A Phase III Open-Label Multi-Center Study of the Pharmacokinetics, Safety, and Efficacy of Coagadex in the Treatment of Adults With Acquired Factor X Deficiency Associated With Light Chain Amyloidosis

The purpose of this study is to evaluate the efficacy and safety of Coagadex in treating active bleeds and to manage peri-operative bleeding in participants with acquired factor X deficiency associated with AL amyloidosis.

开始日期2025-12-01

申办/合作机构

Kedrion SpA

NCT03161626

/ CompletedN/A

A Multicenter, Post-Marketing Registry Study of COAGADEX® in the Peri-operative Management of Patients With Moderate or Severe Hereditary Factor X Deficiency Undergoing Major Surgery

This is a non-interventional, multicenter, post-marketing registry study in three patients with moderate or severe hereditary FX deficiency, to assess Coagadex administered peri-operatively for hemostatic cover in major surgery during routine post-marketing use.

开始日期2018-02-27

申办/合作机构

Bio Products Laboratory USA, Inc.

NCT01721681

/ Completed临床3期

A Phase III Open, Multicentre Study to Investigate the Safety, Pharmacokinetics and Efficacy of BPL's High Purity Factor X in the Prophylaxis of Bleeding in Factor X Deficient Children Under the Age of 12 Years

The primary objective of the study is to assess the efficacy of FACTOR X in the prevention of bleeding when given as routine prophylaxis over 12 months.
The secondary objectives of the study are:
1. To assess the pharmacokinetics of FACTOR X after a single dose of 50 IU/kg.
2. To assess the safety of FACTOR X when given as routine prophylaxis over 6 months (26 weeks).

开始日期2015-04-01

申办/合作机构

Bio Products Laboratory USA, Inc.

100 项与人凝血因子X(Bio Products Laboratory) 相关的临床结果

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100 项与人凝血因子X(Bio Products Laboratory) 相关的转化医学

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100 项与人凝血因子X(Bio Products Laboratory) 相关的专利（医药）

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项与人凝血因子X(Bio Products Laboratory) 相关的文献（医药）

2023-09-01·Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis

The safety of the combination therapy of recombinant factor VIIa and plasma-derived factor VIIa and factor X for refractory hemorrhage in acquired hemophilia A

Article

作者: Hino, Masayuki ; Sakatoku, Kazuki ; Nakashima, Yasuhiro ; Nishimoto, Mitsutaka ; Koh, Hideo ; Nakamae, Hirohisa ; Okamura, Hiroshi ; Nanno, Satoru ; Okayama, Yusuke ; Bingo, Masato

Acquired hemophilia A (AHA) is a rare, life-threatening hemorrhagic disease caused by autoantibodies against factor VIII (FVIII), and bypassing agents (BPA) are used to control bleeding. However, some cases need a change of BPA or BPAs given sequentially or in combination for refractory bleeding. A 71-year-old man was admitted with subcutaneous hemorrhage. Laboratory investigations showed prolongation of activated partial thromboplastin time (APTT) and low-coagulation FVIII activity and FVIII inhibitor; we, therefore, diagnosed AHA. He was treated with recombinant factor VIIa (rFVIIa) BPA and prednisolone. However, his symptoms did not improve sufficiently, thus we switched BPA to activated prothrombin complex concentrate. Unfortunately, this was not effective and he suffered hemorrhagic shock. Therefore, we selected rFVIIa, with plasma-derived FVIIa and factor X (pd-FVIIa/FX) as combination therapy, and hemostasis was achieved without thrombosis. This case suggests that the combination of rFVIIa and pd-FVIIa/FX short-term can be well tolerated for refractory hemorrhage in AHA.

2022-07-01·HAEMOPHILIA2区 · 医学

A review of the pharmacokinetics, efficacy and safety of high‐purity factor X for the prophylactic treatment of hereditary factor X deficiency

2区 · 医学

Review

作者: Leavitt, Andrew D. ; Payne, Jeanette ; Batsuli, Glaivy ; Mathias, Mary ; McGuinn, Catherine E.

Abstract:

Introduction:

Hereditary factor X (FX) deficiency (FXD) is a rare autosomal recessive bleeding disorder. Plasma‐derived FX (pdFX) is a high‐purity FX concentrate approved in the United States and Europe for the treatment and prophylaxis of bleeding episodes and for peri‐operative management in patients with hereditary FXD (HFXD).

Aim:

To review pharmacokinetic dosing, efficacy, and safety data for pdFX as routine prophylaxis for HFXD.

Methods:

Summary of the published pharmacokinetic and safety data from TEN01, TEN02, TEN05, and real‐world publications of pdFX for prophylaxis.

Results:

Pharmacokinetic modelling data from the phase 3 TEN01 study supported administration of pdFX 25 IU/kg twice weekly for routine prophylaxis in adolescents/adults (aged ≥12 years). Results from nine paediatric patients in the phase 3 TEN02 study and eight adolescents/adults (aged ≥12 years) in the retrospective data‐collection TEN05 study, along with real‐world evidence, showed that routine prophylaxis with pdFX ≈40 IU/kg twice weekly in patients aged <12 years and pdFX ≈25 IU/kg twice weekly in patients aged ≥12 years was effective in bleeding prevention.

Conclusions:

pdFX was well tolerated in clinical studies, with no new safety signals identified during routine prophylactic use. Based on current evidence, it is recommended that routine prophylaxis with pdFX be initiated at 25 IU/kg twice weekly in adults/adolescents ≥12 years of age, and at a dosage of 40 IU/kg twice weekly in children <12 years of age. Thereafter, FX levels should be closely monitored, and dosages should be adjusted according to clinical response and to maintain trough levels ≥5 IU/dl.

