更新于：2024-05-01

aFGF

成纤维细胞生长因子1

更新于：2024-05-01

基本信息

别名

成纤维细胞生长因子1、Acidic fibroblast growth factor、aFGF

+ [17]

简介

Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro. Acts as a ligand for FGFR1 and integrins. Binds to FGFR1 in the presence of heparin leading to FGFR1 dimerization and activation via sequential autophosphorylation on tyrosine residues which act as docking sites for interacting proteins, leading to the activation of several signaling cascades. Binds to integrin ITGAV:ITGB3. Its binding to integrin, subsequent ternary complex formation with integrin and FGFR1, and the recruitment of PTPN11 to the complex are essential for FGF1 signaling. Induces the phosphorylation and activation of FGFR1, FRS2, MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:18441324, PubMed:20422052). Can induce angiogenesis (PubMed:23469107).

关联

项与 aFGF 相关的药物

Muparfostat sodium

磺酸化单磷酸甘露寡聚糖

靶点

VEGF-A x aFGF x bFGF

作用机制

VEGF-A抑制剂 [+2]

在研机构

基亚生物科技股份有限公司 [+2]

原研机构

Australian National University Library

在研适应症

肝炎 [+2]

非在研适应症

晚期癌症 [+12]

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

RG-8803

靶点

EGF x aFGF

作用机制

EGF抑制剂 [+2]

在研机构-

原研机构

Repligen Corp.

在研适应症-

非在研适应症

糖尿病性视网膜病变 [+1]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

Fibroblast growth factor-2 (Neurobiological Technologies)

靶点

aFGF

作用机制

aFGF刺激剂

在研机构-

原研机构

Neurobiological Technologies, Inc. [+1]

在研适应症-

非在研适应症

亨廷顿舞蹈病

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 aFGF 相关的临床试验

NCT01402908 / Terminated临床3期

A Prospective, Randomized, Double-blind, Placebo Controlled, Parallel-group, International Multicenter Phase III Trial of PI-88 in the Adjuvant Treatment of Subjects With Hepatitis Virus Related HCC After Surgical Resection

The purpose of this study is to determine if PI-88 is effective and safe in patients who have had surgery to remove primary liver cancer.

开始日期2011-08-01

申办/合作机构

乾境生物技术有限公司

[+1]

EUCTR2007-005011-25-ES / Unknown statusN/A

A prospective, randomised, double-blind, placebo-controlled, parallel-group, international multicentre phase III trial of PI-88 in the adjuvant treatment of post-resection hepatocellular carcinomaEstudio Fase III, internacional, multicéntrico, prospectivo, aleatorizado, doble-ciego y controlado con placebo, de grupos paralelos de PI-88 en el tratamiento adyuvante de carcinoma hepatocelular post-resección (Pathway) - PATHWAY

开始日期2008-02-13

申办/合作机构-

NCT00568308 / Terminated临床3期

A Prospective, Randomized, Double-blind, Placebo-controlled, Parallel-group, International, Multicentre Phase III Trial of PI-88 in the Adjuvant Treatment of Post-resection Hepatocellular Carcinoma

The purpose of this study is to determine if PI-88 is effective and safe in patients who have had surgery to remove primary liver cancer.

开始日期2007-12-01

申办/合作机构

Progen Pharmaceuticals, Inc.

100 项与 aFGF 相关的临床结果

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100 项与 aFGF 相关的转化医学

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0 项与 aFGF 相关的专利（医药）

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3,832

项与 aFGF 相关的文献（医药）

2024-12-01·Computational and structural biotechnology journal

Large language models assisted multi-effect variants mining on cerebral cavernous malformation familial whole genome sequencing.

Article

作者: Yiqi Wang ; Jinmei Zuo ; Chao Duan ; Hao Peng ; Jia Huang ; Liang Zhao ; Li Zhang ; Zhiqiang Dong

Cerebral cavernous malformation (CCM) is a polygenic disease with intricate genetic interactions contributing to quantitative pathogenesis across multiple factors. The principal pathogenic genes of CCM, specifically KRIT1, CCM2, and PDCD10, have been reported, accompanied by a growing wealth of genetic data related to mutations. Furthermore, numerous other molecules associated with CCM have been unearthed. However, tackling such massive volumes of unstructured data remains challenging until the advent of advanced large language models. In this study, we developed an automated analytical pipeline specialized in single nucleotide variants (SNVs) related biomedical text analysis called BRLM. To facilitate this, BioBERT was employed to vectorize the rich information of SNVs, while a deep residue network was used to discriminate the classes of the SNVs. BRLM was initially constructed on mutations from 12 different types of TCGA cancers, achieving an accuracy exceeding 99%. It was further examined for CCM mutations in familial sequencing data analysis, highlighting an upstream master regulator gene fibroblast growth factor 1 (FGF1). With multi-omics characterization and validation in biological function, FGF1 demonstrated to play a significant role in the development of CCMs, which proved the effectiveness of our model. The BRLM web server is available at http://1.117.230.196.

