COCCIMETRICS: A Phase II, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate Measures for Endpoint Derivation in Patients With Progressive or Refractory Disseminated Coccidioidomycosis (DCM) Treated With Olorofim Plus Baseline Standard of Care (SOC) or With Placebo Plus Baseline SOC

The purpose of this study is to test measurement tools (questionnaire about symptoms and a questionnaire about quality of life) to assess usability in the assessment of treatment effectiveness for people with disseminated coccidioidomycosis (DCM).

开始日期2026-12-01

申办/合作机构

F2G Ltd.

[+1]

NCT07385638

/ Recruiting临床2期IIT

Phase 2, Open-label Evaluation of Olorofim in Early Coccidioidal Meningitis

This research study is being conducted to learn more about the use of olorofim in Coccidioidal (Cocci) meningitis, a rare but serious fungal infection that affects the brain and spinal cord. The study is exploratory, meaning that early information is being gathered to better understand the effectiveness of olorofim in coccidioidal meningitis in its early stages. The study plans to enroll approximately 10 to 12 participants who have been recently diagnosed-within the last 4 to 8 weeks-and who do not have a ventriculoperitoneal (VP) shunt, a medical device sometimes used to relieve pressure in the brain. Participants will be followed for approximately 6 months, during which health information will be collected to evaluate disease progression and response to treatment. Participants may have the opportunity to enroll in the olorofim Managed Access Program to continue treatment after completion of the study period.

开始日期2026-06-01

申办/合作机构

University of Arizona

[+1]

CTR20232748

/ Active, not recruiting临床1期

一项在健康中国人受试者中评估Olorofim单次口服给药的药代动力学和安全性的I期研究

本临床试验的主要目的是在中国健康受试者中评估Olorofim单次口服给药的PK，次要目的是在中国健康受试者中评估Olorofim单次口服给药的安全性和耐受性。

开始日期2023-11-09

申办/合作机构

盐野义有限公司

[+2]

100 项与 Olorofim 相关的临床结果

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100 项与 Olorofim 相关的转化医学

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100 项与 Olorofim 相关的专利（医药）

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115

项与 Olorofim 相关的文献（医药）

2026-09-01·CLINICAL MICROBIOLOGY AND INFECTION

New antifungals for the treatment of invasive mould disease

Review

作者: Aitken, Samuel L ; Rausch, Caitlin R ; McClung, David R ; Vuong, Nancy N

BACKGROUND:

Invasive fungal infections are emerging as a critical threat to healthcare, yet the disparity in development and approval of new antifungal agents has only recently been addressed. In 2022, the WHO published the first global priority list of fungal pathogens (Fungal Priority Pathogens List) in order to promote public health awareness, encourage research and development, and propose actions and strategies for stakeholders to target in combatting the rise of fungal infections.

OBJECTIVES:

This review provides a summary of recent data of recently approved and/or investigational antifungals targeted at invasive mould infections, collating updated information on clinical findings of antifungal agents with potential use or activity against moulds listed on the WHO Fungal Priority Pathogens List.

SOURCES:

A PubMed literature search 'Aspergillus fumigatus', 'Fusarium', 'Mucorales', 'Eumycetoma', 'Scedosporium', and 'Lomentospora' with names of antifungal agents 'rezafungin', 'ibrexafungerp', 'oteseconazole', 'opelconazole', 'fosmanogepix', 'olorofim', 'BAL2062', 'mandimycin', 'ATI-2307', 'MAT2203', 'TFF voriconazole', and 'miltefosine' was conducted.

CONTENT:

Preclinical and clinical trial data published within the last 5 years are discussed. The recent approvals of three new antifungals by the US Food and Drug Administration are a significant accomplishment in the advancement of antifungal therapies. Approvals, current indications, and investigations for rezafungin, ibrexafungerp, and oteseconazole as antimould agents are discussed. Additionally, information on fosmanogepix, opelconazole, and olorofim, as well as reformulated agents and those in the pipeline, is included. Clinical data, where available, were the primary focus of the article.

IMPLICATIONS:

Development of new antifungal agents is challenging because of limited target sites, emergence of resistance, and adverse toxicity profiles. However, clinical data from fosmanogepix, olorofim, and encochleated amphotericin B are promising in both clinical efficacy and safety for the treatment of invasive mould infections. These new agents offer alternative options for difficult-to-treat infections, while providing promising efficacy and improved safety outcomes.

2026-09-01·MYCOSES

Central Nervous System Aspergillosis: Advances in Diagnosis, Therapeutics, and Multidisciplinary Management (2026 Update)

Review

作者: Mostafa, Hamdi Nabawi ; Helmy, Mohamed H. ; Mansour, Moustafa A. ; Wahid, Mohamed ; Adel, Taha Mohammed ; El Molla, Mohamed A. S.

ABSTRACT:

Background:

Central nervous system (CNS) aspergillosis is a life‐threatening infection with mortality rates exceeding 50%, especially in immunocompromised patients. Significant challenges persist due to limited antifungal drug penetration into the CNS, emerging resistance, and diagnostic delays, despite advancements in therapy and diagnostics.

Objective:

This comprehensive review aims to synthesize pivotal advances in the management of CNS aspergillosis from 2020 to 2026 and to provide a multidisciplinary framework for addressing these ongoing challenges.

Methods:

We conducted a comprehensive evaluation of the latest clinical data, pharmacokinetic studies, and expert recommendations from the specified period. The review critically appraises evidence on pharmacological therapies, diagnostic technologies, and adjunctive treatment strategies.

