2014年全球药物研发热门靶点

作者：疑夕     来源：新浪博客

周末看了一下Novartis, Merck, Sanofi, Pfizer, Glaxosmithkline, Bristol-Myers Squibb, Johnson & Johnson, Roche, Boehringer Ingelheim, Takeda, Amgen, AstraZeneca, AbbVie, Eli Lilly几家公司的pipeline，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-amyloid beta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-Myers Squibb、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-C 50%，Pfizer立马跟了上来，今年一看Roche、Eli Lilly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。

（5）小分子
现在小分子抗癌药主要集中在PI3K/Akt/mTOR、RAF/MEK两条信号通路，其余都是每个靶点各有几个分子。JAK1/2/3抑制剂涉及肿瘤、自身免疫性疾病，做得也是热火朝天。DPP-4、SGLT1/2都是日薄西山了，BACE抑制剂失败了好几个，大伙都小心翼翼。

靶点	适应症	在研药物
PI3K抑制剂	实体瘤、淋巴瘤、白血病	Idelalisib (filed), BKM120 (phase III), BYL719 (phase II), pictilisib (phase II), XL765 (phase II), PF-05212384 (phase II), PF-04691502 (phase II), GS-9820 (phase II), dactolisib (phase II), copanlisib (phase II), GDC-0941 (phase II), GSK2141795 (phase II), RG7422 (phase II), BGT226 (phase I/II), XL147 (phase I), SAR260301 (phase I), GSK2636771 (phase I), GSK2269557 (phase I), GSK2126458 (phase I), GSK1059615 (phase I, failed?), RG7604 (phase I), RG7666 (phase I), AMG 319 (phase I), MLN1117 (phase I), AZD5363 (phase I), AZD8186 (phase I), AZD6482 (phase I)
mTOR抑制剂	实体瘤	MK-8669 (phase II), XL765 (phase II), dactolisib (phase II), PF-05212384 (phase II), PF-04691502 (phase II), BGT226 (phase I/II), GSK1059615 (phase I, failed?), AZD8055 (phase I)
Akt抑制剂	实体瘤	MK-2206 (phase II), ipatasertib (phase II), GSK2110183 (phase I), GSK2141795 (phase I), GSK690693 (phase I, failed?), RG7440 (phase I)
Raf抑制剂	黑素瘤	Vemurafenib (approved), Dabrafenib (approved), LGX818 (phase II), RG7304 (phase I), MLN2480 (phase I)
MEK1/2抑制剂	黑素瘤、卵巢癌	Trametinib (approved), MEK162 (phase III), pimasertib (phase II), RG7167 (phase I), TAK-733 (phase I)
EGFR/HER2抑制剂	非小细胞肺癌、乳腺癌	Gefitinib (approved), erlotinib (approved), afatinib (approved), lapatinib (approved), dacomitinib (phase III, failed), AZD8931 (phase II), AEE788 (phase I/II, failed?), AZD9291 (phase I/II)
FGFR抑制剂	实体瘤	BGJ398 (phase II), LY2874455 (phase II), AZD4547 (phase II)
多靶点RTK抑制剂	实体瘤	TKI258 (phase III), nintedanib (phase III), motesanib (phase III)
Syk抑制剂	类风湿性关节炎、肿瘤	Fostamatinib (phase III, failed), GS-9973 (phase II), TAK-659 (phase I)
Aurora激酶抑制剂	白血病、淋巴瘤	MLN8237 (phase III), AZD1152 (phase II/III), tozasertib (phase II, failed?), AMG 900 (phase I), MK-5108 (phase I, failed?), TAK-901 (phase I, failed?), GSK1070916 (phase I, failed?), PF-03814735 (phase I, failed?)
ALK抑制剂	非小细胞肺癌	Crizotinib (approved), LDK378 (phase III), RG7853 (phase II)
Bcl-2抑制剂	白血病、淋巴瘤	RG7601 (phase II), ABT-199 (phase II), ABT-737 (phase II), ABT-263 (phase II)
HDM2/p53抑制剂	实体瘤	SAR405838 (phase I), RG7388 (phase I), JNJ-26854165 (phase I)
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 (phase III), baricitinib (phase III), LY2784544 (phase II), GSK2586184 (phase II), GLPG0634 (phase II), AZD1480 (phase I, failed)
c-Met抑制剂	实体瘤	Crizotinib (approved), foretinib (phase II), LY2801653 (phase II), SAR125844 (phase I), AMG 208 (phase I), AMG 337 (phase I)
HDAC抑制剂	多发性骨髓瘤、淋巴瘤	Vorinostat (approved), romidepsin (approved), LBH589 (phase III), JNJ-26481585 (phase II)
Hedgehog通路抑制剂	基底细胞癌、急性粒细胞白血病	Vismodegib (approved), erismodegib (phase II), BMS-833923 (phase II), LY2940680 (phase II), PF-04449913 (phase I)
ChK1抑制剂	实体瘤、淋巴瘤	MK-8776 (phase II), LY2603618 (phase II, failed), RG7741 (phase I), AZD7762 (phase I, failed)
