Arimoclomol

CELEBRATION, Fla., Dec. 29, 2025 (GLOBE NEWSWIRE) -- Zevra Therapeutics, Inc. (NasdaqGS: ZVRA) (Zevra, or the Company), a commercial-stage company focused on providing therapies for people living with rare disease, today announced that the Company has executed an exclusive expanded access distribution agreement with Uniphar, an Ireland-based pharmaceutical services provider with a proven record of success in global warehousing, distribution and supply chain management. The agreement enables Niemann-Pick Disease Type C (NPC) patients to access MIPLYFFA® (arimoclomol), for reimbursed named patient supply in select territories outside of Europe. NPC is an ultra-rare, relentlessly progressive, genetic disorder that leads to premature mortality. MIPLYFFA, used in conjunction with miglustat, is the only treatment shown to halt disease progression by addressing the underlying pathology of NPC with improvement seen at the first evaluation at week 12, and durable effect for more than five years. “There remains a clear unmet need within the rare disease community and this distribution agreement enables us to further our mission by expanding access and supporting a greater number of patients and families living with NPC,” said Neil F. McFarlane, Zevra's President and Chief Executive Officer. “By leveraging Uniphar’s leadership and infrastructure, we have an opportunity to initially address a select patient population, while continuing to prioritize our U.S. commercial launch and prepare for a potential EU approval.” Commenting on the agreement, Brian O’Shaunnessy, Chief Commercial Officer at Uniphar, said, “Uniphar is proud to partner with Zevra to expand global access to MIPLYFFA. We believe our proven expertise in global distribution and supply chain management combined with Zevra's innovative approach to rare disease therapies will help make a life-changing difference to patients living with NPC.” MIPLYFFA is approved by the U.S. Food and Drug Administration and is commercially available in the U.S. A Marketing Authorisation Application for the evaluation of arimoclomol for the treatment of NPC has been validated and is under review by the European Medicines Agency (EMA). About MIPLYFFA® (arimoclomol) MIPLYFFA (arimoclomol) is Zevra’s approved therapy for the treatment of Niemann-Pick disease type C (NPC). Approved by the U.S. Food and Drug Administration on Sep. 20, 2024, MIPLYFFA (arimoclomol) increases the activation of the transcription factors EB (TFEB) and E3 (TFE3) resulting in the upregulation of coordinated lysosomal expression and regulation (CLEAR) genes. MIPLYFFA has also been shown to reduce unesterified cholesterol in the lysosomes of human NPC fibroblasts. The clinical significance of these findings is not fully understood. In the pivotal phase 3 trial, MIPLYFFA halted disease