2022-01-01·SAGE open medical case reports

A case report of congenital factor X deficiency in an adult patient

作者: Aljarah, Nasser ; AL-Ansari, Rehab Y ; Woodman, Alexander ; Alofi, Ghufran

Factor X deficiency is one of the rarest coagulation disorders representing 10% of all rare bleeding diseases with a frequency of 1:1,000,000. A 39-year-old male patient with no previous medical conditions was admitted to the hospital with a left carpal ganglion for surgical excision. Routine preoperative laboratory examination revealed a high international normalized ratio of 5.4 IU (0.8–1.1) and a prothrombin time of 72.2 s (10.9–13.6), with an isolated factor X level of less than 5%. Genetic testing for congenital factor X deficiency identified a homozygous mutation c.271 > A (p.Glu91). Vitamin K supplementation did not improve his international normalized ratio or increase factor X levels; hence, surgery was delayed. The patient was re-hospitalized to remove a wisdom tooth, during which fresh frozen plasma was administered. An allergic reaction complicated this procedure in the form of a rash on the body. As a result, the tooth was removed without active bleeding. This report presents a unique factor X deficiency case with limited treatment options to improve factor X levels after failed vitamin K administration and an allergic reaction to fresh frozen plasma. A physician’s observation and ongoing follow-up were the only reasonable approaches in treating the patient with mild to moderate factor X deficiency due to lack of prothrombin complex concentrates or factor X replacement at the center at the time.

项与人凝血因子X(Bio Products Laboratory) 相关的新闻（医药）

2025-07-29

·PRNewswire

Kedrion Biopharma Receives Orphan Drug Designation for COAGADEX® for Acquired Factor X Deficiency (aFXD) and Starts Clinical Trial to Evaluate Efficacy and Safety

FORT LEE, N.J., July 29, 2025 /PRNewswire/ -- Kedrion Biopharma is proud to announce that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to Coagulation Factor X human (tradename COAGADEX) for the treatment of acquired Factor X Deficiency (aFXD), a rare hematologic disorder with a global prevalence of < 1 in 1,000,000 people¹. In addition, the FDA has provided a "Study may proceed letter" for the initiation of a clinical trial to evaluate the efficacy and safety of Coagadex in treating active bleeding episodes and managing peri-operative bleeding in patients with aFXD associated with AL amyloidosis. COAGADEX is a plasma-derived human coagulation factor concentrate. It is currently approved in 38 countries for treatment of Hereditary Factor X deficiency in adults and children. It is specifically indicated for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes and perioperative management of bleeding in patients with mild, moderate, and severe hereditary Factor X deficiency. Important Safety Information for COAGADEX is provided at the end of this release. "Receiving orphan drug designation for COAGADEX in aFXD is a significant milestone for Kedrion," said Bob Rossilli, Chief Commercial Officer and US General Manager at Kedrion Biopharma. "This designation underscores the unmet need for therapies to treat aFXD and the potential of COAGADEX in this space. Kedrion is committed to advancing care for patients with rare conditions, and we look forward to seeing the results of this clinical study." The most common cause of acquired FX (aFX) deficiency is AL amyloidosis. —Amyloid fibrils bind to and reduce circulating Factor X levels, shortening its half-life and significantly increasing the risk of bleeding. A clinical trial aimed at addressing this treatment gap has commenced to evaluate COAGADEX's ability to restore hemostasis in this vulnerable population, and patient recruitment is currently ongoing. The first trial site is being activated and will focus on both moderate and severe forms of aFXD, defined by Factor X coagulant activity (FX:C) levels below 50% of normal. "This study represents a pivotal step in evaluating the therapeutic potential of COAGADEX beyond HFXD." said Nisha Jain, VP Global Clinical Development and Strategy. "By targeting aFXD in patients with light chain amyloidosis, we are advancing our commitment to precision treatment in rare bleeding disorders. The orphan drug designation and the FDA's green light for this trial validates the urgency and potential of our work." For more information about the trial, visit Study Details | A Study Investigating Coagadex in the Treatment AFXD Associated With AL Amyloidosis | ClinicalTrials.gov About COAGADEX COAGADEX is currently approved for the treatment and perioperative management of bleeding episodes in patients with hereditary Factor X deficiency. It is manufactured by Bio Products Laboratory Limited and distributed in the United States by Kedrion Biopharma Inc. For more information about COAGADEX visit: Kedrion Biopharma is a biopharmaceutical company that collects and fractionates blood plasma to produce and distribute worldwide plasma-derived therapies for use in treating and preventing rare and debilitating conditions like Coagulation and Neurological Disorders, Primary Immunodeficiencies, and Rh sensitization, which can lead to Hemolytic Disease of the Fetus and Newborn. Kedrion is a global player in plasma derivatives and rare disease medicines, employing over 5,200 people worldwide. ¹Orphanet: Prevalence_of_rare_diseases_by_decreasing_prevalence_or_cases.pdf Important Safety Information for COAGADEX Allergic type hypersensitivity reactions, including anaphylaxis, are possible with COAGADEX. If symptoms occur, patients should discontinue use of the product immediately, contact their physician, and administer appropriate treatment. The formation of neutralizing antibodies (inhibitors) to factor X is a possible complication in the management of individuals with factor X deficiency. Carefully monitor patients taking COAGADEX for the development of inhibitors by appropriate clinical observations and laboratory tests. COAGADEX is made from human plasma and may contain infectious agents, e.g. viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases, vCJD or CJD, have been associated with the use of COAGADEX. In clinical studies, the most common adverse reactions (frequency ≥5% of subjects) with COAGADEX were infusion site erythema, infusion site pain, fatigue and back pain. Media Contact: Jennifer Donegan, US Communications Lead [email protected] SOURCE Kedrion Biopharma WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