2024-02-07·Cells

FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist.

Article

作者: Chih-Chieh Chang ; Yoko K Takada ; Chao-Wen Cheng ; Yukina Maekawa ; Seiji Mori ; Yoshikazu Takada

FGF9 is a potent mitogen and survival factor, but FGF9 protein levels are generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies showed that FGF1 and FGF2 directly bind to integrin αvβ3, and this interaction is critical for signaling functions (FGF-integrin crosstalk). FGF1 and FGF2 mutants defective in integrin binding were defective in signaling, whereas the mutants still bound to FGFR suppressed angiogenesis and tumor growth, indicating that they act as antagonists. We hypothesize that FGF9 requires direct integrin binding for signaling. Here, we show that docking simulation of the interaction between FGF9 and αvβ3 predicted that FGF9 binds to the classical ligand-binding site of αvβ3. We show that FGF9 bound to integrin αvβ3 and generated FGF9 mutants in the predicted integrin-binding interface. An FGF9 mutant (R108E) was defective in integrin binding, activating FRS2α and ERK1/2, inducing DNA synthesis, cancer cell migration, and invasion in vitro. R108E suppressed DNA synthesis and activation of FRS2α and ERK1/2 induced by WT FGF9 (dominant-negative effect). These findings indicate that FGF9 requires direct integrin binding for signaling and that R108E has potential as an antagonist to FGF9 signaling.

2024-02-06·Bone

Complex intrinsic abnormalities in osteoblast lineage cells of X-linked hypophosphatemia: Analysis of human iPS cell models generated by CRISPR/Cas9-mediated gene ablation.

Article

作者: Tatsuro Nakanishi ; Miwa Yamazaki ; Kanako Tachikawa ; Ayu Ueta ; Masanobu Kawai ; Keiichi Ozono ; Toshimi Michigami

X-linked hypophosphatemia (XLH) is caused by inactivating variants of the phosphate regulating endopeptidase homolog X-linked (PHEX) gene. Although the overproduction of fibroblast growth factor 23 (FGF23) is responsible for hypophosphatemia and impaired vitamin D metabolism, the pathogenesis of XLH remains unclear. We herein generated PHEX-knockout (KO) human induced pluripotent stem (iPS) cells by applying CRISPR/Cas9-mediated gene ablation to an iPS clone derived from a healthy male, and analyzed PHEX-KO iPS cells with deletions extending from exons 1 to 3 and frameshifts by inducing them to differentiate into the osteoblast lineage. We confirmed the increased production of FGF23 in osteoblast lineage cells differentiated from PHEX-KO iPS cells. In vitro mineralization was enhanced in osteoblast lineage cells from PHEX-KO iPS cells than in those from isogenic control iPS cells, which reminded us of high bone mineral density and enthesopathy in patients with XLH. The extracellular level of pyrophosphate (PPi), an inhibitor of mineralization, was elevated, and this increase appeared to be partly due to the reduced activity of tissue non-specific alkaline phosphatase (TNSALP). Osteoblast lineage cells derived from PHEX-KO iPS cells also showed the increased expression of multiple molecules such as dentine matrix protein 1, osteopontin, RUNX2, FGF receptor 1 and early growth response 1. This gene dysregulation was similar to that in the osteoblasts/osteocytes of Phex-deficient Hyp mice, suggesting that common pathogenic mechanisms are shared between human XLH and Hyp mice. Moreover, we found that the phosphorylation of CREB was markedly enhanced in osteoblast lineage cells derived from PHEX-KO iPS cells, which appeared to be associated with the up-regulation of the parathyroid hormone related protein gene. PHEX deficiency also affected the response of the ALPL gene encoding TNSALP to extracellular Pi. Collectively, these results indicate that complex intrinsic abnormalities in osteoblasts/osteocytes underlie the pathogenesis of human XLH.