progression compared to placebo over the one-year duration of the trial when measured by the only validated disease progression measurement tool, the NPC Clinical Severity Scale. MIPLYFFA has also received Orphan Medicinal Product designation by the European Medicines Agency (EMA) for the treatment of NPC. The extensive data generated for MIPLYFFA has shown long-term, meaningful clinical outcomes with more than 5 years of patient experience across more than 270 NPC patients worldwide through a Phase 2/3 clinical trial, Open-Label Extension (OLE) study, Expanded Access Programs (EAP), and a pediatric sub-study, which is the most expansive clinical development program in NPC to date. Zevra has submitted a Marketing Authorization Application to the European Medicines Agency for the evaluation of arimoclomol for the treatment of Niemann-Pick disease type C. INDICATIONS AND USAGE MIPLYFFA is indicated for use in combination with miglustat for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adult and pediatric patients 2 years of age and older. IMPORTANT SAFETY INFORMATIONHypersensitivity Reactions: Hypersensitivity reactions such as urticaria and angioedema have been reported in patients treated with MIPLYFFA during Trial 1: two patients reported both urticaria and angioedema (6%) and one patient (3%) experienced urticaria alone within the first two months of treatment. Discontinue MIPLYFFA in patients who develop severe hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, stop MIPLYFFA and treat promptly. Monitor the patient until signs and symptoms resolve. Embryofetal Toxicity: MIPLYFFA may cause embryofetal harm when administered during pregnancy based on findings from animal reproduction studies. Advise pregnant females of the potential risk to the fetus and consider pregnancy planning and prevention for females of reproductive potential. Increased Creatinine without Affecting Glomerular Function: Across clinical trials of MIPLYFFA, mean increases in serum creatinine of 10% to 20% compared to baseline were reported. These increases occurred mostly in the first month of MIPLYFFA treatment and were not associated with changes in glomerular function. During MIPLYFFA treatment, use alternative measures that are not based on creatinine to assess renal function. Increases in creatinine reversed upon MIPLYFFA discontinuation. The most common adverse reactions in Trial 1 (≥15%) in MIPLYFFA-treated patients who also received miglustat were upper respiratory tract infection, diarrhea, and decreased weight. Three (6%) of the MIPLYFFA-treated patients had the following adverse reactions that led to withdrawal from Trial 1: increased serum creatinine (one patient), and progressive urticaria and angioedema (two patients). Serious adverse reactions reported in MIPLYFFA-treated patients were hypersensitivity