Findings:

Key findings include: Pharmacotherapy : Voriconazole remains the cornerstone of therapy due to its superior CNS penetration (CSF:Plasma ratio ~50%). The roles of alternatives like isavuconazole, salvage combination regimens, and novel agents (e.g., olorofim, fosmanogepix) are evolving. Diagnostics : Cutting‐edge tools such as AI‐assisted imaging, metagenomic next‐generation sequencing (mNGS), and MR spectroscopy for trehalose detection show significant potential for enabling earlier and more accurate diagnosis. Adjunctive Strategies : Neurosurgical intervention, immunomodulation, and therapeutic drug monitoring (TDM) are critical for optimizing outcomes. Emerging strategies like nanoparticle‐based drug delivery and host‐directed therapies (e.g., PD‐1/PD‐L1 blockade) offer promising avenues to overcome the blood–brain barrier.

Conclusion:

This review integrates the latest evidence to provide a timely and actionable resource for clinicians. It bridges gaps in existing guidelines by offering a multidisciplinary approach that addresses the complex management of CNS aspergillosis, with particular relevance for high‐risk populations such as COVID‐19 and immunocompromised patients.

2026-09-01·Medical Mycology Case Reports

Man-in-the-barrel syndrome caused by cervical arachnoiditis in refractory coccidioidal meningitis

Article

作者: Ng, Kwan L ; Pelayo Tran, Sophia Marie ; Thompson, George R ; Savenka, Tanya

We report a case of refractory coccidioidal meningitis presenting with bilateral upper-extremity weakness in a man-in-a-barrel distribution caused by cervical arachnoiditis, adhesive bands, and spinal cord compression. The patient was treated sequentially with fluconazole, other azole therapy, liposomal amphotericin B, intrathecal amphotericin B, and olorofim, with only partial disease control. Neuroimaging demonstrated progressive cervical leptomeningeal inflammation, cord tethering, and CT myelography illustrated adhesive arachnoiditis. Surgical lysis of adhesions and placement of a spinal Ommaya reservoir for intrathecal amphotericin delivery above and below the obstructed segment resulted in partial neurologic improvement. This case broadens the differential diagnosis of man-in-a-barrel syndrome to include active fungal meningitis with compressive cervical myelopathy and highlights the role of combined surgical-medical management in complicated fungal arachnoiditis.

项与 Olorofim 相关的新闻（医药）

2026-10-06

·BioSpace

F2G Announces Abstracts Accepted for Oral and Poster Presentation at IDWeek 2026

Phase 3 OASIS Data Accepted for Late-Breaking Oral Abstract Presentation on October 22 MANCHESTER, United Kingdom, Oct. 06, 2026 (GLOBE NEWSWIRE) -- F2G Ltd. today announced abstracts accepted for oral and poster presentation at IDWeek 2026, taking place October 21–24, 2026, at the Walter E. Washington Convention Center in Washington, D.C. The Global Phase 3 OASIS data have been accepted for late-breaking oral abstract presentation building on the positive topline results announced in June. The oral presentation will be accompanied by poster presentations highlighting long-term follow-up data and health-related quality-of-life outcomes in patients with invasive fungal infections who have limited or no treatment options following treatment with olorofim. The OASIS study was a collaboration between F2G and Shionogi & Co.Ltd. Details of the IDWeek 2026 presentations include: Session: Late Breaking Abstracts: Antimicrobials Session Type: Oral Abstract Presentation: (LB-2201.2) Olorofim versus AmBisome ® -Based Standard of Care (SOC) for Treatment of Invasive Aspergillosis (IA) in Patients for Whom a Mold-Active Azole Antifungal (MAA) is Inappropriate or Ineffective (OASIS): A Phase 3, Randomized, Controlled, Adjudicator-Blinded Non-Inferiority (NI) Trial ( NCT05101187 ). Presenter: John H. Rex, MD, Chief Medical Officer, F2G Date and Time: Thursday, October 22, 2026, 10:30 AM – 11:45 AM ET Location: Room 206 Poster Session: Novel Agents (Poster P-4) Poster: Long-Term Follow-Up of Study 32 (S32LTFU): A Retrospective Observational Study to Collect Long-Term Follow-Up Data from Patients in Study 32, an Open-Label Single-Arm Phase IIb Study of Olorofim as Treatment of Invasive Fungal Infections due to Lomentospora prolificans, Scedosporium spp., Aspergillus spp ., and Other Resistant Fungi in Patients Lacking Suitable Alternative Treatment Options ( NCT03583164 ). Presenter: George R. Thompson, MD, Professor of Medicine at the University of California, Davis, School of Medicine Date and Time: Thursday, October 22, 2026, 12:15 PM – 1:30 PM ET Location: Poster Hall B-C Poster Session: Medical Mycology Poster: Health-Related Quality of Life in Patients with Invasive Fungal Infections with Limited or No Treatment Options: An Analysis of the Phase 2b Olorofim Trial Data. Presenter: Belinda Lovelace, PharmD, MS, MJ, Executive Director, Health Economics and Outcomes Research, F2G Date and Time: Saturday, October 24, 2026, 12:15 PM – 1:30 PM ET Location: Poster Hall B-C About the Phase 3 OASIS Study The Phase 3 OASIS (Olorofim Aspergillus Infection Study) trial ( NCT05101187 ) was a global, randomized study that evaluated the efficacy and safety of olorofim versus AmBisome ® followed by standard of care in adult patients with invasive aspergillosis whose infection is either refractory to or unsuitable for azole therapy. OASIS was designed as a non-inferiority study using a non-inferiority margin of 20% comparing outcomes in 225 subjects randomized 2:1 to olorofim or AmBisome-based standard of care. Invasive aspergillosis is a life-threatening fungal infection with limited treatment options due to rising drug resistance and toxicity concerns 1,2,4 . The study’s primary endpoint was all-cause mortality at Day 42, with additional measures of clinical response, safety, and quality of life. About Study 32 Study 32 was a multicenter, open-label, Phase 2b study to evaluate the safety and efficacy of olorofim (formerly F901318) in patients ≥ 18 years of age with probable pulmonary invasive aspergillosis or proven invasive fungal infections due to Lomentospora prolificans , Scedosporium spp., Aspergillus spp., and other resistant fungi with limited or no treatment options. It enrolled patients between June 2018 and September 2022. Enrolled patients received an initial loading dose of 150 mg BID (twice a day) of oral olorofim on day one, and subsequent oral doses of 90 mg BID for up to 90 days. Patients were followed for another four weeks after the end of treatment, while some received extended therapy for as long as thought clinically beneficial. For more information on Study 32, visit ClinicalTrials.gov ( NCT03583164 ). These data enable continued clinical development and support future regulatory and commercial planning. About Olorofim Olorofim (formerly, F901318) is F2G’s leading candidate from the orotomide class and has been studied in a recently completed global Phase 3 trial (“OASIS”, NCT05101187 ). Olorofim is a first-in-class antifungal with a novel mechanism of action, oral dosing, and activity against a wide range of Aspergillus species, including strains that are resistant to currently approved agents 1 . If approved based on the Phase 3 OASIS data, olorofim will be the first novel mechanism agent for invasive aspergillosis in more than 20 years 1,2 . In the U.S., olorofim has received orphan drug status from the FDA for the treatment of invasive aspergillosis, scedosporiosis, invasive scopulariopsis, and coccidioidomycosis[ 5 ]. Olorofim has been granted Qualified Infectious Disease Product (QIDP) designation for several invasive fungal infections, including invasive aspergillosis and coccidioidomycosis 1 . Additionally, olorofim has also received two Breakthrough Therapy designations (BTD) from the FDA 1 . The first BTD was for the treatment of invasive mold infections in patients with limited or no treatment options, including aspergillosis refractory or intolerant to currently available therapy, and infections due to Lomentospora prolificans, Scedosporium and Scopulariopsis species 1 . The second BTD was for the treatment of central nervous system (CNS) coccidioidomycosis refractory or otherwise unable to be treated with standard of care therapy 1 . In Europe, olorofim has been granted orphan designation from the European Medicines Agency for the treatment of invasive aspergillosis, scedosporiosis, and invasive scopulariopsis 1 . Olorofim is an investigational therapy and has not been approved by any regulatory authorities. About F2G F2G is a clinical-stage biopharmaceutical company with operations in the UK, US, and Austria focused on the discovery and development of novel therapies to treat potentially life-threatening invasive fungal infections. F2G has discovered and developed a completely new class of antifungal agents called the orotomides, which selectively target a key enzyme in the pyrimidine biosynthesis pathway, a novel mechanism of action that is distinct from currently marketed antifungal agents. This mechanism provides the orotomides with fungicidal activity against a broad range of rare and resistant fungal mould infections. For more information, please visit: F2G Media Contact: Luke Shiplo LifeSci Communications F2GMedia@lifescicomms.com AmBisome ® is a registered trademark of Gilead Sciences, Inc. All other trademarks are the property of their respective owners. References: Vanbiervliet, Y., Van Nieuwenhuyse, T., Aerts, R. et al. Review of the novel antifungal drug olorofim (F901318). BMC Infect Dis 24 , 1256 (2024). Oliver et al. (2016). F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proceedings of the National Academy of Sciences of the United States of America , 113 (45), 12809–12814. Maertens JA, Thompson GR 3rd, Spec A, et al. Olorofim for the treatment of invasive fungal diseases in patients with few or no therapeutic options: a single-arm, open-label, phase 2b study. Lancet Infect Dis . 2025;25(11):1177-1188. doi:10.1016/S1473-3099(25)00224-5) Centers for Disease Control and Prevention. Data and statistics on aspergillosis . (Accessed June 2026) US Food & Drug Administration. Orphan drug designations and approvals for olorofim. Available at: (Accessed June 2026)