项与 aFGF 相关的新闻（医药）

2024-02-11

·药明康德

1月，11款创新靶点值得关注（附PDF下载）

▎药明康德内容团队编辑近三年，FDA批准的新药里具有创新机制的药物占比均超过一半。由于基于靶点的筛选是过去几十年新药研发的主要方式，这些创新药物的起点往往都是相关靶点的发现和验证。这也意味着医药行业的不断创新仰赖对新靶点及其生物学机理的不断挖掘。正如多位嘉宾在药明康德BOLD系列论坛中指出的那样，很多“容易的靶点”已经转化为了创新疗法，如今的新药发现公司需要探索更为复杂、更难治疗的疾病，而这个过程依赖于对于靶点及其生物学的深度认知，也需要前沿科技的更多进步。药明康德内容团队盘点了2024年1月发布于国际知名科研期刊中的潜力靶点，以供各位医药界的朋友们参考。这些潜力靶点涵盖癌症、中枢神经系统疾病、心血管、罕见病等多个方向，有的是新的肿瘤合成致死靶点，有的为罕见病提供了全新治疗方案，都具有潜在转化价值。在这篇文章中，我们优选3个值得关注的靶点做详细报道。点击“阅读原文”或扫描文中二维码并填写文中调查问卷，留下您的邮箱，即可申请获得完整11个靶点列表。▲点击“阅读原文”或扫描以上二维码并填写问卷，以申请获得《2024年1月潜在可转化创新靶点》分析报告靶点：APOE3ch应用：诠释一种拮抗阿尔茨海默症的基因突变机理期刊 / PMID：《细胞》 / 38086389发现：一个病例报告研究显示APOE3 Christchurch（APOE3ch）突变纯合携带者对PSEN1-E280A突变引起的常染色体显性阿尔茨海默病（AD）具有抵抗力。本论文的研究人员构建了人源化APOE3ch敲入小鼠。与病例报告类似，在该小鼠模型里APOE3ch表达导致外周血脂异常和斑块相关的tau病理学显著减少。淀粉样蛋白反应减少与斑块周围的小胶质细胞反应增强。这些结果显示APOE3ch影响小胶质细胞对Aβ斑块的反应，抑制Aβ诱导的tau蛋白播种和扩散，也为Aβ诱导的tau蛋白病变提供了新的药物研发思路。▲APOE3ch表达导致外周血脂异常和斑块相关的tau病理学显著减少（图片来源：参考资料[1]）靶点：B3GALT6应用：清除导致复发的难治性残留肿瘤细胞期刊 / PMID：Cancer Cell / 38065100发现：无法治愈的复发是乳腺癌等肿瘤致死的主要原因，这种复发被认为来自休眠的、难治性残留肿瘤细胞（RTC）播种。因此，了解RTC存活的机制对改善癌症治疗至关重要。在这篇论文里，作者通过体内CRISPR-Cas9筛选细胞休眠相关的候选基因，确定半乳糖基转移酶B3GALT6是RTC适应性的功能调节因子。B3GALT6是糖胺聚糖（glycosaminoglycan，GAG）与蛋白质连接，生成蛋白聚糖所必需的代谢酶，种系功能缺失会导致骨骼发育不良。而研究人员发现B3GALT6介导的硫酸乙酰肝素GAG生物合成可预测肿瘤患者预后不良。机理上，B3GALT6-硫酸乙酰肝素/HS6ST1-乙酰肝素6-O-硫酸化/FGF1-FGFR2信号通路能提高休眠RTC的存活率，促进复发。该研究表明B3GALT6与癌症有关，抑制B3GALT6相关通路，包括抑制FGFR2是一种潜在的根除休眠RTC，预防复发的手段。▲B3GALT6在微环境诱导的肿瘤休眠模型中促进肿瘤细胞存活及生长（图片来源：参考资料[2]）靶点：KMT2E应用：肺动脉高压关键靶点期刊 / PMID：Science Translational Medicine / 38198571发现：肺动脉高压（PAH）是一种由依赖缺氧诱导因子（HIF）的血管功能障碍驱动的疾病，HIF-2α促进邻近基因KMT2E-AS1和KMT2E的表达。在功能上，KMT2E-AS1是一种长非编码RNA（lncRNA），可稳定KMT2E蛋白，增加表观遗传组蛋白H3的4号位赖氨酸三甲基化（H3K4me3），驱动依赖HIF-2α的代谢和致病性内皮活性。该lncRNA信号通路还增加了表观遗传、转录和转录后环境中的HIF-2α表达，从而形成正反馈，进一步增强HIF-2α活性。在本研究中，作者在PAH患者队列以及全球荟萃分析中确定了KMT2E内含子内的一个单核苷酸变异（SNV）rs73184087与PAH疾病的遗传风险相关。该SNV特定的等位基因与HIF-2α形成关联，参与长程染色质相互作用，并在缺氧细胞中诱导KMT2E-AS1和KMT2E的相互作用。体内实验中，KMT2E-AS1缺失可以保护小鼠免受PAH侵害，通过药物抑制大鼠组蛋白甲基化也有相同作用。而与之对应的，强制这一lncRNA表达会形成更严重的疾病表现。因此，KMT2E-AS1/KMT2E介导HIF-2α病理，是肺动脉高压的关键临床靶点。▲KMT2E-AS1诱导HIF-2α激活并阻止HIF-2α降解，从而驱动内皮病理表型（图片来源：参考资料[3]）潜在靶点众多，限于篇幅，本文不一一进行介绍。请点击“阅读原文”或扫描文中二维码并填写文中调查问卷，留下您的邮箱，即可申请获得完整靶点列表。▲点击“阅读原文”或扫描以上二维码并填写问卷，以申请获得《2024年1月潜在可转化创新靶点》分析报告大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Chen, Yun et al. “APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread.” Cell vol. 187,2 (2024): 428-445.e20. doi:10.1016/j.cell.2023.11.029[2] Sreekumar, Amulya et al. “B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling.” Cancer cell vol. 42,1 (2024): 52-69.e7. doi:10.1016/j.ccell.2023.11.008[3] Tai, Yi-Yin et al. “Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension.” Science translational medicine vol. 16,729 (2024): eadd2029. doi:10.1126/scitranslmed.add2029免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

