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中国药师 >药品前沿信息
药物快讯-2017年7月
发布人:

抗肿瘤药物

2017年7月31日,化合物KPM-2有望用于肿瘤和神经退行性疾病的治疗

NAD依赖的蛋白去乙酰化酶SIRT2属于组蛋白去乙酰化酶家族,尽管其在神经细胞和肿瘤细胞中的功能还没有被完全揭示,但由于它被认为与肿瘤和神经退行性疾病相关联,故针对SIRT2抑制剂的研究具有重要意义。来自Ono Pharmaceutical公司的研究人员和合作者们基于对化合物与SIRT2蛋白的复合物X-ray晶体结构研究发现了一个全新的抑制剂KPM-2。该化合物能够结合在SIRT2的活性位点而发挥活性,形成稳定的KPM-2-ADP-ribose复合物,竞争性的夺取NAD+与蛋白的结合。KPM-2可以抑制癌细胞的增殖和促进神经突起生长。研究结论显示,KPM-2有望用于肿瘤和神经退行性疾病的治疗。(Itoh, Y. et al. 11th AFMC Int Med ChemSymp (AIMECS) (July 23-26, Melbourne) 2017, Abst).

图为KPM-2结构

JUL 31, 2017
KPM-2 SHOWS PROMISE IN CANCER AND NEURODEGENERATIVE DISORDERS

NAD-dependent protein deacetylase sirtuin-2 (SIRT2), a member of the histone deacetylase family, is thought to be involved in cancer progression as well as in neurodegeneration, although its function in neurons and cancer cells is still not well understood. The discovery of novel SIRT2 inhibitors is of high importance for treating these severe conditions. Researchers at Ono Pharmaceutical and collaborators discovered a novel SIRT2 inhibitor, KPM-2, based on the X-ray crystal structure of SIRT2 shown in complex with a known weak inhibitor. KPM-2 was found to be a potent SIRT2 inhibitor by occupying the active site of SIRT2, which is competed as well by NAD+. This turns into a stable KPM-2-ADP-ribose conjugate that occupies the NAD+-binding site of SIRT2 among others. KPM-2 showed antiproliferative activity in cancer cell studies as well as neurite growth activity. In conclusion, KPM-2 appears to be an interesting approach as a SIRT2 inhibitor for the treatment of cancer progression and neurodegenerative disorders (Itoh, Y. et al. 11th AFMC Int Med ChemSymp (AIMECS) (July 23-26, Melbourne) 2017, Abst).

抗肿瘤药物

2017年7月18日,FDA批准NERLYNX用于早期 HER2 阳性乳腺癌的延长辅助治疗

FDA批准了Puma Biotechnology 公司的Nerlynx(来那替尼,Neratinib,曾用代号PB-272),一个日服一次的口服酪氨酸激酶抑制剂,用于成人早期受体酪氨酸激酶ErbB-2阴性/HER2 阳性的乳腺癌在服用曲妥珠单抗(Trastuzumab)后的延长辅助治疗,并将于今年九月份上市。该药的获批基于一项名为ExteNET的有安慰剂对照的多中心随机双盲III期临床试验结果(ClinicalTrials.gov编号NCT00878709)。该研究针对2840 名在2年内使用过Trastuzumab 治疗的HER2 阳性的早期患者进行了为期1年的随机分组治疗:Neratinib组1420人和安慰剂组1420人。两年后的随访表明,94.2%的Nerlynx治疗患者未经历癌症复发或死亡,而安慰剂组的这一比例为91.9%。Neratinib的常见副作用(> 5%)包括腹泻、恶心、腹痛、疲劳、呕吐、皮疹、口腔炎、食欲减退、肌肉痉挛、消化不良、AST 或 ALT 酶升高、指甲疾病、皮肤干燥、腹胀、体重减轻和尿路感染。Neratinib用药组有16.8%由于严重腹泻造成治疗中止,这是导致治疗中止的最普遍副作用。患者在接受Nerlynx 治疗的前 56 天应使用洛派丁胺治疗腹泻,之后按需使用。另有1.7%的用药患者出现肝毒性或转氨酶水平上升。该药目前已提交欧盟并正在评审过程中。(Puma Biotechnology公司新闻稿;FDA新闻稿)。

图为Neratinib结构

JUL 18, 2017
FDA APPROVES NERLYNX AS EXTENDED ADJUVANT THERAPY FOR EARLY STAGE HER2-POSITIVE BREAST CANCER

The FDA has approved Puma Biotechnology's Nerlynx (neratinib; formerly PB-272), a once-daily oral tyrosine kinase inhibitor for the extended adjuvant treatment of adult patients with early-stage receptor tyrosine-protein kinase erbB-2-negative (HER2)-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy. Puma expects neratinib to become commercially available in September. Approval was based on the phase III ExteNET trial, a multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment (ClinicalTrials.gov Identifier NCT00878709). Women with early-stage HER2-positive breast cancer and within 2 years of completing adjuvant trastuzumab were randomized to receive either neratinib (n = 1420) or placebo (n = 1420) for 1 year. After 2 years of follow-up, invasive disease-free survival (iDFS) was 94.2% in patients treated with neratinib compared with 91.9% in those receiving placebo. The most common adverse reactions (> 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight loss and urinary tract infection. The most common adverse reaction leading to discontinuation was diarrhea, which was observed in 16.8% of neratinib-treated patients. Patients should be given loperamide for the first 56 days of treatment with Nerlynx and as needed thereafter to help manage diarrhea. Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of neratinib-treated patients. An MAA for neratinib is under review by the EMA (Puma Biotechnology News Release; FDA News Release).

