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另外，分享一个近期的会议活动给您，中国科学院和我们连续几年发布《研究前沿》。10月31日(星期一)下午， 2016研究前沿发布暨研讨会将在中国科学院学术会堂举行。按照会议议程，中国科学院院长白春礼院士将为会议致辞，副院长李静海院士参与主持会议，高福院士、方忠研究员、张伟贤教授等科学家将进行相应学科的研究前沿解读。详细议程见附件，或会议网站：http://science.thomsonreuters.com.cn/research_fronts_2016/index.htm

欢迎您的关注，或转发给您认为感兴趣的老师，同事。

如下是药物快讯，由于工作交接，耽误了一些时间，请理解。

每月药物快讯-2016年9月

肿瘤

2016年9月2日 ，基因泰克发表新的CREB结合蛋白抑制剂

基因泰克的科学家报告发现一种CREB结合蛋白（CBP）布罗莫结构域的体内探针。应用一种限制功能的多元组件筛选CBP后发现GNE-272。该化合物的CBP 的IC50 = 0.021 mcM, CBP BRET 细胞的l IC50 = 0.41 mcM ，BRD4的 IC50 = 12 mcM。GNE-272在MOLM-16急性髓性白血病移植瘤中显示了疗效，在一个Myc MOLM-16药代动力学/药效动力学模型中显示了活性，可以降低Myc的转录水平(Romero, A. 252nd Am Chem Soc (ACS) Natl Meet (Aug 21-25,费城) 2016, Abst MEDI 255)。

SEP 02, 2016
GENENTECH DESCRIBES NEW CREB-BINDING PROTEIN INHIBITORS

Investigators from Genentech have reported the discovery of an in vivo probe for the brodomain of CREB-binding protein (CBP). Screening CBP with a property-restricted diversity set led to the identification GNE-272. The compound had a CBP IC50 = 0.021 mcM, CBP BRET cell IC50 = 0.41 mcM and BRD4 IC50 = 12 mcM. GNE-272 showed efficacy in a MOLM-16 acute myeloid leukemia xenograft model and activity in a Myc MOLM-16 pharmacokinetic/pharmacodynamic model, reducing Myc transcript levels (Romero, A. 252nd Am Chem Soc (ACS) Natl Meet (Aug 21-25, Philadelphia) 2016, Abst MEDI 255).

GNE-272

2016年9月1日，欧盟批准辉瑞的克唑替尼治疗ROS-1阳性的非小细胞肺癌

辉瑞报告欧盟已经批准Xalkori(R)（克唑替尼）用于治疗成人ROS1阳性的非小细胞肺癌。该药物也适用于治疗成人间变性淋巴瘤激酶（ALK）阳性的进展期非小细胞肺癌。FDA于3月批准Xalkori(R)用于ROS1阳性的转移性非小细胞肺癌。该药物是目前唯一被欧盟和美国批准的生物标志物驱动的治疗，用于ALK阳性或ROS1阳性的进展期NSCLC（辉瑞新闻发布）。

SEP 01, 2016
EUROPEAN COMMISSION APPROVES PFIZER'S CRIZOTINIB FOR ROS-1 POSITIVE NSCLC

Pfizer has reported that Xalkori(R) (crizotinib) was approved by the European Commission to treat adults with ROS1-positive advanced non-small-cell lung cancer (NSCLC) in the EU. The drug is also indicated to treat adults with anaplastic lymphoma kinase (ALK)-positive advanced NSCLC. The FDA approved Xalkori in March to treat those with metastatic NSCLC whose tumors are ROS1-positive. The drug is now the only biomarker-driven treatment that is approved to treat ALK-positive or ROS1-positive advanced NSCLC in the EU and the U.S (Pfizer News Release).

克唑替尼 Crizotinib

肿瘤免疫治疗

2016年9月8日 肿瘤免疫治疗，日本批准OPDIVO静脉输注治疗不可切除的或转移性肾细胞癌

Ono制药和施贵宝于2016年8月26日宣布Ono制药在日本获得对于静脉输注（20和100毫克）Opdivo(R) (纳武单抗)生产和销售授权进行部分改动的批准，该药用于治疗不可切除的或转移性肾细胞癌。Opdivo是一种纯人类抗人类程序性细胞死亡蛋白1（PD-1）单克隆抗体。作为免疫检查点抑制剂可以阻断PD-1受体与配体的相互作用。是第一个该类抗体显示可以延长既往接受过抗血管生成治疗的不可切除的或转移性肾细胞癌患者的总体生存。对一项开放，随机III期名为CheckMate-025的临床试验(ClinicalTrials.gov Identifier NCT01668784)进行的中期分析显示，Opdivo组的中位总体生存为25个月，对照组everolimus为19.6个月，有显著延长。2014年7月，Opdivo在日本获得治疗黑色素瘤的生产和销售授权，这是世界首次批准
纯人类抗人类PD-1单克隆抗体用于该适应症。Opdivo也于2015年12月获得治疗不可切除的，进展期或复发的非小细胞肺癌的适应症，已经递交的补充申请有复发或耐药的何杰金氏淋巴瘤和复发或转移性头颈癌。在日本以外，作为Ono和BMS合作的一部分，Opdivo已经获得54个国家的法规批准。在日本，Ono和BMS是战略伙伴，共同开发，共同商业化和共同推广多个免疫疗法，治疗日本的癌症病人。Ono期望进一步搜集临床数据以保证更适当地和更有效果地使用Opdivo。遵守条件性审批，Ono承诺采取必要的行动保证恰当地使用Opdivo，包括实施上市后的应用结果调查（所有病例的监测）和搜集关于安全和疗效的临床数据（Ono制药新闻发布）。