临床3期孤儿药临床2期临床结果合格传染病产品

2026-09-10

·广州市第一人民医院重症医学科

文献分享（247）：中枢神经系统曲霉病：诊断、治疗与多学科管理进展（2026年更新）

摘要背景：中枢神经系统（central nervous system，CNS）曲霉病是一种危及生命的感染，死亡率超过50%，在免疫功能低下患者中尤为突出。尽管治疗和诊断已有进步，但抗真菌药物进入CNS受限、耐药性出现以及诊断延迟仍构成重大挑战。目的：本综合性综述旨在汇总2020年至2026年CNS曲霉病管理的关键进展，并为应对持续存在的挑战提供多学科框架。方法：我们对规定期间内最新的临床资料、药代动力学研究及专家建议进行了综合评价，并批判性评估药物治疗、诊断技术和辅助治疗策略的证据。结果：主要发现包括：药物治疗方面，伏立康唑因CNS渗透性优异（脑脊液∶血浆比约50%）仍是治疗基石；艾沙康唑等替代药物、挽救性联合方案及新型药物（如olorofim、fosmanogepix）的作用正在演变。诊断方面，人工智能（artificial intelligence，AI）辅助影像、宏基因组下一代测序（metagenomic next-generation sequencing，mNGS）及利用磁共振波谱检测海藻糖等前沿工具，显示出实现更早、更准确诊断的显著潜力。辅助策略方面，神经外科干预、免疫调节和治疗药物监测（therapeutic drug monitoring，TDM）对于优化结局至关重要。纳米颗粒药物递送及宿主导向治疗（如PD-1/PD-L1阻断）等新兴策略，为克服血脑屏障提供了有前景的途径。结论：本综述整合最新证据，为临床医师提供及时且可操作的参考。文章以多学科方法弥补现有指南的不足，处理CNS曲霉病复杂的管理问题，尤其适用于COVID-19患者及免疫功能低下患者等高危人群。关键词：抗真菌治疗；血脑屏障；CNS曲霉病；诊断进展；免疫调节；新型抗真菌药物缩略语：CAPA，COVID-19相关肺曲霉病；CEST，化学交换饱和转移；CNS，中枢神经系统；CSF，脑脊液；ELISA，酶联免疫吸附试验；HSCT，造血干细胞移植；LA，乳胶凝集；mNGS，宏基因组下一代测序；MR，磁共振；MRS，磁共振波谱；TDM，治疗药物监测。图像摘要 1｜引言中枢神经系统曲霉病（central nervous system aspergillosis）是一种破坏性真菌感染，死亡率极高，尤其影响免疫功能低下患者。最新流行病学资料显示，尽管治疗有所进步，挑战仍持续存在。特定危险因素包括使用Bruton酪氨酸激酶（Bruton tyrosine kinase，BTK）抑制剂，其与CNS曲霉病发生率升高相关。即使抗真菌治疗取得进展，总体病死率仍约为58%；骨髓移植受者可高达86.7%，CNS或播散性曲霉病病例可高达88.1%。两性霉素B等传统治疗因CNS渗透性差而疗效有限。伏立康唑作为CNS渗透性更好的较新型抗真菌药物，可改善结局，35%的患者获得完全或部分缓解。可实施时，神经外科干预与单纯药物治疗相比可提高生存率。CNS曲霉病虽主要发生于免疫抑制者，但免疫功能正常者亦可发生，提示有必要改进诊断和治疗策略。现行国际指南主要涉及一般侵袭性曲霉病，尚无针对CNS受累的专门建议。本综述通过总结2020—2026年诊断、治疗及多学科管理的关键进展，旨在弥补这一空白。 2｜流行病学与危险因素 2.1｜发病率与趋势造血干细胞移植（hematopoietic stem cell transplantation，HSCT）、实体器官移植、长期中性粒细胞减少或血液系统恶性肿瘤患者发生侵袭性曲霉病（invasive aspergillosis，IA）的比例为0.5%—3.2%，取决于移植类型。约3%的异基因HSCT受者发生CNS受累，移植后中位发病时间为124天。这些人群生存改善可能反而延长发生CNS曲霉病等机会性感染的时间窗口。 2.2｜新出现的高危人群近年来出现了新的高危队列，其中一类是COVID-19相关肺曲霉病（COVID-19-associated pulmonary aspergillosis，CAPA）患者。多篇病例报告和病例系列记录了危重、机械通气患者发生CNS播散。另一个重要因素是免疫检查点抑制剂的使用；此类药物可能反常地破坏免疫稳态，使患者易发生包括CNS曲霉病在内的机会性真菌感染。 2.3｜病原体多样性近期研究日益认识到非烟曲霉物种在IA中的作用，强调准确鉴定和抗真菌药物敏感性试验的重要性。黄曲霉（A. flavus）、土曲霉（A. terreus）、黑曲霉（A. niger）和构巢曲霉（A. nidulans）等对标准抗真菌药物常具有固有耐药性或MIC升高，使治疗更加复杂。黄曲霉是IA中第二常见物种；构巢曲霉常与原发性免疫缺陷及播散性感染有关。烟曲霉复合群中的隐蔽物种，如A. lentulus和A. udagawae，常被误鉴定并可能具有唑类耐药。特异性基因测序、多重PCR及基质辅助激光解吸电离飞行时间质谱（matrix-assisted laser desorption/ionization time-of-flight mass spectrometry，MALDI-TOF MS）等先进技术，对准确鉴定到种至关重要。改进诊断与药敏试验，是优化非烟曲霉感染管理的必要条件。 3｜诊断挑战与进展 3.1｜影像技术 CNS曲霉病在MRI上通常表现为单发或多发环形强化病灶，常伴周围血管源性水肿、弥散受限或出血成分。