论文骨髓增生性肿瘤的分类和个体化预后

Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment.展开>><<收起

N Engl J Med 2018; 379:1416-1430  0
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Gritstone登陆纳斯达克 打造个体化抗癌疗法

新闻Gritstone登陆纳斯达克 打造个体化抗癌疗法

本周,生物技术公司在纳斯达克市场掀起了一波IPO的热潮,共有5家公司先后上市。其中,今日上市的Gritstone Oncology作为打造个体化抗癌疗法的新锐,广受业界看好。 Gritstone成立于2015年,是一家专注开发肿瘤特异性免疫疗法的生物技术公司。我们知道,在不同患者的不同肿瘤上,会出现具有高度特异性的新抗原。如果能靶向这些新抗原开发免疫疗法,就有望对这些患者的癌症进行有效治疗。 然而在肿瘤细胞中,只有少量的DNA突变会转化为新抗原,这也给新抗原的鉴定带来了困难。目前,常规技术无法精准预测肿瘤特异的新抗原,因此也给免疫疗法的开发带来了困难。 为了解决这一难题,Gritstone开发了一款叫做EDGE的人工智能平台。利用海量的人类肿瘤数据,这一人工智能平台有望从中寻找到“鉴别肿瘤新抗原”的洞见,并将其应用于临床。目前,这一平台上已经获取了300多位患者的数据,多肽数量超过100万条。值得一提的是,这些患者罹患多种肿瘤类型,且祖源来自全球各地。这些多样化的数据,有助于提升其人工智能平台的能力。 目前,Gritstone已有两款免疫疗法进入了临床前阶段。第一款叫做GRANITE-001,针对患者特异新抗原所开发。具体来看,这款疗法会先从患者体内获取活检组织,对肿瘤进行测序。随后,EDGE人工智能平台会对肿瘤新抗原进行预测,从而推动个体化疗法的设计与使用。Gritstone相信,在罹患常见肿瘤的患者群体中,大约有70%-80%的患者有望从中受益。 其另一款疗法SLATE-001则有所不同。如果说GRANITE-001是一种疗法治疗一位患者,SLATE-001就是一种疗法治疗多名患者。这是由于不同的患者可能具有共同的突变(如常见的癌症驱动基因突变)。因此,针对特定新抗原的免疫疗法,有望使多名患者从中受益。 Gritstone的治疗理念得到了业界的普遍看好,并已和bluebird bio等公司达成合作协议。先前,这家公司的A轮与B轮融资总额约2亿美元,参与投资的包括Versant Ventures、The Column Group、Clarus Funds、Frazier Healthcare Partners、Redmile Group、Casdin Capital、Lilly Asia Ventures、Trinitas Capital、GV、Alexandria Venture Investments、以及Bay City Capital等知名风投机构。2017年,它也入选了“生物技术猛公司”(FierceBiotech's 2017 Fierce 15)榜单。评语指出,“这些公司有着杰出的科学平台,有着卓越的管理团队,有着光明的未来前景”。 我们期待随着成功登陆纳斯达克市场,Gritstone能进一步获得资本助力,推进个体化肿瘤免疫疗法的研发,为全球更多患者带来创新抗癌方案。详情>>

2018-09-30 00:00:00

论文成人斯蒂尔病发病机制、生物标志物和治疗靶点

Adult-onset Still’s disease (AoSD) is a rare but clinically well-known, polygenic, systemic autoinflammatory disease. Owing to its sporadic appearance in all adult age groups with potentially severe inflammatory onset accompanied by a broad spectrum of disease manifestation and complications, AoSD is an unsolved challenge for clinicians with limited therapeutic options. This Review provides a comprehensive insight into the complex and heterogeneous nature of AoSD, describing biomarkers of the disease and its progression and the cytokine signalling pathways that contribute to disease. The efficacy and safety of biologic therapeutic options are also discussed, and guidance for treatment decisions is provided. Improving the approach to AoSD in the future will require much closer cooperation between paediatric and adult rheumatologists to establish common diagnostic strategies, treatment targets and goals.展开>><<收起