SEP 08, 2016
OPDIVO INTRAVENOUS INFUSION APPROVED IN JAPAN FOR TREATMENT OF UNRESECTABLE OR METASTATIC RCC

Ono Pharmaceutical and Bristol-Myers Squibb (BMS) announced that on August 26, 2016, Ono Pharmaceutical received approval for a partial change in approved items of the manufacturing and marketing authorization of Opdivo(R) (nivolumab) intravenous infusion (20 and 100 mg) for the treatment of unresectable or metastatic renal cell carcinoma (RCC) in Japan. Opdivo is a human anti-human programmed cell death protein 1 (PD-1) monoclonal antibody. This immune checkpoint inhibitor, which blocks the interaction of the PD-1 receptor with its ligands, is the first to demonstrate the extension of overall survival (OS) in patients with unresectable or metastatic RCC who have received prior antiangiogenic therapy. In the interim analysis of the open-label, randomized, phase III CheckMate-025 clinical trial (ClinicalTrials.gov Identifier NCT01668784), Opdivo demonstrated a median OS of 25 months versus 19.6 months for the active comparator everolimus, which offered a significant OS extension. In July 2014, Opdivo received manufacturing and marketing approval for treatment of unresectable melanoma in Japan, making it the first human anti-human PD-1 monoclonal antibody to be approved for this indication anywhere in the world. Opdivo also received additional approval for the indication of unresectable, advanced or recurrent non-small cell lung cancer in December 2015, and supplemental applications have been submitted for the indications of relapsed or refractory Hodgkin's lymphoma and recurrent or metastatic head and neck cancer. Outside of Japan, Opdivo has regulatory approval in 54 countries as part of the Ono and BMS collaboration. In Japan, Ono and BMS have formed a strategic partnership that includes codevelopment, co-commercialization and copromotion of multiple immunotherapies for patients with cancer in Japan. Ono hopes to gather further clinical data in order to ensure that Opdivo can be used more properly and effectively. In accordance with the conditional approval, Ono is committed to taking actions necessary for the proper use of Opdivo by implementing a postmarketing use-results survey (all-case surveillance) and collecting clinical data on the safety and efficacy of Opdivo (Ono Pharmaceutical News Release).

2016年9月2日，FDA批准BLINCYTO用于治疗儿童PH阴性前体B细胞ALL

FDA批准安进关于Blincyto(R) (blinatumomab)的补充BLA，申请包括支持治疗儿童PH阴性复发或耐药的前体B细胞ALL的数据。该适应症属于加速审批，后续的批准将基于随后试验对于临床获益的验证。批准基于研究205的结果，这是一项开放，多中心，单组的I/II期试验，入组93例患有复发或耐药的前体B细胞ALL的儿童患者(继发或延后的骨髓复发, 任何异体造血干细胞抑制后的骨髓复发或对其他治疗耐受且骨髓有>25% 的急变) (ClinicalTrials.gov Identifier NCT01471782)。该研究的治疗已经完成，正在对受试者的长期疗效进行监测。Blincyto曾经获得FDA的突破性疗法，优先审评和孤儿药资格（安进新闻发布）。

SEP 02, 2016
FDA APPROVES BLINCYTO FOR PEDIATRIC PATIENTS WITH PH-NEGATIVE B-CELL PRECURSOR ALL

The FDA has approved Amgen's supplemental BLA for Blincyto(R) (blinatumomab) to include new data supporting the treatment of pediatric patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). This indication is approved under accelerated approval, and continued approval may be contingent upon verification of clinical benefit in subsequent trials. Approval was based on results from Study 205, an open-label, multicenter, single-arm phase I/II trial in 93 pediatric patients with relapsed or refractory B-cell precursor ALL (second or later bone marrow relapse, any marrow relapse after allogeneic hematopoietic stem cell transplantation, or refractory to other treatments and had >25 percent blasts in bone marrow) (ClinicalTrials.gov Identifier NCT01471782). Treatment in this study has been completed and subjects are being monitored for long-term efficacy. Blincyto was previously granted breakthrough therapy, priority review and orphan drug designations by the FDA (Amgen News Release).

心血管疾病

2016年9月16，FDA批准ARALEZ 制药的YOSPRALA

Aralez制药说FDA批准了每日一次的 Yosprala(TM), 这是一种固定剂量的复方药物，包括阿司匹林，一种抗血小板药物和奥美拉唑，一种质子泵抑制剂。该药用于需要阿司匹林作为心血管和脑血管事件二级预防且伴有发生阿司匹林相关胃溃疡风险的患者。Aralez扩大了美国的销售队伍，销售代表从85人增至110人。该公司计划于10月的第一周开始美国的推广（Aralez制药信息发布）。

SEP 16, 2016
FDA APPROVES ARALEZ PHARMACEUTICALS' YOSPRALA

Aralez Pharmaceuticals said the FDA approved once-daily Yosprala(TM), a fixed-dose combination ofaspirin, an antiplatelet agent, and omeprazole, a proton pump inhibitor. It is indicated for patients who require aspirin for secondary prevention of cardiovascular and cerebrovascular events and who are at risk of developing aspirin-associated gastric ulcers. Aralez is expanding its U.S. sales force by 85 people to a total of 110 sales representatives. It plans to begin the U.S. promotional launch the first week in October (Aralez Pharmaceuticals News Release).