孤儿药上市批准临床研究

2025-06-09

·药智网

靶向MYC的抗肿瘤药物研究进展

骨髓细胞瘤病毒癌基因同源物（myelocytomatosis viral oncogene homolog，MYC）是人类癌症中最常失调的驱动基因之一，其表达失调与多种肿瘤的发生和发展密切相关，其编码的MYC蛋白主要作为转录因子发挥作用，参与调节多种细胞过程，包括细胞生长、分裂、分化、代谢和凋亡，因此，靶向MYC蛋白是治疗肿瘤的潜在策略。然而，由于MYC缺乏合适的结合口袋与小分子化合物结合，MYC一直被认为是“不可成药”靶点。概述MYC的结构与功能，汇总分析现阶段正在研发的直接或间接靶向MYC的抗肿瘤药物，为靶向MYC的药物开发提供参考。癌症是全球性重大公共卫生问题，也是我国第三大死因 [1] 。癌症发生常伴随基因表达失调。骨髓细胞瘤病毒癌基因同源物（myelocytomatosis viral oncogene homolog， MYC）是人类癌症中常见的突变及过表达基因，其编码蛋白作为转录因子，调控约15%的基因组转录，在细胞生长、周期、分化、凋亡、血管生成、代谢、DNA修复、蛋白质翻译、免疫反应及干细胞形成等过程中发挥关键作用 [2] 。 MYC 表达失调见于多种癌症，是近 70% 恶性肿瘤的驱动基因 [3]。研究表明，MYC异常表达促进肿瘤发展，与肿瘤“标志性”特征相关。MYC驱动的肿瘤细胞通常依赖其表达维持生长，抑制MYC信号传导可使肿瘤持续消退[4-5]。因此，抑制MYC是潜在的癌症治疗策略。然而，直接靶向MYC的药物研发困难重重：其一，MYC广泛参与机体正常生理功能，直接靶向易引发机体毒性；其二，MYC蛋白缺乏合适的药物结合口袋，低分子量抑制剂难以与之高亲和力结合；此外，MYC与MYC相关因子X（MYC-associatedfactorX，MAX）亲和力高，且MYC家族成员存在部分功能冗余，加之MYC的核定位特性，都给设计有效的MYC抑制剂带来长期阻碍[6]。目前，多数针对MYC的药物仍处于研究阶段。临床在研药物主要通过间接途径靶向MYC，如阻断MYC-MAX异二聚体化、稳定MAX-MAX同二聚体化、抑制MYC-MAX与DNA结合来发挥作用。近期研究还出现了降解MYC和表观遗传调控等方法，用于抑制MYC驱动的肿瘤。这些创新策略拓展了对MYC通路调控的认知，为肿瘤治疗开辟了新方向。本文将阐述MYC的概念与作用，探讨不同靶向MYC药物的作用机制，以期为靶向MYC药物的研发提供参考。MYC的结构与功能MYC癌基因家族由C-MYC（定位于8q24）、N-MYC（定位于2p24）和L-MYC（定位于1p34）组成，属于碱性-螺旋-环-螺旋-亮氨酸拉链（basic-helix-loop-helix-leucine zipper，b-HLH-LZ）转录调节因子超家族[7-8]。这些基因分别编码C-MYC，N-MYC和L-MYC蛋白。其中，C-MYC在机体内广泛表达，N-MYC主要在神经和神经内分泌组织表达，L-MYC主要在肺组织表达[9]。这3种蛋白质均含有多个高度保守的片段，称为MYC同源盒（MYC box，MB）。C-MYC和N-MYC中有6个MB，分别为MB0，MBI，MBII，MBIIIa，MBIIIb和MBIV，而L-MYC缺少MBIIIa；MB0，MBI和MBII位于MYC蛋白的反式激活域内，其余MB位于蛋白的中心区域（见图1）[6]。由于每个MB会与多个“伙伴”相互作用，且这些“伙伴”又涉及多个过程和途径，目前尚无法确定每个MB的独特功能[10]。图片来源：药学进展MYC蛋白在人体主要行使转录因子的功能。正常情况下，MYC与MAX形成异二聚体，通过其b-HLH-LZ结构域结合靶DNA序列或增强子盒（enhancer box，E-box，序列通式为CANNTG），刺激正性转录延伸因子b（positive transcription elongation factor b，P-TEFb）募集，进而调控下游基因转录[11]。这些下游基因在细胞周期、增殖、分化和凋亡等多个生物学过程中发挥作用[12]。总体而言，MYC蛋白在调控细胞生物学过程中作用复杂且关键，其功能的正常调控对维持细胞正常生理状态至关重要。MYC在肿瘤中的作用原癌基因MYC在维持正常细胞功能方面至关重要，其表达失调可能引发细胞异常增殖，甚至诱发肿瘤疾病。在人类癌症中，MYC异常表达现象极为普遍，高达70%的病例受其影响，涵盖肺癌、胃癌、结直肠癌、侵袭性淋巴瘤、卵巢癌和胰腺癌等[5,7]。多种因素，如基因扩增、染色体易位、突变以及上游调控途径改变等，均可导致人类癌症中MYC激活。其中，基因扩增是人类实体瘤中MYC激活的常见机制之一，约28%的肿瘤存在MYC基因过表达，这被视为多数人类癌症发生的生物学基础之一[5,12]。在生理状态下，MYC通常与活跃转录基因的启动子结合。一旦MYC过度表达，它不仅会增加与活性启动子的结合，还会“侵入”活性增强子，占据亲和力较低的E-box序列，进而引发活性基因的全局转录扩增[13]。即在MYC过表达的肿瘤组织中，当典型MYC结合位点饱和后，MYC会以较低亲和力占据非典型结合位点，致使与恶性转化相关的基因上调，推动肿瘤发生进程。因此，在MYC高表达的组织中，它如同通用的基因激活放大器，放大现有基因表达程序的输出（见图2）[14]。