许老师，您好！

开工愉快！尽管不得不承认还是有点儿假期综合症，但2015年的最后一个季度扑面而来啊，需要加满油，继续努力！请查看9月药物快讯（中英文版本）。近期汤森路透官方微信发布的文章有：

Ø歌礼：羽翼渐丰振翅欲飞

Ø免疫肿瘤学发展趋势：治疗性疫苗和检查点抑制剂

Ø《财经》专稿—看汤森路透如何玩转生物医学大数据

ØIxazomib：首个多发性骨髓瘤口服蛋白酶抑制剂前景良好

请扫描我们的官方微信二维码，查看以上文章。也可以加我的个人微信（Jingzhi_1987_Sara），我会定期在朋友圈分享汤森路透的重磅文章，网络在线培训，线下活动等。

最后一个季度，希望继续得到您的支持与帮助！

祝，周末愉快！

汤森路透生命科学制药官方微信：

汤森路透2015年9月药物快讯—帮助您及时掌握药物研发最新动态

镇痛与麻醉 Analgesia & Anesthesia

Zecuity在美国上市

Teva制药公司宣布Zecuity（舒马曲坦离子导入经皮给药系统）于美国上市，可凭处方从专业药房购买该药。Zecuity是首个且唯一一种偏头痛贴皮剂处方药。该舒马曲坦经皮给药系统为一次性使用贴皮剂，可贴于上臂或大腿，每次4小时，用于治疗成人先兆性或无先兆的急性偏头痛。一项临床研究中，将Zecuity和无疗效贴皮剂系统进行比较，使用2小时后，Zecuity组报告头痛消失的患者显著多于对照（18% vs. 9%），达到该研究次要终点。该研究次要终点还显示，使用2小时后Zecuity组报告如下项目的比例高于对照组：无恶心感受（84 vs. 63%），对声音不敏感（55 vs. 39%），对光不敏感（51 vs. 36%）和头痛缓解（53 vs. 29%）。Zecuity最常见副作用包括疼痛、刺痛、瘙痒、发热感或使用部位不适或皮肤颜色改变（Teva制药信息发布）。

Teva于2014年收购NuPathe后获得Zecuity（参见Thomson Reuters Drug News, January 22, 2014）。Zecuity于2013年1月获得FDA批准（参见Thomson Reuters Drug News, January 18, 2013）。

Zecuity now available in the U.S.

Teva Pharmaceutical Industries has announced that Zecuity(R) (sumatriptan iontophoretic transdermal system), the first and only patch system designed to provide relief from migraine, is now available by prescription through specialty pharmacies in the U.S. The single-use, disposable patch system delivers sumatriptan through the skin and is designed to be worn for a 4-hour period either on the upper arm or thigh. It is used for the acute treatment of migraine headaches with or without aura in adults. In a clinical study, at 2 hours following application, significantly more patients using Zecuity versus a non-medicated patch system reported no headache pain (18 versus 9%), the study's primary endpoint. The secondary endpoints of the study showed that, at 2 hours following application, significantly more patients reported no nausea (84 versus 63%), no sensitivity to sound (55 versus 39%), no sensitivity to light (51 versus 36%), or headache pain relief (53 versus 29%). The most common side effects reported for Zecuity included pain, tingling, itching, warmth, discomfort or a change in the skin color at the application site of Zecuity (Teva Pharmaceutical News Release).
Teva obtained Zecuity via its acquisition of NuPathe in 2014 (see Thomson Reuters Drug News, January 22, 2014). Zecuity was approved by the FDA in January 2013 (see Thomson Reuters Drug News, January 18, 2013).

癌症 Cancer

治疗脑肿瘤的新型BET抑制剂

Epigenetix、IntelliSYn制药和NeoMed的科学家合作研发获得新型BET（bromodomain and extraterminal motif）抑制剂，该抑制剂具有CNS渗透活性，可用于脑部肿瘤研究和治疗。通过基于结构的设计发现了EP-13，该分子具对含溴蛋白4（BRD4）具有高亲和性（IC50 = 7 nM），对BRD4的选择性比其他BRD高38倍。体外研究还发现其具有高细胞活性和低外排量。EP-13还对HL60早幼粒细胞白血病细胞具有抗增殖活性。其体内暴露量与剂量成正比，对U87人脑胶质瘤移植瘤荷瘤啮齿类动物给药，30天内观察到剂量依赖性的脑部肿瘤缩减（Albert, J. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 71）。

Novel BET inhibitors designed for treating brain cancer

A collaboration between Epigenetix, IntelliSYn Pharma and NeoMed Institute scientists has yielded novel BET (bromodomain and extraterminal motif) inhibitors with CNS-penetrant capability, making them suitable for investigation as treatments for brain cancer. Structure-based design efforts led to the identification of EP-13, with high bromodomain-containing protein 4 (BRD4) potency (IC50 = 7 nM) and selectivity 38-fold greater for BRD4 than other BRDs. High cellular permeability and low efflux liabilities were also observed in vitro. EP-13 also had antiproliferative effects against HL60 promyelocytic leukemia cells. Dose-related exposure was seen in vivo, as was dose-dependent brain tumor reduction within 30 days in rodents with U87 human glioblastoma tumor xenografts (Albert, J. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 71).

