Phase 3, Randomized, Double-blind, Placebo-controlled, Safety and Efficacy Study of Dutogliptin in Co-administration With Filgrastim in Early Recovery Post-myocardial Infarction

The goal of this phase 3, randomized, double-blind, placebo-controlled clinical trial is to explore the safety and efficacy of dutogliptin administered subcutaneously (SC) in co-administration with filgrastim in adult patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).
The primary objective is to evaluate the efficacy of dutogliptin compared with placebo in STEMI patients within 180 days of randomization measured by the time of first occurrence of a composite endpoint of cardiovascular (CV) death and worsening heart failure (HF) within 180 days. Participants will receive dutogliptin twice daily subcutaneously (SC) for 14 days and filgrastim (SC) daily for 5 days or placebo.

开始日期2023-09-01

申办/合作机构

Recardio, Inc.

NCT03486080 / Completed临床2期

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Safety and Efficacy Study of Dutogliptin in Combination With Filgrastim in Early Recovery Post-Myocardial Infarction

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Safety and Efficacy Study of Dutogliptin in Combination with Filgrastim in Early Recovery Post-Myocardial Infarction

开始日期2018-12-07

申办/合作机构

Recardio, Inc.

EUCTR2009-017524-36-HU / Not yet recruiting临床3期

A Phase III, Multicenter, Double-blind, Active-Controlled, 52-Week Extension Study to Evaluate the Safety and Efficacy of Dutogliptin in Patients With Type 2 Diabetes Mellitus Receiving Background Treatment With Glimepiride Alone or in Combination With Metformin or With Pioglitazone Alone

开始日期2010-05-18

申办/合作机构-

100 项与度格列汀酒石酸盐相关的临床结果

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100 项与度格列汀酒石酸盐相关的转化医学

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100 项与度格列汀酒石酸盐相关的专利（医药）

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项与度格列汀酒石酸盐相关的文献（医药）

2022-08-26·Current Cancer Drug Targets4区 · 医学

Dietary Flavonoids with Catechol Moiety Inhibit Anticancer Action of Bortezomib: What about the other Boronic Acid-based Drugs?

4区 · 医学

Article

作者: Sak, Katrin

Abstract::

Approval of the first boronic acid group-containing drug, bortezomib, in 2003 for the treatment of multiple myeloma sparked an increased interest of medicinal chemists in boronic acidbased therapeutics. As a result, another boronic acid moiety-harboring medication, ixazomib, was approved in 2015 as a second-generation proteasome inhibitor for multiple myeloma; and dutogliptin is under clinical investigation in combination therapy against myocardial infarction. Moreover, a large number of novel agents with boronic acid elements in their structure are currently in intensive preclinical studies, allowing us to suppose that at least some of them will enter clinical trials in the near future. On the other hand, only some years after bortezomib approval, direct interactions between its boronic acid group and catechol moiety of green tea catechins as well as some other common dietary flavonoids like quercetin and myricetin were discovered, leading to the formation of stable cyclic boronate esters and abolishing the anticancer activities. Although highly relevant, to date, no reports on possible co-effects of catechol group-containing flavonoids with new-generation boronic acidbased drugs can be found. However, this issue cannot be ignored, especially considering the abundance of catechol moiety-harboring flavonoids in both plant-derived food items as well as over-thecounter dietary supplements and herbal products. Therefore, in parallel with the intensified development of boronic acid-based drugs, their possible interactions with catechol groups of plant-derived flavonoids must also be clarified to provide dietary recommendations to patients for maximizing therapeutic benefits. If concurrently consumed flavonoids can indeed antagonize drug efficacy, it may pose a real risk to clinical outcomes.

2020-12-01·Trials4区 · 医学

“Protocol for a phase 2, randomized, double-blind, placebo-controlled, safety and efficacy study of dutogliptin in combination with filgrastim in early recovery post-myocardial infarction”: study protocol for a randomized controlled trial

4区 · 医学

ArticleOA

作者: Kubica, Jacek ; Wallner, Markus ; Nix, Darrell ; von Lewinski, Dirk ; Povsic, Thomas J ; Selvanayagam, Joseph B ; Schatz, Richard A ; Jilma, Bernd ; Henauer, Stephan

Abstract:

Background:

Regenerative therapies offer new approaches to improve cardiac function after acute ST-elevation myocardial infarction (STEMI). Previous trials using bone marrow cells, selected stem cell populations, or cardiac stem cell progenitors require invasive procedures and had so far inconclusive results. A less invasive approach utilizes granulocyte-colony stimulating factor (G-CSF) to mobilize stem cells to circulating blood and induce neovascularization and differentiation into endothelial cells and cardiomyocytes. Stromal cell-derived factor 1 alpha (SDF-1α) is an important chemokine for initiating stem cell migration and homing to ischemic myocardium. SDF-1α concentrations can be increased by inhibition of CD26/DPP4. Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model.

Methods:

We test the safety and tolerability and efficacy of dutogliptin in combination with filgrastim (G-CSF) in patients with STEMI (EF < 45%) following percutaneous coronary intervention (PCI). Preliminary efficacy will be analyzed using cardiac magnetic resonance imaging (cMRI) to detect > 3.8% improvement in left ventricular ejection fraction (LV-EF) compared to placebo. One hundred forty subjects will be randomized to filgrastim plus dutogliptin or matching placebos.

Discussion:

The REC-DUT-002 trial is the first to evaluate dutogliptin in combination with G-CSF in patients with STEMI. Results will lay the foundation for an appropriately powered cardiovascular outcome trial to test the efficacy of this combined pharmacological strategy.

Trial registration:

EudraCT no.: 2018-000916-75. Registered on 7 June 2018. IND number: 123717

2020-05-01·British journal of clinical pharmacology2区 · 医学

Safety, tolerability, pharmacokinetics and pharmacodynamics of parenterally administered dutogliptin: A prospective dose‐escalating trial

2区 · 医学

Article

作者: Schwameis, Michael ; Derhaschnig, Ulla ; Buchtele, Nina ; Jilma, Bernd ; Schenk, Roman ; Schoergenhofer, Christian ; Nix, Darrell ; Firbas, Christa ; Karch, Rudolf

Aims:

Animal studies suggest that inhibition of dipeptidyl peptidase 4 (DPP‐IV) may improve heart function and survival after myocardial infarction by increasing cardiac myocytes’ regenerative capacity. Parenterally administered dutogliptin may provide continuous strong DPP‐IV inhibition to translate these results into humans. This trial investigated the safety and tolerability, as well as pharmacokinetics and pharmacodynamics, of parenterally administered dutogliptin after single and repeated doses.

Methods:

In an open‐label trial, volunteers received dutogliptin at increasing doses of 30–120 mg subcutaneously or 30 mg intravenously in the single‐dose cohorts. Subjects in the multiple‐dose cohort received 60, 90 or 120 mg dutogliptin subcutaneously once daily on 7 consecutive days.