reactions including urticaria and angioedema. To report SUSPECTED ADVERSE REACTIONS, contact Zevra Therapeutics, Inc. at toll-free phone 1-844-600-2237 or FDA at 1 800-FDA-1088 or www.fda.gov/medwatch.Drug Interaction(s): Arimoclomol is an inhibitor of the organic cationic transporter 2 (OCT2) transporter and may increase the exposure of drugs that are OCT2 substrates. When MIPLYFFA is used concomitantly with OCT2 substrates, monitor for adverse reactions and reduce the dosage of the OCT2 substrate. Use in Females and Males of Reproductive Potential: Based on animal findings, MIPLYFFA may impair fertility and may increase post-implantation loss and reduce maternal, placental, and fetal weights. Renal Impairment: The recommended dosage of MIPLYFFA, in combination with miglustat, in patients with an eGFR ≥15 mL/minute to <50 mL/minute is lower than the recommended dosage (less frequent dosing) in patients with normal renal function. MIPLYFFA capsules for oral use are available in the following strengths: 47 mg, 62 mg, 93 mg, and 124 mg. About Zevra Therapeutics, Inc. Zevra Therapeutics, Inc. is a commercial-stage company focused on addressing unmet needs for the treatment of rare diseases. Our mission is to bring life-changing therapeutics to people living with rare diseases. With unique, data-driven development and commercialization strategies, the Company is overcoming complex drug development challenges to make new therapies available to the rare disease community. Expanded access programs are made available by Zevra Therapeutics, Inc. and its affiliates and are subject to the Company's Expanded Access Program (EAP) policy, as published on its website. Participation in these programs is subject to the laws and regulations of each jurisdiction under which each respective program is operated. Eligibility for participation in any such program is at the treating physician's discretion. About Uniphar Uniphar is a trusted global partner to pharma, medtech and biotech, delivering solutions that connect medicines and technologies with patients worldwide. With over 57 years of experience and partnerships with 200+ multinational clients, Uniphar combines deep expertise, infrastructure and market insight to meet the evolving needs of the life sciences sector. Uniphar Pharma integrates Development, Clinical, Access, Medical, Commercial, Distribution and Global Sourcing to support the full product lifecycle – from early-stage research through to commercialization and beyond. Uniphar’s unified platform spans medical affairs, regulatory strategy, market access, patient engagement, commercial services, distribution and supply chain. With a team of 3,500+ across 180 countries, Uniphar bridges manufacturers, healthcare providers and patients, ensuring innovative therapies reach those who need them – driving