然而，这些表现缺乏特异性，与其他CNS感染、肿瘤及脱髓鞘病变显著重叠。值得注意的是，脑曲霉病在中性粒细胞减少与非中性粒细胞减少患者中的表现不同。前者通常炎症轻微、病灶边界不清、存在出血性梗死且对比增强稀少；后者更常形成边界清楚的脓肿，伴环形强化和周围水肿，反映免疫介导组织损伤和真菌血管侵袭的差异。灌注加权成像和磁共振波谱（magnetic resonance spectroscopy，MRS）等高级影像技术，有望区分真菌脓肿与细菌性或肿瘤性病灶，但其可及性常限于三级医疗中心。多项研究在真菌感染中发现3.6—3.8 ppm的特征峰，归因于真菌所含二糖海藻糖；芽生菌病和隐球菌病等多种真菌感染均可见该峰。海藻糖峰有助于将真菌脓肿与化脓性脓肿、恶性肿瘤及胶质瘤区分。部分研究在真菌脓肿中发现提示坏死的脂质信号，但海藻糖峰仍是更具特异性的真菌感染标志物。化学交换饱和转移（chemical exchange saturation transfer，CEST）MRI亦显示出检测海藻糖的潜力，并可通过高空间分辨率识别隐球菌瘤并将其与胶质瘤区分。 3.2｜AI辅助诊断 AI在诊断CNS曲霉病及其他真菌感染方面显示出潜力。AI系统可在组织病理图像中区分曲霉与毛霉目，从而可能提高诊断准确性。机器学习算法已用于预测CNS感染患者的死亡及治疗结局，有望支持快速诊断和早期治疗。AI还可增强慢性肺曲霉病CT影像分析，但建立专用影像数据库及协调标注仍具挑战。要充分发挥AI在CNS曲霉病诊断与管理中的潜力，尚需进一步研究。3.3｜CSF与分子诊断脑脊液（cerebrospinal fluid，CSF）诊断在发现CNS曲霉病中发挥关键作用。CSF半乳甘露聚糖检测的特异性较高（94.4%），但敏感性较低（69.0%）。CSF曲霉PCR结果具有前景：研究分别报告75%和100%的敏感性，以及98.3%和93%的特异性。这些PCR试验可能减少疑似病例接受侵入性脑活检的需要。另一项研究中，5例CNS曲霉病患者的CSF-PCR均为阳性，而传统培养均为阴性。CSF标本的酶免疫测定（enzyme immunoassay，EIA）和乳胶凝集试验（latex agglutination，LA）也显示出诊断潜力。CSF β-D-葡聚糖和细胞因子谱等新兴辅助指标可能提高诊断把握度，但尚未成为标准诊疗。 CSF mNGS已成为诊断包括脑曲霉病在内的CNS感染的重要工具。研究显示其检测CSF曲霉物种具有较高敏感性和特异性，一项研究报告敏感性85.71%、特异性84.62%。mNGS可准确识别多种曲霉及共病原体，从而可能指导靶向抗微生物治疗。一项大型前瞻性研究显示，mNGS在不同CNS感染中的效能不同，对脑曲霉病的敏感性为80%。该技术尤其有助于诊断非典型病原体，并理解免疫功能低下及免疫功能正常患者CNS曲霉感染的临床表现。以上结果提示，mNGS有望减少脑活检等侵入性操作；但高成本、可及性有限及污染风险是其应用的主要限制。既往抗真菌治疗对检测敏感性的影响是一项关键临床考虑。经验性治疗，特别是伏立康唑或脂质体两性霉素B，可在采样前抑制真菌细胞壁成分和DNA，因而可能降低CSF半乳甘露聚糖和PCR的敏感性。不过，这一担忧主要由血清及支气管肺泡灌洗液（bronchoalveolar lavage，BAL）检测资料外推而来，CSF特异性证据仍有限。此问题对常接受预防或经验性治疗的中性粒细胞减少患者尤为相关。因此，对已使用抗真菌药物者的CSF阴性结果应谨慎解释，并应尽可能在开始治疗前采样。表1汇总了已发表的CSF诊断试验性能，包括敏感性、特异性和研究人群。将弥散加权MRI与CSF检测等方法联合，可能提高CNS曲霉病的早期检出率。CSF诊断，特别是PCR和半乳甘露聚糖检测，是诊断CNS曲霉病的有价值工具，尤其适用于传统方法失败时。表1 诊断CNS曲霉病的CSF生物标志物及分子诊断性能特征检测敏感性特异性研究人群主要参考研究 CSF半乳甘露聚糖（EIA） 69.0% 94.4% 混合免疫功能低下人群 Komorowski等 CSF曲霉PCR（巢式） 100% 93% 免疫功能低下（HSCT、血液系统疾病） Reinwald等 CSF曲霉PCR（实时） 75% 98.3% 血液系统恶性肿瘤 Imbert等 CSF mNGS 85.7% 84.6% 疑似CNS感染 Xing等 CSF β-D-葡聚糖不定中等混合人群 Mikulska等注：本表汇总疑似CNS曲霉病患者CSF半乳甘露聚糖（GM）EIA、曲霉PCR（巢式和实时）、mNGS及CSF β-D-葡聚糖（BDG）已发表的敏感性和特异性。研究主要纳入免疫功能低下人群（如HSCT受者和血液系统恶性肿瘤患者）。关键限制是既往抗真菌治疗会显著降低所有CSF检测的敏感性，尤其是GM和PCR；因此，接受经验性或预防性抗真菌药物的患者不能因结果阴性而排除疾病。多数试验特异性较高，阳性结果具有确诊价值。mNGS还可检出非曲霉霉菌和共病原体。 4｜抗真菌治疗：药代动力学与临床资料 4.1｜CNS渗透与药理学抗真菌药物治疗CNS曲霉病的疗效，很大程度上取决于其穿过血脑屏障并在CSF与脑实质中达到治疗浓度的能力（表2）。测量CNS药物浓度仍具挑战。CSF浓度最容易获得，但可能无法准确反映脑实质浓度，尤其是伏立康唑等亲脂性药物；其脑组织渗透良好，却可表现为较低CSF浓度。同样，两性霉素B及其脂质制剂在CSF中分布有限，但脑实质浓度较高，这可能解释其在CSF渗透不佳时仍具有临床疗效。