND® Revenues: Generated $8.7 million in net revenue for the first quarter of 2025, compared to $8.2 million in the first quarter of 2024. A total of 234 unique patients have completed prescription enrollment forms, representing an increase of 5 percent over the fourth quarter of 2024. A total of 136 patients are on PYRUKYND therapy, inclusive of new prescriptions and continued therapy, as compared to 130 patients at the end of the fourth quarter 2024. Thalassemia: The U.S. Food and Drug Administration (FDA) accepted the company’s supplemental New Drug Application (sNDA) for PYRUKYND for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia. The Prescription Drug User Fee Act (PDUFA) goal date is September 7, 2025. The FDA has communicated that at this time no advisory committee meeting is planned, and the review is ongoing. Sickle Cell Disease: The Phase 3 RISE UP study evaluating mitapivat for the treatment of sickle cell disease patients who are 16 years of age or older continued to progress as anticipated. This 52-week Phase 3 study completed enrollment in October 2024 , enrolling more than 200 patients worldwide. Advanced final preparations to initiate a Phase 2 clinical trial of tebapivat in patients with sickle cell disease in mid-2025. Pediatric Pyruvate Kinase (PK) Deficiency: Reported positive topline results from the ACTIVATE-Kids Phase 3 study of mitapivat in children aged 1 to <18 years with PK deficiency who are not regularly transfused. Safety was consistent with the profile for mitapivat previously observed in adults with PK deficiency who are not regularly transfused. ACTIVATE-Kids is the first study to demonstrate efficacy of an oral therapy for children with PK Deficiency who are not regularly transfused. Lower-risk Myelodysplastic Syndromes (LR-MDS): Progressed patient enrollment in the Phase 2b study of tebapivat in LR-MDS. Corporate: Krishnan Viswanadhan , Pharm. D, joined Agios as Chief Corporate Development and Strategy Officer, responsible for leading the company’s corporate strategy, business development, and long-term growth initiatives. Previously, he served as President and Chief Operating Officer of Be Biopharma and at various senior roles at both Bristol Myers Squibb and Celgene. The U.S. Food and Drug Administration (FDA) accepted the company’s supplemental New Drug Application (sNDA) for PYRUKYND for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia. The Prescription Drug User Fee Act (PDUFA) goal date is September 7, 2025. The FDA has communicated that at this time no advisory committee meeting is planned, and the review is ongoing. The Phase 3 RISE UP study evaluating mitapivat for the treatment of sickle cell disease patients who are 16 years of age or older continued to progress as anticipated. This 52-week Phase 3 study completed enrollment in October 2024 , enrolling more than 200 patients worldwide. Advanced final preparations to initiate a Phase 2 clinical trial of tebapivat in patients with sickle cell disease