2023-11-19

·药时代

百亿美金蓝海市场，NASH药物进展如何？

全球有很多NASH患者，如美国约有1500-3000万NASH患者，中国约有5000万，但是目前美国和中国都没有一款NASH药物获批上市，大量的临床治疗需求仍未得到满足。据Frost & Sullivan数据分析，预计2025年NASH市场将达107亿美元，2030年达到322亿美元，百亿美元市场亟待瓜分。NASH药物由于巨大的市场前景而备受关注，很多国内外药企纷纷加入布局，如Madrigal、礼来、诺和诺德、默沙东、歌礼制药、拓臻生物、海思科和雅创医药等。临床上有很不同类型在研的NASH药物，根据靶点主要可以分为以下几类：FXR（Farnesoid X受体）激动剂、THR-β（甲状腺激素受体β亚型）激动剂、GLP-1R激动剂、FGF19（成纤维细胞生长因子19）和FGRF21（成纤维细胞生长因子21）类似物和FASN（脂肪酸合成酶）抑制剂等。NASH的形成及药物类型非酒精性脂肪性肝病（NAFLD）包括一系列肝脏表现，从肝脂肪变性开始，并可能发展为非酒精性脂肪性肝炎（NASH）、肝硬化甚至肝细胞癌（图1）[1]。图1. NAFLD进展从市场前景来看，NASH拥有庞大的患者基础，但大量的临床治疗需求仍未得到满足。流行病学数据显示，美国约有1500-3000万NASH患者，而中国约有5000万。据Frost & Sullivan分析数据，全球NAFLD/NASH药物市场已从2016年的17亿美元增至2020年的19亿美元，CAGR为 3.2%。预计未来会呈现快速增长趋势，2025年将达107亿美元，并于2030年达322亿美元，CAGR分别为41.8%和24.6%。2020年3月，印度制药企业Zydus Cadila研发的PPARα/PPARγ的双重激动剂Saroglitazar获得了印度药品管理局批准，用于非肝硬化性NASH的治疗，成为全球首个获批用于NASH治疗的药物，不过Saroglitazar的市场表现不佳。FDA或NMPA都没有批准过治疗NASH的药物，但是临床上有很多不同类型的NASH药物在研，从代谢和抗纤维化等方面来治疗NASH，包括FXR激动剂、THR-β激动剂、GLP-1R激动剂、FGF19和FGRF21类似物和FASN抑制剂等（图2）[2]。图2. 治疗NASH不同的药物类型 FXR激动剂FXR是核受体（NR）超家族的成员，被鉴定为胆汁酸（BA）结合转录因子，FXR激动剂通过纠正中间代谢和脂质积累的异常、抑制代谢应激诱导的p53激活、抑制纤维化的进展和减少炎症，具有治疗肝脏疾病的治疗潜力。FXR激动剂用于治疗NASH的开发命运多舛，此前有在临床2期终止试验的cilofexor（GS-9674）、LMB763和EDP-305等，今年奥贝胆酸（Obeticholic acid）在6月份因疗效不佳且副作用明显而被FDA拒绝批准其上市申请。但是，临床上还有很多在研的用于治疗NASH的FXR激动剂，如HTD1801、TERN-101、ASC42和HEC-96719等（图3）。图3. 部分在研治疗NASH的FXR激动剂HTD1801是由君圣泰医药独立自主研发针对代谢及消化系统疾病的原创口服小分子新药。今年的EASD会议上，北京大学人民医院内分泌科主任、北京大学糖尿病中心主任纪立农教授报道了HTD1801用于改善T2DM患者的血糖控制的最新2期研究结果：HTD1801能够在有效降糖的同时改善肝功能相关指标，且安全性和耐受性良好，提示其对于T2DM合并NAFLD患者的治疗潜力。ASC42是由歌礼制药自主研发的新型高效选择性非甾类FXR激动剂，用于治疗NASH和慢性乙型肝炎（CHB）。ASC42于2020年10月获得FDA批准在NASH患者中开展临床试验，随后12月份被FDA授予治疗NASH快速通道资格，目前处于临床2期。 THR-β激动剂THR-β在肝脏中高度表达，THR-β激动剂被证实在人体中具有降低低密度脂蛋白（LDL）、甘油三酯（TG）和肝脏脂肪变性的活性。与此同时，THR-β还可以通过促进脂肪酸的分解和刺激线粒体的生物发生来减少脂肪毒性并改善肝功能，进而减少肝脏脂肪。因此，THR-β激动剂具备调控多种肝脏代谢通路来治疗NASH的潜力。临床在研的用于治疗NASH的THR-β激动剂药物有Madrigal Pharmaceuticals的Resmetirom、歌礼制药的ASC41、拓臻生物的TERN-501、海思科的HSK31679和Viking的VK2809等（图4）。图4. 