图片来源：药学进展在MYC驱动的肿瘤中，MYC不仅通过调控癌细胞的增殖、代谢、侵袭、血管生成以及蛋白质和核糖体生物合成等内在过程，促进癌细胞生长与存活，还会阻断分化、衰老等细胞保护机制，加速癌症进展[5]。肿瘤血管生成是肿瘤细胞持续生存发展的必要条件，在肿瘤细胞的生长、侵袭和转移过程中发挥关键作用[15]。研究发现，在胰腺癌中，MYC参与肿瘤的血管生成、转移和化疗耐药过程；在能量不足时，还会提高谷氨酸的生物利用度，为肿瘤细胞提供能量[16]。此外，MYC表达会加速上皮-间质转化（epithelial-mesenchymal transformation，EMT），而EMT是恶性细胞生长和增殖的重要驱动因素[17-18]。MYC还能调节肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）、自然杀伤细胞（natural killer cell，NK cell）、T细胞、B细胞以及程序性死亡受体配体1（programmed death-ligand 1，PD-L1）和分化抗原47（cluster of differentiation 47，CD47）的表达，使癌细胞逃避免疫监视，保障自身生存[5,19]。例如，在三阴性乳腺癌研究中发现，MYC在体内可致使肿瘤免疫微环境中免疫浸润减少、细胞活性降低[20]。类似地，在胰腺癌的研究中发现，MYC下调会削弱T调节细胞的免疫抑制功能，增强效应T细胞的抗癌能力[16]。此外，有证据表明，MYC甚至还通过抑制肿瘤微环境中免疫细胞的活化来推动肿瘤进展[19]。由此可见，MYC可借助免疫系统调节肿瘤生长。综上所述，MYC是驱动恶性细胞生长和增殖的关键因素。靶向MYC的药物3.1 通过干扰蛋白质相互作用或与DNA 结合而起作用的抑制剂作为转录因子，MYC需与MAX形成异二聚体，并与MYC反应元件E-box基序结合以发挥生理功能。因此，调控MYC-MAX相互作用是抑制MYC功能的有效途径。目前，多种调控该相互作用的药物处于研发阶段，根据作用机制可分为3类：MYC-MAX异二聚体抑制剂、MAX-MAX同二聚体稳定剂、MYC-MAX-DNA结合干扰剂[21]。3.1.1 MYC-MAX异二聚体抑制剂迄今为止，开发临床适用的MYC小分子抑制剂的工作大多聚焦于靶向MYC-MAX异二聚体[6]。MYCMI-6是一种MYC-MAX异二聚体小分子抑制剂，它以高亲和力直接且选择性地结合MYC的b-HLH-LZ结构域，抑制MYC与MAX的相互作用。这种抑制作用减少了MYC驱动的转录，以MYC依赖的方式抑制细胞生长，降低细胞存活率。此外，在MYC依赖性的体内肿瘤模型中，该化合物显示出显著的抗癌活性，且对正常人体细胞无细胞毒性[22]。这些结果表明，该治疗方法具有高度的肿瘤选择性，具有良好的治疗潜力。与MYCMI-6类似，MYCMI-7也能抑制MYC-MAX相互作用，不同的是，它可下调MYC蛋白表达，可能具有更高的治疗效能[23]。此外，还有其他类型的小分子MYC抑制剂，如MYci361和MYci975。这些抑制剂不仅直接靶向细胞内的MYC，还通过调节MYC-苏氨酸58的磷酸化水平，降低MYC蛋白稳定性，促进其泛素化降解[24]。值得一提的是，MYci975是对MYci361改进后的产物，耐受性更佳。实际上，强效的小分子MYC-MAX二聚化抑制剂的治疗效果一直受限于生物利用度差、代谢快和靶点渗透不足等问题。近年来，蛋白质和肽类抑制剂的研究取得了较大进展。Omomyc是研究最多的多肽类MYC-MAX抑制剂，它是由MYC的b-HLH-LZ结构域衍生的显性阴性突变体，能自发渗透到癌细胞中，有效干扰MYC转录活性[25]。研究表明，omomyc不仅可结合MAX阻碍MYC介导的基因转录，自身还能形成同二聚体，直接结合MYC调节基因启动子中的E-box，甚至导致MYC降解[26]。重要的是，它具有靶向药物的优势，即对癌细胞的影响大于对周围正常组织的影响[27]。3.1.2 MAX-MAX同二聚体稳定剂MAX除了与MYC形成蛋白复合物介导多种细胞功能外，还能形成MAX-MAX同二聚体，竞争性抑制MYC相关基因的转录[28]。因此，稳定MAX同二聚体以阻止异二聚体形成，被视为治疗MYC失调引发癌症的一种替代方法。据报道，KI-MS2-008可通过时间依赖的方式稳定MAX-MAX同二聚体，阻断MYC-MAX异二聚体与DNA结合，进而减弱MYC驱动的转录，且在MYC诱导的更广泛癌症模型中显示出疗效[29]。新型双靶向C-MYC抑制剂D347-2761，可同时靶向C-MYC/MAX异二聚体和C-MYC不稳定结构域，抑制骨髓瘤生长[30]。这为靶向MYC提供了另一种可行途径。3.1.3 MYC-MAX-DNA结合干扰剂MYC与MAX结合形成的二聚体需与靶基因转录调节区域的保守E-box DNA序列结合才能发挥作用。因此，直接干扰MYC-MAX与E-box的相互作用，是设计抗MYC治疗候选药物的可行策略。目前，一些天然分子已被证实可与MYC-MAX异二聚体直接相互作用。例如，雷公藤红素这种萜类化合物，能与C-MYC-MAX结合，改变预先形成二聚体的四级结构，消除其与DNA的结合能力[31]。此外，针对小分子抑制剂也开展了相关研究，如VPC-70619和KSI-3716。VPC-70619可阻断N-MYC-MAX二聚体与DNA的E-box序列结合，对N-MYC依赖性细胞系有强抑制活性。