Results:

Forty healthy males were included in the trial. No related serious adverse events occurred. Mild local injection site reactions with no requirement for intervention comprised 147 of 153 (96%) related adverse events. Subcutaneous bioavailability was approximately 100%. Multiple injections at daily intervals did not lead to the accumulation of the study drug. The accumulation ratios based on AUC0‐24h range from 0.90 to 1.03, supporting this argument. All subjects receiving ≥60 mg dutogliptin yielded a maximum DPP‐IV inhibition >90%. The duration of DPP‐IV inhibition over time increased in a dose‐dependent manner and was highest in the 120‐mg multiple‐dosing cohort with a maximum AUEC0‐24h of 342 h % (standard deviation: 73), translating into 86% DPP‐IV inhibition 24 hours after dosing.

Conclusion:

Parenteral injection of dutogliptin was safe and subcutaneous bioavailability is excellent. DPP‐IV inhibition increased dose dependently to >86% over 24 hours after multiple doses of 120 mg dutogliptin.

项与度格列汀酒石酸盐相关的新闻（医药）

2023-06-30

·生物制品圈

GPCR ADC —— 挑战与机遇并存

G蛋白偶联受体(G protein-coupled receptors, GPCR)，也被称为七次跨膜受体，是真核生物中最大的细胞表面受体家族[1]。GPCR是最成功的治疗靶点之一，占已批准药物的近35%。 01 GPCR是ADC新晋靶点集中在临床前阶段人体中约有800个GPCR，根据氨基酸序列相似性将它们分为六大类：A类-视紫红质样受体，B类-分泌素受体家族，C类-代谢型谷氨酸受体，D类-真菌交配信息素受体，E类-环腺苷酸受体，F类-卷曲受体[2]。在人体中只发现其中四类-A、B、C和F类。靶向GPCR的药物主要包括小分子、天然产物、多肽、抗体等，其中小分子类药物占比大于90%，抗体类药物占比不足2%[4]。因为针对GPCR的抗体筛选困难。除了GPCR本身蛋白体外表达困难、GPCR蛋白胞外区较小之外，其核心功能区域在物种间非常保守，常规的免疫方式难以获得针对功能区域的抗体应答。但随着晶体学、抗体筛选等方面取得的重大进展，包括抗体类药物在内的生物制剂数量正在逐年攀升[5]。目前，有3种FDA批准的靶向GPCR或其相关配体的单克隆抗体用于非肿瘤适应证：抗CCR4单抗（mogamulizumab）、抗降钙素基因相关肽（CGRP）1型受体单克隆抗体（erenumab）和抗CGRP单抗（eptinezumab）。截至2019年的数据，估计至少有146个GPCR靶向的mAb处于发现阶段，另有45个处于临床试验阶段，目前估计更多。随着基于GPCR抗体的疗法不断扩大并进入市场，获批药物的形式可能会超越mAb，包括bsAb、纳米抗体、ADC等。毫无疑问，GPCR也开始成为ADC的新晋靶点，开始扩展ADC的应用前景。表1：目前有7款在临床和临床前阶段的GPCR ADC表2：靶向GPCR的ADC安全性研究 02 CXCR4CXCR4属于A类GPCR，其在细胞迁移、增殖、造血和组织再生方面发挥重要功能。由于其在许多血液癌和实体瘤类型中高表达，因此CXCR4成为有吸引力的肿瘤治疗靶点[6]。第一个靶向CXCR4的ADC由美国斯克利普斯研究所（Scripps Research Institute）Peter G. Schultz教授组开发，研究其对CXCR4+转移性肿瘤的治疗效果[7]。使用不可裂解的亲水性Linker-Payload (MMAF-PEG4-ONH2)与非天然氨基酸对乙酰基苯丙氨酸(p-acetylphenylalanine, pAcF)进行位点特异性偶联成肟生成高亲和力的抗CXCR4 ADC (IgGX-MMAF)，DAR=2 (图2A)。MMAF含有末端羧基，细胞渗透性极小，几乎无旁观者效应，可降低对非复制造血干细胞的脱靶细胞毒性。利用高表达CXCR4的人骨肉瘤细胞系(SJSA-1-met)评估体外疗效，经IgGX-MMAF处理后，SJSA-1-met细胞活力显著降低(IC50=0.08 nM)，而CXCR4 mAb处理没有明显抑制效果(图2B)；同时，IgGX-MMAF对CXCR4阴性细胞无抑制效果。体内功效研究表明，使用CXCR4 mAb或IgGX-MMAF进行肺部肿瘤治疗，IgGX-MMAF在第8天时几乎无法检测到肿瘤，而CXCR4 mAb治疗的肿瘤与对照组相当(图2C)。目前，尚未报告该ADC的后续疗效或安全性研究。图2. IgGX-MMAF ADC的构建及其体内外活性评价除上述研究外，该课题组还开发了另一款靶向CXCR4的ADC的药物[8]。利用自身前期研究成果牛抗体(BLV1H12)[9]中超长的重链CDR3移植到Trastuzumab中，替换Trastuzumab CDR3H中的原始Trp99-Met107环肽，得到人源化抗体HLCX (图3A)[9]。经流式检测发现HLCX对CXCR4的选择性和亲和力并未受到太大影响；同时，HLCX也具有较高内化效率。利用随机偶联的方式经两步反应引入含有不同Linker (可切割/不可切割)的淋巴细胞特异性蛋白酪氨酸激酶(Lck)抑制剂-Dasatinib (图3B)，DAR≈3，由此产生的ADC可抑制T细胞受体(TCR)介导的T细胞活化和细胞因子表达，EC50较低，且对细胞活力的影响极小(图3C)。该ADC的成功构建可能会带来一类新型的选择性免疫抑制药物，其安全性得到提高，并将ADC策略扩展到肿瘤学以外的适应症，用于激酶抑制剂的靶向递送。图3. 含Dasatinib ADC的构建及其对细胞因子分泌的影响辉瑞(Pfizer)科研人员为改善治疗指数降低靶向CXCR4 ADC的脱靶毒性，筛选了含有不同Linker、Payload、DAR、mAb亲和力和Fc形式的ADC[10]。经实验评价，Payload选择Aur0131，其对肿瘤细胞具有细胞毒性作用，但对外周血单核细胞(PBMC)没有毒性。候选ADC在NHL、ALL、MM和AML等癌细胞异种移植模型中进行活性测试，数据表明活性较优的ADC由较低亲和力的mAb组成，其Fc介导的效应功能也相应降低。ADC 713通过mAbs上的赖氨酸残基与不可裂解的Linker-Payload进行随机偶联而构建(AmPEG6C2-Aur0131; DAR=4，图4A)。针对CXCR4 mAb耐药的MOLP-8 MM细胞异种移植模型，ADC 713 (0.15 mg/kg)可导致肿瘤消退并显著延长生存期(图4B)。