部分在研治疗NASH的THR-β激动剂Resmetirom是由Madrigal Pharmaceuticals研发的每日一次的口服THR-β选择性激动剂，旨在针对肝脏NASH的关键潜在原因。9月13日，Madrigal宣布FDA已接受Resmetirom用于治疗患有肝纤维化的成年NASH患者的新药申请（NDA）审查。FDA 已授予优先审查，处方药使用者费用法案日期（PDUFA）是2024 年 3 月 14 日[3]。11月10日，Madrigal Pharmaceuticals公布了来自3期MAESTRO-NASH试验的新数据，证明了Resmetirom对肝脏健康非侵入性措施的广泛治疗效果，主要肝活检终点和降低低密度脂蛋白胆固醇的关键次要终点均达到。MAESTRO-NASH是一项随机、双盲、安慰剂对照的3期系列肝活检试验评估Resmetirom在活检证实的NASH成人中的疗效和安全性（NCT03900429）[4]。在MAESTRO-NASH中，Resmetirom治疗帮助肝活检诊断为严重纤维化（F2/F3）的NASH患者实现肝酶、磁共振成像-质子密度脂肪分数（MRI-PDFF）、磁共振弹性成像（MRE）、FibroScan 振动控制瞬时弹性成像（VCTE）、FibroScan 控制衰减参数（CAP）和增强的肝纤维化（ELF）测试的改善（图5）[5]。Resmetirom还降低了低密度脂蛋白胆固醇和其他与心脏病相关的脂质的水平。图5. MAESTRO-NASH结果绝大多数（>70%）接受Resmetirom 100 mg治疗的患者具有≥30%的MRI-PDFF反应。MRI-PDFF降低≥30%与NASH消退（96%的患者）和纤维化改善（88%的患者）密切相关。该组MRI-PDFF的中位降低总体为 52%[4]。 GLP-1R激动剂GLP-1类药物因其显著的降糖减重效果而备受关注，随着研究的深入，人们发现GLP-1类药物也能治疗NASH。临床上有很多GLP-1R激动剂或GLP-1R/GIPR双重激动剂用于治疗NASH，其中司美格鲁肽进展最快，处于临床3期（图6）。图6. 部分在研的GLP-1R类用于治疗NASH的药物诺和诺德的司美格鲁肽是目前进展最快的治疗NASH的GLP-1类药物，此前一项在治疗NASH的2期临床结果显示司美格鲁肽0.1 mg、0.2 mg和0.4 mg治疗组分别有47.3%、46.8%和66.7%患者的NASH症状得到消除（图7）[6]。图7. 司美格鲁肽治疗NASH的2期结果 FGF19和FGF21类似物据报道，成纤维细胞生长因子（FGF）家族的几个成员（即FGF1、FGF19和FGF21）为对NAFLD有益的代谢激素。这些 FGF受核受体的转录控制，如即FXR调节FGF19，而 PPARγ和α分别调节 FGF1和21。FGF19是一种在肠道中产生的激素，调节胆汁酸的产生和能量代谢。重组FGF19的药物给药在改善T2D和NAFLD/NASH等代谢紊乱方面显示出显著的临床前疗效。FGF21是FGF家族的另一个成员，通过与跨膜蛋白βKlotho（KLB）复合的FGF受体（FGFRs）结合发挥其生物学作用，导致各种典型信号通路的激活，如丝裂原活化蛋白激酶（MAPK）和PI3K-PKB/AKT[7]。然而天然FGF在患者中有几个缺点，包括不良反应和半衰期短，因此人们开发它们的类似物，希望改善药代动力学和药效学特征，如图8所示。图8. 部分临床在研的FGF19和FGF21类似物Aldafermin（NGM282）是由NGM Bio研发的人类激素FGF19的工程变体，每日注射一次用于治疗非酒精性脂肪性肝炎（NASH）。今年5月份，NGM 公布了NGM282的一项为期48周的2b期ALPINE 4 的顶线研究数据，该研究招募了160名因 NASH（肝纤维化 4 期或 F4）引起的代偿性肝硬化患者，评估了1 mg和3 mg剂量的NGM282与安慰剂相比的疗效、安全性和耐受性。该研究达到了其主要终点，与接受安慰剂的患者相比，接受3 mg NGM282治疗的患者从基线到第 48 周的增强型肝纤维化（ELF）评分在统计学上显着降低。NGM282已在800多名患者和健康志愿者中给药，涉及多种肝脏和代谢疾病，包括400多名NASH患者，并且在迄今为止的临床试验中普遍耐受性良好[8]。其它类型的NASH药物除了上述治疗NASH药物类型，还有很多不同机制的NASH药物，如FASN抑制剂和PPAR激动剂等（图9）。图9. 部分在研的其它类型NASH药物FASN是肝脏脂质合成的关键酶，肝脏过量的脂质沉积是基于脂质合成增多、分解减少、转运增多，因此抑制FASN可以用于治疗NASH。