除外科切除或尸检外，脑组织采样通常不可行。微透析和PET成像等新兴技术未来可能提供更精确的药代动力学资料。临床医师应认识到，CSF谷浓度可能低估感染部位的治疗效果。表2 CNS曲霉病抗真菌药物的药代动力学与关键考量药物 CSF∶血浆比一线用药？关键考量伏立康唑约50% 是需要TDM；CYP450代谢；视觉和肝脏不良反应艾沙康唑 30%—50% 替代药物 CNS不良反应较少；半衰期长；通常无需TDM 脂质体两性霉素B < 5% 辅助药物 CNS渗透差；肾毒性泊沙康唑约25% 挽救治疗 CNS渗透资料有限；可用于联合方案 Olorofim 实验性否 CNS生物利用度前景良好；对唑类耐药菌株有活性注：比较CNS曲霉病所用抗真菌药物的CSF-血浆渗透比、一线推荐及关键药理学考量。数据凸显伏立康唑因CNS渗透较好（约50%）而成为首选药物；olorofim等实验性治疗对耐药菌株显示潜力。缩略语：CYP450，细胞色素P450酶系统；TDM，治疗药物监测。 4.2｜治疗流程 CNS曲霉病的治疗结合抗真菌药物、存在指征时的外科干预，以及免疫受损宿主的免疫调节（表3）。伏立康唑因CNS渗透性优异并具有生存获益，仍为一线药物。艾沙康唑药物相互作用较少，是较安全的替代选择；脂质体两性霉素B用于唑类难治或存在禁忌者。疾病进展时可考虑挽救性联合方案，如伏立康唑联合棘白菌素或两性霉素B，但证据主要来自回顾性研究。虽然近期一项前瞻性随机临床试验评价了联合治疗，但在无难治性疾病时仍不建议常规联合。ESCAI研究最新资料进一步支持艾沙康唑作为安全有效的替代药物，其相互作用少于伏立康唑。辅助措施包括对> 2.5 cm脓肿行神经外科清创，以及免疫调节（如慢性肉芽肿病使用干扰素-γ），对于降低真菌负荷和改善结局至关重要。可行时外科切除与生存改善有关，但总体死亡率仍高，合并脑积水者尤甚。TDM对于优化伏立康唑和泊沙康唑浓度非常重要，CNS内亚治疗浓度可导致治疗失败。疗程通常较长（6—12个月或更久），并依据临床反应、影像学病灶消退及宿主免疫状态进行个体化调整。表3 CNS曲霉病治疗流程：一线、挽救及辅助策略 1. 一线抗真菌治疗 A. 伏立康唑（首选一线） • 负荷剂量：6 mg/kg IV，每12 h一次，共24 h。 • 维持剂量：4 mg/kg IV，每12 h一次（若口服吸收可靠，可用200 mg PO，每12 h一次）。 • TDM：目标谷浓度2—5 mg/L（根据CNS渗透调整）。 • 关键考量：监测肝毒性、神经毒性和视觉障碍；注意CYP450相互作用（如利福平降低浓度；SSRIs增加毒性）。 B. 艾沙康唑（替代一线） • 负荷剂量：200 mg IV/PO，每8 h一次，共48 h。 • 维持剂量：200 mg IV/PO，每日一次。 • 优点：药物相互作用较少，耐受性优于伏立康唑。 • TDM：不常规开展，但CNS疾病可考虑（目标谷浓度> 2 mg/L）。 C. 脂质体两性霉素B（L-AMB；唑类禁忌时） • 剂量：5 mg/kg IV，每日一次。 • 局限：CNS渗透差（< 5%）；需监测肾毒性。 2. 挽救治疗（难治性/进展性疾病） A. 联合治疗 • 伏立康唑 + L-AMB：具有协同潜力；高质量资料有限，但临床常用。 • 伏立康唑 + 棘白菌素（如卡泊芬净）：病例报告提示获益，但棘白菌素CNS渗透极低。 B. 替代唑类 • 泊沙康唑：300 mg PO/IV，每日一次（首选缓释片）。TDM目标谷浓度> 1.25 mg/L。 • 高剂量艾沙康唑：200 mg，每12 h一次（研究性用法，资料有限）。 C. 实验性药物 • Olorofim：可通过同情用药用于唑类耐药菌株（如TR34/L98H）；尚未获FDA批准。 3. 辅助干预 A. 神经外科清创/引流 • 指征：脓肿> 2.5 cm、占位效应或梗阻性脑积水。 • 目标：降低真菌负荷并改善药物渗透。 B. 免疫调节（免疫功能低下宿主） • 粒细胞输注：用于长期中性粒细胞减少。 • 干扰素-γ（IFN-γ）：100—150 mcg SC，每周3次（如慢性肉芽肿病）。 C. 糖皮质激素 • 谨慎使用：仅用于严重水肿/占位效应（如地塞米松4—6 mg/day）。 4. 监测与疗程 A. 治疗药物监测（TDM） • 伏立康唑/泊沙康唑：必须监测（每周测谷浓度直至稳定）。 • 艾沙康唑：CNS疾病中考虑监测。 B. 疗程 • 最短：6—12个月（或直至影像学病灶消退且免疫恢复）。 • 慢性抑制：持续免疫功能低下宿主可能需终身使用唑类。 C. 随访影像 • 脑MRI：2—4周时复查，之后每3个月一次，直至稳定。 5. 特殊考量 • 抗真菌耐药检测：治疗失败时开展（如用EUCAST肉汤微量稀释法检测唑类耐药）。 • HIV/免疫功能低下宿主：优化ART或减轻免疫抑制（如移植患者逐渐减量糖皮质激素）。 • 儿科考量：儿童常需更高的伏立康唑体重剂量（如7—9 mg/kg IV q12h）。因药代动力学变异及肝毒性、视觉障碍风险增加，应密切监测药物浓度。注：本流程将抗真菌治疗、神经外科干预和免疫调节相结合。伏立康唑仍为一线药物，需调整剂量并开展TDM（目标谷浓度2—5 mg/L）以优化CNS渗透。挽救方案包括联合治疗（如伏立康唑 + 脂质体两性霉素B）及研究性药物（如olorofim）。辅助措施强调对> 2.5 cm脓肿行外科清创，以及免疫功能低下宿主使用IFN-γ。