FDA批准Varubi治疗与癌症化疗有关的恶心和呕吐

FDA已经批准Tesaro制药公司Varubi（TM）（rolapitant）与其他止吐剂联用预防成人初次或多次致吐性癌症化疗相关的迟发性恶心呕吐，其中包括但不仅限于高度致吐性化疗。Varubi是一种选择性竞争性人类神经激肽NK1受体拮抗剂。三项随机双盲对照试验将rolapitant和格拉司琼、地塞米松联用与对照组（安慰剂，格拉司琼和地塞米松）进行对比，试验面向2800例接受化疗的患者，包括高度致吐和中度致吐化疗。与对照治疗相比，接受rolapitant的患者的恶心次数以及迟发期恶心呕吐急救药物的使用明显减少。Rolapitant治疗患者中最常见副作用包括白细胞计数降低、打嗝、食欲下降和头晕。由于rolapitant抑制CYP2D6酶，因此严禁与经CYP2D6酶代谢药物联用（Tesaro新闻发布；FDA新闻发布）。

FDA approves Varubi for nausea and vomiting associated with cancer chemotherapy

The FDA has approved Tesaro's Varubi(TM) (rolapitant) in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Varubi is a selective and competitive antagonist of human tachykinin NK1 receptor. Three randomized, double-blind, controlled trials compared rolapitant in combination with granisetron and dexamethasone to a control therapy (placebo, granisetron and dexamethasone) in 2,800 patients receiving a chemotherapy regimen that included highly emetogenic and moderately emetogenic chemotherapy. Those patients treated with rolapitant had a greater reduction in vomiting and use of rescue medication for nausea and vomiting during the delayed phase compared to those receiving the control therapy. The most common side effects in patients treated with rolapitant include neutropenia, hiccups, decreased appetite and dizziness. As rolapitant inhibits the CYP2D6 enzyme, it is contraindicated with the use of thioridazine, a drug metabolized by the CYP2D6 enzyme (Tesaro News Release; FDA News Release).

心血管疾病Cardiovascular Disorders

日本批准Terumo自体骨骼肌成肌细胞片治疗心衰

日本厚生劳动省批准Terumo公司自体骨骼肌成肌细胞片用于治疗慢性缺血性心脏疾病导致的严重心衰。该治疗包括培养从患者大腿肌肉提取的肌细胞并将其种植到患者心脏内。这是心脏再生组织治疗法首次在日本获得批准（Terumo新闻发布）。

Terumo's autologous skeletal myoblast sheets approved in Japan for heart failure

Japan's Ministry of Health, Labour and Welfare has approved Terumo's autologous skeletal myoblast sheets for the treatment of severe heart failure caused by chronic ischemic heart disease. The therapy involves culturing myoblasts derived from a patient's thigh muscle and transplanting them into the patient's heart. It is the first cardiac regenerative tissue therapy to be approved in Japan (Terumo News Release).

眼科疾病Eye Disorders

Santhera公司治疗Leber遗传性视神经病变药物Raxone欧洲获批准

Santhera制药公司Raxone（idebenone）获欧盟委员会批准，成为首个在欧盟所有28个成员国、挪威、冰岛和列支敦士登上市的治疗Leber遗传性视神经病变导致视觉损伤的青少年和成人患者的药物。该口服药物批准剂量为900 mg（非空腹情况下服用，每日三次，一次2片）。其疗效数据来自Santhera公司进行的随机安慰剂对照RHODOS试验和开放标签的扩展入组项目，均证明患者服用该产品可起到调节或逆转视觉损伤的作用（ClinicalTrials.gov编号NCT00747487）（Santhera制药新闻发布）。

Santhera receives European approval for Raxone in Leber's hereditary optic neuropathy

The European Commission has granted marketing authorization to Santhera Pharmaceuticals' Raxone(R) (idebenone) as the first approved medicine available in all 28 member states of the E.U., Norway, Iceland and Liechtenstein for the treatment of visual impairment in adolescent and adult patients with Leber's hereditary optic neuropathy. The oral medication is authorized at a daily dose of 900 mg (given as two tablets three times a day with food). Efficacy data come from Santhera's randomized, placebo-controlled RHODOS trial and from the open-label expanded access program, which together have demonstrated that vision loss can be mitigated or reversed in patients treated with the product (ClinicalTrials.gov Identifier NCT00747487) (Santhera Pharmaceuticals News Release).

血液和凝血障碍Hematological & Blood Coagulation Disorders

美国批准Rockwell Medical上市Triferic治疗铁缺乏.