奥美拉唑 Omeprazole

阿司匹林 Aspirin

内分泌疾病

2016年9月20日，GUB09-145对老鼠的HBA1C,体重和葡萄糖稳态的作用显著

Gubra ApS的研究者发表了GUB09-145的一项临床前研究结果，GUB09-145是促胰岛素胰高血糖素样肽-1(GLP-1)和肠生长激素GLP-2的双重类似物。研究目的是确定其做为Roux-en-Y胃引流术的模拟对体重降低和改善葡萄糖稳态的潜在作用。结果显示GUB09-145 q.d. 或 b.i.d.给药 一周后(t1/2 of 2.7 h) ，对C57/BI6小鼠的进食具有显著作用，结果与利拉鲁肽相似(t1/2 of 4.4 h)。另外GUB09-145给药一周后也显示对小肠重量具有显著作用 。在db/db小鼠中, 给与该协同激动剂50 nmol s.c. b.i.d后，自治疗第3天开始，与空白对照相比，其对于体重和体重改变的作用有意义，GUB09-145和利拉鲁肽均降低食物和水的摄入。对于葡萄糖稳态，该化合物显示对第10和第20天喂食葡萄糖后的作用显著，结果与利拉鲁肽和对照相比分别为< 10 nmol/L， > 10和 > 15 nmol/L 。HbA1c也显著降低约5%。GUB09-145和利拉鲁肽均降低db/db小鼠口服葡萄糖耐受实验（OGTT）的基础和葡萄糖波动，两者均不会对胃排空产生持续作用。该协同激动剂在这些实验中显示的长效作用提示联合促胰岛素和肠生长作用有望成为一种治疗肥胖症和糖尿病的策略。(Jelsing, J. et al. 第52届欧洲糖尿病研究协会（EASD）年会 (9月12-16, 慕尼黑) 2016, Abst 787)。

SEP 20, 2016
GUB09-145 EXERTS MARKED EFFECTS ON HBA1C, BODY WEIGHT AND GLUCOSE HOMESTASIS IN MICE

Investigators from Gubra ApS presented the results of a preclinical study on GUB09-145, a dual analogue of the insulinotropic hormone glucose-like peptide-1 (GLP-1) and the intestinotropic hormone GLP-2, to determine its potential as a Roux-en-Y gastric bypass (RYGB) mimetic to reduce body weight and improve glucose homeostasis. Results demonstrated a significant effect on food intake (24 h) in C57/BI6 mice after 1 week of q.d. or b.i.d. dosing GUB09-145 (t1/2 of 2.7 h), a result similar to that with liraglutide (t1/2 of 4.4 h). Additionally, administration of GUB09-145 (10 nmol s.c. b.i.d.; 50 nmol s.c. q.d.; and 50 nmol s.c. b.i.d.) for 1 week showed a marked effect on small intestine weight. In db/db mice, the co-agonist had a meaningful effect on body weight and body weight change compared to vehicle, from day 3 after the treatment, and at 50 nmol s.c. b.i.d., both GUB09-145 and liraglutide reduced food and water intake. In terms of glucose homeostasis, the candidate showed marked effects on fed blood glucose at days 10 and 20, with levels at < 10 nmol/L compared to > 10 and > 15 nmol/L for liraglutide and vehicle, respectively. HbA1c was also significantly reduced to approximately 5%. Both GUB09-145 and liraglutide reduced basal and glucose excursions during a terminal oral glucose tolerance test (OGTT), and neither of them caused any sustained effect on gastric emptying in db/db mice. The effects exerted by the long-acting co-agonist in these studies suggest the combination of insulinotrophic and intestinotrophic actions can be a promising strategy to treat obesity and diabetes (Jelsing, J. et al. 52nd Annu Meet Eur Assoc Study Diabetes (EASD) (Sept 12-16, Munich) 2016, Abst 787).

2016年9月5日，中国医学科学院发现新的FBPASE 1抑制剂

中国医学科学院的科学家介绍了他们靶向果糖-1,6-二磷酸酶（FBPase 1）做为治疗糖尿病方法的工作。他们合成了一些新的吲哚衍生物作为FBPase 1抑制剂，干预糖异生通路。发现一个有希望的候选化合物:BJB-2936 (IC50 = 6.2 x 10[-8] M)。在糖尿病鼠模型(KKAgamma 鼠和db/db 鼠)中，BJB-2936显著降低葡萄糖和HbA1c。分别给与50和200 mg/kg BJB-2936后，KKAgamma鼠肝脏FBPase活性分别下降40%和98%。大鼠口服200 mg/kg的平均t1/2 为3.26 h, 平均tmax 为2.00 h, 平均AUC0-t 为386.13 h*mcg/mL， 平均Cmax为34.92 mcg/mL (Bie, J. et al. 24th Int Symp Med Chem (8月 28日-9月1日, 曼彻斯特) 2016, Abst P448).

