Mavorixafor

胃癌铂类化疗耐药始终是临床治疗的"拦路虎"。传统思路大多聚焦DNA损伤修复、药物外排、凋亡逃逸，却仍无法完全解释肿瘤耐药异质性。安徽医科大学、郑州大学、香港中文大学合作团队，依托耐药移植瘤转录组与药理基因组数据库筛选，鉴定出支架蛋白PHB2是胃癌顺铂耐药的关键驱动分子。 该研究揭示全新脂质代谢轴：PHB2结合脂质代谢酶ACSL3，重塑细胞膜磷脂组分，帮助肿瘤细胞逃逸铁死亡，进而产生化疗抵抗；通过虚拟筛选找到FDA已上市药物Mavorixafor，可打断二者蛋白互作，重新唤醒铁死亡。研究特别借助患者来源类器官（PDO）+细胞系移植瘤（CDX）两套贴近临床的模型完成药效验证，为耐药胃癌提供可快速转化的老药复用策略。 现实困境：顺铂耐药胃癌 铂类药物是晚期胃癌一线化疗的基石，但不少患者会出现原发或获得性顺铂耐药，整体预后很差。现有研究表明，抑制铁死亡（由铁离子、脂质过氧化介导的程序性细胞坏死），是肿瘤产生化疗耐药的重要特征。 细胞膜磷脂的组分直接决定细胞对铁死亡的敏感程度：富含多不饱和脂肪酸（PUFA）的磷脂极易发生过氧化，进而触发铁死亡；而单不饱和脂肪酸（MUFA）整合进入磷脂后，会减弱脂质过氧化，帮助肿瘤细胞逃避铁死亡。ACSL3能够激活单不饱和脂肪酸，但其上游调控机制一直尚不明确。 多数耐药研究仅依赖传统肿瘤细胞系开展实验，然而长期传代的细胞系会丢失大量患者肿瘤的真实特征，动物移植瘤同样存在固有局限。患者来源类器官PDO可保留原发肿瘤的基因组与病理特征，被称为"迷你肿瘤"，是打通基础研究与临床转化的理想模型。本研究便将PDO作为核心验证工具，评估Mavorixafor的临床应用潜力。 本研究要解决的核心科学问题 1PHB2通过怎样的脂质代谢机制介导胃癌顺铂耐药？ 2能否找到小分子药物阻断PHB2‑ACSL3相互作用，恢复铁死亡？ 3在更贴近临床的PDO、CDX模型上，该药物联合顺铂是否可以逆转耐药？药效是否依赖铁死亡通路？ 实验拆解：从分子挖掘到药效闯关 整套研究按照"分子筛选→机制解析→药物发现→类器官+动物模型验证"层层递进。 ◆1. 耐药靶点初筛：挖掘PHB2的耐药角色 构建顺铂耐药AGS移植瘤模型，对比耐药/敏感肿瘤转录组，结合NCI‑60数据库，锁定PHB2。临床胃癌样本显示，顺铂耐药患者肿瘤中PHB2蛋白显著高表达；细胞和小鼠体内实验证实，敲低PHB2可以恢复耐药肿瘤对顺铂的敏感性，过表达PHB2则诱导耐药。 ◆2. 机制深挖：PHB2搭伙ACSL3改写细胞膜脂质，关掉铁死亡开关 KEGG富集提示铁死亡通路在耐药肿瘤中显著改变。一系列细胞实验证明PHB2抑制铁死亡，IP‑MS筛选出互作蛋白ACSL3。PHB2结合ACSL3的AMP结合结构域（关键残基W244/H254/E260），不改变ACSL3蛋白表达，但是提升它的酶活性，促进MUFA整合进细胞膜磷脂，压低脂质过氧化水平，让癌细胞抵抗铁死亡。 ◆3. 老药"捡宝"：虚拟筛选锁定Mavorixafor，拆散PHB2‑ACSL3蛋白复合物 针对ACSL3的PHB2结合口袋开展分子对接虚拟筛选，从药物库中锁定已经获批的CXCR4拮抗剂Mavorixafor。Co‑IP证实药物可以直接破坏PHB2与ACSL3的相互作用；脂质组学证明给药后，细胞膜上单不饱和脂肪酸磷脂下降、多不饱和脂肪酸磷脂上升，脂质过氧化水平上升。 铁死亡抑制剂Liproxstatin‑1可以完全抵消Mavorixafor带来的脂质过氧化，证明药物的作用完全依赖铁死亡通路。 ◆4. 药效终局闯关：CDX与PDO双重模型，迷你肿瘤给出临床提示 研究搭建两套体内/体外类器官模型： 细胞来源移植瘤CDX（体内）：顺铂单独给药几乎不能抑制耐药肿瘤生长；Mavorixafor联合顺铂，肿瘤增殖被显著压制。但如果同时加入铁死亡抑制剂Liproxstatin‑1，联合治疗的抑瘤效果直接消失。 IHC染色结果也佐证：联合组增殖标记Ki‑67显著下调，脂质过氧化标记4‑HNE大量积累；添加Liproxstatin‑1之后，Ki‑67回升，4‑HNE减少。血清生化检测证实，该联合方案没有带来明显肝肾毒性，安全性良好。 患者来源胃癌类器官PDO（体外"迷你肿瘤"）：这套模型直接取自临床顺铂耐药胃癌患者的肿瘤组织，最大程度复刻真实患者肿瘤特征。 ① 仅用顺铂处理PDO，类器官依旧旺盛生长，完美复刻临床上的耐药现象； ② Mavorixafor+顺铂联合处理，类器官的存活能力大幅下降； ③ 当加入Liproxstatin‑1抑制铁死亡后，联合用药的杀伤效果几乎被完全逆转，类器官重新恢复生长。 研究者同时做CEA、CK‑7染色确认类器官保留胃癌上皮来源特征，进一步证明实验体系可靠。PDO的结果和CDX动物模型高度呼应，提示这个治疗策略在真实患者肿瘤中具备可行性。 图6 药效验证 Mavorixafor通过铁死亡在CDX和PDO模型中使耐药胃癌细胞敏感化 小思考：很多候选药物在细胞实验效果亮眼，进入动物实验就失效，更不用说临床。本研究先动物，再用患者类器官做二次校验，相当于在细胞和临床试验中间加了一道"过滤器"，大大提升研究结果的参考价值。 总结与观点 这项研究构建了"临床样本‑分子挖掘‑机制解析‑老药重定位‑类器官预临床验证"完整研究闭环，为棘手的胃癌顺铂耐药问题交出一份高质量的临床前研究结果。 科学创新 多数铁死亡研究聚焦GPX4、SLC7A11等经典抗氧化通路，而该研究另辟蹊径，关注蛋白‑蛋白互作介导的脂质重塑。PHB2以往被认为是线粒体相关蛋白，本研究揭示其胞质"兼职"功能：PHB2不改变ACSL3的表达水平，仅通过蛋白结合提升ACSL3酶活性，重塑细胞膜脂肪酸组分，促使肿瘤细胞逃逸铁死亡。这也提示，传统线粒体蛋白的非经典胞质功能，是肿瘤靶点挖掘值得关注的方向。 药物转化 研究选用已获FDA批准的Mavorixafor开展老药新用。依托已有人体安全数据，可大幅缩减临床试验的时间与研发成本。该小分子仅阻断PHB2‑ACSL3的相互作用，保留PHB2原有生理功能，相比敲除PHB2，能够规避线粒体代谢紊乱带来的毒副作用，为PPI（蛋白‑蛋白互作）药物研发提供新思路。 类器官验证 患者来源类器官PDO进一步提升研究可靠性。区别于驯化的肿瘤细胞系与存在物种差异的小鼠移植瘤，PDO复刻患者肿瘤的顺铂耐药特征，并与CDX体内实验结果相互印证。未来PDO还有望实现个体化药敏检测，指导胃癌精准治疗。 研究局限 全部结果均处于临床前阶段，模型无法完全模拟人体复杂肿瘤微环境，疗效有待临床试验确认；PHB2‑ACSL3通路在其他铂耐药肿瘤中的普适性尚不明确；Mavorixafor仍会作用于原有靶点CXCR4，潜在副作用有待评估，且PDO缺失完整免疫微环境。后续需要开发高特异性小分子，结合免疫共培养类器官开展更深探索。 总体而言，本研究跳出凋亡通路的固有思路，以脂质重塑和铁死亡为突破口对抗胃癌化疗耐药，建立了一套从临床问题出发的研究范式，期待后续推进转化，造福耐药胃癌患者。 原文链接 https://pubmed.ncbi.nlm.nih.gov/42627686/ 编辑：盛合瑞类器官 · 小蕊 校对：盛合瑞类器官 · 灰灰 排版：盛合瑞类器官 · 苍南