研究表明，VPC-70619不仅可作为联合致癌治疗方案的一部分，还具备单药治疗的潜力[32]。在一项针对膀胱癌的研究中发现，小分子抑制剂KSI-3716可通过特异性干扰MYC-MAX异二聚体的形成及其与DNA的结合来抑制MYC转录活性，膀胱内给药实验证实其能有效抑制肿瘤生长，且对吉西他滨耐药的肿瘤仍保持疗效，同时未观察到明显全身毒性[33]。这些研究为开发靶向MYC-MAX-DNA相互作用的高效低毒抗肿瘤药物提供了重要理论依据和实验基础。3.2 调控MYC表达的抑制剂3.2.1 溴结构域蛋白4抑制剂溴结构域蛋白4（bromodomain-containing protein 4，BRD4）属于溴结构域和超末端结构域（bromodomain and extra-terminal domain，BET）家族，是重要的转录激活蛋白，可招募P-TEFb，促进转录延伸[34]。BRD4表达上调与多种恶性肿瘤的发生发展密切相关。有文献表明，BRD4能激活包括MYC在内的多种转录因子，抑制BRD4活性可下调MYC等转录因子水平，具有良好的抗肿瘤效果[35]。JQ1作为BRD4抑制剂，可强烈抑制MYC表达，显著减轻肿瘤负担，延长动物总生存期[34]。鉴于其对MYC转录的激活作用，BRD4被广泛视作MYC驱动型癌症的治疗靶点。然而，也有研究表明，BRD4自身可通过磷酸化促使MYC蛋白泛素化和降解，降解BRD4会产生减少MYC转录但增加MYC稳定性的矛盾效应[36]。因此，BRD4在肿瘤发展中扮演着复杂的调控角色，虽可作为治疗靶点，却可能产生因影响MYC稳定性带来的不利影响，这一点需重点关注。3.2.2 周期蛋白依赖性激酶7/9抑制剂在人体中，周期蛋白依赖性激酶（cyclin-dependent kinase，CDK）家族不仅调节细胞周期进程，在RNA转录（如CDK7/9）方面也发挥着关键作用：CDK7(Ser5,Ser7)通过磷酸化RNA Pol II C末端结构域，启动新RNA的合成，CDK9(Ser2)则促进暂停的RNA Pol II进入延伸阶段[37]。鉴于CDK7和CDK9在蛋白质生成中的重要调控作用，靶向CDK7/9成为MYC抑制剂研究策略之一。在MYC驱动的肿瘤中，MYC可通过增强PD-L1的表达促进肿瘤免疫逃逸。在非小细胞肺癌（non-small cell lung cancer，NSCLC）中，尤其是预后较差的NSCLC，MYC常发生扩增[38]。THZ1是新型的CDK7共价抑制剂，研究发现，THZ1可抑制NSCLC中MYC活性，下调PD-L1表达，并通过招募浸润的CD8+T细胞，增强抗程序性死亡受体1（programmed death-1，PD-1）治疗在体内的抗肿瘤免疫作用[39]。CDK9在多种癌症中显著上调，对MYC表达影响重大[40]。作为BRD4募集至MYC启动子的P-TEFb复合物的部分，CDK9负责调控转录延伸和mRNA成熟[41]。抑制CDK9活性，不仅能抑制MYC转录，还可促进MYC蛋白降解[42]。以AZD4573为例，这种高选择性CDK9强效抑制剂能够快速诱导多数血液癌细胞的死亡。其作用不局限于抑制MYC表达，还可间接下调髓细胞性白血病1（myeloid cell leukemia 1，MCL-1）的表达，从而产生协同抗肿瘤效应[40]。MCL-1是衰老肿瘤细胞中高表达的抗凋亡基因，抑制MCL-1表达或功能，可有效阻断肿瘤进展和转移[43]。在一项弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma，DLBCL）研究中，AZD4573可下调MYC与MCL-1蛋白水平，抑制DLBCL细胞系的细胞增殖并诱导其凋亡[37]。3.2.3 阻断MYC mRNA翻译的抑制剂磷脂酰肌醇3-激酶（phosphoinositide 3-kinase，PI3K）/蛋白激酶B（protein kinase B，PKB，又称AKT）/哺乳动物雷帕霉素靶蛋白（mammaliantargetofrapamycin，mTOR）通路在MYC翻译过程中起重要作用，PI3K，AKT和mTOR均为MYC表达的关键调节因子。有文献表明，PI3K/AKT/mTOR途径是C-MYC过表达致瘤的潜在机制，抑制该通路可下调C-MYC水平[44]。抑制AKT是阻断MYC mRNA翻译的策略之一。MK2206是在研的AKT抑制剂，能抑制AKT激酶的所有亚型（AKT1，AKT2和AKT3），是极具潜力的抗癌药物[45]。据报道，MK2206可抑制C-MYC过表达的胃癌细胞系增殖，并抑制C-MYC转基因小鼠肿瘤的起始[46]。此外，研究显示，AKT失活可通过增强糖原合成酶激酶3β（glycogen synthase kinase-3β,GSK-3β)活性，使C-MYC在T58位点磷酸化，进而导致其降解。同样，抑制PI3K和mTOR也是阻断MYC mRNA翻译的有效手段。Bimiralisib(PQR309)是口服生物可利用的PI3K和mTOR选择性双抑制剂，目前已进入临床研究阶段（临床试验编号：NCT01940133）。研究发现，该双重抑制剂可抑制C-MYC及其靶基因表达。在二维和三维细胞培养模型中，它还能降低子宫内膜癌细胞活力，诱导细胞周期细胞G1期阻滞和细胞死亡[44]。