Rockwell Medical日前将Triferic(TM)（焦磷酸铁柠檬酸）推向市场，用于预防血液透析依赖性慢性肾病（CKD）成人患者的铁缺乏。Triferic是通过FD批准的首个替代铁并维持血液透析患者血红蛋白水平的药物。该药于2015年1月获批（见Thomson Reuters Drug News, January 27, 2015）。Triferic在透析过程中给药，无需每周静脉给药，且与铁转运蛋白迅速结合。这意味着其无需与铁蛋白结合并在肝脏中蓄积导致铁过载，表现出相对其他铁替代产品的优势（Rockwell Medical新闻发布）。

Rockwell Medical launches Triferic for iron deficiency in the U.S.

Rockwell Medical has launched Triferic(TM) (ferric pyrophosphate citrate) for the prevention of iron deficiency in adults with hemodialysis-dependent chronic kidney disease (CKD). Triferic is the only iron product approved by the FDA to replace iron and maintain hemoglobin in patients undergoing hemodialysis. It was approved in January 2015 (see Thomson Reuters Drug News, January 27, 2015). Triferic is administered during dialysis, rather than in a weekly intravenous dose, and rapidly binds transferrin. This means that it does not bind to ferritin and accumulate in the liver resulting in iron overload, which is an advantage over previous iron replacement products (Rockwell Medical News Release).

Acoalan日本计划上市

日本血液制品组织（JB）将于2015年9月7日在日本上市重组抗凝血酶剂Acoalan（抗凝血酶γ）注射剂600，用于治疗先天性抗凝血酶缺乏症（CAD）和弥散性血管内凝血（DIC）伴抗凝血酶（AT）减少导致的血栓好发体制。Acoalan是一种重组AT药物，具有与人天然AT相同的氨基酸序列和糖链结构。该药由Kyowa Hakko Kirin研发，该公司同时是Acoalan的授权批准公司（见Thomson Reuters Drug News, July 6, 2015）。基于Kyowa Hakko Kirin和JB间的营销许可协议，将由JB负责该产品向医疗机构的销售和推广（日本血液制品组织新闻发布）。

First launch planned for Acoalan in Japan

On September 7, 2015, Japan Blood Product Organization (JB) will launch the recombinant antithrombin agent Acoalan(R) (antithrombin gamma) Injection 600 in Japan for the treatment of thrombophilia due to congenital antithrombin deficiency (CAD) and disseminated intravascular coagulation (DIC) accompanied by a decrease in antithrombin (AT). Acoalan is a recombinant AT agent with the same amino acid sequence and carbohydrate structure as the human natural AT. It is being developed by Kyowa Hakko Kirin, which is the approval authorization holder of the product (see Thomson Reuters Drug News, July 6, 2015). Based on the marketing license agreement between Kyowa Hakko Kirin and JB, JB is responsible for marketing and promotion of the product for medical institutions (Japan Blood Product Organization News Release).

日本批准盐野义制药Mulpleta用于血小板减少症治疗

日本批准盐野义制药公司新药Mulpleta（lusutrombopag）用于与慢性肝病相关的血小板减少症择期手术的患者的治疗。该药是一种小分子血小板生成素受体激动剂。III期试验中，术前接受7天3 mg lusutrombopag治疗，每日一次，可显著减少血小板输血量。该公司计划在该药纳入获得国家健康保险价格后推广上市（盐野义制药新闻稿）。

Shionogi's Mulpleta approved in Japan for thrombocytopenia

Shionogi's small-molecule thrombopoietin receptor agonist Mulpleta(R) (lusutrombopag) has been approved in Japan for the treatment of patients undergoing elective invasive procedures who have thrombocytopenia associated with chronic liver disease. In phase III trials, treatment with 3 mg lusutrombopag once daily for 7 days prior to the procedure significantly reduced the need for platelet transfusion before the procedure. The company expects to launch the product as soon as ithas received National Health Insurance price listing (Shionogi News Release).

免疫调节药物　Immunomodulating Agents

ALK治疗屋尘螨过敏药物于欧洲11国获批

ALK-Abello公司生产的屋尘螨（HDM）舌下过敏免疫治疗（SLIT）片剂在奥地利、捷克、丹麦、芬兰、法国、德国、意大利、挪威、波兰、斯洛伐克和瑞典审批通过。该药物适用于治疗年龄在18-65周岁的成人持久中度到重度HDM诱发的症状缓解药物无效的过敏性鼻炎，以及吸入糖皮质激素难以控制的HDM诱导性过敏性哮喘伴HDM过敏性鼻炎。ALK预计产品将于6个月内上市。默克公司和Torii公司分别在北美和日本进行SLIK开发。雅培和bioCSL则分别面向俄国和澳大利亚、新西兰开发该治疗（ALK-Abello新闻发布）。

ALK's house dust mite allergy immunotherapy approved in 11 European countries

ALK-Abello's house dust mite (HDM) sublingual allergy immunotherapy (SLIT) tablet has been approved in Austria, Czech Republic, Denmark, Finland, France, Germany, Italy, Norway, Poland, Slovakia and Sweden. It is indicated for the treatment of adults aged 18-65 years who have persistent moderate-to-severe HDM-induced allergic rhinitis despite the use of symptom-relieving medication or HDM-induced allergic asthma that is not well controlled by inhaled corticosteroids and is associated with HDM allergic rhinitis. ALK expects to launch the product with the next 6 months. Merck & Co. is developing the tablet in North America and Torii is developing it in Japan. Abbott holds rights in Russia, while bioCSL is developing the therapy in Australia and New Zealand (ALK-Abello News Release).