BOSTON, Aug. 06, 2026 (GLOBE NEWSWIRE) -- X4 Pharmaceuticals (Nasdaq: XFOR), a company focused on improving the lives of people with rare hematology diseases, today reported financial results for the second quarter ended June 30, 2026 and provided a corporate update. “Since we began leading X4 last August, we have taken meaningful actions to strengthen the execution of the mavorixafor Phase 3 4WARD trial in chronic neutropenia, positioning 4WARD for the successful completion of enrollment,” said Adam Craig, M.D., Ph.D., Executive Chairman of X4 Pharmaceuticals. “Following our complete overhaul of the clinical operating infrastructure and engagement of a top oncology Clinical Research Organization (CRO) to manage the Phase 3 trial, we are now in a position to revisit the sample size of the study with the FDA. We expect to provide an update on our meeting with the FDA and the completion of enrollment by the end of the third quarter.” “Alongside these operational improvements, we continue to actively engage with the medical community to educate physicians on the potential benefits of mavorixafor as an improved treatment option for patients, including a strong presence at this year’s EHA Congress. During the quarter, we also achieved an important milestone with the European Commission’s marketing authorization of XOLREMDI® for WHIM syndrome, supporting the therapeutic potential of mavorixafor across rare hematologic conditions,” concluded, Dr. Craig. Recent Accomplishments and Updates Transitioned management of the Phase 3 4WARD trial to a premier Clinical Research Organization (CRO) to further strengthen the study execution and support completion of enrollment. Advanced enrollment in the global 4WARD Phase 3 trial of oral, once-daily mavorixafor (with or without G-CSF) in patients with congenital, acquired primary autoimmune, or idiopathic chronic neutropenia, supported by several targeted initiatives including activation of over 110 active clinical trial sites worldwide, ongoing Medical Affairs engagement, and utilizing data-driven approaches to identify potential participants. Continued to expand awareness in the medical community with a strong presence at the European Hematology Association (EHA) Congress including a publication entitled, “A Pivotal Phase 3 Study To Investigate Efficacy, Safety, and Tolerability of Mavorixafor in Participants with Primary Chronic Neutropenia”. The Medical Affairs team also hosted a booth and held an investigator meeting to engage with physicians regarding the 4WARD trial and the potential benefits of mavorixafor in chronic neutropenia. Received marketing authorization for XOLREMDI® (mavorixafor) by the European Commission for the treatment of patients with WHIM syndrome in the European Union (EU). The approval follows a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). European commercialization will be led by X4 Pharmaceuticals’ partner, Norgine. In July 2026, the EU marketing authorization was transferred to Norgine. Under the terms of the license and supply agreement, X4 could receive up to an additional €221 million contingent upon the achievement of certain regulatory and commercial milestones, in addition to escalating double-digit royalties of up to the mid-twenties on any future net sales in the licensed territories. First Quarter Financial Results Cash Position: As of June 30, 2026, the Company’s cash position was $208.0 million. Revenue: Revenue was $8.8 million and $11.5 million for the three and six months ended June 30, 2026, respectively. Revenue included net product sales of $2.4 million and $4.8 million for the