2014年全球在研热门药物靶点

2014年全球在研热门药物靶点2014年药物研发主要分布肿瘤、丙肝、高血脂三大块，加上高风险的阿尔兹海默病（BACE抑制剂、anti-amyloidbeta单抗）、即将谢幕的糖尿病（GLP-1类似物、DPP-4抑制剂、SGLT1/2抑制剂）、新兴的偏头痛（anti-CGRP单抗，大分子治中枢神经系统疾病，有意思）三小块。相比于2013年，主要动向体现在以下几个方面：（1）癌症免疫疗法人类研究癌症免疫已经好多年了，以前主要是做体液免疫，抗体做得很成功，疫苗做得很憋屈，现在重心转移到了细胞免疫上，包括PD1/PDL1、CTLA4、CAR、TCR几类，Bristol-MyersSquibb、Merck、Roche、Novartis、Glaxosmithkline、AstraZeneca、Servier等都有T细胞免疫疗法项目或已找到合作伙伴。（2）组合抗丙肝疗法2013年谈论最多的是纯口服抗丙肝，2014年改成组合抗丙肝了，sofosbuvir+ledipasvir、MK-5172+MK-8742、ABT-450/r+ABT-267+ABT-333、daclatasvir+asunaprevir+BMS-791325都获得了FDA的突破性药物资格，都不需要联用干扰素且SVR12应答率都在90%以上，Gilead率先递交sofosbuvir+ledipasvir的上市申请。（3）自身免疫性疾病这个领域好像从来就没冷过，类风湿性关节炎、牛皮癣、多发性硬化症、系统性红斑狼疮都很折磨人。就市场而言仅次于肿瘤，比糖尿病、心血管的市场还要大，阿达木单抗2013年销售额达到106.59亿美元，超级重磅炸弹、重磅炸弹是一大堆。就靶点而言，大分子以前主要是anti-TNFα单抗，现在针对白介素的最多，小分子主要是JAK抑制剂。（4）高血脂CETP抑制剂是指望不上了，失败了几个，剩下两个半死不活，主要还是看Anti-PCSK9。去年年初还没这么火的，下半年Amgen、Sanofi公布的临床数据都显示能够降低LDL-C50%，Pfizer立马跟了上来，今年一看Roche、EliLilly也追来了。数量上虽然没几个，但这都是烧钱的货，III期得做20000例以上，小公司砸锅卖铁也做不起。靶点适应证在研药物PI3K抑制剂实体瘤、淋巴瘤、白血病Idelalisib(filed),BKM120(phaseIII),BYL719(phaseII),pictilisib(phaseII),XL765(phaseII),PF-05212384(phaseII),PF-04691502(phaseII),GS-9820(phaseII),dactolisib(phaseII),copanlisib(phaseII),GDC-0941(phaseII),GSK2141795(phaseII),RG7422(phaseII),BGT226(phaseI/II),XL147(phaseI),SAR260301(phaseI),GSK2636771(phaseI),GSK2269557(phaseI),GSK2126458(phaseI),GSK1059615(phaseI,failed?),RG7604(phaseI),RG7666(phaseI),AMG319(phaseI),MLN1117(phaseI),AZD5363(phaseI),AZD8186(phaseI),AZD6482(phaseI)mTOR抑制剂实体瘤MK-8669(phaseII),XL765(phaseII),dactolisib(phaseII),PF-05212384(phaseII),PF-04691502(phaseII),BGT226(phaseI/II),GSK1059615(phaseI,failed?),AZD8055(phaseI)Akt抑制剂实体瘤MK-2206(phaseII),ipatasertib(phaseII),GSK2110183(phaseI),GSK2141795(phaseI),GSK690693(phaseI,failed?),RG7440(phaseI)Raf抑制剂黑素瘤Vemurafenib(approved),Dabrafenib(approved),LGX818(phaseII),RG7304(phaseI),MLN2480(phaseI)MEK1/2抑制剂黑素瘤、卵巢癌Trametinib(approved),MEK162(phaseIII),pimasertib(phaseII),RG7167(phaseI),TAK-733(phaseI)EGFR/HER2抑制剂非小细胞肺癌、乳腺癌Gefitinib(approved),erlotinib(approve*******tinib(approved),lapatinib(approved),dacomitinib(phaseIII,failed),AZD8931(phaseII),AEE788(phaseI/II,failed?),AZD9291(phaseI/II)FGFR抑制剂实体瘤BGJ398(phaseII),LY2874455(phaseII),AZD4547(phaseII)多靶点RTK抑制剂实体瘤TKI258(phaseIII),nintedanib(phaseIII),motesanib(phaseIII)Syk抑制剂类风湿性关节炎、肿瘤Fostamatinib(phaseIII,failed),GS-9973(phaseII),TAK-659(phaseI)Aurora激酶抑制剂白血病、淋巴瘤MLN8237(phaseIII),AZD1152(phaseII/III),tozasertib(phaseII,failed?),AMG900(phaseI),MK-5108(phaseI,failed?),TAK-901(phaseI,failed?),