in mid-2025. Reported positive topline results from the ACTIVATE-Kids Phase 3 study of mitapivat in children aged 1 to <18 years with PK deficiency who are not regularly transfused. Safety was consistent with the profile for mitapivat previously observed in adults with PK deficiency who are not regularly transfused. ACTIVATE-Kids is the first study to demonstrate efficacy of an oral therapy for children with PK Deficiency who are not regularly transfused. Progressed patient enrollment in the Phase 2b study of tebapivat in LR-MDS. Key Upcoming Milestones & Priorities Agios expects to achieve the following key milestones in 2025: Thalassemia: Receive FDA regulatory decision for PYRUKYND for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia (PDUFA goal date is September 7, 2025). Continue progressing the review of regulatory applications with health authorities in the European Union , Kingdom of Saudi Arabia and United Arab Emirates . Sickle Cell Disease: Announce topline results from the Phase 3 RISE UP study of mitapivat in sickle cell disease in late 2025, with a potential U.S. commercial launch in 2026. Additionally, begin patient enrollment for the Phase 2 study of tebapivat in sickle cell disease in mid-2025. LR-MDS: Complete patient enrollment in the Phase 2b study of tebapivat for LR-MDS in late 2025. Early-Stage Pipeline: File an Investigational New Drug Application for AG-236, an siRNA targeting TMPRSS6 intended for the treatment of polycythemia vera, in mid-2025. First Quarter 2025 Financial Results Revenue: Net product revenue from sales of PYRUKYND for the first quarter of 2025 was $8.7 million , compared to $8.2 million for the first quarter of 2024. Cost of Sales: Cost of sales for the first quarter of 2025 was $1.1 million . Research and Development (R&D) Expenses: R&D expenses were $72.7 million for the first quarter of 2025, compared to $68.6 million for the first quarter of 2024. The year-over-year increase was primarily attributed to an increase in workforce-related expenses and costs associated with clinical trials of tebapivat in LR-MDS and sickle cell disease, partially offset by lower costs associated with the clinical trials of mitapivat in thalassemia and pediatric PKD. Selling, General and Administrative (SG&A) Expenses: SG&A expenses were $41.5 million for the first quarter of 2025 compared to $31.0 million for the first quarter of 2024. The year-over-year increase was primarily attributable to an increase in commercial-related activities, including headcount, as the company prepares for the potential approval of PYRUKYND in thalassemia. Net Loss: Net loss was $89.3 million for the first quarter of 2025 compared to $81.5 million for the first quarter of 2024. Cash Position and Guidance: Cash, cash equivalents and marketable securities as of March 31, 2025 , were $1.4 billion compared to $1.5 billion as of December 31, 2024 . Agios expects that its cash, cash equivalents and marketable securities, together with anticipated