此外，该ADC也可提高化疗药吉西他滨在CXCR4+患者来源的非小细胞肺癌异种移植模型中的疗效(图4C)。目前，该款ADC仍处在临床前研究。图4. ADC 713偶联位点、Linker-Payload及其活性评价 03 CXCR5CXCR5是趋化因子CXCL13的受体，在大多数B细胞恶性肿瘤中表达，包括弥漫性大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(FL)和慢性淋巴细胞白血病(CLL)[11]。对复发性DLBCL患者肿瘤活检的评估表明，CXCR5染色仍然很高，这表明它可能是探索非霍奇金淋巴瘤(NHL)治疗的相关靶点。BAY-924是由拜耳(Bayer)研发的一款新型首创ADC，由纺锤体驱动蛋白抑制剂(Kinesin Spindle Protein inhibitor, KSPi)与人源化抗CXCR5 IgG1抗体组成[12]。值得注意的是，研究人员对ADC的结构进行针对性优化，使其代谢模式与KSPi作用模式相匹配，并能够最大程度地提高肿瘤细胞内的有效载荷。SPR显示该抗体与CXCR5具有高亲和力(2.5 nM)，通过流式细胞术测量不同CXCR5+淋巴瘤细胞系中ADC的亲和力为0.8-10 nM。在体外实验中，BAY 924在不同CXCR5表达水平的肿瘤细胞系中具有高选择性和抗增殖活性(<0.03-2 nM; IC50)。在包括CXCR5+ MCL REC-1细胞在内的多种细胞系中观察到Ab的有效内化和溶酶体共定位。在体内实验中，BAY-924在多种CXCR5+淋巴瘤模型中具有高度活性；与肝脏、脾脏和肾脏等器官相比，肿瘤中的Payload有特定的积累，血浆中几乎检测不到。在大尺寸肿瘤(～500 mm3) REC-1模型中，以10 mg/kg、Q7D静脉注射2次BAY-924后可观察到持久的肿瘤消退。在恶性ABC DLBCL模型OCI-LY1中，单次注射10 mg/kg BAY-924可诱导10/10小鼠完全缓解(直至治疗后第95天)。在此模型中，头对头比较显示，BAY-924与利妥昔单抗、苯达莫司汀、来那度胺相比具有更优异的活性。鉴于其独特的结构，使得BAY-924具有高稳定性；同时HSPi可被困在肿瘤细胞内而不会发生细胞渗透性游离，预计BAY-924将显示出良好的安全性。总体而言，这些结果支持BAY-924作为治疗CXCR5+非霍奇金淋巴瘤的创新方法的进一步开发。 04 LGR5LGR5属于A类GPCR，活化经典Wnt/β-catenin信号传导[13]并介导细胞间粘附[14]。LGR5在许多胃肠道(GI)癌症中高表达，正常组织低表达，并标记肿瘤起始癌症干细胞(CSC)，使其成为有利的治疗靶点。UTHealth分子医学研究所的研究人员开发了靶向LGR5的ADC，该ADC由大鼠-人嵌合LGR5 mAb与MMAE偶联组成[15]。利用两种不同Linker (MC-VC-PAB vs MP)进行ADC构建，二者均与链间半胱氨酸残基偶联(DAR=4，图5A)，并显示能够以高亲和力特异性结合LGR5、内化并转运至溶酶体，与母体mAb相当。在LGR5高表达的LoVo (结直肠)和AGS (胃癌)癌细胞中，具有可裂解Linker的ADC比具有不可裂解Linker的ADC表现出11倍的效力(IC50分别为2–4.5 nM与47–51nM)，因此含可裂解Linker的ADC被选为体内研究的先导药物(图5B)，且该ADC对LGR5阴性癌细胞系没有影响，证明其靶标特异性。在LoVo CRC异种移植模型中，含可裂解Linker的ADC治疗可导致肿瘤消除，并且没有观察到脱靶毒性(图5C)。图5. 靶向LGR5 ADC的构建及其活性测试尽管尚未报道该ADC的进一步开发情况，但该组研究人员于2021年开发了靶向LGR5及其相关受体LGR4和LGR6的肽体药物偶联物(peptibody drug conjugate, PDC)[16]。该肽体包含RSPO4的弗林蛋白酶结构域，结合LGR4-6，但不增强Wnt信号传导，与抗体Fc区融合。利用微生物转谷氨酰胺酶进行位点特异性的偶联，引入含有可裂解(VC) Linker的MMAE或Duocarmycin SA (DMSA) (图6A)。在LGR4/5高LoVo细胞中，两种PDC的效力比抗LGR5-MMAE ADC强约3倍(图6B)，LoVo异种移植模型中的PDC治疗导致肿瘤显著消退并延长生存期(图6C)。该类PDC进一步的体内功效和耐受性研究尚未有报道。图6. 肽体药物偶联物的构建示意图及其活性评价Genentech报道了两款抗LGR5 ADC，一款是通过链间半胱氨酸将蛋白酶可切割的MC-VC-PAB-MMAE与人源化LGR5 mAb偶联所得，DAR=3.5；另一款是通过重链上工程化的半胱氨酸将可酸水解的NMS818与人源化LGR5 mAb偶联所得，DAR=2[17] (图7A)。NMS818中含有PNU159682，其是一种插入DNA的蒽环类药物，可抑制拓扑异构酶II。MMAE在分裂细胞中表现出高效力，而PNU15982在亚纳摩尔浓度下表现出更高的效力，并在非分裂细胞中表现出细胞杀伤作用。这表明抗LGR5-NMS818可能具有更广泛的细胞杀伤范围，但也可能会增加正常组织毒性。该两款ADC在LGR5高表达D5124原代人胰腺癌异种移植模型中表现出相似的效力，导致肿瘤停滞或消退；裸抗和同种型对照抗体对肿瘤生长均没有显著影响，对照组ADC可导致肿瘤有一定程度的消退，但与靶向LGR5的ADC相比效果要差得多(图7B)。抗LGR5-NMS818显示出严重的肠道和肝脏毒性，而抗LGR5-MMAE治疗的小鼠则没有这种毒性，表明Linker-Payload的选择对于ADC耐受性至关重要。在APCmin/+; KRASLSL-G12D/+; Villin-Cre基因工程小鼠肠道肿瘤发生模型中进一步评估抗LGR5-MMAE的活性，长期治疗可显著提高生存率并缩小肿瘤体积(图7C)；然而，与对照组相比，肿瘤总数没有变化。这与MMAE已被证明对胃肠道肿瘤相对无效有关。因此研究其他Linker-Payload组合将会更有意义。与其他小组的研究相结合，这些发现展现出靶向LGR5治疗不同类型癌症的潜力。图7.不同载荷ADC的活性评价 05 FZD7FZD7是一种Frizzled家族GPCR (F类)，可介导经典的β-catenin和非经典c-Jun激酶依赖性Wnt信号通路[18]。FZD7在卵巢癌中高表达，表达量与患者的中位生存期密切相关[19]，这表明它可能是ADC开发的一个极有吸引力的靶点。加州大学圣地亚哥分校(UCSD)的研究人员开发了一款抗FZD7的ADC-Septuximab vedotin，由嵌合人-小鼠FZD7 mAb通过可裂解MC-VC-PABC-MMAE偶联，DAR=4 (图8A)。与FZD7敲除(KO)的(OVCAR3和MA-148 FZD7-KO; IC50=25–60 nM)卵巢癌细胞系相比，Septuximab vedotin在FZD7+ (MA-148和PA-1; IC50=5 nM)中的效力增强。使用表达荧光素酶的MA-148、PA-1和MA-148 FZD7-KO异种移植模型测试其体内活性，MA-148和PA-1肿瘤能够得到明显消退，而在MA-148 FZD7-KO中未观察到显著的肿瘤生长抑制(图8B)。由于Septuximab vedotin特异性结合人FZD7，因此使用CRISPR-Cas9对小鼠进行工程改造，将Fzd7上的mAb表位从小鼠序列转换为人序列(Fzd7hF7/hF7)，未观察到对小肠隐窝/绒毛结构的明显毒性或损伤。此外，该ADC避免了全局Wnt抑制相关的脱靶效应。这些初步结果使该ADC在PDX和免疫活性模型中的进一步测试合理化，以评估其临床潜力。