表1总结了靶向MYC的抑制剂研发情况。图片来源：药学进展3.3降解类药物许多蛋白，如“MYC”，因缺乏结合口袋而无法被直接靶向抑制。为突破现有药物研发技术的诸多瓶颈，靶向蛋白降解（targeted protein degradation，TPD）技术应运而生，并在近年来取得了迅猛发展，为药物开发开辟了新路径。目前，较为常用的蛋白降解剂主要有蛋白降解靶向嵌合体（proteolysis-targeting chimera，PROTAC）与分子胶（molecular glue，MG）[47]。它们突破了传统的“抑制”方式，借助泛素-蛋白酶体途径实现对蛋白质的降解，为疾病治疗提供了有效手段[48]。目前，已成功研发出可直接降解MYC的分子胶[49]。WBC100是一种新型口服活性分子胶，它通过E3泛素连接酶CHIP介导，经26S蛋白酶体诱导C-MYC蛋白降解。此外，在多个异种移植小鼠模型中发现，WBC100能有效抑制多种C-MYC过表达的肿瘤生长[50]。这为干预C-MYC癌基因提供了新视角。理论上，PROTAC和分子胶均可降解传统意义上“不可成药”的蛋白。然而，目前尚未出现直接靶向MYC的PROTAC药物。相反，研究人员通常通过降解其他与MYC相关的蛋白，来间接影响MYC的表达或功能。例如，MZ1是一种PROTAC类BET抑制剂，它利用E3泛素连接酶VHL（von Hippel-Lindau蛋白）促使BRD4蛋白降解，进而影响细胞中C-MYC及其他蛋白的表达水平，发挥抗癌作用[51]。ARV-825也是一种PROTAC类药物，通过E3连接酶CRBN（Cereblon蛋白）诱导BRD4蛋白降解，从而有效调控包括MYC在内的靶标。值得注意的是，与已知的小分子BRD4抑制剂相比，ARV-825在抑制BRD4信号传导方面表现出更为优异的效能[52]。另外，在一项针对多发性骨髓瘤（multiple myeloma，MM）的研究中发现[53]，ARV-825能够克服MM细胞的耐药性，与小分子抑制剂联合治疗具有显著的协同效应。3.4表观遗传调控疗法在肿瘤发展过程中，癌细胞常同时出现遗传和表观遗传改变，进而产生恶性表型。鉴于大多数基因改变被视为不可逆，研究者对引发癌症的表观遗传改变给予了广泛关注[54]。表观遗传调节剂成为新药研发持续探索的方向之一。研究表明，C-MYC的表观遗传修饰在肿瘤细胞重编程、进展及化疗耐药中发挥重要作用[55]。靶向C-MYC的表观遗传修饰因子可成功抑制癌细胞增殖，使化疗耐药细胞重新敏感，提高患者生存率。因此，对于MYC驱动的肿瘤，通过表观遗传修复途径进行治疗是一种颇具潜力的策略。OTX-2002是一种借助脂质纳米颗粒递送给患者的mRNA表观遗传调控疗法。该因子通过表观遗传调节在转录前下调MYC表达，同时克服MYC的自动调节。研究发现，OTX-2002能降低肝癌细胞中的MYC mRNA、蛋白质水平，减弱细胞活力[56]。目前，一项关于OTX-2002的临床试验（NCT05497453）正在积极开展，该试验聚焦于复发或难治性肝细胞癌（hepatocellular carcinoma，HCC）以及其他与MYC癌基因相关的实体肿瘤。在试验中，OTX-2002作为单药的疗效，以及与酪氨酸激酶抑制剂（tyrosine kinase inhibitors，TKIs）或PD-(L)1抑制剂联合使用的效果均被评估。期待该研究成果能为MYC相关疾病的治疗开辟新途径。总结与展望原癌基因MYC稳态的维持对正常细胞功能极为关键。MYC过度表达可引发癌症，因此靶向MYC是一种颇具潜力的抗肿瘤策略。在细胞中，MYC主要作为转录因子发挥作用，且需先与MAX形成异二聚体，再结合MYC反应元件E-box基序才能行使功能，不少药物正是基于这一机制研发。此外，也有通过不同手段，从上游干扰MYC表达或在下游降解MYC蛋白来阻止其发挥作用。靶向蛋白降解技术凭借其独特优势，突破了传统药物研发中因蛋白质缺乏结合口袋而难以靶向抑制的难题。尽管理论上靶向蛋白降解剂，如PROTAC和分子胶，均有降解MYC蛋白的潜力，但目前仅有分子胶实现了对MYC蛋白的直接降解。不过，尽管靶向蛋白降解剂具有显著治疗潜力，脱靶效应仍是该技术亟待解决的关键问题之一。通过精细的药物设计、全面的生物学评估以及合理的组合疗法策略，可有效降低脱靶效应，提升药物的安全性和有效性。未来的研究与开发应着重关注这一方面，以确保靶向蛋白降解剂在临床治疗中充分发挥最大潜力与价值。目前，用于癌症治疗的化疗药物多通过与多个细胞靶点相互作用诱导细胞死亡。然而，随着时间推移，癌细胞常逐渐产生对化疗药物的耐药性。越来越多的报道显示，表观遗传修饰在赋予癌细胞化疗耐药性方面起着关键作用。在针对MYC驱动的肿瘤治疗研究中，已有通过调控表观遗传修饰的药物进入临床试验，这种针对MYC的方法可能代表一种具有差异化且可行的潜在治疗途径，为人类癌症治疗带来新的可能。本文概述了靶向MYC的药物研发进展，阐明了现阶段具有潜力的药物形式及可能取得的成果。期望通过对MYC生物学功能的深入探究，早日开发出具有临床价值的药物。同时，也期待更多高效药物进入临床，为广大患者提供更优的治疗选择。参考文献：[1] Xia C, Dong X, Li H, et al. 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2025-03-22