value, access and better outcomes worldwide. From molecule to market and beyond. Cautionary Note Concerning Forward-Looking Statements This press release may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements that do not relate solely to historical or current facts, including without limitation statements regarding the Company’s expanded access program. Forward-looking statements are based on information currently available to Zevra and its current plans or expectations. They are subject to several known and unknown uncertainties, risks, and other important factors that may cause our actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. These and other important factors are described in detail in the "Risk Factors" section of Zevra’s Annual Report on Form 10-K for the year ended December 31, 2024, filed on March 12, 2025, Quarterly Report on Form 10-Q for the three and nine months ended September 30, 2025, filed on November 5, 2025, as well as Zevra’s other filings with the Securities and Exchange Commission. While we may elect to update such forward-looking statements at some point in the future, except as required by law, we disclaim any obligation to do so, even if subsequent events cause our views to change. Although we believe the expectations reflected in such forward-looking statements are reasonable, we cannot assure that such expectations will prove correct. These forward-looking statements should not be relied upon as representing our views as of any date after the date of this press release. Investor Contact Nichol Ochsner +1 (732) 754-2545 nochsner@zevra.com Media Contact Julie Downs+1 (508) 246-3230 jdowns@zevra.com

期刊： Brain 发表时间：2025年 影响因子：10.8 文章速览 2025年，加拿大皇家科学院厉良院士与拉瓦尔大学Chantelle F. Sephton团队在《Brain》上发表重要研究，该研究通过综合运用代谢组学技术、免疫标记和分子生物学方法，首次系统揭示了脂滴（LDs）异常积累在FUS基因突变导致肌萎缩侧索硬化（FUS-ALS)发病中的关键作用，并发现药物Arimoclomol可通过促进线粒体β-氧化有效缓解神经元和星形胶质细胞的脂毒性损伤。 研究利用表达人FUS R521G突变的转基因小鼠模型、原代神经元与星形胶质细胞培养体系以及FUS-ALS患者尸检脊髓组织，多层次证实了脂代谢紊乱是FUS-ALS的共性病理特征。并阐明了Arimoclomol通过CPT1依赖性机制增强脂滴-线粒体接触，促进脂肪酸氧化（FAO）的全新作用通路，为ALS的代谢靶向治疗提供了新的理论依据和潜在干预靶点。 迈理奥在加拿大皇家科学院厉良院士全程指导下，搭建了基于高效化学同位素双标记的颠覆性创新代谢组学平台，具备最强的代谢标志物发现能力： 超高覆盖: 全套优化的衍生化试剂，检测灵敏度提升10-1000倍，稳定识别并定量代谢物10000+，鉴定1400+。 精准定量: 为所有检测代谢物匹配一一对应的全同位素内标，实现定量金标准。 超高稳定: 为所有待测样本制备统一的参考样本，大幅降低批次效应。 背景介绍 肌萎缩侧索硬化（ALS）是一种致死性神经退行性疾病，以运动神经元进行性丢失为核心病理特征。近年研究证实，能量代谢紊乱是ALS发病的重要驱动因素，患者普遍存在静息能量消耗异常升高与全身性能量代谢失衡的病理表型。 在家族性ALS中，约5-10%的病例由FUS基因突变引起。该蛋白作为RNA结合蛋白，在转录后调控和RNA代谢中发挥核心功能。值得注意的是，FUS突变携带者常伴随脂代谢异常表型，但其具体分子机制及治疗价值仍不明确。最新研究表明，FUS突变可导致线粒体功能障碍和脂滴异常积累，进而引发神经元能量代谢危机。由于代谢稳态失衡可能通过影响疾病进程关键节点（如发病年龄和疾病进展速度），解析细胞应对能量波动的代谢调控网络，对于揭示ALS的病理机制具有重要科学价值。 研究亮点 多模型验证：结合体内小鼠模型、体外细胞培养和人类尸检组织，全面验证脂代谢异常在FUS-ALS中的普遍性。 机制深度解析：从脂滴积累、酰基肉碱代谢到线粒体功能异常，系统阐明脂毒性产生的完整通路。 治疗靶点创新：首次发现Arimoclomol通过CPT1依赖性机制促进脂滴分解，而非传统的热休克蛋白诱导途径。 临床转化价值：为FUS-ALS提供了首个以“脂代谢调控”为靶点的治疗策略，目前已完成III期临床试验的患者招募，具备快速转化的潜力。 研究结果 1. 