Nature Reviews Rheumatology,Published: 14 September 2018  0
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Cell:上海药物所发现肿瘤表观遗传靶点EZH2调控新模式及个性化治疗新策略

新闻Cell:上海药物所发现肿瘤表观遗传靶点EZH2调控新模式及个性化治疗新策略

2018年9月13日,生物学权威杂志《细胞》(Cell)刊登中国科学院上海药物研究所耿美玉课题组、丁健课题组和谭敏佳课题组联合攻关的针对肿瘤表观遗传异常的精准治疗策略研究成果。该研究针对目前肿瘤表观遗传抗肿瘤药物的临床用药困境,揭示了决定组蛋白甲基转移酶EZH2抑制剂实体瘤疗效响应的核心机制,提出了新的肿瘤分群策略和联合用药方案,为广大EZH2高表达肿瘤的个性化治疗指明了方向。 表观遗传是控制基因组序列信息到蛋白功能和细胞功能的大门,是后天因素以及环境与人体信息交流的途径。表观遗传异常是导致肿瘤发生的重要因素。染色体中组蛋白的修饰特征是表观遗传的重要表现形式,通过控制基因转录的开与关决定着癌基因和抑癌基因的转录调控。组蛋白甲基转移酶EZH2是表观领域备受关注的抗肿瘤靶点,已有多个抑制剂处于临床研究。但是,现有的临床前和临床前研究证据均表明,EZH2抑制剂仅对个别含有EZH2激活突变的血液系统肿瘤具有一定的治疗效果,对实体瘤治疗基本无效,从而极大的限制了这类抑制剂的临床研究与应用空间。 研究团队通过对近百株肿瘤细胞EZH2抑制剂的敏感性和表观遗传动态修饰变化进行系统筛查,结合基于蛋白组组学的组蛋白修饰全景检测分析发现,抑制EZH2会影响数十种组蛋白修饰状态改变,导致肿瘤细胞蛋白修饰谱的重塑。其中,组蛋白H3K27位上的甲基化(H3K27me)与乙酰化(H3K27ac)之间的相互转化,启动不同肿瘤细胞中癌基因信号通路的差异活化,是导致EZH2抑制剂耐药的重要原因。 研究团队进一步研究发现,肿瘤细胞中本底另一组蛋白甲基转移酶MLL1的表达水平差异,是决定H3K27me与H3K27ac转化的关键。在大多数的肿瘤特别是实体瘤中,EZH2和MLL1均高表达,因此,EZH2抑制剂在抑制H3K27甲基化的同时,MLL1会招募p300和CBP形成复合物并催化H3K27乙酰化,加速H3K27me与H3K27ac之间的转化。这一发现打破了EZH2在大多数肿瘤中独立存在、发挥生物学功能认识的局限,揭示EZH2生物学功能的发挥与H3K27甲基化与乙酰化互为依存、相互牵制的调控模式密切相关,为EZH2抑制剂、p300和BRD4抑制剂联合应用提供合理依据。 表观遗传的异常在得到抑制剂控制的状态下,反馈性激活激酶信号通路可能是肿瘤细胞产生耐药、赖以生存的重要原因。团队研究人员进一步通过系统性多维组学的分析,从组蛋白修饰谱-转录谱-蛋白质谱-磷酸化谱的协同差异化分析发现,H3K27甲基化与乙酰化同时抑制时,能够导致激酶MAPK信号通路的异常激活,证实表观遗传调控与细胞磷酸化信号网络的交互调控在表观遗传药物耐药产生的作用。 该研究的发现突破现有认识局限,有望将EZH2抑制剂的应用推广到EZH2高表达的实体肿瘤,极大地拓展了这类抑制剂的临床应用空间,并为难治性肿瘤三阴性乳腺癌、胰腺癌和肝癌提供了治疗方案。重要的是,该项研究首次提出的基于MLL1生物标志物指导的针对EZH2高表达肿瘤的三级治疗策略,特别是提出的联合临床现有药物BRD4或MAPK通路抑制剂,有望实现较广范围覆盖EZH2高表达肿瘤群体的精准治疗方案,同时为其他类型表观遗传抑制剂的个性化治疗提供了成功范例,具有普遍的指导意义。 本研究受到中国科学院战略性先导科技专项,国家自然科学基金(创新群体项目,重大研究计划),国家重点基础研究发展计划(973计划)和国家重点研发计划精准医学研究重点专项的资助。 链接:https://www.cell.com/cell/fulltext/S0092-8674(18)31119-X MLL1介导的H3K27乙酰化增加促进癌基因转录介导EZH2抑制剂耐药;依据MLL1表达量和反馈性MAPK活化状态的分群和治疗策略详情>>