product revenue and interest income, will provide the financial independence to prepare for potential PYRUKYND launches in thalassemia and sickle cell disease, advance existing programs, and to opportunistically expand its pipeline through both internally and externally discovered assets. Conference Call Information Agios will host a conference call and live webcast today at 8:00 a.m. ET to discuss the company’s first quarter 2025 financial results and recent business highlights. The live webcast will be accessible on the Investors section of the company's website (www.agios.com) under the “Events & Presentations” tab. A replay of the webcast will be available on the company’s website approximately two hours after the event. About Agios Agios 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, myelodysplastic syndromes (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-236 and AG-181; Agios’ plans, strategies and expectations for its preclinical, clinical and commercial advancement of its drug development, including PYRUKYND®, tebapivat, AG-236 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 2025; 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 royalty payments related to the sale of its oncology business or any milestone or royalty payments related to its in-licensing of AG-236, 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 Contact Chris Taylor , VP, Investor Relations and Corporate Communications Agios Pharmaceuticals IR@agios.com Media Contact Eamonn Nolan , Senior Director, Corporate Communications Agios Pharmaceuticals media@agios.com Source: Agios Pharmaceuticals, Inc.

关注并星标CPHI制药在线上文简述了线粒体与癌症的关系，以及亲脂性阳离子小分子化合物，改变线粒体膜通透性的小分子化合物和靶向己糖激酶 2(hexokinase 2，HK2)的小分子抑制剂，本文继续介绍靶向ETC的小分子化合物，靶向三羧酸（TCA）循环的小分子化合物，靶向线粒体DNA 的小分子化合物和多肽类靶向序列。相关阅读：《靶向线粒体在肿瘤治疗中的研究进展（一）》04靶向ETC的小分子化合物电子传递链（ETC）是由铁硫蛋白、黄素蛋白、辅酶 Q10 及细胞色素等递电子体/递氢体组成的级联反应体系，其通过有序传递还原型烟酰胺腺嘌呤二核苷酸（NADH）和还原型黄素腺嘌呤二核苷酸（FADH2）中的电子，驱动质子跨膜梯度形成以合成 ATP，为细胞提供约 95%的能量供应。作为细胞能量代谢的核心枢纽，ETC 同时也是内源性活性氧（ROS）的主要来源。当 ETC 功能异常时，电子泄漏会导致ROS过量生成，引发线粒体氧化损伤及代谢重编程，这种功能紊乱与多种恶性肿瘤的演进密切相关。因此，选择性抑制 ETC 关键复合物（CⅠ~CⅤ）或调控其 ROS 生成能力已成为肿瘤治疗的重要方向。①线粒体复合物Ⅰ（CI）抑制剂作为线粒体电子传递链（ETC）核心元件，NADH 脱氢酶复合体（CI）通过介导NADH 的2 个电子经铁硫蛋白传递至辅酶Q，驱动跨膜质子梯度形成。靶向抑制CI可阻断电子传递过程，导致 ATP 合成障碍而发挥抗肿瘤效应。经典降糖药二甲 双胍可依赖膜电位蓄积于线粒体，在 5 mmol·L⁻¹浓度下显著抑制 CI 活性，对乳腺癌及结直肠癌模型显示出治疗潜力。其结构类似物苯乙双胍对 CI 的抑制效力提升了20 倍，在人血小板模型中 IC50 达55 μmol·L⁻¹。新型抑制剂 IACS-010759能通过选择性破坏糖酵解缺陷型缺氧肿瘤细胞的线粒体功能实现精准杀伤，在保持正常细胞安全的前提下，已进入乳腺癌与急性髓系白血病的 I期临床研究（NCT03291938/NCT02882321）。基于高通量筛选发现的 SMIP004采用泛醌非竞争性抑制机制，通过阻断 NADH 氧化引发氧化应激级联反应，最终诱导 LNCaP S14CI 细胞周期停滞。经结构优化获得的衍生物 SMIP004-7通过增强靶标结合能力，抗肿瘤活性提升了 5倍，展现出更优的体内药效转化前景。②线粒体复合物Ⅱ（CⅡ）抑制剂CⅡ是由琥珀酸脱氢酶(SDH)和铁硫蛋白组成，将从琥珀酸得到的电子传递给辅酶Q，再通过辅酶Q传输到CIII，之后经过CⅣ和CⅤ(ATP合酶)生成ATP。靶向 CⅡ的α-生育酚琥珀酸酯（α-TOS）可通过竞争性占据 SDH 泛醌结合位点，诱导肿瘤细胞特异性 ROS 爆发及线粒体功能障碍，实现选择性杀伤效应。该化合物作为二线抗肿瘤辅助剂，在急性淋巴细胞白血病治疗中显示出临床转化潜力。此外，研究发现通过三苯基鏻（TPP+）基团对其结构进行线粒体靶向修饰，可使促其凋亡活性提升10-100 倍，显著增强对耐药肿瘤的清除能力。③调控活性氧自由基（ROS）的小分子药物活性氧自由基（ROS）是一类高活性含氧自由基，其过量积累可引发氧化应激损伤，与多种疾病进程密切相关。肿瘤细胞因代谢异常常处于高 ROS 水平，通过选择性增强其氧化应激可触发肿瘤细胞死亡。