疗程通常为6—12个月，并由影像学和免疫恢复情况指导。缩略语：ART，抗逆转录病毒治疗；L-AMB，脂质体两性霉素B。 5｜未来方向 5.1｜新型治疗药物三唑类耐药曲霉菌株出现，加之现有抗真菌药物CNS渗透有限，推动了新型药物研发。 ·Olorofim：首创类别的二氢乳清酸脱氢酶（dihydroorotate dehydrogenase，DHODH）抑制剂，对包括唑类耐药菌株在内的烟曲霉具有强效活性。与三唑类不同，它靶向嘧啶生物合成，降低交叉耐药风险。目前一项2期试验正在评估olorofim治疗包括CNS疾病在内的侵袭性霉菌感染，初步结果提示安全性和疗效良好。侵袭性曲霉病小鼠模型中，无论中性粒细胞减少或慢性肉芽肿病小鼠，其生存率均显著改善，真菌负荷降低。该药独特的作用机制可能有助于应对抗真菌药物耐药，并为难治性感染提供新选择。临床资料虽有限，但正在开展的人体试验将进一步评价其疗效和安全性。 ·Fosmanogepix（APX001）：manogepix的前药，是一种新型广谱抗真菌药物，目前正开展侵袭性真菌感染2期临床试验。其对多种念珠菌和曲霉物种（包括耐药菌株）以及赛多孢霉和多育节荚孢（Lomentospora prolificans）等罕见霉菌均有强效活性。Manogepix抑制参与糖基磷脂酰肌醇（glycosylphosphatidylinositol，GPI）锚定生物合成的真菌酶Gwt1。体内外研究显示其对广泛真菌病原体有效，包括对其他药物类别耐药者。临床试验显示其口服生物利用度高、药物相互作用谱良好且组织分布广，使其成为侵袭性真菌感染的有吸引力选择。后续研究将进一步评估其治疗难治性真菌感染的潜力。 5.2｜药物递送创新克服血脑屏障仍是CNS曲霉病治疗的主要挑战。新兴策略包括： ·纳米颗粒/脂质体制剂：近期研究凸显脂质和聚合物纳米颗粒系统在改善CNS药物递送方面的潜力。脂质体与聚合物纳米颗粒可绕过外排泵并提高药物稳定性，从而增强CNS递送。这类纳米载体适合递送溶解度差、毒性高的广谱抗真菌药两性霉素B（amphotericin B，AmB）。脂质体AmB等脂质制剂已显示毒性降低、疗效改善。聚己内酯等聚合物制成的纳米颗粒也显示出递送AmB的潜力，具有较高包封率，且对利什曼原虫的活性优于游离AmB。这些先进递送系统有望优化药物靶向、稳定性和释放模式，进而改善CNS疾病治疗结局。 ·鞘内抗真菌药物给药：鞘内给药在难治性CNS感染中显示出潜力，但已有化学性脑膜炎、蛛网膜炎和神经毒性等严重毒性报告。因此，美国感染病学会（Infectious Diseases Society of America，IDSA）曲霉病指南明确不建议常规鞘内治疗。在所有系统治疗均失败的高度选择性挽救病例中，也仅应在专科中心严密监测下实施。静脉给药失败后，连续鞘内应用脂质体两性霉素B曾成功治疗一例难治性新型隐球菌脑炎。 5.3｜宿主导向治疗免疫调节是一项有前景的辅助策略，尤其适用于移植后或血液系统恶性肿瘤等免疫抑制患者。 ·检查点抑制剂（PD-1/PD-L1阻断）：近期研究提示免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）可能增强抗真菌免疫。在肺曲霉病和毛霉病小鼠模型中，PD-1/PD-L1阻断可改善生存、降低真菌负荷并增加促炎细胞因子；与卡泊芬净联合呈协同效应。但ICI也可能造成免疫失调，并增加单核细胞增生李斯特菌等机会性感染风险。临床前研究和病例报告支持ICIs作为真菌感染辅助免疫增强策略，但知识空白仍然显著。未来需建立更精细的动物模型，并研究联合治疗、潜在耐药及免疫微环境影响，以明确ICIs在医学真菌学中的最佳应用。 ·个体化免疫治疗：CARD9缺陷是一种使个体易发生真菌感染的遗传状态，尤其与肺外曲霉和念珠菌感染有关。该缺陷损害促炎细胞因子和中性粒细胞募集趋化因子的产生，即使外周血中性粒细胞计数正常，感染部位的中性粒细胞积聚仍不足。CARD9蛋白在先天免疫信号传导、特别是对真菌病原体的应答中发挥关键作用。CARD9突变患者的Th17细胞减少，而Th17对抗真菌免疫十分重要。宿主针对曲霉的防御涉及复杂细胞因子网络：TNF启动先天反应；Th1相关细胞因子IL-12、IL-18和IFN-γ发挥保护作用；Th2细胞因子IL-4和IL-10则促进感染进展。宿主基因组分析（如CARD9突变）及细胞因子调节（如IFN-γ、GM-CSF）的进步，可能指导个体化治疗。 6｜结论 CNS曲霉病仍是一种罕见但破坏性极强、死亡率持续较高的疾病。2020—2026年间，AI辅助诊断、分子检测及抗真菌药物治疗均取得显著进展。将影像、靶向治疗、外科干预和免疫调节相结合的个体化多学科方案，为改善患者结局提供了最佳机会。文献来源：Mansour MA, Wahid M, El Molla MAS, Helmy MH, Adel TM, Mostafa HN. Central Nervous System Aspergillosis: Advances in Diagnosis, Therapeutics, and Multidisciplinary Management (2026 Update). Mycoses. 2026 Sep;69(9):e70214. doi: 10.1111/myc.70214. PMID: 42703182; PMCID: PMC13547976. 文献翻译：杨智排版编辑：刘威审核：曾军、杨智