2018-09-14 00:00:00
又一家中国 AI 医疗新锐崛起!视见科技完成 1 亿元 A 轮融资

新闻又一家中国 AI 医疗新锐崛起!视见科技完成 1 亿元 A 轮融资

近日,人工智能医疗公司视见科技宣布,已完成 A 轮追加融资,投资方为招商局创投。视见科技于 2018 年 3 月完成 A 轮融资,由深创投领投。至此,视见科技完成总额为 1 亿元人民币的 A 轮融资。 视见医疗科技是一家将人工智能应用于医学影像领域的创新型公司,核心是依托人工智能深度学习和计算机医学影像分析技术,开发出高质量的医学影像分析软件和大规模影像分析平台,对医学影像大数据进行智能化识别和分析,快速、精确地提供辅助诊疗方案建议,从而提高临床诊疗的精准度和效率。 据公司官网信息,视见医疗产品和服务涉及放射、病理和放疗三大领域,主要包括:大规模病理显微图像分析、肺癌早期 CT 筛查、放射靶区勾勒和规划、CT/MRI 三维器官建模、TCT 宫颈癌人工智能筛查系统、内窥镜影响分析等。 视见科技所提供的产品和服务可广泛应用于医院、独立影像和检验中心、远程诊断云平台、医学成像设备厂商、医学教研机构和患者等用户群体。目前,视见医疗已经获得香港创新科技署数百万港币资助和联想创投两千万元投资。视见医疗总部位于深圳,现设有深圳、香港、成都、北京四大研发中心。 视见科技的本轮融资将继续聚焦于产品研发,在团队组建和产品矩阵上持续追加投入,并加快推进临床应用场景探索,推动公司快速发展。 ▲视见科技创始人兼联席 CEO 陈浩博士(图片来源:视见科技官网) 对于视见科技本次融资,视见科技创始人兼联席 CEO 陈浩博士介绍道:“一方面说明视见科技成立一年多以来,公司的团队、产品和市场进度,得到了资本市场的充分认可;另一方面,人工智能在医疗领域的真正大规模落地应用,还需要一个较长的时间。从技术、产品、市场以及政策层面,都开始进入攻坚阶段,需要摒弃浮躁的心态。有了资本的助力,我们就更能沉下心来专注于把技术研发和产品开发做好,同时探索更多的临床应用场景。” 我们祝贺视见科技获得此次融资,也祝愿未来的中国医疗 AI 事业可以更加蓬勃发展。详情>>