图8. Septuximab vedotin模式图及其体外活性测试 06 CTR降钙素受体(CTR)属于B类GPCR，广泛表达于成人组织中，尤其是骨骼中。CTR在恶性神经胶质瘤和神经胶质瘤干细胞的致死性脑肿瘤胶质母细胞瘤的活检中广泛表达。墨尔本大学和莫纳什大学的研究人员开发了一款靶向CTR的ADC，该ADC由mAb2C4抗体通过赖氨酸末端ε-氨基与可裂解Linker-Payload (OSu-Glu-VC-PAB-MMAE)偶联组成，DAR=7[20]。此外，还利用SPDP linker构建了含有Dianthin-30[His6]或Gelonin的抗体偶联物。使用高度CTR阳性神经胶质瘤SB2b和JK2细胞以及U87MG GBM细胞评估抗CTR-MMAE活性，在SO1861 (一种促进溶酶体逃逸的三萜糖苷)存在情况下，抗CTR-MMAE的效力增加10倍(EC50=25.1 vs. 2.5 nM，表1)。关于此款ADC的体内研究和未来开发均未有报道。表1. 免疫毒素与ADC在SB2b、U87MG和JK2细胞系中的活性比较 07 GPR56GPR56是粘附类GPCR家族的成员，在大脑发育、免疫调节、HSC生成和肿瘤发生中具有重要功能。GPR56在多种肿瘤类型中高表达，包括结直肠癌、乳腺癌、肝癌、胰腺癌、肺癌和卵巢癌等[21]。GRP56的缺失可以抑制结直肠肿瘤的生长并使癌细胞对标准化疗敏感。GPR56在肿瘤发生中的潜在作用以及在各种肿瘤类型中的高表达为靶向GPR56 ADC的开发提供了理论依据。UTHealth分子医学研究所的科研人员基于已有10C7 mAb开发靶向GPR56的ADC[22]。10C7以高亲和力与GPR56的胞外结构域结合，并增强下游Src-Fak信号传导，被用于治疗CRC，特别是微卫星稳定亚型(MSS)[23]。为了确定最佳的ADC有效负载，研究人员筛选了一系列细胞毒素，探究其在CRC细胞中的效力。根据实验结果，选择含有可裂解Linker (VC)的DNA烷化剂DMSA与10C7通过链间半胱氨酸残基偶联，DAR=3.54 (图9A)。在具有不同GPR56表达水平的CRC细胞系中测试发现，在GPR56高表达CRC细胞系(SW620、SW403和HT-29；IC50=3.7–29.4 nM)中观察到有效的细胞毒性，而对GPR56阴性CRC细胞系没有影响；对照ADC没有诱导显著的抑制活性，表明该杀伤机制是GPR56依赖性(图9B)。同时，10C7 ADC在转移性直肠癌的GPR56+患者来源的肿瘤类器官(PDO)模型中进行活性研究，结果表明与对照ADC的抑制活性相比，10C7 ADC几乎可以完全杀死肿瘤细胞(图9C)。此外，10C7 ADC在MSS CRC细胞异种移植模型中显示出显著的抗肿瘤功效(图9D)。在免疫功能正常的小鼠中进行的初步安全性研究并未显示任何明显的毒性迹象，但由于小鼠和人之间10C7结合表位的序列差异，靶标介导的毒性可能被低估。图9.GPR56 (10C7) ADC的构建及其体内外活性评价 08 CCR2CCR2在肿瘤浸润性骨髓细胞(包括肿瘤相关巨噬细胞)表达，并通过限制 CD8+ T细胞浸润来促进免疫逃逸。TAK-500[24]是一款免疫刺激抗体偶联物(Immune-stimulating antibody conjugate, ISAC)，由三部分组成：基于TAK-676的STING激动剂作为Payload (目前正在进行Ⅰ期临床评估[NCT04420884、NCT04879849])、IgG1抗CCR2抗体和一个自降解的含有马来酰亚胺的蛋白酶可切割的多肽Linker。TAK-500具有三种可能的作用机制：激活IFN反应、将抑制性肿瘤内CCR2+细胞重编程为炎症表型，以及阻断抑制性肿瘤相关巨噬细胞募集。因此，TAK-500有潜力克服CPI耐药性，用于难治性和免疫排除或荒芜的肿瘤(Immunologically excluded or deserted tumors)治疗。目前，TAK-500已进入Ⅰ期临床试验(NCT05070247, Recruiting)[25]，联合或不联合Pembrolizumab用于患有特定局部晚期或转移性实体瘤的成人患者的治疗。 09 CCR7CCR7属于A类GPCR，在肿瘤细胞迁移、转移和免疫细胞招募中发挥重要作用。CCR7在许多癌症类型中高表达，并与较差的预后相关，使其成为癌症治疗中极具吸引力的靶点。诺华(Novartis)开发了一款靶向CCR7的ADC-JBH492，用于治疗CLL和NHL[26]。JBH492由IgG1抗体组成，通过可裂解Linker与Ravtansine (DM4)偶联(细节暂未批露)。体外研究表明，与正常免疫细胞相比，JBH492优先结合CCR7高表达的肿瘤细胞，并通过DM4介导的细胞毒性和抑制配体诱导的CCR7信号传导发挥作用。在弥漫性大B细胞淋巴瘤PDX模型中JBH492实现部分或完全逆转，在非人类灵长类动物中没有明显的毒性或循环免疫细胞群的变化。JBH492单药疗法目前正在进行I期临床试验(NCT04240704, Recruiting)，用于治疗复发/难治性CLL和NHL患者，同时评估其安全性。 10 GPR20GPR20是一种在胃肠道间质瘤(GIST)中过表达的A类GPCR孤儿受体，大多数成人GIST是由原癌基因受体酪氨酸激酶(KIT)或血小板衍生生长因子受体α (PDGFRA)的激活突变驱动的。目前，唯一批准的GIST疗法是酪氨酸激酶抑制剂(TKI)，但肿瘤经常在KIT中产生继发性耐药突变，亟需更有效的治疗方案来克服这种耐药性。第一三共(Daiichi Sankyo)开发了DS-6157a，将GPR20 mAb通过高度稳定的组织蛋白酶可裂解的Gly-Gly-Phe-Gly (GGFG)四肽Linker与Deruxtecan (DXd)偶联，DAR=8 (图10A)[27]。在过表达重组GPR20 (GIST-T1/GPR20)的GIST-T1细胞和GPR20-NCI-N87胃癌细胞中DS-6157a仅在GIST-T1/GPR20细胞中表现出活性(IC50=156 ng/mL)，证明其对GPR20的特异性(图10B)。在GIST-T1异种移植模型中，使用DS-6157a治疗的两种模型中均观察到显著的TGI；值得注意的是，在GIST-T1异种移植模型中，DS-6157a导致肿瘤消退在治疗终止后持续8周；GPR20 mAb和对照ADC均不影响肿瘤生长，表明TGI依赖于GPR20和DXd (图10C)。重要的是，无论KIT突变状态如何，DS-6157a都能阻止PDX肿瘤生长，而TKI治疗的疗效因获得性或内在耐药性而变化(图10D)。图10. DS-6157a的构建、活性测试及其克服耐药性的试验安全性研究显示DS-6157a对猴子的毒性极小或轻微，最高非严重毒性剂量为30 mg/kg (人体等效剂量=9.6 mg/kg)，以上数据支持DS-6157a进入临床试验(起始剂量=1.6 mg/kg)。评估DS-6157a单药疗法的安全性、有效性和药代动力学的I期临床试验于2020年5月开始(NCT04276415)。不幸的是，几乎所有患者都经历了轻度至重度治疗引起的和相关的不良事件，其中出现一例治疗相关性死亡(肝功能衰竭)，因此该临床试验被第一三共终止。 11 GPRC5DGPRC5D属于是GPCR孤儿受体，在原代多发性骨髓瘤细胞表面高表达，在正常组织的表达仅限于免疫赦免性的毛囊区域。GPRC5D的过表达与多发性骨髓瘤患者的不良预后和肿瘤负荷有关，这种关联使其成为治疗多发性骨髓瘤的潜在候选靶点。国内礼新医药利用其自有专利技术平台-LX-ADC™-开发了一种新型抗GPRC5D ADC：LM-305[28]，由抗GPRC5D单克隆抗体、蛋白酶可降解Linker和MMAE组成。