SEP 05, 2016
NEW CLASS OF FBPASE 1 INHIBITORS IDENTIFIED AT CHINESE ACADEMY OF MEDICAL SCIENCES

Scientists from the Chinese Academy of Medical Sciences have described their efforts in targeting fructose-1,6-bisphosphatase (FBPase 1) as a means of treating diabetes. To intervene in the gluconeogenesis pathway, novel indole derivate FBPase 1 inhibitors were synthesized, with a promising candidate identified:BJB-2936 (IC50 = 6.2 x 10[-8] M). Significant glucose lowering and HbA1c reduction was observed with BJB-2936 in diabetic mouse models (KKAgamma mice and db/db mice). Liver FBPase activity was reduced 40% and 98% by BJB-2936 doses of 50 and 200 mg/kg, respectively, in KKAgamma mice. Oral dosing of 200 mg/kg in rats was associated with a mean t1/2 of 3.26 h, mean tmax of 2.00 h, mean AUC0-t of 386.13 h*mcg/mL and a mean Cmax of 34.92 mcg/mL (Bie, J. et al. 24th Int Symp Med Chem (Aug 28-Sept 1, Manchester) 2016, Abst P448).

眼部疾病

2016年9月30日，MIKELUNA在日本获批治疗青光眼和眼高压

大冢制药获得在日本生产和销售Mikeluna(R) (carteolol hydrochloride/latanoprost)复方滴眼液治疗青光眼和眼高压。Mikeluna滴眼液含有一种非选择性beta受体抑制剂和一种前列腺素类似物。大冢将于Senju制药共同推广该药物（大冢制药新闻发布）。

SEP 30, 2016
MIKELUNA APPROVED IN JAPAN FOR GLAUCOMA AND INTRAOCULAR HYPERTENSION

Otsuka Pharmaceutical has obtained Japanese manufacturing and marketing approval for Mikeluna(R) (carteolol hydrochloride/latanoprost) combination ophthalmic solution for glaucoma and intraocular hypertension. Mikeluna, an eye drop combining a non-selective beta-blocker and a prostaglandin analogue, will be copromoted with Senju Pharmaceutical (Otsuka Pharmaceutical News Release).

Carteolol hydrochloride

Latanoprost

血液和凝血功能疾病

2016年9月6日，施贵宝发布有望成为抗凝血药物的新PAR-4抑制剂

近期在罗马结束的ESC会议和在曼彻斯特举行的第24届EFMC 药物化学国际会议 (EFMC-ISMC 2016)上，施贵宝的研究者报告了新蛋白酶活化受体 4（PAR-4）拮抗剂作为抗血小板治疗候选化合物的体外和体内数据。应用全血流式细胞分析对530例已知遗传背景的健康受试者进行检测，测量中等浓度PAR-4激动肽情况下的血小板活性。获得了个体间血小板对PAR-4激动肽的反应，个体PAR-4激动肽引起的血小板激活随着时间的推移保持一致。受试者开始试验后一年开始出现反应（高，中和低），在体外测量增加新PAR-4拮抗剂，UDM-002555的浓度对于抑制血小板激活的效果。结果显示UDM-002555对PAR-4介导的血小板激活的抑制具有剂量依赖性，未发现无反应者。UDM-002555的IC50值与不同反应者的血小板激活程度呈正相关，虽然程度中等。在高，中和低反应者中纤维蛋白原的IC50值分别为0.94, 0.67, 0.59 nM，P-选择素为1.46, 1.21和1.06 nM 。总体来说，该研究结果未显示UDM-002555的效价和效力有显著的变化 (Downes, K. et al. ESC Congr (Aug 27-31, Rome) 2016, Abst P5000)。
在电诱导颈动脉血栓形成（ECAT）模型和猴子中评估单剂量UDM-002555 (0.02, 0.1, 0.25, 0.5, 2.5 mg/kg) 或UDM-002555 (0.25 mg/kg)联合静脉阿司匹林(4 mg/kg/h)对抗凝血和出血时间（BT）的作用。体外研究中，UDM-002555在人和猴子中均可以抑制PAR-4激动肽诱导的血小板聚集，IC50值相近，分别为2.3 and 1 nM，这一发现支持在猴子中开展体内实验。2.5 mg/kg 的UDM-002555不能抑制PAR-1激动肽， ADP和胶原诱导的血小板聚集，不影响体外凝血时间，提示对PAR-4的选择性。在ECAT模型中，0.02, 0.1, 0.25, 0.5 和2.5 mg/kg的UDM-002555分别减少的血栓重量 (TW)为 20, 25, 47, 48 和51%。该候选化合物对稳态的影响有限，0.02到2.5 mg/kg剂量下对比空白对照仅分别提高1.6倍肾脏BT (KBT) 和1.3倍肠系膜动脉BT (MBT)。最大抗血小板剂量的阿司匹林轻度减少9%的TW，但是KBT和MBT分别显著增加2.7倍和2.4倍。联合应用阿司匹林和UDM-002555减少64%的TW且对比阿司匹林，不引起KBT和 MBT的额外增加(2.5和2.3倍) 。在同期的猴子研究中，标准抗血小板药物氯吡格雷 (0.3 mg/kg/day)减少49%的TW ，但是分别增加KBT和MBT达7.4和8.1倍。这些结果显示在猴子中单用或联合阿司匹林,与标准抗血小板药物氯吡格雷和阿司匹林相比，UDM-002555的抗血栓作用有效，对稳态影响有限 数据提示PAR-4拮抗有望成为一种有潜力的新型抗血小板治疗选择。(Wong, P. et al. ESC Congr (8月27-31, 罗马) 2016, Abst P5001)。
UDM-002555已经申请专利 (WO 2013163279)。在EFMC-ISMC 2016大会上对发现BMS-986120进行了描述。这是一种强效，选择性和可逆的小分子PAR-4拮抗剂。BMS-986120具有对PAR-4的选择性抑制 (IC50 = 0.56), 对一系列凝血蛋白酶和多种受体，酶及离子通道无抑制活性。体内实验中，该候选化合物跨物种的药代动力学数据可接受，在大鼠，狗和恒河猴中的半衰期分别为7.5, 27 和27小时, 清除率为2.6, 4.1和19 mL/min/kg, 口服生物利用度为 98, 19和 29%。在恒河猴血栓模型中，通过测量血流和血栓重量显示BMS-986120具有很强的剂量依赖性的抗血栓活性。此外，在有效剂量水平，比较标准抗血小板药物氯吡格雷，BMS-986120显示具有极低的出血可能。BMS-986120 目前已进入人体临床试验 (ClinicalTrials.gov Identifier NCT02208882; ClinicalTrials.gov Identifier NCT02439190) (Priestley, E.S. et al. 24th Int Symp Med Chem (8月 28日-9月1日, 曼彻斯特) 2016, Abst LE033)。