2018-06-29 00:00:00
生物技术公司IPO大潮来势凶猛

新闻生物技术公司IPO大潮来势凶猛

【新闻事件】:继上周多个生物技术公司IPO共融资7.18亿美元后本周又有四家生物技术成功上市,共融资5.46亿,令过去10天的IPO总量达到12.7亿美元。今年半年不到美国已经上市30家生物技术企业,接近去年全年的31个,融资总量达到32.5亿美元。本周四个IPO各具特色,开发CKD的Tricida融资2.2亿,是少见的已经完成三期临床的IPO。开发mRNA药物的Translate Bio融资1.22亿,成为首家在美国上市的mRNA企业。开发CD47激动剂的Forty Seven 刚成立两年,这次融资1.12亿。另一家免疫疗法公司、开发肿瘤疫苗的Neon 融资1亿。 【药源解析】:资本以创纪录速度流入生物制药有多种因素,既有刚性需求也有一定泡沫成分。现在生物技术的大环境非常有利,是主要驱动力。FDA连续几年批准远高于历史平均水平的新分子药物,而且继续显示与制药工业合作尽快上市颠覆性新药的友好态度。现在只要产品没问题FDA极少会成为你赢利障碍。支付方面虽然压力很大,但受到挤压较多是传统me-too常见大众病药物。颠覆性疗法相比之下受到支付部门青睐,而这些药物是生物技术公司的主攻方向,所以资本大量涌入。另一个重要因素是虽然特朗普总统宣称要限制药价,但总是雷声大、雨点小,宣布限制药价新政当天制药股普遍上扬。 生物技术生存环境的另一个主要方面是技术进步本身。随着基础研究的进步和临床前、临床研究的精准化,现在研发效率有所改善。挣扎多年的几个主要技术如RNA、基因疗法、细胞疗法几乎同时进入收获季节,令投资者热情高涨。最近几年一个重要治疗板块是肿瘤免疫疗法,这种疗法不是直接杀死肿瘤、而是破坏肿瘤的生存环境,通常安全性比传统化疗要好。更重要的是免疫疗法的应答持久性远高于传统疗法,第一次令晚期肿瘤治愈成为触手可及的目标。免疫系统十分庞大复杂、介入点很多,所以吸引了大量资本从不同角度、不同通路调控这个天然抗癌系统。最后,近几年一个明显的趋势是开创新技术的著名大学教授纷纷下海、经验丰富的世界主要药厂高管也大量涌入初创生物技术公司,这令生物技术公司的技术和执行力都有较大提高,也成为吸引投资者的一个重要因素。 当然这些有利条件必然会导致一定程度泡沫。很多投资者怀着不想错过下一个PD-1的心理,类似当年淘金、有点赌博成分。现在投资进程不仅前移、A轮基本就是原来的天使,而且单项投入力度明显上升。很多临床证据不多、甚至没有临床数据的企业也参加IPO,虽然早期阳性数据相对容易得到但假阳性也更多,这可能会导致更高的失败率。早期项目区分更加困难,和买彩票类似、人的本性都认为自己投的项目最可能赢,但市场的容量是有限的,最后必须有人失败。目前制药业对有些高新技术的早期评价也存在不足,如免疫疗法现在还没有可靠的评价系统。这些因素可能导致重复盲目投入、甚至养育一些南郭先生,但大量资本涌入的确给颠覆性技术一个快速成长的机会。现在家喻户晓的PD-1药物五年前即使专业人员也没几个知道,这可能是现在生物技术IPO如此火爆的最核心因素。详情>>