PARP抑制剂	乳腺癌、卵巢癌	Veliparib (phase III), olaparib (phase III), rucaparib (phase III), niraparib (phase III), AZD2461 (phase I, failed), iniparib (phase III, failed)
CDK抑制剂	乳腺癌	Palbociclib (phase III), dinaciclib (phase III), LEE011 (phase II), LY2835219 (phase II), BAY 1000394 (phase I/II), AZD5438 (phase I, failed?)
p38 MAPK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 (phase II), dilmapimod (phase II), LY2228820 (phase II)
Notch通路抑制剂	实体瘤	MK-0752 (phase I/II, failed?), PF-03084014 (phase I), LY3039478 (phase I)
BACE抑制剂	阿尔兹海默病	LY450139 (phase III, failed), MK-8931 (phase II/III), BMS-708163 (phase II, failed?), LY2811376 (phase I, failed?), AZD3839 (phase I, failed?)
SGLT1/2抑制剂	II型糖尿病	Canagliflozin (approved), dapagliflozin (approved), empagliflozin (filed), ertugliflozin (phase II), LIK066 (phase II), GSK 1614235 (phase I)
NS3/4A蛋白酶抑制剂	HCV感染	Telaprevir (approved), boceprevir (approved), simeprevir (approved), asunaprevir (phase III), ABT-450 (phase III), vaniprevir (phase III), faldaprevir (phase III), MK-5172 (phase II), danoprevir (phase II), GS-9451 (phase I)
NS 5A抑制剂	HCV感染	Ledipasvi (filed), daclatasvir (phase III), GS-5816 (phase II), MK-8742 (phase II), GSK2336805 (phase II), alisporivir (phase II)
NS 5B抑制剂	HCV感染	Sofosbuvir (approved), deleobuvir (phase III), ABT-267 (phase III), ABT-333 (phase III), mericitabine (phase II), setrobuvir (phase II), GS-9669 (phase II), tegobuvir (phase II, failed?)
CETP抑制剂	高血脂	Evacetrapib (phase III), anacetrapib (phase III)
Anti-PCSK9单抗	高血脂	Alirocumab (phase III), bococizumab (phase III), AMG 145 (phase III), LY3015014 (phase II), RG7652 (phase II)
Anti-CGRP单抗	偏头痛	LY2951742 (phase II), AMG 334 (phase I)
Anti-amyloid beta单抗	阿尔兹海默病	Gantenerumab (phase III), solanezumab (phase III), crenezumab (phase II)
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 (phase III), nivolumab (phase III), MPDL3280A (phase I), AMP-514 (phase I), AMP-224 (phase I), CTL019 (phase I)
Anti-EGFR, HER2, HER3, PDGFR, VEGF(R), Tie2, c-Met, CSF-1R, TGF(R), IGF-1R单抗	实体瘤、AMD	Bevacizumab (approved), pertuzumab (approved), ranibizumab (approved), cetuximab (approved), panitumumab (approved), ramucirumab (filed), onartuzumab (phase III), necitumumab(phase III), olaratumab (phase II), icrucumab (phase II), LJM716 (phase II), trebananib (phase II), RG7597 (phase II), fresolimumab (phase II), SAR256212 (phase II), LY3016859 (phase II), LY2382770 (phase II), cixutumumab (phase II), icrucumab (phase II), RG7116 (phase I), AMG 780 (phase I), RG7155 (phase I), RG7221 (phase I), SAR307746 (phase I)
Anti-CD19, CD20, CD32, CD38, CD319单抗	淋巴瘤、白血病、自身免疫性疾病	Rituximab (approved), ibritumomab (approved), ofatumumab (approved), obinutuzumab (approved), ocrelizumab (phase III), elotuzumab (phase III), SAR3419 (phase II), SAR650984 (phase I), AMG 729 (phase I)
Anti-IL单抗（IL-4, IL-5, IL-6, IL-13, IL-17, IL-18, IL-23）	自身免疫性疾病、炎症、哮喘、糖尿病	Ustekinumab (approved), tocilizumab (approved), secukinumab (filed), ixekizumab (phase III), lebrikizumab (phase III), brodalumab (phase III), mepolizumab (phase III), MK-3222 (phase III), sirukumab (phase III), sarilumab (phase III), RG7624 (phase II), GSK1070806 (phase II), dupilumab (phase II), SAR156597 (phase II), sarilumab (phase II), clazakizumab (phase II)
抗体偶联药物	肿瘤	SGN-35 (approved), T-DM1 (approved), RG7593 (phase II), RG7596 (phase II), ABT-414 (phase I/II), AMG 172 (phase I), RG7450 (phase I), RG7458 (phase I), RG7598 (phase I), RG7599 (phase I), RG7600 (phase I), RG7636 (phase I), AMG 172