SEP 06, 2016
BRISTOL-MYERS SQUIBB PRESENTS NOVEL PAR-4 ANTAGONISTS AS PROMISING ANTITHROMBOTIC AGENTS

At the recently concluded ESC Congress in Rome and the XXIV EFMC International Symposium on Medicinal Chemistry (EFMC-ISMC 2016) in Manchester, researchers from Bristol-Myers Squibb presented in vitro and in vivo data for novel proteinase-activated receptor 4 (PAR-4) antagonists being developed as antiplatelet therapy candidates.
Whole blood flow cytometric assays were used to measure platelet activity in response to a mid-range concentration of a PAR-4 agonist peptide in 530 healthy individuals whose genetic background is available. Inter-individual platelet responsiveness to the PAR-4 agonist peptide was established, and it was observed that platelet activation via PAR-4 agonist peptide within an individual was consistent over time. Subjects exhibiting a range of responses (hyper-, median- or hypo-responsive) were recalled approximately 1 year after initial testing, and the effectiveness of increasing concentrations of the novel PAR-4 antagonist, UDM-002555, to inhibit platelet activation in vitro was measured. The results revealed that UDM-002555 dose-dependently inhibited PAR-4-mediated platelet activation, with no nonresponders being identified. The UDM-002555 IC50 values demonstrated a positive, although modest, association with the extent of platelet activation between variable responders. The IC50 values in the hyper-, median- and hypo-responders were 0.94, 0.67, 0.59 nM for fibrinogen and 1.46, 1.21 and 1.06 nM for P-selectin, respectively. Overall, the results of the study do not indicate a significant shift in potency or efficacy of UDM-002555 (Downes, K. et al. ESC Congr (Aug 27-31, Rome) 2016, Abst P5000).
The antithrombotic and bleeding time (BT) effects of single oral dose of UDM-002555 (0.02, 0.1, 0.25, 0.5, 2.5 mg/kg) or UDM-002555 (0.25 mg/kg) in combination with intravenous aspirin (4 mg/kg/h) were evaluated in models of electrically mediated carotid artery thrombosis (ECAT) and in monkeys. In vitro, UDM-002555 inhibited platelet aggregation induced by PAR-4 agonist peptide in human and monkey blood with similar IC50 values of 2.3 and 1 nM, respectively, a finding that supported the use of monkeys for in vivo studies. UDM-002555 at 2.5 mg/kg did not inhibit platelet aggregation induced by PAR-1 agonist peptide, ADP and collagen, or affect ex vivo clotting times, which suggests PAR-4 selectivity. In the ECAT model, UDM-002555 at 0.02, 0.1, 0.25, 0.5 and 2.5 mg/kg reduced thrombus weight (TW) by 20, 25, 47, 48 and 51%, respectively. The drug candidate demonstrated a limited impact on hemostasis, with doses of 0.02 to 2.5 mg/kg leading to increases in BT in kidney (KBT) and mesenteric artery (MBT) by up to only 1.6-fold and 1.3-fold compared to vehicle, respectively. A maximum antiplatelet dose of aspirin slightly reduced TW by 9% but increased KBT and MBT significantly by 2.7- and 2.4-fold, respectively. Coadministration of aspirin and UDM-002555 reduced TW by 64% and did not cause additional increases in KBT and MBT (2.5- and 2.3-fold, respectively) over aspirin alone. In companion monkey studies, the standard of care antiplatelet agent clopidogrel (0.3 mg/kg/day) reduced TW by 49%, but increased KBT and MBT by 7.4- and 8.1-fold, respectively. These results demonstrated that UDM-002555 alone, or in combination with aspirin, provides effective antithrombotic activity with limited impact on homeostasis as compared to the standard antiplatelet agents, clopidogrel and aspirin, in monkeys. This data suggest that PAR-4 antagonism provides a potential, novel and promising antiplatelet therapeutic option (Wong, P. et al. ESC Congr (Aug 27-31, Rome) 2016, Abst P5001).
UDM-002555 has been described in the patent literature (WO 2013163279).
The discovery of the potent, selective and reversible small-molecule PAR-4 antagonist BMS-986120 was described at EFMC-ISMC 2016. BMS-986120 showed selectivity against PAR-4 (IC50 = 0.56), with no activity seen when evaluated against a panel of coagulation proteases and a broad panel of receptors, enzymes and ion channels. In vivo, the drug candidate demonstrated acceptable pharmacokinetic profile across species, with a half-life of 7.5, 27 and 27 hours, clearance of 2.6, 4.1 and 19 mL/min/kg, and oral bioavailability of 98, 19 and 29%, in rat, dog and cynomolgus monkey, respectively. In cynomolgus monkey thrombosis model, BMS-986120 showed strong dose-dependent antithrombotic efficacy as measured by blood flow and thrombus weight. Additionally, at the efficacious doses, BMS-986120 showed much lower bleeding liability than standard of care antiplatelet clopidogrel. BMS-986120 has recently advanced into human clinical studies (ClinicalTrials.gov Identifier NCT02208882; ClinicalTrials.gov Identifier NCT02439190) (Priestley, E.S. et al. 24th Int Symp Med Chem (Aug 28-Sept 1, Manchester) 2016, Abst LE033).