例如，雌二醇代谢物2-甲氧基雌二醇（2-ME）可通过诱导亚硝基化应激及自由基生成发挥抗肿瘤作用，但因缺乏雌激素受体结合活性而具有更优选择性。尽管在多种实体瘤中推进至 II 期临床试验（如 NCT00444314），但均因疗效或安全性问题未能获批。研究显示，维生素 K3（VK3）作为经典 ROS 诱导剂，经结构优化可显著提升抗肿瘤效能。通过阳离子靶向基团修饰获得的 MitoVK3可高效蓄积于线粒体，通过抑制硫氧还蛋白还原酶2（TrxR2）引发 ROS 爆发，其促氧化活性较母体化合物提升了6倍。此外，基于非甾体抗炎药吲哚美辛与布洛芬设计的三苯基膦靶向衍生物，可通过诱导线粒体外膜透化（MOMP）诱导线粒体损伤，从而产生 ROS。05靶向三羧酸（TCA）循环的小分子化合物TCA循环是需氧生物能量代谢的核心通路，通过一系列酶促循环反应，为细胞提供生物能量、生物合成原料及氧化还原平衡支持。尽管肿瘤细胞因“Warburg效应”倾向于糖酵解供能，但其快速增殖仍高度依赖TCA 循环产生的 ATP 及代谢中间产物。研究表明，肿瘤基因与抑癌基因的失衡导致肿瘤细胞对 TCA 循环的代谢依赖性增强，而循环关键酶的突变或失调（如乌头酸水合酶（AH）、异柠檬酸脱氢酶（IDH）、延胡索酸酶（FH）、琥珀酸脱氢酶（SDH）及α-酮戊二酸脱氢酶复合物（KGDHC））可通过干扰燃料分解与代谢流重编程促进肿瘤进展，这为靶向 TCA 循环的抗肿瘤策略提供了理论依据。谷氨酰胺作为TCA 循环的重要碳源，其分解代谢对肿瘤增殖至关重要。小分子谷氨酰胺酶（GLS）抑制剂 CB-839可通过阻断谷氨酰胺向谷氨酸的转化，抑制 TCA 循环中间产物生成及谷胱甘肽合成，目前已进入三阴性乳腺癌的Ⅰ/Ⅱ期临床试验（NCT03875313）。此外，KGDHC作为TCA 循环限速酶，其抑制剂 CPI-613通过靶向二氢硫辛酰胺琥珀酰转移酶（DLST）和二氢硫辛酰胺脱氢酶（DLD），诱导线粒体活性氧（ROS）爆发并诱导肿瘤细胞凋亡，现已在胰腺癌等实体瘤的Ⅱ/Ⅲ期临床试验中评估疗效（EUCTR2018-001587-32-IT）。IDH 突变可致α-酮戊二酸异常转化为致癌代谢物2-羟基戊二酸（2-HG），促进肿瘤发生。突变型 IDH 抑制剂恩西地平（AG-221）和 AG-881通过占据酶活性位点阻断2-HG 生成，其中AG-221已获批用于急性髓系白血病治疗，AG-881则在胶质瘤和胆道肿瘤的Ⅲ期临床试验中展现潜力（NCT04164901）。SDH 作为TCA 循环中的肿瘤抑制因子，其活性受丙酮酸脱氢酶激酶（PDK）调控。PDK 抑制剂二氯乙酸（DCA）通过激活 SDH 增强 TCA 循环活性，逆转糖酵解代谢偏好，诱导氧化应激与凋亡信号，目前已作为代谢调节剂用于肿瘤治疗研究。06靶向线粒体DNA 的小分子化合物哺乳动物线粒体 DNA（mtDNA）是一种长度为 16~18 kb 的环状双链 DNA 分子，包含 2 个核糖体 RNA（rRNA）、 22个转运 RNA（tRNA）和 13 个编码氧化磷酸化系统的多肽链基因。mtDNA 通过转录和翻译生成的蛋白质在调控细胞生长、能量代谢及线粒体稳态中发挥核心作用，其基因变异或表达失调与肿瘤发生发展密切相关。研究表明，阻断 mtDNA 的转录或翻译过程可显著抑制肿瘤细胞增殖，因此 mtDNA 已成为疾病、肿瘤及进化研究中的重要遗传标志物，靶向干预 mtDNA 为抗肿瘤治疗提供了新方向。近年来，针对 mtDNA 的小分子抑制剂开发取得了突破性进展。德国马克斯·普朗克研究所与瑞典哥德堡大学的联合研究团队发现了一种名为 IMT1B 的小分子化合物，它能特异性靶向抑制人类线粒体 RNA 聚合酶（POLRMT），从而完全阻断 mtDNA 的转录过程。机制研究表明，IMT1B 通过结合 POLRMT 的活性位点，破坏线粒体基因组的 RNA 合成，最终导致肿瘤细胞因能量代谢崩溃而死亡。作为首个高选择性 POLRMT 抑制剂，IMT1B 在临床前小鼠模型中展现出显著的抗肿瘤效果，且对正常细胞毒性较低，有望开发为针对实体瘤或代谢依赖性癌症的创新疗法。07多肽类靶向序列①线粒体穿透肽（MPP）相较于小分子化合物，多肽类靶向配体（如线粒体穿透肽，MPP）凭借其优异的生物相容性和低毒性，在构建线粒体靶向递送系统中展现出显著优势。MPP 可通过膜穿透效应将化疗药物或生物活性分子精准递送至线粒体功能位点，并借助自组装特性调控细胞功能，在选择性杀伤肿瘤细胞的同时避免对正常组织的损伤，从而显著抑制肿瘤生长。例如，基于 SS-31 肽羟基化修饰的新型线粒体细胞穿透肽（mtCPP-1）在浓度高达 100 mmol·L⁻¹时仍无细胞毒性，且不影响线粒体功能，其机制可能与线粒体主动摄取肽分子有关。此类特性使 mtCPP-1成为高效、安全的线粒体靶向载体候选分子。有研究开发了一种 MPP 修饰的多柔比星（MPP-Dox）共聚物递送系统：线粒体靶向的 HPMA 共聚物（PM）通过破坏线粒体功能诱导细胞凋亡并抑制转移，而核靶向的 HPMA 共聚物（PN）则通过干预细胞核功能抑制增殖。实验表明，该双靶向系统可显著抑制乳腺癌 4T1 细胞的体内生长，同时克服肿瘤耐药性，为转移性癌症的联合治疗提供了创新策略。②短杆菌肽S短杆菌肽S作为一类多肽抗生素，可通过线粒体膜靶向递送自由基清除分子，在抗氧化应激领域具有独特价值。其衍生物JP4-039由氮氧自由基与短杆菌肽 S偶联而成，能高效富集于线粒体并清除氧自由基，抑制亚硫酸盐诱导的氧化损伤和细胞凋亡。尽管目前尚无短杆菌肽 S及其衍生物直接用于抗肿瘤的报道，但 JP4-039 在胱氨酸尿症治疗中的成功应用提示，此类分子可通过靶向线粒体调控氧化应激通路，未来或可拓展至肿瘤治疗领域，尤其在放疗或化疗引发的线粒体氧化损伤修复中具有潜在开发价值。多重机制共同构成了线粒体参与癌症发生发展的多维网络，从凋亡调控到氧化还原稳态，从离子平衡到遗传物质变异，每个环节均存在促癌与抑癌的动态博弈。当前研究聚焦于开发靶向线粒体 ROS 生成、 MCU 功能或 mtDNA代谢的药物，但其临床应用仍需解决选择性毒性、耐药性及生物个体差异等挑战。例如，针对 MCU 抑制剂的剂量优化需避免干扰正常细胞钙稳态，而调控 ROS 的策略需在促凋亡与保护正常组织间取得平衡。随着单细胞测序与代谢组学技术的发展，未来或可实现对线粒体功能异常的精准解析，或为个体化抗癌治疗提供新路径。参考资料：[1]黄佳藤,王甜甜,刘华,等.线粒体靶向小分子化合物在肿瘤研究中的应用[J].中国现代应用药学,2024,41(22):3245-3254.[2]邹鑫,黄璨,李佳良,等.靶向线粒体在癌症治疗中的作用研究进展[J].肿瘤药学,2024,14(02):166-172.作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。END2025金笔奖征文即将截止，速来投稿！领取CPHI & PMEC China 2025展会门票智药研习社课程预告来源：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~