LFB公司静脉注射免疫球蛋白Iqymune英国和丹麦获批准

LFB宣布，该公司生产的10%静脉注射免疫球蛋白Iqymune已经在英国和丹麦获批用于免疫缺陷障碍治疗。该公司预计未来几个月内该药还将通过奥地利、德国、比利时、西班牙、芬兰、希腊、匈牙利、意大利、卢森堡、荷兰、捷克共和国、斯洛伐克和瑞典批准，并计划于2016年初上市。LFB计划2016年到2020年间于欧盟以外的33个国家推出该药。面向多发性运动神经病变（ClinicalTrials.gov Identifier NCT01951924）和慢性炎症性脱髓鞘性多发性神经病变（CIDP）的III期试验正在进行中。LFB希望这些研究获得的结果将支持欧盟批准用于对应适应症的治疗（LFB新闻稿；ClinicalTrials.gov网站）。

LFB's IVIg Iqymune approved in U.K. and Denmark

LFB has announced that its 10% intravenous immunoglobulin (IVIg) Iqymune(R) has been approved in the U.K. and Denmark for the treatment of immune deficiencies and disorders. The company expects approvals in Austria, Germany, Belgium, Spain, Finland, Greece, Hungary, Italy, Luxembourg, the Netherlands, the Czech Republic, Slovakia and Sweden during the next few months, with launches expected to start in 2016. LFB is planning for launches in 33 additional countries outside of Europe during 2016 to 2020. Phase III trials are underway in patients with multifocal motor neuropathy (ClinicalTrials.gov Identifier NCT01951924) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). LFB hopes that results from these studies will support European approval in these indications (LFB News Release; ClinicalTrials.gov Web site).

代谢紊乱疾病Metabolic Disorders

FDA批准Xuriden治疗遗传性乳清酸尿症

FDA批准Wellstat Therapeutics公司的Xuriden(TM)（尿苷三乙酸酯）用于遗传性乳清酸尿症患者治疗。该药是首个通过FDA批准的治疗该适应症的药物。FDA同时授予Wellstat罕见儿科疾病优先审批资格。一项单组6周开放标签的试验对Xuriden的安全性和疗效进行了评估，受试者为4名患有遗传性乳清酸尿症患者，年龄在3-19岁之间，该试验还设有6个月扩展期（ClinicalTrials.gov编号NCT02110147）。该研究对患者试验期间血液学参数变化进行评估。在6周及6个月的评价中，所有4名临床试验患者在使用Xuriden治疗后血液学参数得到稳定。尿苷替代疗法的安全性与有效性得到了现有文献报道案例的进一步支持。治疗到9 个月时，在 Xuriden治疗患者中未观察到有副作用。Xuriden是一种用于替代尿苷的口服药物，遗传性乳清酸尿症患者自身无法合成尿苷。Xuriden作为一种口服颗粒获得批准，它可与食物混合，或混到牛奶或婴儿配方奶粉中，每天服用一次。Wellstat Therapeutics预计于2016年上半年将Xuriden推向市场（FDA新闻发布；Wellstat Therapeutics网站）。

FDA approves Xuriden for hereditary orotic aciduria

The FDA has approved Wellstat Therapeutics' Xuriden(TM) (uridine triacetate) for patients with hereditary orotic aciduria. It is the first FDA approved treatment for this indication. The agency also granted Wellstat a rare pediatric disease priority review voucher. The safety and effectiveness of Xuriden were evaluated in a single arm, 6-week, open-label trial in four patients with hereditary orotic aciduria aged 3-19 years, and in a 6-month extension phase (ClinicalTrials.gov Identifier NCT02110147). The study assessed changes in the patients' prespecified hematologic parameters during the trial period. At both the 6-week and 6-month assessments, Xuriden treatment resulted in stability of the hematologic parameters in all four clinical trial patients. The safety and effectiveness of uridine replacement therapy were further supported by case reports from the published literature. No side effects were observed in patients treated with Xuriden for up to 9 months. Xuriden is an orally administered product intended to replace uridine, which the body cannot synthesize in patients with hereditary orotic aciduria. Xuriden is approved as oral granules that can be mixed with food, milk or infant formula, and is administered once daily. Wellstat Therapeutics expects to launch Xuriden in early 2016 (FDA News Release; Wellstat Therapeutics Web site).