2018-06-29 00:00:00
艾伯维与 Calibr 大合作,开发实体瘤 CAR- T 疗法

新闻艾伯维与 Calibr 大合作,开发实体瘤 CAR- T 疗法

今日,艾伯维(AbbVie)与 Calibr 宣布将合作开发 T 细胞疗法,主要针对实体瘤等癌症。此次合作拓宽了艾伯维的肿瘤学研究领域,使其获得先进的精准医学技术,从而扩大可改善癌症患者生活的治疗方法的开发。 Calibr 是一家致力于开发下一代药物的非营利性转化研究机构。作为 Scripps Research 的一部分,Calibr 位于美国圣地亚哥市的 Torrey Pines Mesa 生物医学研究中心,拥有从早期发现到临床项目的广泛研发产品线,在研新药类型包括小分子、多肽、生物治疗药物和细胞疗法等。 嵌合抗原受体 T 细胞(CAR-T)疗法利用癌症患者自身免疫系统的力量,来攻击和摧毁癌细胞。虽然该疗法在恶性血液病方面取得了令人鼓舞的结果,但目前针对实体瘤开发的 CAR- T 疗法依然存在局限性,它们由 CAR- T 细胞的快速激活和扩增引起,可能导致严重的不良事件。Calibr 的新型细胞疗法项目由 Calibr 蛋白质科学主管 Travis Young 博士领导,旨在通过使用一种专有的模块化“可切换”CAR- T 细胞(使用抗体开关分子来控制 CAR- T 细胞的激活和抗原特异性),来增强治疗的安全性、多功能性和功效。Calibr 的专利技术可以促进 CAR- T 通用疗法在多种类型的血液和实体肿瘤中的开发。 根据此次合作协议条款,艾伯维将向 Calibr 支付前期许可费,并获得 Calibr 可切换 CAR- T 平台的独家使用权,期限长达四年。两家机构将共同合作开发针对由艾伯维确定的实体瘤靶点的 T 细胞疗法。艾伯维还可以选择开发针对其提名靶点的其他细胞疗法,并获得正在开发的 Calibr 细胞治疗项目的许可(包括 Calibr 的主要候选药物),用于血液和实体癌症。Calibr 计划于 2019 年将该候选药物推向临床研究。此外,该协议还规定艾伯维有权在合作的头四年内获得 Calibr 可切换 CAR- T 平台和项目的独家许可。两家机构将分担临床前开发责任,艾伯维负责临床开发和推广,Calibr 有资格获得里程碑付款和特许权使用费。 “Calibr 组建了一支优秀的科学团队,开发了一种创新的细胞疗法技术,可以将我们带到癌症治疗的下一个前沿,”艾伯维副总裁兼肿瘤早期研发主管 Mohit Trikha 博士说:“艾伯维的肿瘤发现和早期研发专长与 Calibr 的新型可切换 CAR- T 治疗平台的结合,旨在推进当前的护理标准,并有可能为患者快速推出新的治疗方案。” “我们很高兴能与像艾伯维这样的强大合作伙伴一起工作,扩大 CAR- T 细胞领域对更广泛癌症的影响。”Calibr 和 Scripps Research 首席执行官 Peter Schultz 博士说。详情>>