脂代谢紊乱是FUS-ALS的核心病理特征 研究团队利用代谢组学技术，在表达人源FUS R521G突变（hFUSR521G）的小鼠皮层组织中，检测到包括短链与长链组分在内的多种酰基肉碱分子显着累积（图1A），提示脂肪酸氧化通路存在特异性障碍。组织与细胞水平分析进一步证实，脂滴（LDs）在hFUSR521G小鼠的神经元及星形胶质细胞中大量聚集（图1C-H），且伴随脂质过氧化产物4-HNE与氧化DNA损伤标志物8-OHdG水平的显著升高（图1J, K），共同揭示了脂代谢紊乱引发的氧化应激损伤。 图1 hFUS R521G小鼠皮层中酰基肉碱积累与脂质代谢异常 2.人类病例验证脂代谢异常在FUS-ALS中的普遍性 在FUS R495X及K510E突变患者的脊髓样本中，研究同样观察到星形胶质细胞内存在显著的脂滴积累（图2A, B），且脂质过氧化水平显着高于对照组（图2C, D）。这一发现将在体模型中的发现成功转化至人类疾病情境，证实脂代谢失调是FUS-ALS跨物种存在的关键病理环节。 图2 人类ALS-FUS病例中脂滴积累验证 3.Arimoclomol有效逆转脂毒性 药物干预实验表明，热休克蛋白共诱导剂Arimoclomol（20 mg/kg，28天）治疗可显着减轻hFUSR521G小鼠脑内的脂滴累积、脂质过氧化及DNA损伤（图3C-F）。相干拉曼光谱分析显示，该药物能使疾病模型脊髓的异常脂质谱恢复正常（图3I）。靶向代谢组学数据进一步证实，Arimoclomol可促使升高的酰基肉碱水平趋于正常（图3J），凸显其调节脂代谢的潜力。 图3  Arimoclomol的治疗效果评估 4. 药效机制独立于抗炎作用 在机制层面，研究发现促炎因子TNF-α会加剧培养的FUS R521G神经元及星形胶质细胞中的脂滴积累（图4C-F）。值得注意的是，在炎症环境下，Arimoclomol仍能有效减少脂滴，表明其作用不依赖于单纯的抗炎效应，而是直接作用于脂代谢通路。 图4 炎症环境下Arimoclomol的作用 5. 通过肉碱穿梭系统促进脂滴分解 深入研究揭示，Arimoclomol的作用依赖于完整的肉碱穿梭系统。CPT1抑制剂etomoxir可完全阻断其减少脂滴的效应（图5A-F）。同时，该药物显着增加了脂滴与线粒体之间的接触（图5G-J），表明其通过增强脂肪酸的线粒体β-氧化来促进脂质分解。 6. 通过肉碱穿梭系统促进脂滴分解 最终，团队在星形胶质细胞中证实，Arimoclomol能恢复因FUS突变而受损的、由脂肪酸β-氧化贡献的耗氧率（图6A），并改善线粒体膜电位。代谢物分析显示，药物处理增强了细胞对脂滴内三酰甘油和胆固醇酯的分解代谢。这些发现共同描绘了Arimoclomol通过促进脂质利用、改善线粒体功能来缓解脂毒性的完整作用通路。 研究结论 核心重点：脂代谢紊乱是FUS相关ALS的核心病理特征，通过CPT1依赖性机制增强线粒体β-氧化可有效缓解脂毒性 脂滴积累的普遍性与病理意义：脂滴异常积累在FUS相关ALS的实验模型和人类病例中普遍存在，脂滴积累伴随酰基肉碱增加和脂质过氧化，表明脂代谢系统紊乱，神经元对脂毒性诱导的氧化DNA损伤更为敏感，星形胶质细胞因抗氧化防御较强而相对耐受。 代谢重编程的特征：FUS R521G星形胶质细胞中CPT1a、CPT2和SLC25A20表达上调，表明细胞试图通过增强脂肪酸利用来代偿代谢紊乱，然而在线粒体功能障碍背景下，增强的β-氧化可能产生适应性不良，导致不完全氧化和ROS生成 Arimoclomol的新型作用机制：Arimoclomol通过CPT1依赖性机制促进脂滴分解，而非传统认识的热休克蛋白诱导途径，药物增强脂滴-线粒体接触，提高β-氧化效率，恢复代谢平衡，这种作用在炎症条件下仍然有效，表明其直接靶向脂代谢通路。 治疗启示与临床意义：研究为ALS的代谢靶向治疗提供了新的理论依据，针对脂代谢的治疗策略需要考虑ALS亚型的代谢异质性，结合抗炎效果、增强β-氧化和保持糖酵解通量的综合治疗策略可能更为有效。 知识拓展 项目文章(Nature)|高效化学同位素标记(HP-CIL)技术助力T细胞的功能与分化研究 项目文章丨厦门大学附属第一医院团队最新成果：多组学评估间充质干细胞（MSC）在衰老中的治疗潜力 合作文章丨DeepMarker MT代谢组学平台助力高盐发酵食品代谢物变化新发现，研究成果发表J Agric Food Chem 合作文章（Cell）| 再登顶刊！创新代谢组学技术联合揭秘非工业化饮食的神奇功效 行业前沿丨高效化学同位素标记（HP-CIL)代谢组学技术揭示乌帕替尼治疗强直性脊柱炎新机制 王牌产品|全球领先的DeepMarker MT代谢组学平台 重磅新品|全球领先的DeepMarker LT脂质组学平台震撼上线!!! ···  关于迈理奥  ··· 迈理奥以国际化项目经验丰富的归国博士为核心，加拿大皇家科学院厉良院士担任首席科学家（人类代谢组计划联合发起人、人类代谢组学数据库HMDB联合创始人、加拿大国家代谢组学创新中心联合主任，加拿大阿尔伯塔大学终身教授），是福建省引才“百人计划”、厦门市“双百计划”人才创业企业，厦门市未来产业骨干企业，国家级高新技术企业，提供专业化、高水平、一站式的代谢组学、脂质组学科研服务及相关产品的研发和转化。 DeepMarker MT代谢组学平台采用加拿大皇家科学院厉良院士独创的高效化学同位素标记（HP-CIL）技术，结合自主研发的IsoMS Pro数据分析系统，完美融合非靶与靶向优势，实现前所未有的代谢标志物发现能力。与常规方法相比，代谢物检测鉴定数量提升5-10倍，可检测代谢物10,000+，鉴定代谢物1,400+，并为代谢物生成一一对应的同位素内标，实现代谢物的精准定量。 DeepMarker LT脂质组学平台由加拿大皇家科学院厉良院士领衔研发，采用自主合成的近20种稳定同位素内标，并根据样本类型定制不同的内标组合，精准追踪变化，最大程度降低基质与批次效应，结合自主研发的Lipid Screener数据分析系统，提供稳定、可重复的数据支持。脂质识别数量远超常规方法，检测脂质8000+，鉴定脂质3000+。 截至2025年01月，相关成果已在各研究领域累计发表文章数百篇，包括综合性顶刊《Cell》，《Nature》、化学顶刊《Analytical Chemistry》、医学顶刊《Brain》、农林科学《Journal of Agricultural and Food Chemistry》等。 点击蓝字 关注我们 厦门市迈理奥科技有限公司 公司地址：福建省厦门市海沧区翁角西路2052号（厦门生物医药产业园）B2栋703室 联系电话：0592-6882803 邮箱：mlo_service@meliomics.cn 扫描二维码 添加客服微信 联系我们-了解更多