体外研究表明，LM-305以高亲和力与GPRC5D过表达细胞系和GPRC5D内源表达的MM细胞结合，并呈剂量依赖性。它可以被GPRC5D表达细胞有效内化，并进一步在溶酶体中裂解。当与MM肿瘤细胞(NCI-H929和MM.1R)共培养时，LM-305显示出有效的细胞毒性，IC50值范围为0.1-0.3 nM。体内肿瘤异种移植模型表明，LM-305治疗可对荷瘤小鼠的肿瘤生长产生剂量依赖性抑制；同时，LM-305在GPRC5D高表达MM CDX模型中以3mg/kg 的剂量表现出完全缓解(CR)。此外，LM-305 在动物研究中表现出良好的安全性。基于以上可喜的数据，2023年5月12日，礼新医药已与阿斯利康就临床前阶段的LM-305项目达成全球独家授权协议。根据协议条款，阿斯利康将获得LM-305的研究、开发和商业化的独家全球许可[29]。礼新医药将有资格获得包括首付款在内共计5500万美元的近期付款，以及最高达5.45亿美元的潜在开发和商业里程碑付款，外加全球净销售额的分级特许权使用费。此次授权(Licence-Out)，又是我国本土创新药企昂首挺胸进入全球化“深海”的典范。目前，LM-305已经入Ⅰ/Ⅱ临床试验(NCT05647512; Not yet recruiting)，用于复发性或难治性多发性骨髓瘤(RRMM)和其他浆细胞疾病的治疗，期待能够有好的临床试验结果。 12 US28US28 (四种人巨细胞病毒编码的病毒GPCR之一)已在多种肿瘤中检测到，包括神经胶质瘤、结直肠癌和前列腺癌等；US28可激活致癌信号通路，并在胶质母细胞瘤等肿瘤的进展中发挥肿瘤调节作用[30]。Vrije Universiteit Amsterdam和Utrecht University的科研人员开发了一种靶向US28的纳米抗体偶联物(VUN100-PS)，利用已有的US28-Nb[31]通过其C端未配对的半胱氨酸与水溶性光敏剂Mal-IRDye700DX偶联获得，不影响Nb的结合亲和力(图11)[32]。该偶联物可选择性杀死2D培养物以及3D球体中表达US28的胶质母细胞瘤细胞。这些数据表明靶向GPCR纳米抗体在光动力疗法(Photodynamic therapy, PDT)领域的潜力。图11. 纳米抗体光动力疗法选择性杀死表达病毒GPCR的胶质母细胞瘤细胞 13 多款靶向GPCR的ADC被暂停除上述处于临床前/临床试验的ADC外，还有多款靶向GPCR的ADC终止研究或出于无进展状态(表2)[33, 34]。表2. 临床试验终止或无进展的ADC药物ADC是增长最快的癌症治疗药物之一，已证明其具有良好的抗肿瘤功效，并已获得FDA批准用于治疗多种实体瘤和血液恶性肿瘤。目前生物制药行业和学术界正在为改善癌症治疗做出广泛努力，有理由推断，针对GPCR的ADC数量在未来几年将继续增加，GPCR超家族将会成为ADC开发的热门靶点。免责声明：本文仅作信息交流之目的，文中观点不代表个人立场，亦不代表个人支持或反对文中观点。本文并非治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。刍荛之作，若有纰漏/不足，欢迎各位批评指正(dyc21@mails.tsinghua.edu.cn)，谢谢！主要参考文献 1. Hauser, A.S., et al., Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov, 2017. 16(12): p. 829-842.2. Congreve, M., et al., Impact of GPCR Structures on Drug Discovery. Cell, 2020. 181(1): p. 81-91.3. Hutchings, C.J., et al., Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat Rev Drug Discov, 2017. 16(9): p. 787-810.4. https://gpcrdb.org.5. Yang, D., et al., G protein-coupled receptors: structure-and function-based drug discovery. Signal transduction and targeted therapy, 2021. 6(1): p. 7.6. Buck, A.K., et al., CXCR4-targeted theranostics in oncology. Eur J Nucl Med Mol Imaging, 2022. 49(12): p. 4133-4144.7. Kularatne, S.A., et al., A CXCR4-targeted site-specific antibody-drug conjugate. Angew Chem Int Ed Engl, 2014. 53(44): p. 11863-7.8. Wang, R.E., et al., An immunosuppressive antibody-drug conjugate. J Am Chem Soc, 2015. 137(9): p. 3229-32.9. Liu, T., et al., Rational design of CXCR4 specific antibodies with elongated CDRs. J Am Chem Soc, 2014. 136(30): p. 10557-60.10. Costa, M.J., et al., Optimal design, anti-tumour efficacy and tolerability of anti-CXCR4 antibody drug conjugates. Scientific Reports, 2019. 9(1).11. Wang, B., et al., CXCL13-CXCR5 axis: Regulation in inflammatory diseases and cancer. Biochim Biophys Acta Rev Cancer, 2022. 1877(5): p. 188799.12. Johannes, S., et al., Preclinical characterization of BAY-924, a first in class ADC targeting CXCR5-positive B-cell malignancies, with a KSP inhibitor as novel payload. Cancer Research, 2019. 79(13_Supplement): p. 4825-4825.13. Park, S., et al., Unlike LGR4, LGR5 potentiates Wnt–β-catenin signaling without sequestering E3 ligases. Science signaling, 2020. 13(660): p. eaaz4051.14. Carmon, K.S., et al., LGR5 receptor promotes cell–cell adhesion in stem cells and colon cancer cells via the IQGAP1–Rac1 pathway. Journal of Biological Chemistry, 2017. 292(36): p. 14989-15001.15. Gong, X., et al., LGR5-Targeted Antibody-Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence. Mol Cancer Ther, 2016. 