UDM-002555

感染

2016年9月2日，邓迪大学和葛兰素史克共同开发治疗利什曼病的新化合物

邓迪大学与葛兰素史克合作，共同开发可以治疗内脏利什曼病的化合物。这种疾病在88个国家流行，3亿5千万人受到威胁，每年有5万人死亡且目前的治疗不足。需要低价，口服，疗程短且安全的药物。通过构效关系发现一种化合物，在小鼠中具有可以接受的口服药代动力学数据，即50 mg/kg b.i.d.，给药10天后可以减少95%以上的寄生虫。解决溶解度低的问题后获得DDD-85365，该化合物由于具有较好的线性药代动力学和可以接受的治疗指数而被继续开发。其体内实验效力为6.0，即25 mg/kg b.i.d.给药10天，可以减少>95%的寄生虫血症。hERG IC50 值为> 30, CYP3A4 pIC50值<4.4. 在大鼠中最高1000 mg/kg水平也未发现显著的心血管作用。该化合物为一种激酶抑制剂，目前正在开展发现其作用靶点的研究(Thomas, M.G. et al. 24th Int Symp Med Chem (8月 28日-9月1日, 曼彻斯特) 2016, Abst LE038)。
DDD-85365已申请专利 (WO 2016116563)。

SEP 02, 2016
UNIVERSITY OF DUNDEE, GLAXOSMITHKLINE DEVELOP NOVEL COMPOUND FOR LEISHMANIASIS

The University of Dundee has collaborated with GlaxoSmithKline on the development of compounds for the potential treatment of visceral leishmaniasis. This disease is endemic in 88 countries with 350 million people at risk; there are 50,000 deaths a year and current treatments are inadequate. There is a need for low cost, oral, short course and safe medicine. Structure-activity-relationship work led to a compound showing an acceptable oral pharmacokinetic profile in mice with an > 95% parasite reduction seen at 50 mg/kg b.i.d. over 10 days. Due to a low solubility further compounds were sought, leading to DDD-85365, which was chosen for further development due to better linearity in pharmacokinetics and an acceptable therapeutic index. The compound showed in vivo efficacy of 6.0, with > 95% reduction in parasitemia at 25 mg/kg b.i.d. at 10 days. Its hERG IC50 value was > 30, with a CYP3A4 pIC50 value of <4.4. In rats there were no significant cardiovascular effects noted up to 1000 mg/kg. The compound is a kinase inhibitor, and work is ongoing to identify which kinases it targets (Thomas, M.G. et al. 24th Int Symp Med Chem (Aug 28-Sept 1, Manchester) 2016, Abst LE038)
DDD-85365 has been described in the patent literature (WO 2016116563).

DDD-853651

2016年9月1日，SK化学在南韩上市SKYCELLFLU四价流感疫苗

SK化学宣布在南韩上市其基于细胞培养的四价流感疫苗SKYCellflu Quadrivalent。由SK化学开发的SKYCellflu Quadrivalent是世界首个基于细胞培养的四价流感疫苗，单次接种可以预防四种流感病毒。该疫苗可以预防两种B型病毒的亚型（Yamagata and Victoria）和两种A型病毒的亚型(H1N1 and H3N2)。SKYCellflu Quadrivalent是唯一一个国产的四价流感疫苗用于3岁及以上人群。在全国3岁及以上人群进行了临床试验，有1,503名成人和454名儿童入组，证明了其免疫原性。上个月，SK化学与 JW Shinyak 签署了共同推广这一疫苗的协议。(SK化学新闻发布)。

SEP 01, 2016
SK CHEMICALS LAUNCHES SKYCELLFLU QUADRIVALENT INFLUENZA VACCINE IN SOUTH KOREA

SK Chemicals has announced the launch of its cell-culture quadrivalent influenza vaccine SKYCellflu Quadrivalent in South Korea. Developed by SK Chemicals, SKYCellflu Quadrivalent is the world's first cell-culture quadrivalent influenza vaccine capable of protecting against four strains of influenza viruses with just a single vaccination. The vaccine protects against two subtypes of type-B viruses (Yamagata and Victoria) and two subtypes of type-A viruses (H1N1 and H3N2). SKYCellflu Quadrivalent is the only domestically produced quadrivalent influenza vaccine ready for use in patients age 3 years and older. National clinical trials conducted in 1,503 adults and 454 children proved the vaccine to be immunogenic in patients age 3 years and older. Last month, SK Chemicals signed a joint marketing agreement with JW Shinyak for the vaccine (SK Chemicals News Release).