2018-06-26 00:00:00
骨关节炎遗传学大数据

新闻骨关节炎遗传学大数据

The largest study to date on the genetics of hip and knee osteoarthritis (OA) has yielded new associations with genes encoding a cytokine, a kinase and a transcriptional repressor, as well as genetic correlations with other diseases. Can these clues help to unravel details of the pathogenesis of OA? Refers to Zengini, E. et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat. Genet. 50, 549–558 (2018) Osteoarthritis (OA) is the most common joint disorder worldwide and a top contributor to global disability, yet no disease-modifying drugs exist to treat OA. To develop such drugs, a deeper understanding of the molecular pathogenesis of OA has been pursued through genetics, among other approaches, owing to the strong heritability of OA1,2. As of the end of 2017, 21 independent susceptibility loci for OA had been reported in various genome-wide association studies (GWAS) of hip, knee and hand OA, including a variety of phenotypes such as radiographic OA, total joint replacement and minimum joint space width (mJSW), a proxy for cartilage thickness1,2. These GWAS have yielded only a fragmented view of the molecular pathogenesis of OA, and one of the main hindrances has been the lower sample sizes used in these studies compared with GWAS in other complex diseases. However, the limitation caused by sample size has now been tackled by Zengini et al.3 in a new GWAS of knee and hip OA that illuminates many aspects of OA genetics, including the finding of novel genes associated with OA, that could open new areas of research in the pathogenesis of this disease. This impressive GWAS3 adds to what is known about the genetic architecture of hip and knee OA by contributing data from the UK Biobank that have been replicated and combined with data from individuals from Iceland. The UK Biobank data include the results of five GWAS on partially overlapping cohorts of self-reported and/or hospital-diagnosed patients with hip or knee OA and controls from the UK Biobank (~10,000 each of self-reported and hospital-diagnosed patients and ~40,000 controls). The top 200 single nucleotide polymorphisms (SNPs) were replicated in samples from the ~18,000 patients with OA and 246,000 controls from Iceland. The results of this study3 refine and confirm ideas that have already been derived from previous studies1,2, but also include the identification of nine new OA-associated loci and a wide exploration of genetic correlations between OA and other traits and diseases (Box 1). The genetic architecture of OA is that of a highly polygenic disease. The complexity of OA means that only ~30 loci have been identified so far, most of which are associated with hip or knee OA, that explain only a small fraction of the disease heritability. These loci mainly contain common variants that have a small effect, with the exception of two rare variants that have a strong effect1,2. These common variants are mainly found outside of gene coding sequences and possibly modify gene regulation, although the hypothesized effects of these variants are difficult to demonstrate. One notable result from this new GWAS3 is the strong genome-wide correlation between hip and knee OA (88%), which had not previously been suspected because loci identified in patients with OA were often joint specific1,2. However, despite this high degree of overall correlation between hip and knee OA, Zengini et al.3 also noted many results that were specific to the particular phenotypes included in this study. The heterogeneity of these phenotypes and the complexity of OA genetics are likely to have contributed to the modest reproducibility of the loci identified with genome-wide significance in previous studies. Zengini and co-workers3 found no strong causal relationships between the nine new loci and potentially important pathways in OA pathogenesis; however, evidence did suggest that three of the loci might be associated with genes that could potentially reveal new insights into OA. One SNP was located in an intron of TGFA, which encodes transforming growth factor-α (TGFα). Previously, this locus has been associated with hip mJSW and with the differential expression of TGFα between cartilage lesions and non-lesioned cartilage4. TGFα also induced many changes typical of OA in cultured rat chondrocytes5. The locus identified by Zengini et al. therefore reinforces the idea that TGFα might be an important cytokine in OA. Another newly associated SNP3 was located