15(7): p. 1580-90.16. Cui, J., et al., Drug Conjugates of Antagonistic R-Spondin 4 Mutant for Simultaneous Targeting of Leucine-Rich Repeat-Containing G Protein-Coupled Receptors 4/5/6 for Cancer Treatment. J Med Chem, 2021. 64(17): p. 12572-12581.17. Junttila, M.R., et al., Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer. Sci Transl Med, 2015. 7(314): p. 314ra186.18. Zeng, C.M., Z. Chen, and L. Fu, Frizzled Receptors as Potential Therapeutic Targets in Human Cancers. Int J Mol Sci, 2018. 19(5).19. Tan, M., et al., The FZD7-TWIST1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma. Mol Oncol, 2019. 13(4): p. 757-780.20. Gilabert-Oriol, R., et al., Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an anti-calcitonin receptor antibody, are differentially potent in vitro in high-grade glioma cell lines derived from glioblastoma. Cancer Immunol Immunother, 2017. 66(9): p. 1217-1228.21. Liu, Z., et al., Expression of orphan GPR56 correlates with tumor progression in human epithelial ovarian cancer. Neoplasma, 2017. 64(1): p. 32-39.22. Jacob, J., et al., An antibody-drug conjugate targeting GPR56 demonstrates efficacy in preclinical models of colorectal cancer. Br J Cancer, 2023. 128(8): p. 1592-1602.23. Chatterjee, T., et al., Anti-GPR56 monoclonal antibody potentiates GPR56-mediated Src-Fak signaling to modulate cell adhesion. J Biol Chem, 2021. 296: p. 100261.24. Diamond, J.R., et al., Abstract CT249: First-in-human study of TAK-500, a novel STING agonist immune stimulating antibody conjugate (ISAC), alone and in combination with pembrolizumab in patients with select advanced solid tumors. Cancer Research, 2022. 82(12_Supplement): p. CT249-CT249.25. Diamond, J.R., et al., Phase 1a/1b study design of the novel STING agonist, immune-stimulating antibody-conjugate (ISAC) TAK-500, with or without pembrolizumab in patients with advanced solid tumors. 2022, American Society of Clinical Oncology.26. Dang, A., et al., A Novel Antibody-Drug Conjugate Targeting CCR7 in Hematologic Malignancies. Blood, 2022. 140(Supplement 1): p. 11564-11565.27. Iida, K., et al., Identification and Therapeutic Targeting of GPR20, Selectively Expressed in Gastrointestinal Stromal Tumors, with DS-6157a, a First-in-Class Antibody–Drug Conjugate. Cancer Discovery, 2021. 11(6): p. 1508-1523.28. Huang, W., et al., Preclinical activity of LM-305 targeting G-protein-coupled receptor class 5 member D (GPRC5D) antibody drug conjugate for the treatment of multiple myeloma. Cancer Research, 2022. 82(12_Supplement): p. 6020-6020.29. https://www.lanovamedicines.com/news-center/press-release/55.html.30. Soroceanu, L., et al., Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype. Cancer Res, 2011. 71(21): p. 6643-53.31. Heukers, R., et al., The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth. Oncogene, 2018. 37(30): p. 4110-4121.32. De Groof, T.W.M., et al., Nanobody-Targeted Photodynamic Therapy Selectively Kills Viral GPCR-Expressing Glioblastoma Cells. Mol Pharm, 2019. 16(7): p. 3145-3156.33. Khongorzul, P., et al., Antibody–Drug Conjugates: A Comprehensive ReviewAntibody–Drug Conjugates in Cancer Immunotherapy. Molecular Cancer Research, 2020. 18(1): p. 3-19.34. https://synapse-zhihuiya-com.libproxy1.nus.edu.sg/.