今年EASL大会上，美国O'Farrell在口头报告中介绍了FASN抑制剂denifanstat治疗活检证实NASH的多中心、随机、双盲、安慰剂对照2b期试验FASCINATE-2研究的26周中期分析结果：使用50 mg/d denifanstat可以显著抑制NASH患者FASN的功能和显著改善NASH患者的肝脏损伤[9]。小结NASH市场前景巨大，全球的患者逐年增加，迫切需要新机制NASH药物来满足临床需求。目前全球尚无FDA或NMPA批准治疗NASH的药物，但是临床上有很不同类型在研的NASH药物，此前，FXR激动剂进展最快的奥贝胆酸折戟而归，不过THR-β激动剂Resmetirom的上市申请获FDA受理且纳入优先审评，近期，Resmetirom的一项MAESTRO-NASH显示超过70%患者NASH关键指标改善，该突破性疗法有望明年获批。临床上还有很多在研的NASH药物，未来十年或将获批十余款NASH药物。ReferencesThierry Huby and Emmanuel L. Gautier, Immune cell-mediated features of non-alcoholic steatohepatitis, Nat Rev Immunol. 2022 Jul;22(7):429-443.Stephen A. Harrison , Alina M. Allen, Julie Dubourg, Mazen Noureddin & Naim Alkhouri, Challenges and opportunities in NASH drug development, Nature Medicine | Volume 29 | March 2023 | 562–573https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-nda-acceptance-and-priorityhttps://ir.madrigalpharma.com/node/15071/pdfhttps://ir.madrigalpharma.com/static-files/e8a35f47-f841-49d4-9c21-781f41177609https://investor.novonordisk.com/q2-2023-presentation/?page=303Cristy R.C. Verzijl, Ivo P. Van De Peppel, Dicky Struik and Johan W. Jonker, Pegbelfermin (BMS-986036): an investigational PEGylated fibroblast growth factor21 analogue for the treatment of nonalcoholic steatohepatitis, EXPERT OPINION ON INVESTIGATIONAL DRUGS2020, VOL. 29, NO. 2, 125–133https://www.ngmbio.com/pipeline/O’Farrell M, Grimmer K, Zetter A, et al. Multicenter, randomized, double-blind, placebo-controlled trial of Fatty Acid Synthase (FASN) inhibitor, denifanstat, versus placebo in the treatment of biopsy-proven NASH: A 26-week interim analysis of the FASCINATE-2 Phase 2B trial. Journal of Hepatology 2023 vol. 78(S1) | S1–S99. EASL 2023. Abstract OS-061.封面图来源：123rf药时代BD-092项目 | 高活性，低风险THRβ靶向NASH新药寻求合作药时代BD-053项目 | 与奥贝胆酸同靶点临床II期NASH口服小分子寻求合作药时代BD-034项目 | KHK靶向安全、有效BIC潜质口服小分子 NASH I期项目药时代BD-033项目 | FXR靶向安全有效潜在BIC小分子 NASH I期项目药时代BD项目 | 具有独特MOA且安全、有效的美国IIb期NASH项目寻求中国权益转让药时代BD项目 | 潜在更优THR-β激动剂，目标适应症：NASH和血脂异常。寻找全球或中国权益合作伙伴点击在看共济新药研发浪潮