欧盟首次批准LAL-D治疗药物Kanuma

亚力兄制药宣布，欧盟委员会已批准 Kanuma（sebelipase alfa）用于所有年龄的溶酶体酸脂酶缺乏（LAL-D）患者长期酶替代治疗。sebelipase alfa是欧盟批准的首款用于 LAL-D患者的治疗药物，通过减少细胞的溶酶体底物在包括肝脏等器官的全身积聚，解决导致该疾病的潜在病因，避免重要器官损伤和过早死亡。亚力兄制药预计下月起在德国开始为患者提供这款药物，目前该公司正与主要欧盟国家的医保机构商谈报销程序。该批准基于两项临床研究和一项支持性开放标签的扩展研究所得数据，研究包括患有LAL-D的婴儿、儿科和成人患者。研究结果显示该药可为婴儿期发病LAL-D的12个月以上患者提供生存获益，其中接受治疗组生存率（67%，9例中6例存活）高于未治疗历史对照（21例患者全部死亡）。接受sebelipase alfa治疗的婴儿患者同时表现包括ALT和AST在内的肝脏参数改善，治疗开始数周内体重增加。儿科和成人LAL-D患者中与安慰剂组相比，sebelipase alfa治疗后ALT恢复正常，肝脏脂肪含量减少，其他肝脏损伤指标降低，通过LDL胆固醇和HDL反映脂质蓄积也有显著改善。对双盲期服用sebelipase alfa 随后在开放标签扩展阶段继续服药的患者，ALT水平降低的疗效保持，且LDL和HDL胆固醇有进一步改善。临床试验中出现最严重不良反应的患者比例占3%，不良反应表现和症状与过敏一致。症状包括胸部不适、结膜充血、呼吸困难、全身性皮疹发痒、充血、轻度眼睑水肿、流鼻涕、严重呼吸窘迫、心动过速、呼吸急促和荨麻疹。美国FDA接受Kanuma BLA优先审评资格（参见Thomson Reuters Drug News, December 3, 2014），在日本也获得相同批准（参见Thomson Reuters Drug News, May 27, 2015）（Alexion Pharmaceuticals新闻发布）。

Kanuma becomes first approved treatment in E.U. for LAL-D

The European Commission has approved Alexion Pharmaceuticals' Kanuma(TM) (sebelipase alfa) for long-term enzyme replacement therapy in patients of all ages with lysosomal acid lipase deficiency (LAL-D). As the first approved treatment in the E.U. for patients with LAL-D, sebelipase alfa is designed to address the underlying cause of the disorder by aiming to reduce substrate accumulation in the lysosomes of cells throughout the body, including the liver, to prevent vital organ damage and premature death. Alexion expects to launch the product in Germany next month and is commencing reimbursement processes with healthcare authorities in major European countries. Approval was based on data from two clinical studies and a supporting open-label extension study comprising infant, pediatric and adult patients with LAL-D. Study results showed significant benefit in terms of survival (67%, or 6 out of 9) in patients with the infant form of LAL-D beyond 12 months, compared with 0 out of 21 patients in an untreated historical cohort. Infant patients treated with sebelipase alfa also had improvements in liver parameters, including ALT and AST, as well as weight gain within the first several weeks of treatment. In pediatric and adult patients with LAL-D, treatment with sebelipase alfa resulted in normalization of ALT, reduction in liver fat content and other markers of liver injury compared to placebo, as well as significant improvements in lipid accumulation as measured by LDL cholesterol and HDL cholesterol. In patients who received sebelipase alfa during the double-blind period and subsequently entered the open-label extension period, reductions in ALT levels were maintained and further improvements were seen in LDL and HDL cholesterol. The most serious adverse reactions experienced by 3% of the patients in clinical trials were signs and symptoms consistent with anaphylaxis. Symptoms included chest discomfort, conjunctival injection, dyspnea, generalized and itchy rash, hyperemia, mild eyelid edema, rhinorrhea, severe respiratory distress, tachycardia, tachypnea and urticaria. In the U.S., the FDA has accepted the Kanuma BLA for priority review (see Thomson Reuters Drug News, December 3, 2014), and approval has also been sought in Japan (see Thomson Reuters Drug News, May 27, 2015) (Alexion Pharmaceuticals News Release).

ZP-I-98：一种新的GIP受体激动剂

研究观察发现，胰高血糖素样肽-1（GLP-1）受体激动剂（一种广泛使用的抗糖尿病药物）不仅能控制血糖，而且往往可引起体重减轻。最近研究表明，提高葡萄糖依赖性促胰岛素多肽（GIP）活性可增强GLP-1R的减重作用。Zealand Pharma发布了一种新型GIP受体激动剂ZP-I-98和该化合物与GLP-1受体激动剂（如liraglutide）联合给药的作用。研究人员首先就ZP-I-98对GIP受体、GLP-1受体和胰高血糖素受体体外激活作用进行了研究，结果显示对GIP的选择性（EC50 = 9 pM）高于GLP-1和胰高血糖素受体（EC50 = 3300 and > 10[5] pM）。药代动力学数据显示，对小鼠和猴以50 nmol/kg剂量经静脉给药，两者的清除率分别为11和1.8 mL/h/kg（3 nmol/kg皮下注射给药时清除率分别为11和2.1 mL/h/kg）。小鼠和猴中经静脉给药的半衰期分别为15和57小时，皮下注射给药半衰期分别为17和55小时。对小鼠和猴皮下注射给药的生物利用度分别为98和81%。这些数据支持ZP-I-98每周给药一次。葡萄糖耐受试验中，ZP-I-98表现出显著降糖作用，该作用呈剂量依赖性，其降糖效果作用比liraglutide低30 nmol/kg。与liraglutide单独给药相比，ZP-I-98与liraglutide联合给药对饮食诱导肥胖小鼠的减重作用显著增强，两组对比摄食量无显著差异（Noerregaard, P. et al. 51st Annu Meet Eur Assoc Study Diabetes (EASD) (Sept 14-18, Stockholm) 2015, Abst 838）。