肌肉骨骼和结蹄组织疾病

2016年9月26日，FDA批准阿达木单抗的生物类似药AMJEVITA

FDA批准了安进的Amjevita(TM) (adalimumab-atto)用于其参考药物Humira(R) (adalimumab)所有适合的适应症。Amjevita是FDA批准的第一个阿达木单抗生物类似药，用于治疗严重炎症性疾病，包括中重度类风湿关节炎, 中重度多关节幼年型特发性关节炎, 银屑病关节炎,强直性脊柱炎, 中重度慢性斑块型银屑病, 成人中重度克隆氏病及中重度溃疡性结肠炎。批准是基于一个综合性的数据集合，支持其与阿达木单抗的相似性。数据来自分析，非临床，药物代谢动力学和临床试验, 其中包括在中重度慢性斑块型银屑病和中重度类风湿关节炎病人中进行的两项III期临床试验结果，III期研究达到主要终点，显示与阿达木单抗具有临床等同性。对Amjevita的安全性和免疫原性也与阿达木单抗进行了比较。与Humira一致, Amjevita 的说明书也包括关于导致住院或死亡的严重感染风险增加的加框警示。加框警示也提及在接受包括阿达木单抗在内的TNF阻断剂治疗的儿童和青少年病人中，有淋巴瘤和其他恶性肿瘤，一些致死案例的报告。安进的阿达木单抗生物类似药正在接受EMA的审评，该申请于去年12月递交 (安进新闻发布; FDA新闻发布)。

SEP 26, 2016
FDA APPROVES ADALIMUMAB BIOSIMILAR AMJEVITA

The FDA has approved Amgen's Amjevita(TM) (adalimumab-atto) across all eligible indications of the reference product, Humira(R) (adalimumab). Amjevita is the first adalimumab biosimilar approved by the FDA and has been approved for the treatment of seven inflammatory diseases, including moderate to severe rheumatoid arthritis, moderate to severe polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, moderate to severe chronic plaque psoriasis, adult moderate to severe Crohn's disease and moderate to severe ulcerative colitis. Approval was based on a comprehensive data package supporting biosimilarity to adalimumab based on analytical, nonclinical, pharmacokinetic and clinical data, including results from two phase III studies conducted in moderate to severe plaque psoriasis and moderate to severe rheumatoid arthritis. The phase III studies each met their primary endpoint showing clinical equivalence to adalimumab. Safety and immunogenicity of Amjevita were also comparable to adalimumab. Like Humira, the labeling for Amjevita contains a Boxed Warning regarding an increased risk of serious infections leading to hospitalization or death. The Boxed Warning also notes that lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including adalimumab products. Amgen's biosimilar adalimumab is also under review by the EMA, following its submission in December last year (Amgen News Release; FDA News Release).

神经疾病

2016年9月20日，FDA给与EXONDYS 51加速批准治疗杜兴氏肌肉营养不良症

FDA加速批准了Sarepta 治疗公司的Exondys 51(TM) (eteplirsen)，给药按30 mg/kg，每周一次静脉输注，治疗可以通过外显子51跳跃缓解的确认具有DMD基因突变的杜兴氏肌肉营养不良症（DMD）。商业化上市将很快开始。这一适应症是基于在一些接受eteplirsen治疗的病人中发现骨骼肌中的肌营养不良蛋白增加。Eteplirsen的临床获益未显现。该适应症的持续批准依赖于确证性试验中临床受益的确认。与安慰剂组相比，最常见的不良反应为呕吐 (38%)，平衡障碍(38%), 脑挫伤，表皮擦伤, 关节痛，皮疹, 导管部位疼痛和上呼吸道感染也比安慰剂组更常发生(10% 或以上) (Sarepta治疗新闻发布)。

SEP 20, 2016
FDA GRANTS ACCELERATED APPROVAL TO EXONDYS 51 FOR DUCHENNE MUSCULAR DYSTROPHY

The FDA has granted accelerated approval to Sarepta Therapeutics' Exondys 51(TM) (eteplirsen) as a once-weekly intravenous infusion of 30 mg/kg for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation in the DMD gene that is amenable to exon 51 skipping. A commercial launch will begin immediately. This indication is based on an increase in dystrophin in skeletal muscles observed in some patients treated with eteplirsen. A clinical benefit of eteplirsen has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. The most common adverse reactions compared to a placebo group were vomiting (38%) and balance disorder (38%), with contusion, excoriation, arthralgia, rash, catheter site pain and upper respiratory tract infection also reported more frequently than placebo (10% or greater) (Sarepta Therapeutics News Release).