临床研究申请上市临床申请

2026-09-01

·BioSpace

F2G Announces Posters Accepted for Presentation at Upcoming Medical Meetings

MANCHESTER, United Kingdom, Sept. 01, 2026 (GLOBE NEWSWIRE) -- F2G Ltd., today announced abstracts accepted for presentation at the MSGERC 2026 Biennial Meeting in September and ISPOR Europe 2026 in November. Details of Abstract Presentations Below: MSGERC 2026 Biennial Meeting (September 9 – 11, 2026) Poster Patient-Reported Health Status in People Living with Disseminated Coccidioidomycosis Who Have Limited or No Treatment Options Presenter Fariba Donovan, MD, PhD, FIDSA, FACP, Valley Fever Center for Excellence, Division of Infectious Diseases, Department of Medicine, University of Arizona Poster Retrospective Analysis estimating Independent Reviewer’s Counterfactual Outcome in Patients from a Phase IIB Salvage Study (S32-NCT03583164) with Prolonged Prior History of Invasive Fungal Infection Presenter Daniela Zinzi, Vice President, Clinical R&D, F2G Date and Time Wednesday September 9 th 6:30pm – 7:30pm MT Thursday September 10 th 5:45pm – 7:00pm MT Location Omni Interlocken Hotel, Denver, Colorado ISPOR Europe 2026 (November 8 – 11, 2026) Poster Health-Related Quality of Life in Patients with Rare Mold Infections: EQ-5D-5L Results from a Phase IIb Trial Evaluating Olorofim in Adults with Invasive Fungal Infections and Limited or No Treatment Options Presenter Craig I. Coleman, PharmD, Professor of Pharmacy Practice, University of Connecticut, School of Pharmacy and Pharmaceutical Sciences Poster Session Poster Session 4 Poster Code: CO149 Date and Time Tuesday, 10 November, 16:00-19:00 CET Discussion Period 18:00-19:00 CET Location Austria Center Vienna, Vienna, Austria About F2G F2G is a clinical-stage biopharmaceutical company with operations in the UK, US, and Austria focused on the discovery and development of novel therapies to treat potentially life-threatening invasive fungal infections. F2G has discovered and developed a completely new class of antifungal agents called the orotomides, which through research have shown to selectively target a key enzyme in the pyrimidine biosynthesis pathway, a novel mechanism of action that is distinct from currently marketed antifungal agents. It is believed that this mechanism provides the orotomides with fungicidal activity against a broad range of rare and resistant fungal mould infections. Orotomides are investigational agents, safety and efficacy have not been established and have not been approved by regulatory authorities. For more information, please visit: F2G Media Contact: Luke Shiplo LifeSci Communications F2GMedia@lifescicomms.com