ZP-I-98: a novel GIP receptor agonist

It has been observed that glucagon-like peptide 1 (GLP-1) receptor agonists (widespread antidiabetic drugs) not only control glycemia but often cause weight loss. Recent studies have shown that glucose-dependent insulinotropic polypeptide (GIP) activity enhances the GLP-1R weight-lowering effect. Zealand Pharma has presented a novel GIP receptor agonist, ZP-I-98 and its effect when coadministered with GLP-1 receptor agonist liraglutide. Firstly, the effect of ZP-I-98 in activating GIP receptor, GLP-1 receptor and glucagon receptor in vitro was studied, showing greater selectivity towards GIP (EC50 = 9 pM) compared to GLP-1 and glucagon receptors (EC50 = 3300 and > 10[5] pM). Pharmacokinetic data showed clearance rates of 11 and 1.8 mL/h/kg in mice and monkeys, respectively, at a 50 nmol/kg i.v. dose (11 and 2.1 mL/h/kg for a 3 nmol/kg s.c. dose). The t1/2 for mice and monkeys was 15 and 57 hours (i.v.), respectively, and 17 and 55 (s.c.), respectively. Bioavailability was 98 and 81% for the s.c. doses in mice and monkeys, respectively. These data supported the potential for once-weekly dosing of ZP-I-98. In the glucose tolerance test, ZP-I-98 demonstrated significant glucose-lowering effect in a dose-dependent manner, with a dose of 30 nmol/kg lowering glucose more than liraglutide. Regarding weight-loss, ZP-I-98 in combination with liraglutide showed more efficacy than liraglutide alone in diet-induced obese mice, with no differences in food intake (Noerregaard, P. et al. 51st Annu Meet Eur Assoc Study Diabetes (EASD) (Sept 14-18, Stockholm) 2015, Abst 838).

神经疾病Neurologic Disorders

百时美施贵宝披露新抗阿尔斯海默γ-分泌酶调节剂

百时美施贵宝公司研究者以BMS-932481为起点，开发出一种对阿尔斯海默症（AD）具潜在治疗作用的γ-分泌酶调节剂。
用烷氧基取代芳环以增加极性，通过结构-活性关系（SAR）研究发现先导化合物BMT-124180，该分子对β-淀粉样蛋白（Abeta42）的IC50为7 nM。接受剂量为10 mg/kg BMT-124180的小鼠中，脑内Abeta42降低75%（注射后3小时）。该化合物在大鼠中有Abeta42 ED50 = 10 mg/kg，血浆浓度为2.2 mM（Zhang, Y. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 434）。
第二项研究中，SAR研究获得一系列新的双环嘧啶类化合物。化合物BMS-893204对Abeta42 IC50 = 2 nM。该化合物在大鼠、犬类和猴中清除率低，且具有中等生物活性（Xu, L. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 435）。

Bristol-Myers Squibb discloses new gamma-secretase modulators for AD

Investigators from Bristol-Myers Squibb have developed gamma-secretase modulators for the potential treatment of Alzheimer's disease (AD) using BMS-932481 as a starting point.
The aryl ring was replaced with alkoxy substituents to increase polarity. Structure-activity relationship (SAR) studies led to the identification of a lead compound, BMT-124180, with beta-amyloid (Abeta42) IC50 = 7 nM. Mouse treated with BMT-124180 at 10 mg/kg showed a 75% reduction in brain Abeta42 (3 hours post infusion). The compound in rats displayed an Abeta42 ED50 = 10 mg/kg and a plasma concentration of 2.2 mM (Zhang, Y. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 434).
In the second study, SAR studies led to the identification of a novel series of bicyclic pyrimidines. The lead compound (BMS-893204) with an Abeta42 IC50 = 2 nM. The compound had low clearance in rats, dogs and monkeys, and moderate bioavailability (Xu, L. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 435).

呼吸疾病 Respiratory Disorders

Vernalis公司Tuzistra XR于美国上市

Vernalis公司的Tuzistra XR（codeine polistirex/chlorpheniramine polistrex）四月通过FDA审批后于美国上市，该药是一种缓释口服混悬液CIII（DEA III类管制药品），用于缓解18岁以上患者咳嗽和与上呼吸道过敏或普通感冒相关症状。Tuzistra XR是目前美国市场上患者和医生可选的唯一含可待因的缓释咳嗽糖浆，采用Tris Pharma公司液体缓释技术LiquiXR(R)开发，使得药物可在长达12小时内缓慢释放（Vernalis新闻发布）。

Vernalis launches Tuzistra XR in U.S.