抗体药物偶联物细胞疗法

2023-01-26

·PRNewswire

Myocardial Infarction (MI) Market is Projected to Grow at a Minimal CAGR of 1.61% During the Study Period (2019-2032) | Assesses DelveInsight

Considering the expected launch of new upcoming therapies and greater integration of early patient screening, it can be safely assumed that the MI market will undergo a paradigm shift in the present decade holding new prospects and opportunities for those planning to carve out their niche during the forecast period [2022–2032] LAS VEGAS, Jan. 26, 2023 /PRNewswire/ -- DelveInsight's MI Market Insights report includes a comprehensive understanding of current treatment practices, MI emerging drugs, market share of individual therapies, and current and forecasted market size from 2019 to 2032, segmented into 7MM the United States, EU4 (Germany, France, Italy, and Spain) and the United Kingdom, and Japan. Key Takeaways from the MI Market Report As per DelveInsight analysis, the MI market size in the 7MM was approximately USD 21 billion in 2021 According to the assessment done by DelveInsight, the estimated total MI diagnosed prevalent cases in the 7MM was approximately 15 million in 2021 Leading MI companies such as AstraZeneca, Boehringer Ingelheim and Eli Lilly and Company, Amgen, Novartis, Idorsia Pharmaceuticals, Faraday Pharmaceuticals, CSL Behring, Immediate Therapeutics, Mitsubishi Chemical Group, Kancera, Bayer, Recardio, Mesoblast, and others are developing novel MI drugs that can be available in the MI market in the coming years The promising MI therapies in the pipeline include FARXIGA/FORXIGA (dapagliflozin), JARDIANCE (empagliflozin), Olpasiran (AMG860), Pelacarsen (TQJ230), Selatogrel, FDY-5301, CSL112, IMT-358, CL2020, MEDI6570, KAND567, Asundexian, Dutogliptin, MPC-25-IC , and others In November 2022, Amgen presented end-of-treatment data from its Phase II OCEAN (a)-DOSE study of olpasiran during the Late-Breaking Science Session of the American Heart Association (AHA) Scientific Sessions and simultaneously published in the New England Journal of Medicine As per the Q32022 investor presentation of AstraZeneca data, readouts from the Phase III (DAPA-MI) trial of FARXIGA/FORXIGA is anticipated by 2H 2023. With an estimated key regulatory submission acceptance after 2023 In June 2021, Idorsia announced the initiation of the Phase III registration study "SOS-AMI" to evaluate the efficacy and safety of self-administered SC selatogrel in suspected AMI In September 2020, the FDA granted Fast Track designation for the development of JARDIANCE to prevent hospitalization for heart failure and reduce the risk of mortality in patients with and without diabetes who have had an acute MI In July 2020, AstraZeneca was granted Fast Track designation in the US for the development of FARXIGA to reduce the risk of hospitalization for heart failure (hHF) or cardiovascular (CV) death in adults following an AMI or heart attack Discover which therapies are expected to grab the major MI market share @ MI Market Report. MI Overview MI is pathologically defined as myocardial cell death caused by prolonged ischemia. The first ultrastructural changes are diminished cellular glycogen, relaxed myofibrils, and sarcolemmal disruption, which can be seen as early as 10-15 minutes after the onset of ischemia. Symptoms of MI include chest pain, which may initially manifest as a sensation of tightness or pressure. The pain usually radiates to the left arm, but it can also radiate to the lower jaw, neck, right arm, back, and upper abdomen. Sweating, nausea, vomiting, and fainting may accompany chest pain. The typical clinical features, ECG findings, and elevation of cardiac biomarkers are used for MI diagnosis. Cardiovascular catheterization is required for definitive diagnosis and serves diagnostic and therapeutic purposes. All patients suspected of having ACS should be considered for emergency revascularization; other MI treatment options include anticoagulation, antiplatelet therapy, statin therapy, and other adjunctive measures. MI Epidemiology Segmentation DelveInsight estimates that there were approximately 15 million diagnosed prevalent cases of MI in the 7MM in 2021. Among EU4 countries, Germany had the highest number of diagnosed prevalent cases of MI, while Spain had the lowest prevalent population among the 7MM. The MI market report proffers epidemiological analysis for the study period 2019–2032 in the 7MM segmented into: Diagnosed Prevalent Cases Gender-specific Prevalence Type-specific Prevalence Download the report to understand which factors are driving MI epidemiology trends @ MI Epidemiological Insights. MI Treatment Market The goals of initial MI treatment are to relieve pain, immediately identify ST changes via 12-lead EKG, initiate reperfusion (if the patient is a candidate), and assess and treat hemodynamic abnormalities. Oxygen, nitroglycerin, and morphine sulfate are the most effective pain relievers. Reperfusion therapy is indicated for patients with ST-segment elevation or a new LBBB with symptoms lasting 12 hours or less. MI treatment may be divided into two paths depending on whether the patient has a STEMI or an NSTEMI. The pharmacologic MI treatment is further subdivided into several groups of medications that improve survival, reduce recurrent ischemic events, and provide symptomatic relief. Following the primary MI treatment, a multimodal regimen of therapies is used. To classify the disease, rapid diagnostic tests and serial biomarker analysis are used to begin MI treatment. The current MI market has been segmented into different commonly used therapeutic classes based on the prevailing MI treatment pattern across the 7MM, which exhibits minor variations in the overall prescription pattern. The major classes covered in the forecast model are antiplatelet agents, anticoagulants, vasodilators, beta-blockers, lipid-lowering drugs, Angiotensin-converting enzyme (ACE) inhibitors, ARBs (Angiotensin-II receptor Blockers), and calcium channel blockers. In recent years, it has been demonstrated that pre-hospital thrombolysis has a role in the management of patients seen early after symptom onset in comparison/association with patients who had primary coronary intervention or elective primary coronary intervention. This is an important issue that is still being researched to prevent cardiac arrest, large scares, and again limit the transition to heart failure and improve the survival rate after AMI. To know more about MI treatment guidelines, visit @ MI Management. MI Pipeline Therapies and Key Companies FARXIGA/FORXIGA (dapagliflozin): AstraZeneca JARDIANCE (empagliflozin): Boehringer Ingelheim and Eli Lilly and Company Pelacarsen (TQJ230): Novartis Olpasiran: Amgen Selatogrel: Idorsia Pharmaceuticals FDY-5301: Faraday Pharmaceuticals CSL112: CSL Behring IMT-358: Immediate Therapeutics CL2020: Mitsubishi Chemical Group MEDI6570: AstraZeneca KAND567: Kancera Asundexian: Bayer Dutogliptin: Recardio MPC-25-IC: Mesoblast Learn more about the FDA-approved drugs for MI @ Drugs for MI Treatment. MI Market Dynamics The dynamics of MI market is anticipated to change in the coming years. The growing emphasis on secondary preventive measures to avoid recurrent/new events, lifestyle changes, and the growing number of smokers and cases of obesity, diabetes, hypertension, and others, are expected to fuel MI market growth. Moreover, heart attacks and strokes are major cost drivers in the 7MM healthcare system. The volume of the MI market is enormous. The patient is receiving multiple therapies at the same time. The smallest portion of the patient share can provide pharmaceutical companies with options worth millions of dollars in the MI market. However, several factors are likely to affect the growth of the MI market. Women appear to be underdiagnosed with MI, despite being at higher risk because medical training for healthcare professionals and public information has emphasized the identification of symptoms that typically affect men. This highlights the importance of gender differences in developing strategies for early MI detection and tailored secondary prevention after MI, which should result in a higher rate of MI detection in women. Moreover, off-label therapies and generics account for the majority of the current MI market because they are less expensive and more easily accessible to patients, thus, causing a dip in the MI market growth. Hence, all these factors mentioned above will hamper the MI market growth in the future. Scope of the MI Market Report Therapeutic Assessment: MI current marketed and emerging therapies MI Market Dynamics: MI market drivers and barriers Competitive Intelligence Analysis: SWOT analysis, PESTLE analysis, Porter's five forces, BCG Matrix, Market entry strategies Unmet Needs, KOL's views, Analyst's views, MI Market Access and Reimbursement Discover more about MI drugs in development @ MI Clinical Trials. Table of Contents Related Reports MI Pipeline MI Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key MI companies, including CSL Behring, Immediate Therapeutics, Mitsubishi Chemical Group, Kancera, Bayer, Recardio, among others. MI Epidemiology Forecast MI Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted MI epidemiology in the 7MM, i.e., the United States, EU5 (Germany, Spain, Italy, France, and the United Kingdom), and Japan. Myocarditis Pipeline Myocarditis Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key myocarditis companies, including Cantargia AB, Cardiol Therapeutics, Apitope, among others. Dilated Cardiomyopathy Pipeline Dilated Cardiomyopathy Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key dilated cardiomyopathy companies, including Longeveron, Bristol Myers Squibb, Berlin Cures, Tenaya Therapeutics, Cardior Pharmaceuticals, among others. Cardiac Biomarkers Testing Market Cardiac Biomarkers Testing Market Insight, Competitive Landscape, and Market Forecast – 2027 report delivers an in-depth understanding of market trends, market drivers, market barriers, and key cardiac biomarkers testing companies, including Beckman Coulter, Inc, Siemens Healthcare GmbH, Abbott, among others. Dilated Cardiomyopathy Epidemiology Dilated Cardiomyopathy Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical, and forecasted dilated cardiomyopathy epidemiology in the 7MM. Other Trending Reports Tay-sachs Disease Or Gm2 Gangliosidosis Market | Onycholysis Market | Diagnostic Imaging Equipment Market | Chemotherapy-induced Peripheral Neuropathy Market | Global Electrophysiology Devices Market | Anaphylaxis Market | Atherectomy Devices Market | Helicobacter Pylori Infections Market | Ophthalmic Imaging Equipment Market | Androgenetic Alopecia Market | Allergic Rhinitis Market | Chronic Inflammatory Demyelinating Polyneuropathy Market | Chronic Inflammatory Demyelinating Polyneuropathy Market | Colorectal Cancer Crc Market | Opioid Induced Constipation Market | Vertigo Market | Bone Anchored Hearing Systems Market | Wound Closure Devices Market | Hip Replacement Devices Market | Hemodynamic Monitoring Systems Market | Egfr Non-small Cell Lung Cancer Market | Helicobacter Pylori Infection Market | Hyperkalemia Market | Polycythemia Market Neurostimulation Devices Market | Carpal Tunnel Syndrome Market | Ventilator Market | Cerebral Aneurysm Market | Alpha Antitrypsin Market | Binge Eating Disorder Market | Bunion Market | Concussions Market Size | Exocrine Pancreatic Insufficiency Market | Healthcare Due Diligence Services | Minimal Residual Disease Market | Hypertrophic Scar Market | Lung Fibrosis Market | Anterior Uveitis Market | 22q11.2 deletion syndrome Market | X-Linked Retinitis Pigmentosa (XLRP) Market | Acute Radiation Syndrome Market | Alpha-1 Protease Inhibitor Deficiency Market | Androgenetic Alopecia Market | Hyperlipidemia Market | Cardiotoxicity Market | Hypertrophic Cardiomyopathy Market | Fatty Acid Oxidation Disorders (FAODs) Market | Androgen Insensitivity Syndrome Market | Emphysema Market | Canaloplasty Market | Dravet Syndrome Market | Celiac Disease Market | Chlamydia Infections Market | Syphilis Market | Renal Tubular Acidosis Market | Palmoplantar Pustulosis (PPP) Market | Aplastic Anemia Market | Bacterial Pneumonia Market | B cell Chronic Lymphocytic Leukemia Market | B cell Lymphomas Market | Behcets Disease Market Neoantigen-based Personalized Cancer therapeutic Vaccines Competitive Landscape and Market Forecast—by 2035 | Glioblastoma Market Related Healthcare Blogs Upcoming Cardiovascular Diseases Drugs Key Companies in the Cardiology Segment Heart Failure Market Related Healthcare Services Healthcare Consulting Healthcare Competitive Intelligence Services Healthcare Asset Prioritization Services About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve. Connect with us on: LinkedIn | Facebook | Twitter. Additionally, get in touch with our business executive to explore @ Healthcare Due Diligence Services. Logo - Contact Us: Shruti Thakur [email protected] +1(919)321-6187 SOURCE DelveInsight Business Research, LLP