GSK1070916(phaseI,failed?),PF-03814735(phaseI,failed?)ALK抑制剂非小细胞肺癌Crizotinib(approved),LDK378(phaseIII),RG7853(phaseII)Bcl-2抑制剂白血病、淋巴瘤RG7601(phaseII),ABT-199(phaseII),ABT-737(phaseII),ABT-263(phaseII)HDM2/p53抑制剂实体瘤SAR405838(phaseI),RG7388(phaseI),JNJ-26854165(phaseI)JAK1/2/3抑制剂类风湿性关节炎、银屑病、骨髓增殖性肿瘤Tofacitinib(approved),ruxolitinib(approved),momelotinib(phaseIII),baricitinib(phaseIII),LY2784544(phaseII),GSK2586184(phaseII),GLPG0634(phaseII),AZD1480(phaseI,failed)c-Met抑制剂实体瘤Crizotinib(approved),foretinib(phaseII),LY2801653(phaseII),SAR125844(phaseI),AMG208(phaseI),AMG337(phaseI)HDAC抑制剂多发性骨髓瘤、淋巴瘤Vorinostat(approved),romidepsin(approved),LBH589(phaseIII),JNJ-26481585(phaseII)Hedgehog通路抑制剂基底细胞癌、急性粒细胞白血病Vismodegib(approved),erismodegib(phaseII),BMS-833923(phaseII),LY2940680(phaseII),PF-04449913(phaseI)ChK1抑制剂实体瘤、淋巴瘤MK-8776(phaseII),LY2603618(phaseII,failed),RG7741(phaseI),AZD7762(phaseI,failed)PARP抑制剂乳腺癌、卵巢癌Veliparib(phaseIII),olaparib(phaseIII),rucaparib(phaseIII),niraparib(phaseIII),AZD2461(phaseI,failed),iniparib(phaseIII,failed)CDK抑制剂乳腺癌Palbociclib(phaseIII),dinaciclib(phaseIII),LEE011(phaseII),LY2835219(phaseII),BAY1000394(phaseI/II),AZD5438(phaseI,failed?)p38MAPK抑制剂急性冠脉综合征、慢性阻塞性肺病、急性肺损伤、肿瘤losmapimod(phaseII),dilmapimod(phaseII),LY2228820(phaseII)Notch通路抑制剂实体瘤MK-0752(phaseI/II,failed?),PF-03084014(phaseI),LY3039478(phaseI)BACE抑制剂阿尔兹海默病LY450139(phaseIII,failed),MK-8931(phaseII/III),BMS-708163(phaseII,failed?),LY2811376(phaseI,failed?),AZD3839(phaseI,failed?)SGLT1/2抑制剂II型糖尿病Canagliflozin(approved),dapagliflozin(approved),empagliflozin(filed),ertugliflozin(phaseII),LIK066(phaseII),GSK1614235(phaseI)NS3/4A蛋白酶抑制剂HCV感染Telaprevir(approved),boceprevir(approved),simeprevir(approved),asunaprevir(phaseIII),ABT-450(phaseIII),vaniprevir(phaseIII),faldaprevir(phaseIII),MK-5172(phaseII),danoprevir(phaseII),GS-9451(phaseI)NS5A抑制剂HCV感染Ledipasvi(filed),daclatasvir(phaseIII),GS-5816(phaseII),MK-8742(phaseII),GSK2336805(phaseII),alisporivir(phaseII)NS5B抑制剂HCV感染Sofosbuvir(approved),deleobuvir(phaseIII),ABT-267(phaseIII),ABT-333(phaseIII),mericitabine(phaseII),setrobuvir(phaseII),GS-9669(phaseII),tegobuvir(phaseII,failed?)CETP抑制剂高血脂Evacetrapib(phaseIII),anacetrapib(phaseIII)Anti-PCSK9单抗高血脂Alirocumab(phaseIII),bococizumab(phaseIII),AMG145(phaseIII),LY3015014(phaseII),RG7652(phaseII)Anti-CGRP单抗偏头痛LY2951742(phaseII),AMG334(phaseI)Anti-amyloidbeta单抗阿尔兹海默病Gantenerumab(phaseIII),solanezumab(phaseIII),crenezumab(phaseII)癌症免疫疗法（PD1/PDL1、CTLA4、CAR）黑素瘤、非小细胞肺癌、淋巴瘤Ipilimumab(approved),MK-3475(phaseII