100 项与 Olorofim 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D12505	-	-	DB15245

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
侵袭性真菌感染	申请上市	美国	F2G Ltd.	-
侵袭性曲霉菌病	临床3期	美国	F2G Ltd.	2022-04-29
侵袭性曲霉菌病	临床3期	中国	F2G Ltd.	2022-04-29
侵袭性曲霉菌病	临床3期	日本	F2G Ltd.	2022-04-29
侵袭性曲霉菌病	临床3期	澳大利亚	F2G Ltd.	2022-04-29
侵袭性曲霉菌病	临床3期	比利时	F2G Ltd.	2022-04-29
侵袭性曲霉菌病	临床3期	巴西	F2G Ltd.	2022-04-29
侵袭性曲霉菌病	临床3期	加拿大	F2G Ltd.	2022-04-29
侵袭性曲霉菌病	临床3期	法国	F2G Ltd.	2022-04-29
侵袭性曲霉菌病	临床3期	德国	F2G Ltd.	2022-04-29

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临床结果

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分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03583164 (Pubmed \| Ann Intern Med)	临床2期	球孢子菌病	41	Olorofim	膚膚衊選遞鹹顧壓顧窪(艱憲艱膚構鑰淵蓋夢觸) = 簾艱願獵糧醖選齋鹹選選鬱鬱艱醖鑰鏇範願觸 (構餘遞憲鬱簾餘糧醖窪, 59.7 ~ 87.6) 更多	积极	2026-09-01
NCT02730442 \| NCT04171739 \| NCT03340597 \| NCT02737371 \| NCT03583164 \| NCT02680808 (Pubmed \| Antimicrob Agents Chemother)	临床1期	-	96	Olorofim	築獵觸選鬱獵製鏇製廠(鬱衊糧齋壓鹹製壓顧襯) = 築顧鏇網憲蓋鏇蓋築鹹獵鬱顧願簾膚鹹蓋齋蓋 (壓壓構範觸網艱鹽壓廠 ) 更多	积极	2026-06-03
NCT03583164 (Pubmed \| J Antimicrob Chemother)	临床2期	侵袭性真菌感染	105	Olorofim with concomitant azoles	鏇廠餘襯憲醖廠簾網壓(遞網夢範糧鬱鑰範襯鑰) = 淵選憲鬱鹽繭願顧顧艱艱構夢鹽鹹製齋積壓艱 (鹽鹽鬱繭範願膚鬱願鑰 )	积极	2026-03-04
NCT03583164 (Pubmed \| J Antimicrob Chemother)	临床2期	侵袭性真菌感染	105	Olorofim without concomitant azoles	簾憲膚壓鹽鑰鹹觸窪蓋(網齋襯蓋淵構膚衊糧膚) = 積壓夢鹹齋蓋鑰顧製網襯遞鏇願憲積範觸餘壓 (膚願製構齋蓋夢網廠鏇 )	积极	2026-03-04
NCT03583164 (Pubmed \| Lancet Infect Dis)	临床2期	侵袭性真菌感染	204	Olorofim	鏇憲顧夢築艱醖壓餘鑰(鹽製遞膚夢衊願襯鹽壓) = 網襯遞願艱鹹醖遞範襯簾範積鹹範鹽簾醖夢遞 (蓋餘繭夢鬱選襯鹽齋齋 ) 更多	积极	2025-11-01
EBMT2025	N/A	镰刀菌病	5	Liposomal amphotericin B	襯遞鏇淵餘鹹餘壓鏇鏇(鹽鹹夢簾製構衊醖鏇製) = 鹽艱顧繭齋網獵積鹹範願構壓窪顧糧糧窪齋選 (築衊糧繭觸構糧膚餘製 )	不佳	2025-03-30
NCT03583164 (Study 32 \| FORMULA-OLS, CTgov)	临床2期	侵袭性真菌感染	203	Olorofim	餘網繭壓廠遞鬱醖蓋鏇 = 鏇鬱簾壓糧繭願壓積鏇繭鏇範衊繭蓋襯顧淵窪 (鬱艱夢築鹹鹽製簾鑰鹽, 築鹽鏇選製蓋壓廠範鏇 ~ 蓋廠膚齋鹽顧鹽繭窪選) 更多	-	2024-07-10
NCT03583164 (Study 32, GlobeNewswire) 人工标引	临床2期	侵袭性真菌感染	203	Olorofim	築願觸襯製獵憲齋願構(鑰鹹醖觸膚願餘範築窪) = 鹹鏇獵齋鹹窪淵衊窪壓鑰網簾鏇構範齋齋齋鬱 (構顧鏇積鹽獵積鬱蓋遞 ) 更多	积极	2023-10-31
NCT03583164 (Study 32 \| FORMULA-OLS, GlobeNewswire) 人工标引	临床2期	侵袭性真菌感染	100	Olorofim	鏇蓋齋構膚蓋選蓋襯鹽(醖糧選鹹鏇遞積衊顧鏇) = 餘蓋廠鹹鬱範淵願製範簾廠遞膚積夢鑰襯顧選 (鹹艱鏇夢蓋廠糧願窪構 ) 更多	积极	2022-10-21