·DrugAI

KGML-xDTD：基于知识图谱的药物治疗预测和机制描述机器学习框架

今天我想给大家介绍的论文是《KGML-xDTD: A Knowledge Graph-based Machine Learning Framework for Drug Treatment Prediction and Mechanism Description》，是一个基于知识图谱的机器学习框架，用于药物再利用预测和作用机制解释。一、背景传统药物开发是一个耗时的过程，从最初的化学鉴定到临床试验，最后到食品药品监督管理局批准，大约需要10-15年，并伴随着数十亿美元的投资开销和较高的失败率。考虑到新型疾病进化的速度很快，人们迫切需要找到一种更高效、更经济的药物发现方法。好消息是，一种药物通常可以有效治疗多种疾病。例如，沙利度胺最初被用作抗焦虑药物，后来人们发现它有治疗癌症的能力。因此，药物再利用也被称为“探索现有药物的新用途”，寻求“老药新用”的可能性，可为我们带来希望。阅读大量的文献后，我找到了一个不错的方法——KGML-xDTD：一种基于知识图谱的机器学习框架，用于可解释地预测治疗疾病的药物。它有两个模块，第一个模块可以预测某种药物治疗某种疾病的概率，第二个模块可以通过知识图谱的路径从生物学上解释该药物的作用机制。它可以有效减少“黑箱”问题，进一步加速新兴疾病药物研发的进程。二、数据准备首先是数据准备。随着生物医学数据库的可用性不断提高，将数据整合到生物医学知识图谱(Biomedical Knowledge Graph) 用于药物发现的做法近年变得流行起来。本方法采用的BKG是RTX-KG2c（the canonicalized version of the Reasoning Tool X Knowledge Graph 2），它是最大的开源BKG之一，包含约640万个节点和3930万条边，整合了约70个公共生物医学数据源，其中所有生物学概念（例如“布洛芬”）都表示为顶点，所有谓词概念（例如“布洛芬 - 增加 - GP1BA 基因的活性”）都表示为边。经过数据清洗后，剩下3659165个节点（33 个不同类别，如图）和18291237条边（74个不同类别）。除了RTX-KG2c，作者还用其他人工制作的数据和NLP衍生的数据集扩展BKG数据。 Ground Truth采用DrugMechDB，这是第一个由人工整理的基于路径的数据库，用于解释从一种药物到一种疾病的作用机制，其中有3593条路径，对应3327个独特的药物-疾病对。这些路径是从DrugBank、维基百科和其他文献中提取，然后由专家整理，保证权威。作者通过Node Synonymizer函数将它们与RTX-KG2c中使用的结点和边匹配。由于KGML-xDTD预测的作用机制路径的长度固定为3，即一共涉及4个结点。所以作者规定若这4个结点都完整出现在同一条DrugMechDB路径中，则被认为是正确匹配的路径。三、模型模块模型框架由两个模块组成：一个是药物再利用预测模块，另一个是作用机制路径预测模块，利用强化学习，有四个可学习的网络。首先看药物再利用预测模块，输入药物A和疾病B，输出药物A可用于治疗疾病B的概率。对于每个节点，其嵌入的向量信息为节点属性和节点邻域。节点属性信息由PubMedBERT模型提供，这是一种针对生物医学文本设计的预训练语言模型，根据节点名称和类别为每个节点生成节点属性嵌入。节点邻域信息由GraphSAGE提供。之后，使用PCA将每个节点的嵌入向量压缩到100维，然后药物A和疾病B的向量拼接起来，形成一个更长的向量，作为随机森林模型的输入。随机森林模型将每个药物-疾病对输出为“不治疗”、“治疗”和“未知”类别之一，并给出每个类别的概率。当药物再利用预测模块确定了药物A能治疗疾病B，另一个至关重要的问题随之而来：我们能否从生物学上解释这个预测？A到底是通过什么方法治疗B的？这就用到了作用机制路径预测模块。首先需要有“演示路径（Demonstration Paths，如图）”作为强化学习的指导，即一组生物学上可能的路径（如药物K-> 基因G -> 蛋白质P-> 疾病D），它们是作者依照一定标准从BKG中提取出来的，一共396705条，演示路径可以辅助结点移动。该模块的最终会输出n条路径来解释A如何治疗B。强化学习模型采用对抗性演员-评论家（Adversarial Actor-Critic）模型，其奖励如公式所示。从药A结点开始，不断移动，最终会停留到某一个结点——反复重复这个过程。如果最终停留到疾病B，则奖励为1；如果停留到某个疾病结点，且被药物再利用预测模块归为“治疗”类，则奖励为该模块给出的治疗概率ptreat，证明该路径的起始药物可以治疗一些潜在疾病，但还没有被人们发现；如果停留到某个疾病结点，且被药物再利用预测模块归为“非治疗”类，则奖励为0；如果最终留到某个和疾病无关的结点，则奖励为-1，代表错误决策。对抗性演员-评论家强化学习模型由四个子网络组成，它们使用相同的多层感知机架构，但每个子网络有自己独立的参数，如图： i代表每一个子网络的id：1）i为a时代表Actor网络——主要目标是学习一个路径寻找策略，智能体能够根据奖励指导自己在BKG中找到最佳路径。