ASH会议临床2期快速通道

2023-11-02

·BioSpace

New England Journal of Medicine Publishes Complete Results of Positive Phase 2 Trial of Sibeprenlimab in Treatment of Immunoglobulin A Nephropathy (IgAN)

The sibeprenlimab Phase 2 clinical trial results will also be presented this week at the American Society of Nephrology (ASN) Kidney Week.1 Findings demonstrated that 12 months of sibeprenlimab treatment resulted in significant reductions in proteinuria (protein in urine), a marker of kidney damage compared to placebo in patients with IgAN.1 IgAN, also known as Berger’s disease, is the most common cause of kidney failure in young adults2 and is associated with a 10-year reduction in life expectancy.3 PRINCETON, N.J. & WALTHAM, Mass.--(BUSINESS WIRE)-- Otsuka Pharmaceutical Development & Commercialization, Inc. and Visterra Inc., today announced that the full results of a Phase 2 trial of sibeprenlimab (VIS649) for treatment of immunoglobulin A nephropathy (IgAN; Berger’s disease) have been published in the New England Journal of Medicine.1 The topline findings will also be presented in a late-breaking poster session at the American Society of Nephrology (ASN) Kidney Week meeting in Philadelphia, PA. This press release features multimedia. View the full release here: Sibeprenlimab is an investigational humanized monoclonal antibody that blocks the action of the cytokine A Proliferation Inducing Ligand (APRIL), an immune cell growth factor believed to play a key role in the development and progression of IgAN.1,4,5 The Phase 2 trial randomized 155 adult participants with biopsy-confirmed IgAN to monthly intravenous injections of sibeprenlimab 2, 4, or 8 mg/kg, or placebo for 12 months. The primary outcome measure was the change from baseline in 24-hour urine protein-to-creatinine ratio (uPCR) at month 12. Secondary outcomes included safety and change in estimated glomerular filtration rate (eGFR), a measure of kidney function.1 The study results demonstrated that 12 months of sibeprenlimab treatment in patients with IgAN resulted in significant reductions in proteinuria compared to placebo. At 12 months, geometric mean ratio reduction in 24-hour uPCR from baseline was 47.2%, 58.8%, 62.0%, and 20.0% with sibeprenlimab 2, 4, and 8 mg/kg, and placebo, respectively.1 Beneficial changes in eGFR were also observed in the sibeprenlimab groups compared to placebo. The annual eGFR change was −2.7, +0.2, −1.5, and −7.4 ml/1.73 m2 with sibeprenlimab 2, 4, and 8 mg/kg, and placebo, respectively. This reflects a stabilization of eGFR with sibeprenlimab compared to the eGFR decline observed with placebo.1 The incidence of treatment-emergent adverse events (TEAEs) for patients on sibeprenlimab and placebo was similar. The safety pro sibeprenlimab showed no evidence of undesirable toxicity or clinically meaningful immunosuppression during this trial and follow-up through month 16.1 “IgAN is the most common form of primary glomerulonephritis and is associated with a significant reduction in life expectancy,” said Brian J. G. Pereira, M.D., CEO of Visterra, Inc., and the senior author of the New England Journal of Medicine paper. “Current therapies have modest efficacy, at best, in reducing the rate of chronic kidney disease progression and new disease-specific targeted treatment options would be hugely beneficial.” “We are excited by these results, which bring us one step closer to addressing the critical unmet treatment needs of patients with this complex, life-threatening condition,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. "We look forward to continuing to evaluate the potential of sibeprenlimab in the ongoing Phase 3 trial program." About Immunoglobulin A Nephropathy Immunoglobulin A nephropathy (IgAN; Berger’s disease) is the most common form of primary glomerulonephritis worldwide and is the most common cause of kidney failure in young adults.1,2 The disease is associated with a reduction in life expectancy of 10 years,3 with at least 30% of affected patients progressing to kidney failure within 20 to 30 years, despite optimized standard of care therapy.6,7 Current standard of care management is based on renin-angiotensin aldosterone system (RAAS) blockers and adequate blood pressure control, but the risk of kidney failure remains high.8 About Sibeprenlimab Sibeprenlimab (VIS649) is an investigational humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of the cytokine A PRoliferation Inducing Ligand (APRIL), a key factor in the production of galactose-deficient IgA1 (Gd-IgA1), which has been demonstrated to play a key role in the pathogenesis of IgAN.1,4,5 About the Phase 2 Sibeprenlimab Trial The