Following FDA approval in April, Vernalis has now launched Tuzistra(TM) XR (codeine polistirex/chlorpheniramine polistrex) extended-release oral suspension CIII (DEA Schedule III) in the U.S. for the relief of cough and symptoms associated with upper respiratory allergies or a common cold in adults age 18 years and older. Tuzistra XR is the only codeine-based, extended-release cough cold syrup available to patients and physicians in the U.S. It was developed using Tris Pharma's liquid sustained-release technology LiquiXR(R), which allows for extended drug delivery throughout a 12-hour dosing period (Vernalis News Release).

皮肤病症Dermatological Disorders

葛兰素史克Zagallo日本获批准

日本批准葛兰素史克I型和II型5α还原酶抑制剂Zagollo（度他雄胺）0.1 mg和0.5 mg胶囊用于治疗雄激素性脱发。Zagolla通过抑制I型和II型5α还原酶抑制二氢睾酮（DHT）生成，该激素参与雄激素性脱发。临床研究显示，基于头发数量和头发宽度等终点，可判定该药对雄激素性脱发有效。（葛兰素史克新闻稿）。

GlaxoSmithKline's Zagallo receives approval in Japan

GlaxoSmithKline has received approval for the 5-alpha-reductase type 1 and 2 inhibitor Zagallo(R) (dutasteride) capsules 0.1 and 0.5 mg for androgenic alopecia in Japan. Zagallo inhibits production of dihydrotestosterone (DHT), a male hormone involved in androgenic alopecia, by inhibiting 5-alpha-reductase type 1 and 2. In clinical studies, the agent showed efficacy in androgenic alopecia based on established endpoints such as hair count or hair width (GlaxoSmithKline News Release).

内分泌紊乱病症Endocrine Disorders

日本成为首个批准omarigliptin的国家

默沙东已经获得omarigliptin 12.5和25 mg片剂在日本的上市许可，该药物为缓释二肽基肽酶4（DPP IV）抑制剂，用于II型糖尿病治疗，商品名Marizev（omarigliptin），每周仅需服用一次。这是该新药全球首次获得批准。Marizev是一种新型长效DPP IV抑制剂。日本III期临床研究证实，Marizev与每日服用一次的选择性DPP IV抑制剂Januvia（sitagliptin）的疗效和耐受性相当（默沙东新闻稿）。

Japan first country to approve omarigliptin

MSD K.K. has received marketing approval for the once-weekly sustained selective dipeptidyl peptidase 4 (DDP IV) inhibitor Marizev(R) (omarigliptin) Tablets 12.5 and 25 mg for type 2 diabetes in Japan. This is the first approval of this product in the world. Marizev is a long-acting novel DPP IV inhibitor Merck & Co. The Japanese phase III study confirmed that Marizev has the same efficacy and tolerance as the once-daily selective DPP IV inhibitor Januvia(R) (sitagliptin) (MSD K.K. News Release).

感染 Infections

日本批准Maruho公司新药Zebiax用于细菌性皮肤感染

日本厚生劳动肾（MLWH）批准Maruho公司Zebiax乳液（ozenoxacin）NDA（新药申请）。Ozenoxacin是一种用于治疗浅表皮肤感染和伴有脓性炎症痤疮的喹诺酮类药物。Ozenoxacin以DNA解旋酶和DNA拓扑异构酶IV为靶标，抑制DNA合成，诱导细菌细胞死亡。该药对革兰氏阳性和阴性细菌均有活性，包括金黄色葡萄球菌、表皮葡萄球菌和痤疮丙酸杆菌（Maruho新闻稿）。

Maruho's Zebiax approved in Japan for bacterial skin infections

The Japanese Ministry of Health, Labour and Welfare (MLWH) has approved Maruho's NDA for the Zebiax(R) Lotion (ozenoxacin), a quinolone antibacterial for the treatment of superficial skin infections and acne accompanied by purulent inflammation. Ozenoxacin targets DNA gyrase and DNA topoisomerase IV to inhibit DNA synthesis and induce bacterial cell death. It has activity against Gram-positive and -negative bacteria, including Staphylococcus aureus, Staphylococcus epidermidis and Propionibacterium acnes (Maruho News Release).