three and six months ended June 30, 2026, respectively, attributable to XOLREMDI® product sales in the United States. License and other revenue for the three and six month period ended June 30, 2026 included $6.4 million and $6.7 million, respectively, attributable to the Company’s Norgine license and supply agreement. Revenue was $2.0 million and $30.8 million for the three and six months ended June 30, 2025, respectively. Revenue for the six months ended June 30, 2025 included $27.9 million of license revenue attributable to the Norgine license and supply agreement. Research and Development (R&D) expenses: R&D expenses were $15.1 million and $30.5 million for the three and six months ended June 30, 2026 as compared to $18.4 million and $36.9 million for the same periods in prior year. The decrease in both periods is primarily attributable to decreased headcount following the 2025 strategic restructuring, partially offset by higher clinical costs, primarily CRO costs related to our 4WARD trial. General and Administrative (G&A) expenses: G&A expenses were $8.5 million and $15.5 million for the three and six months ended June 30, 2026 as compared to $9.5 million and $24.6 million for the same periods in the prior year. The decrease in both periods is primarily attributable to a reduction in sales and marketing expenses, a reduction in outside legal expenses, and reductions in compensation costs due to lower head count in general and administrative functions. Net Loss: Net loss for the three months ended June 30, 2026 was $16.2 million, or $(0.13) per share, as compared to net loss for the three months ended June 30, 2025 of $25.7 million, or $(3.47) per share. Net loss for the six months ended June 30, 2026 was $36.4 million, or $(0.29) per share, as compared to net loss of $25.5 million, or $(3.59) per share, for the same period in 2025. About Chronic Neutropenia and Mavorixafor Chronic neutropenia is a primary, rare blood condition characterized by abnormally low levels of circulating neutrophils in the blood lasting more than three months, persistently or intermittently. As a result, people with chronic neutropenia are at an increased risk of serious and life-threatening infections and reduced quality of life. Neutrophils are retained in the bone marrow by the CXCR4/CXCL12 axis, creating a reserve of cells. Mavorixafor is a small molecule delivered in a capsule for oral dosing as a selective antagonist of the chemokine receptor, CXCR4. Down-regulation of the CXCR4 receptor by mavorixafor has been shown to mobilize functional neutrophils from the bone marrow into the peripheral bloodstream across multiple disease states. The level of circulating neutrophils is typically determined by the absolute neutrophil count (ANC) obtained from a blood draw. About the 4WARD Clinical Trial The 4WARD trial is a global, pivotal Phase 3 clinical trial evaluating the efficacy, safety, and tolerability of oral, once-daily mavorixafor (with or without G-CSF) in patients with congenital, acquired primary autoimmune, or idiopathic chronic neutropenia who are experiencing recurrent and/or serious infections. The 52-week trial is a randomized, double-blind, placebo-controlled, multicenter study aiming to enroll 176 patients aged 12 years and older with confirmed trough absolute neutrophil count (ANC) levels less than 1,000 cells per microliter at baseline screening and histories of two or more serious and/or recurrent infections in the prior year. The primary endpoints of the study are the reduction in annualized infection rate and positive ANC response. For more information, visit clinicaltrials.gov (NCT06056297). About X4 Pharmaceuticals X4 Pharmaceuticals is a company focused on improving the lives of people with rare hematology diseases by developing and commercializing innovative therapies in areas with significant unmet needs. Leveraging expertise in diseases of the immune system and CXCR4 biology, X4 has successfully developed mavorixafor, an orally available CXCR4 antagonist that is commercially available in the U.S. as XOLREMDI® in its first indication. The Company is currently conducting a global, pivotal Phase 3 clinical trial (4WARD) evaluating mavorixafor in chronic neutropenic disorders. The U.S. FDA has granted Fast Track designation to mavorixafor for the treatment of chronic neutropenia. X4 is headquartered in Boston, Massachusetts. For more information, please visit www.x4pharma.com. X4 Forward Looking Statements This press release contains forward-looking statements within the meaning of applicable securities laws, including the Private Securities Litigation Reform Act of 1995, as amended. These statements may be identified by the words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target,” or other similar terms or expressions that concern X4’s expectations, strategy, plans, or intentions. Forward-looking statements include, without limitation, implied or express statements regarding the Company’s ability to obtain and maintain regulatory approval for its product candidates, plans for the commercialization of XOLREMDI in the European Union by Norgine, the potential achievement of milestones and receipt of royalties under the Company’s licensing and supply agreement with Norgine, the expected design and enrollment of the Company’s clinical trials, including expected timing for full enrollment in 4WARD, the sufficiency of the Company’s cash resources and its expected cash runway, and future plans for the Company. Any forward-looking statements in this press release are based on management’s current expectations and beliefs. These forward-looking statements are neither promises nor guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond X4’s control, which could cause actual results to differ materially from those contemplated in these forward-looking statements, including the risks that even if approved, mavorixafor may not ultimately be commercially successful; the Company is unable to initiate and complete its clinical trials, including the 4WARD trial; and other risks and uncertainties, including those described in the section entitled “Risk Factors” in X4’s most recent Annual Report on Form 10-K, as well as in other filings X4 makes with the Securities and Exchange Commission, including its Quarterly Reports on Form 10-Q, from time to time. X4 undertakes no obligation to update the information contained in this press release to reflect new events or circumstances, except as required by law. Source: X4 Pharmaceuticals, Inc. Balance Sheet Data (unaudited) X4 Investor Contact: Remy Bernarda Jenny Kobin IR Advisory Solutions IR@X4pharma.com