multicenter, randomized, double-blind, placebo-controlled, multiple-dose, parallel-group study was conducted in adults with biopsy-confirmed IgAN at high risk of disease progression, despite having received standard-of-care treatment. Participants were randomized 1:1:1:1 to intravenous sibeprenlimab 2, 4, or 8 mg/kg or placebo monthly for 12 months.9 The study was designed to test the safety and efficacy of different doses of sibeprenlimab. The main objectives were to evaluate the safety and tolerability of sibeprenlimab and to evaluate the dose response to different doses of sibeprenlimab on proteinuria and eGFR.9 The study was comprised of three main periods, Screening, Treatment (12 months) and Follow-Up (4 months). The findings from this study form the basis for the subsequent clinical development of sibeprenlimab.9 About Otsuka Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy of “Otsuka–people creating new products for better health worldwide”. Otsuka researches, develops, manufactures, and markets innovative products, with a focus on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health. In pharmaceuticals, Otsuka is a leader in the challenging areas of CNS, kidney and cardiovascular health and has additional research programs in oncology and on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does. Otsuka established a presence in the U.S. in 1973 and today its U.S. affiliates include Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Otsuka America Pharmaceutical, Inc. (OAPI). These two companies’ 2,000 employees in the U.S. develop and commercialize medicines in the areas of mental health and kidney diseases, using cutting-edge technology to address unmet healthcare needs. OPDC and OAPI are indirect subsidiaries of Otsuka Pharmaceutical Company, Ltd., which is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 47,000 people worldwide and had consolidated sales of approximately USD 13.1 billion in 2022. All Otsuka stories start by taking the road less traveled. Learn more about Otsuka in the U.S. at and connect with us on LinkedIn and X at @OtsukaUS. Otsuka Pharmaceutical Co., Ltd.’s global website is accessible at About Visterra Visterra is a clinical-stage biotechnology company and a wholly owned subsidiary of Otsuka America Pharmaceutical, Inc. committed to developing innovative antibody-based therapies for the treatment of patients with kidney diseases and other hard-to-treat autoimmune diseases. Its proprietary Hierotope® platform enables the design and engineering of precision biologics-based product candidates that specifically bind to, and modulate, key disease targets that are not adequately addressed by traditional therapeutic approaches. The platform also includes Fc engineering capabilities for half-life extension, bispecific antibodies and antibody-drug conjugates (ADCs). Visterra’s pipeline includes programs targeting IgA nephropathy and other kidney diseases, immunologically-driven diseases and infectious diseases. Prior to its acquisition by Otsuka, Visterra was funded by investments by Polaris Partners, Flagship Pioneering, the Bill and Melinda Gates Foundation, MRL Ventures Fund, Vertex Ventures HC, Serum Institute of India Private Ltd., Temasek Holdings, Omega Funds, Cycad Group, Lux Capital, Alleghany Financial Group Ventures, CTI Life Sciences Fund and Alexandria Equities. For more information, visit . References 1. Mathur M, Barratt J, Chacko B, et al. A Phase 2 Trial of Sibeprenlimab in Immunoglobulin A Nephropathy Patients. NEJM. 2023 2. Floege J, Amann K. Primary glomerulonephritides. Lancet. 2016;387(10032):2036-2048. 3. Hastings MC, Bursac Z, Julian BA, et al. Life Expectancy for Patients From the Southeastern United States With IgA Nephropathy. Kidney Int Rep. 2017;3(1):99-104. 4. Mathur M, Barratt J, Suzuki Y, et al. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VIS649 (Sibeprenlimab), an APRIL-Neutralizing IgG2 Monoclonal Antibody, in Healthy Volunteers. Kidney Int Rep. 2022;7(5):993-1003. 5. Chang S, Li XK. The Role of Immune Modulation in Pathogenesis of IgA Nephropathy. Front Med (Lausanne). 2020;7:92. 6. Lai KN, Tang SC, Schena FP, et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. 7. Gleeson PJ, O'Shaughnessy MM, Barratt J. IgA nephropathy in adults - Treatment Standard [published online ahead of print, 2023 Jul 7]. 8. Rizk DA, Perkovic V, Lafayette R, et al. A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Sibeprenlimab Administered Subcutaneously in Patients With IgAN. Presented at the ASN Kidney Week 2022, November 3–6, 2022, Orlando, FL. 9. ClinicalTrials.gov. National Library of Medicine (U.S.). Safety and Efficacy Study of VIS649 for IgA Nephropathy Identifier: NCT04287985. .

临床结果临床2期并购临床3期