精神疾病

2016年9月26日，FDA批准REXULTI关于精神分裂维持治疗的说明书更新

FDA批准了Rexulti(R) (brexpiprazole)的说明书更新，增加了精神分裂维持治疗的临床数据。批准基于一项在18-65岁成人精神分裂患者中进行的长期，随机，退出试验(ClinicalTrials.gov Identifier NCT01668797)的数据。Brexpiprazole治疗交叉滴定后，经过一个12-36周brexpiprazole单盲稳定期，在稳定期内经brexpiprazole治疗连续12周症状稳定的患者随机分配进入双盲阶段，接受brexpiprazole（n=97）或安慰剂（n=105）治疗。如果病人满足以下预先设定的标准，则认定在双盲阶段复发：根据PANSS 或 CGI-I评分改变定义的症状加重，由于精神症状加重而住院，自杀行为或暴力/攻击性行为。在达到预设复发数后开展一次中期分析（为了减少持续安慰剂的治疗），结果显示与安慰剂相比，brexpiprazole组患者的到复发时间更长，具有统计学意义。该研究由于维持治疗的效果显现而提前终止。最终分析显示brexpiprazole组患者（1-4毫克/日）与安慰剂组患者相比，显著延长到复发时间。而且对于满足复发标准患者的比例这一主要次要终点， brexpiprazole治疗组也显著低于安慰剂组。Rexulti由大冢和Lundbeck共同开发，于去年7月在美国批准，作为抗抑郁药的辅助治疗用于成人重度抑郁症和成人精神分裂的治疗。公司期望向EMA递交MAA用于治疗成人精神分裂 (大冢制药新闻发布)。

SEP 26, 2016
FDA APPROVES REXULTI LABELING UPDATE FOR MAINTENANCE TREATMENT OF SCHIZOPHRENIA

The FDA has approved a labeling update for Rexulti(R) (brexpiprazole) to include clinical data for maintenance treatment of schizophrenia. The approval was based on results from a long-term, randomized, withdrawal trial in adults with schizophrenia aged 18-65 years (ClinicalTrials.gov Identifier NCT01668797). After cross-titration from a prior antipsychotic to brexpiprazole, and a 12-36 week, single-blind brexpiprazole stabilization phase, patients who had been symptomatically stable on brexpiprazole for 12 consecutive weeks in the stabilization phase were randomized in a double-blind treatment phase to either brexpiprazole (n = 97) or placebo (n = 105). Impending relapse during the double-blind phase was determined if patients met any of the following pre-specified criteria: worsening symptoms defined by changes in PANSS or CGI-I scores, hospitalization for worsening psychotic symptoms, suicidal behavior, or violent/aggressive behavior. An interim analysis conducted after a pre-specified number of impending relapses (in order to minimize continued exposure to placebo) demonstrated a statistically significant longer time to relapse in patients randomized to brexpiprazole compared to placebo. The trial was subsequently terminated early because maintenance of efficacy had been demonstrated. The final analysis demonstrated a statistically significant longer time to relapse in patients randomized to brexpiprazole (1-4 mg/day) compared to placebo. The key secondary endpoint, the proportion of subjects who met the criteria for impending relapse, was statistically significantly lower in brexpiprazole-treated patients compared with placebo group. Rexulti, codeveloped by Otsuka and Lundbeck, was approved in the U.S. in July last year as an adjunctive therapy to antidepressants in adults with major depressive disorder and as a treatment in adults with schizophrenia. The companies anticipate submitting an MAA to the EMA for the use of brexpiprazole in the treatment of adult patients with schizophrenia (Otsuka Pharmaceutical News Release).

Brexpiprazole

呼吸系统疾病

2016年9月29日，FDA批准ORKAMBI治疗年轻囊性纤维化

FDA批准Vertex制药的Orkambi(R) (lumacaftor/ivacaftor)用于治疗具有两个拷贝F508del 突变的6-11岁的儿童囊性纤维化。 对于具有这一突变的患者而言，Orkambi 是第一个也是唯一一个针对发病原因的药物。该药已被FDA批准用于治疗具有两个拷贝F508del 突变的12岁及以上的囊性纤维化。Orkambi将很快可以用于6-11岁的儿童。批准基于一项开放的III期安全性研究数据。在欧盟，Vertex计划在明年的上半年递交一项MAA的变动，以获得治疗具有两个拷贝F508del 突变的6-11岁的儿童的许可。这一申请将基于来自一项III期有效性研究的数据，主要终点是肺清除指数（LCI）的绝对改变。这些数据有望于年底前获得（Vertex制药新闻发布）。

SEP 29, 2016
FDA APPROVES ORKAMBI FOR YOUNGER CYSTIC FIBROSIS POPULATION

The FDA has approved Vertex Pharmaceuticals' Orkambi(R) (lumacaftor/ivacaftor) for use in children with cystic fibrosis aged 6-11 years who have two copies of the F508del mutation. Orkambi is the first and only medicine to treat the underlying cause of cystic fibrosis for people with this mutation. It was previously approved by the FDA for use in people age 12 years and older with two copies of the F508del mutation. Orkambi will become available for children aged 6-11 years as soon as possible. Approval was based on data from an open-label phase III safety study. In the E.U., Vertex plans to submit an MAA variation in the first half of next year for children aged 6-11 years who have two copies of the F508del mutation. This application will be based on data from a phase III efficacy study with a primary endpoint of absolute change in lung clearance index (LCI). These data are expected before year-end (Vertex Pharmaceuticals News Release).

Ivacaftor

Lumacaftor

谢谢！祝好！

关永贺（Roger Guan）

大区业务经理

Clarivate Analytics

原汤森路透知识产权与科技事业部

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