欧盟批准VivaGel BV治疗细菌性阴道炎

澳大利亚星法马公司（Starpharma）局部阴道凝胶剂VivaGel BV（astrodimer）通过欧盟批准，用于治疗和快速缓解细菌性阴道炎（BV）及其症状。临床试验中，VivaGel BV每日使用一次，连续使用7天，与安慰剂相比对女性细菌性阴道炎起到显著疗效。VivaGel BV的关键获益表现在其可迅速缓解包括阴道异味和分泌物在内的细菌性阴道炎相关症状。此外，使用VivaGel BV帮助恢复正常阴道pH，抑制导致阴道菌群失调的细菌滋生，后者是细菌性阴道炎的特征性表现。临床试验中，VivaGel引起念珠菌病的比例极低（2-3%）。正式市场调查中获得了相当高的患者总体满意度、舒适程度和使用方便程度报告。目前一系列潜在商业合作伙伴正在处理与VivaGel BV相关的销售权问题。欧盟此次对VivaGel BV的批准也将被视为该药在认可欧盟批准地区发布额外监管批准的基础。VivaGel BV针对预防细菌性阴道炎复发的III期研究正在北美、欧洲和亚洲进行，目前入组的预期患者人数已经过半（星法马公司新闻稿）。

VivaGel BV approved in E.U. for bacterial vaginosis

Starpharma has obtained European marketing approval for its topical vaginal gel VivaGel(R) BV (astrodimer) for the treatment and rapid relief of bacterial vaginosis (BV), including symptoms. In clinical trials, VivaGel BV used once daily for 7 days demonstrated significant benefits over placebo in the treatment of bacterial vaginosis in women. A key benefit of VivaGel BV was the rapid relief of patients' symptoms associated with bacterial vaginosis, including unpleasant vaginal odor and discharge. In addition, use of VivaGel BV helped to normalize vaginal pH and suppress the bacteria that cause the vaginal microflora imbalance that characterizes bacterial vaginosis. In clinical trials VivaGel was associated with very low rates of candidiasis (2-3%). In formal market research, patients reported very high levels of overall satisfaction, comfort and ease of use. Discussions regarding marketing rights for VivaGel BV are under way with a number of potential commercial partners. E.U. approval will also be used as the basis of additional regulatory approvals for VivaGel BV in regions that recognize European approval. The phase III program for VivaGel BV for the prevention of recurrent bacterial vaginosis is also progressing in North America, Europe and Asia, with over half the intended patients now enrolled (Starpharma News Release).

精神疾病Psychiatric Disorders

FDA批准狂躁型抑郁症与精神分裂症新药Vraylar上市

FDA批准VraylarTM（cariprazine hydrochloride，卡利拉嗪盐酸盐）胶囊，一种非典型抗精神病药，用于成人I型狂躁型抑郁症躁动或混合发作急性治疗和精神分裂症治疗。该批准基于三项为期三周的面向成人I型狂躁型抑郁症躁动或混合发作进行的对照试验以及三项为期6周的安慰剂对照成人精神分裂症试验结果。这些实验包括2700余例成人患者，与安慰剂相比，卡利拉嗪治疗组中狂躁型抑郁症患者杨氏躁狂量表（YMRS）总得分改善，精神分裂症患者阳性症状和阴性症状评定量表（PANSS）总得分改善。两种疾病的次要疗效终点临床总体印象量表一疾病严重程度（CGI-S）评分量表也显示卡利拉嗪具有相关疗效。和其他FDA批准的用于治疗精神分裂症和狂躁型抑郁症的药物一样，Vraylar也标有黑框警告，提示对老年痴呆相关精神病患者使用该类药物可能增加死亡风险。卡利拉嗪和此类药物均不可被用于此类患者治疗。卡利拉嗪由Gedeon Richter制药公司发现并参与联合开发，由Forest实验室生产，授权Actavis公司（现Allergan公司）在美国和加拿大销售（Allergan新闻稿，FDA新闻稿）。

FDA approves Vraylar for bipolar disorder and schizophrenia

The FDA has approved Vraylar(TM) (cariprazine hydrochloride) capsules, an atypical antipsychotic, for the acute treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adults. Approval was based on the results of three 3-week controlled trials in adults with manic or mixed episodes of bipolar I disorder and three 6-week placebo-controlled trials in adults with schizophrenia. In these trials involving more than 2,700 adults, cariprazine demonstrated improvement compared to placebo as measured by Young Mania Rating Scale (YMRS) total scores in patients with bipolar mania and by Positive and Negative Syndrome Scale (PANSS) total scores in patients with schizophrenia. Cariprazinealso demonstrated efficacy as measured by the Clinical Global Impressions-Severity (CGI-S) rating scale, the secondary efficacy endpoints for both conditions. Vraylar, along with all other FDA-approved drugs used to treat schizophrenia and bipolar disorder, have a boxed warning regarding an increased risk of death associated with the use of these drugs in older people with dementia-related psychosis. Neither cariprazine nor any other drug in this class is approved to treat such patients. Cariprazine was discovered and codeveloped by Gedeon Richter, is manufactured by Forest Laboratories and is licensed to Actavis, now Allergan, in the U.S. and Canada (Allergan News Release; FDA News Release).

欢迎关注汤森路透生命制药官方微信，为您推送更多药物资讯。

Jingzhi Li(李敬芝)

IP & Science

Thomson Reuters

电话:86-021-61041667

手机: 86-13774461587

地址：上海市浦东新区陆家嘴环路1233号汇亚大厦30层

jingzhi.li@thomsonreuters.com

thomsonreuters.com