2）i为c时代表Critic网络——主要目标是估计在当前状态st下，采取动作at后所能获得的预期奖励QΦ(st,at)。3）i为p时代表Path Discriminator网络——主要目标是解决强化模型仅在路径终点收到奖励的问题，增加了中间奖励，具体操作为判别一个路径片段是来自演示路径（正样本）还是Actor网络自己生成的路径（负样本），通过提供判别结果并给予正负奖励，引导 Actor 网络寻找更合理的生物学的路径。4）i为m时代表Meta-Path Discriminator网络——该网络也提供了一个中间奖励，具体操作为判别一个Actor网络自己生成的路径（负样本）和来自演示路径（正样本）是否相似来给予正负奖励，如果相似则负样本就可以转变成正样本，从而增强Actor网络探索路径的能力。Path Discriminator网络、Meta-Path Discriminator网络提供的中间奖励与到达路径终点收到最终奖励并称为综合奖励。四、结果作者采用基于分类准确性的指标——Accuracy、Macro F1 score与基于排序的指标——平均倒数排名（Mean Reciprocal Rank，计算第一个相关答案的倒数排名，MRR越高，表示真实正样本在排序中越靠前）和前K名排名比例（Hit@K，计算真实正样本出现在前K个预测中的比例，Hit@K越高代表预测越准确）。对于药物再利用模块的概率预测，使用了八个基于知识图谱的药物再利用。SOTA模型作为baseline，和KGML-xDTD及其变体进行比较，结果如图所示：八个baseline的实验超参数如图所示：五、实际案例为了进一步评估KGML-xDTD模型在药物再利用预测与作用机制路径预测上的表现，作者通过两个不同的案例研究来展示该模型的潜力。两个案例研究关注的是两种罕见遗传病，即血友病B（Hemophilia B）和亨廷顿舞蹈症（Huntington’s disease）。血友病B也被称为IX因子缺乏症或圣诞病，是一种罕见的遗传性疾病，患者容易发生持续性出血。它是由位于X染色体上的IX因子（F9）基因的突变引起的。该表列出了由KGML-xDTD模型预测的前十种药物/治疗方法，包括在训练集中使用的药物（用红色标出）和未在训练集中使用的药物：除了训练集中已知的药物/治疗方法外，列表中剩下的七种药物/治疗方法大部分得到了已发布的研究支持，并有潜力用于治疗血友病B。例如，活化的人源性凝血因子VII（Factor VIIa）和重组活化因子VII（rFVIIa）是促进血液凝固的关键蛋白，凝血酶（Thrombin）是维持正常止血功能的关键酶，作为Ground Truth的DrugMechDB仅提供了Eptacog Alfa和Nonacog Alfa这两种治疗血友病B的药物作用机制路径，如图右半部分所示；作者使用它们与KGML-xDTD给出的前10条BKG路径解释路径进行比较，如图左半部分所示，两者相对应的生物学实体用红色高亮显示：由于路径长度的限制以及自定义BKG中缺失某些语义关系，预测路径无法完全与DrugMechDB的路径匹配，但在预测的前10个路径的子图中，仍然可以找到对治疗血友病B至关重要的生物学实体（如factor VII, factor IX, and factor X）。

100 项与人凝血因子X(Bio Products Laboratory) 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	B02BD13	DB13148

研发状态

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
凝血因子X缺乏症	美国	Bio Products Laboratory USA, Inc.	2015-10-20

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临床结果

适应症

分期

评价

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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


NCT00930176 (Pubmed \| Turk J Haematol)	临床3期	凝血因子X缺乏症	6	Plasma-derived factor X (pdFX)	獵鏇鹽壓鹹製製廠餘蓋(製餘餘顧壓艱獵壓鹹壓) = 1 (infusion-site pain) was possibly pdFX-related 鏇構顧鏇網鑰獵鑰積鬱 (鹽淵網蓋築鑰窪獵窪襯 )	-	2018-05-25
NCT00930176 (CTgov)	临床3期	凝血因子X缺乏症	16	Human Coagulation FACTOR X	網簾廠遞壓製簾製壓淵(網觸壓鹹膚構網觸膚糧) = 簾鹹夢鑰壓繭糧醖齋網襯壓觸憲膚糧顧膚淵窪 (簾膚鏇網鬱鬱遞膚鏇醖, 21.01) 更多	-	2014-12-12