临床3期快速通道

100 项与度格列汀酒石酸盐相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09334	-	-	DB11723

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适应症	最高研发状态	国家/地区	公司	日期
ST段抬高心肌梗死	临床3期	-	Recardio, Inc.	2023-09-01
2型糖尿病	临床3期	美国	Phenomix Corp.	2008-07-01
2型糖尿病	临床3期	阿根廷	Phenomix Corp.	2008-07-01
2型糖尿病	临床3期	印度	Phenomix Corp.	2008-07-01
2型糖尿病	临床3期	马来西亚	Phenomix Corp.	2008-07-01
2型糖尿病	临床3期	秘鲁	Phenomix Corp.	2008-07-01
2型糖尿病	临床3期	菲律宾	Phenomix Corp.	2008-07-01
2型糖尿病	临床3期	罗马尼亚	Phenomix Corp.	2008-07-01
2型糖尿病	临床3期	泰国	Phenomix Corp.	2008-07-01
2型糖尿病	临床3期	乌克兰	Phenomix Corp.	2008-07-01

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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


NCT03486080 (ESC2020) 人工标引	临床2期	急性心肌梗塞	24	filgrastim+dutogliptin	艱窪壓廠獵網製艱願鹹(艱願齋艱窪壓壓製製蓋) = 4 rated as serious (hospitalization due to pneumonia N=3, hospitalization due to acute myocardial infarction N=1), and 1 adverse event was rated as severe (fatal pneumonia) 糧淵範鹽夢範鬱網淵遞 (蓋鑰簾鬱醖積齋積鏇觸 ) 更多	积极	2020-11-25
NCT03486080 (ESC2020) 人工标引	临床2期	急性心肌梗塞	24	Placebo		积极	2020-11-25
ESC2018	临床1期	急性心肌梗塞 CD26/dipeptidylpeptidase IV (DPP-IV) \| SDF-1	-	Dutogliptin	願憲膚構齋觸夢糧襯顧(積獵築醖壓構繭淵顧齋) = not observed with daily dosing 蓋鏇廠齋積窪觸醖蓋夢 (夢夢顧蓋遞夢衊醖鹹憲 ) 更多	-	2018-08-25