in an intron of MAP2K6, which encodes dual specificity mitogen-activated protein kinase (MAPK) kinase 6 (MP2K6), a central member of the p38 MAPK pathway. This pathway is involved in the signal transduction of a plethora of cellular processes, including inflammation and chondrocyte apoptosis, and its inhibition has been proposed to be beneficial for OA. However, the overall inhibition of the p38 MAPK pathway has resulted in aggravated disease in mouse models of OA6. The possibility that MP2K6 could provide clues about how to modulate the p38 MAPK pathway in a selective and beneficial way merits additional studies. The third promising gene, BACH1, is located in the vicinity of another newly associated SNP, rs116882138, and showed increased RNA expression in degraded cartilage3. Previous mouse studies have shown that deficiency of Bach1 prevents the development of OA by a combination of reduced oxidative damage and decreased amounts of extracellular matrix-degrading enzymes7, suggesting that this locus could be the first to be related to reactive oxygen species in OA. Understanding the genetic relationships between OA and other traits or clinical conditions can help elucidate cause and effect, as inherited genetic risks cannot be subject to reverse causation. To this end, Zengini and co-workers3 investigated the genetic relationship between OA and other traits using two methods. First, they estimated genetic correlations using cross-trait linkage disequilibrium score regression to assess the heritability explained by common SNPs. This method distinguishes between population stratification and polygenicity in GWAS8. Zengini et al.3 found a genome-wide genetic correlation between OA and 35 of the 219 investigated traits and diseases. The 35 genetically correlated phenotypes fell into several broad categories: BMI and obesity-related traits, type 2 diabetes mellitus, education, depression, parents’ longevity, reproductive phenotypes, smoking and lung cancer. Zengini et al.3 also applied Mendelian randomization to the data sets, in which significantly associated SNPs are used as instrumental variables to quantify causal relationships between risk factors and disease9. The only consistent evidence for causal genetic correlation was identified in obesity-related traits (Box 1). In other words, genetic factors that predispose to various measures of obesity also cause an increased risk of OA, a fact that had previously been reported in smaller data sets than those used by Zengini et al.3 and only for a single obesity-related gene2. Interestingly, Zengini et al.3 did not find a causal effect between metabolic syndrome-related phenotypes (other than obesity) and OA, although an association between metabolic syndrome and OA has been postulated10. These data are relevant as they suggest that although there are likely to be common pathogenic pathways between traits such as dyslipidaemia and OA or type 2 diabetes mellitus and OA, these conditions do not seem to be causally linked. In conclusion, this truly large-scale GWAS3 confirms the complexity of OA at a genetic level and provides some clues that could help to define the molecular pathogenesis of this disease. Among these clues, genetic factors related to obesity but not to other aspects of metabolic syndrome are important as causative contributors to OA in large joints. Box 1 Current understanding of the genetics of hip and knee osteoarthritis Genetic structure The genetics of hip and knee osteoarthritis (OA) are highly polygenic with ~30 known loci explaining only a small fraction (~25%) of the heritability. These loci predominantly involve common risk alleles of small effect and the known loci show modest reproducibility. Phenotype specificity The OA loci are specific to particular OA phenotypes defined by joint, clinical or radiographic assessment, sex and other factors. Zengini et al.3 found a strong genetic correlation between OA in the hip and knee joints. Function of risk variants The function of most putative risk variants is difficult to discern. Available evidence for the function of risk variants includes expression quantitative trait loci and epigenetic modifications that are suggestive of regulatory functions. Disease or trait correlations OA genetics correlate with many other traits, including causal correlations with obesity, height and lumbar spine bone mineral density. No causal genetic links exist between OA and type 2 diabetes mellitus or triglyceride levels.详情>>

Nature Reviews Rheumatology
2018-06-14 00:00:00
增速放缓、数量下滑:2018全球新药研发大数据体现了哪些新趋势?

新闻增速放缓、数量下滑:2018全球新药研发大数据体现了哪些新趋势?

近年来,全球医药产业呈现出稳健发展的势头,新的药物作用靶标以及新的治疗方式不断被发现和应用,2018年全球新药研发也呈现出诸多新的特点。通过对国际知名咨询机构Informa Pharma Intelligence公司的Pharmaprojects数据库数据进行分析,可以帮助我们全面了解2018年全球在研新药市场的一些新变化,及时发现全球新药研发领域的一些新趋势。 在研项目数量: 增速放缓,与化学合成药开发难度增大有关 Pharmaprojects数据库收录的在研药品信息,特指目前处于在研状态的药品研发项目,纳入了处于临床前研究阶段的项目、处于不同临床研究阶段的项目、处于注册阶段的项目,以及增加新适应症的已上市药物。根据最新数据,截至2018年1月,全球在研新药数量为15267个,与2017年的14872个相比,同比增幅仅为2.7%。 从2001-2018年数据看,全球在研新药数量保持持续增长态势,尤其是2011年以来,全球在研新药数量呈现明显增长势头。然而需要特别注意的是,虽然2014年以来全球在研新药数量同比增幅均超过8.0%,但近两年增速逐年放缓,2016年、2017年、2018年全球在研新药数量增幅分别为11.5%、8.4%和2.7%。 2018年全球在研药物数量仅增加395个,与2017年1154个的增量相比,出现了较大幅度的下滑。近年来,化学合成小分子药物开发难度逐年增加,一些在研项目出现了项目终止的状况,进而导致化学合成药物呈现净增长数量下滑,并对全球在研药物数量的下滑产生了一定的影响。 通常,制药业产品管线数量的持续增长与制药业的产出有内在关联。需要注意的是,产品管线扩张速度下滑在2015年时即已出现。以全球上市的NAS(新活性物质)数量为例,其已从2014年的63个下降至2015年的46个,2016年该数字进一步下降至41个,这也是自2011年以来NAS数量连续两次出现下滑。 值得庆幸的是,这种局面在2017年得到了扭转,2017年全球上市的NAS数量为54个,包括47个新分子实体NMEs和7个疫苗类药物。其中,仅美国FDA在2017年批准的新分子实体NMEs药物就已高达34个,这也创造了1997年以来FDA批准NMEs药物数量的峰值。尽管整个制药行业仍未完全走出低谷,但全球在研药物数量继续保持整体增长,仍然是一个积极信号。 不同阶段对比: 注册前和上市阶段项目数减少 从制药研发流程来看,新药研发大概可以分为三个阶段:首先,通过临床前研究发现并确认候选药物;其次,通过临床研究验证候选药物的有效性和安全性;最后,顺利通过注册及上市环节,最终实现候选药物的临床价值。 通过对比2018年和2017年处于不同研发阶段的在研药物规模后发现,所有阶段的在研药物数量基本维持不变或仅有小幅变动。 其中,处于临床前研究阶段的药物数量变化相对明显,2018年处于该阶段的药物数量为8040个,较2017年数量(7493个)增加了547个候选药物,同比增幅为7.3%,远超全球在研药物平均增速,数量更是首次突破8000大关。据统计,2018年统计数据中新进入临床前研究阶段的药物数量为3807个,与去年同期数据(4005个)相比略有下降。在这些临床前研究项目中,许多项目来自小型创业公司。 处于临床研究阶段(包括Ⅰ期、Ⅱ期和Ⅲ期临床阶段)和注册阶段的在研药物数量分别为5493个和150个,同比增幅分别为0.86%和29.3%。 而处于注册前和上市阶段的在研药物数量则出现下滑趋势,在研药物数量分别为214和1199,同比增幅分别为-2.7%和-14.0%。 处于上市阶段的在研药物,一般是指开发新的治疗领域或增加新的适应症的已上市药物,如果没有进一步的研发进展,则会被视为完全上市的药物,并从该类别中移出不再进行统计。进一步分析发现,2018年新增的进入上市阶段的在研药物数量约为100个,但最终处于活跃状态的药物数量却下降了约200个左右,这意味着约有300个项目因为无新的研发进展而被移出统计范畴。 后期项目流失率: Ⅲ期项目数量下滑,影射流失率仍高 对处于临床研究阶段的在研药物数据进一步分析后发现,2018年处于Ⅰ期、Ⅱ期和Ⅲ期临床研究阶段的药物数量分别为2127、2360和1006个,增幅分别为3.1%、0.1%和-1.9%。处于临床Ⅱ期的药物数量基本无变化,但处于临床Ⅲ期的药物数量则出现了小幅下滑,因此不难看出,处于研发后期的品种仍存在流失率较高的情况,应引起注意。 其实,2017年处于Ⅱ期和Ⅲ期临床研究阶段的药物数量增幅已有所放缓,2018年该趋势仍在延续。但这种情况未必完全是件坏事。临床试验往往需要巨大的费用支持,如果不能保证上市药物的持续增加,那么临床阶段药物数量的稳定增长也是无法保证的。从近十年的数据来看,2018年处于各临床研究阶段的药物数量都约为10年前数据的2倍,但上市药物数量却没有这样高的增幅。 获批上市的可能性: 注册前>Ⅲ期临床 对于在研药物市场的评估,在研药物数量情况是一方面,项目质量同样重要。对项目的临床和注册进度进行分析,可评估一种药物获得FDA批准的可能性,并确定一种药物是否较其他同类药物更易获得批准。 从统计数据来看,2018年“注册前”药物获得批准的可能性高于行业平均水平的药物比例约为52.5%,较2017年(49.3%)有所升高;临床Ⅲ期情况则相反,2018年获得批准的可能性高于行业平均水平的药物比例为24.2%,较2017年(25.3%)有所下降。从临床研究阶段的整体数据看,2018年在研药物获批可能性的分布情况,与2017年数据基本一致。详情>>

2018-06-01 00:00:00

论文生物标志物作为药物开发的工具:发现、验证、鉴定和使用

The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.展开>><<收起

Nature Reviews Rheumatology,Published: 14 May 2018  0
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