抗肿瘤免疫治疗

2017年7月3日,欧盟批准辉瑞的INOTUZUMAB OZOGAMICIN

辉瑞公司宣布欧盟批准了旗下药物Besponsa(Inotuzumab ozogamicin)单药治疗复发或难治性的CD22+成人的B细胞前驱急性淋巴细胞白血病(ALL)。欧盟批准Besponsa是基于一项名为INO-VATE ALL的临床研究数据,该研究对比了326例复发或难治性B细胞前驱ALL患者随机接受Besponsa或标准化疗的疗效(ClinicalTrials.gov编号NCT01564784)。Besponsa是一个靶向CD22的抗体偶联药物,目前正在FDA的评审过程中,审批期限为今年8月份。(Pfizer公司新闻稿)。

JUL 03, 2017
EUROPEAN COMMISSION APPROVES PFIZER'S INOTUZUMAB OZOGAMICIN

Pfizer said the European Commission approved Besponsa (inotuzumab ozogamicin) as a monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL). The approval was supported by data from the phase II INO-VATE ALL trial, testing Besponsa compared to standard-of-care chemotherapy in 326 adult patients with relapsed or refractory B-cell precursor ALL (ClinicalTrials.gov Identifier NCT01564784). A BLA for Besponsa, an antibody-drug conjugate targeting CD22, is under review by the FDA with a decision expected in August (Pfizer News Release).

心血管疾病

2017年7月21日,BAY-386,一个有望用于治疗动脉血栓的PAR1受体抑制剂

来自拜耳制药的科学家近日发表了一个新颖的PAR1受体抑制剂BAY-386。抗血小板凝结疗法是缺血性脑血管疾病的重要治疗方法。由于PAR1是凝血酶的主要受体,也是重要和有效的血小板激活因子,故寻找靶向该受体的新疗法至关重要。BAY-386被证实是一个口服有效的新型PAR1受体可逆抑制剂。研究人员通过对化合物库的高通量筛选发现了一类苯基哌啶化合物,并进一步优化得到了BAY-386(IC50 = 0.01 mcM)。它对人体血小板的PAR1结合功能活性为0.056 mcM,并可以阻断由血小板激活的下游通路(IC50 = 5.6 mcM)和由凝血酶诱导的炎症细胞因子mRNA和蛋白的表达。该化合物的药代动力学性质证明它具备口服有效性。以上结论表明BAY-386有望成为治疗包括动脉血栓在内的凝血类疾病的PAR1受体抑制剂。(Gerdes, C. et al. 26th CongrIntSocThrombHaemost (ISTH) (Jul 8-Jul 13, Berlin) 2017, Abst PB 2198)。

JUL 21, 2017
BAY-386, A NOVEL PAR1 RECEPTOR INHIBITOR FOR ARTERIAL THROMBOSIS

Researchers from Bayer presented data on the newly discovered compound BAY-386, a proteinase-activated PAR1 receptor inhibitor. Antiplatelet therapy is important for the prevention of ischemic and cerebrovascular events. As PAR1 is the main receptor for thrombin, the principal and more potent platelet activator, the search for new therapies targeting PAR1 receptor is of vital importance. BAY-386 was presented as a novel reversible PAR1 receptor inhibitor with potential for oral activity. Ultra high-throughput chemical library screening led to the discovery of a phenylpiperidine class of compounds, which were further optimized to BAY-386 (IC50 = 0.01 mcM). BAY-386 showed an IC50 value of 0.056 mcM in PAR1-binding assays on human platelets. The compound blocked the platelet activation downstream cascade in whole blood over collagen (IC50 = 5.6 mcM), as well as it also blocked thrombin-induced proinflammatory cytokines mRNA and protein expression. The DMPK profile showed compatibility with oral activity. In conclusion, BAY-386 was shown to be a potent and reversible PAR1 receptor inhibitor that could have potential for treating coagulation disorders such as arterial thrombosis (Gerdes, C. et al. 26th CongrIntSocThrombHaemost (ISTH) (Jul 8-Jul 13, Berlin) 2017, Abst PB 2198).

皮肤病

2017年7月27日,巴比妥酸和硫代巴比妥酸衍生物可用于治疗脱发

脱发常常给病人带来外表方面的困扰。目前仅有非那雄胺(finasteride)和米诺地尔(minoxidil)被FDA批准用于治疗脱发。近日,Pusan National University的团队合成了一系列巴比妥酸和硫代巴比妥酸衍生物并筛选了它们刺激头发生长的效果。在脱毛小鼠的体内试验中,MHY-511,MHY-681,MHY-684,MHY-694和MHY-700这五个化合物可以刺激毛发生长。其中,化合物MHY-684,MHY-694和MHY-700进一步在C57BL/6小鼠模型中评价了药效,它们的作用机理正在进一步研究中。在共计80余个巴比妥酸和硫代巴比妥酸衍生物中,上述三个化合物对比阳性药米诺地尔具有更好的刺激毛发的生长作用,并能够促进人毛乳头细胞的增殖。该研究表明这类化合物有望用于治疗脱发并唤起对这类药物在化妆品用途的研究兴趣。(Kim, S.J. et al. 11th AFMC Int Med ChemSymp (AIMECS) (July 23-26, Melbourne) 2017, Abst).

JUL 27, 2017
BARBITURATE/THIOBARBITURATE DERIVATIVES SHOW PROMISE FOR HAIR GROWTH

Hair loss (baldness) is a concern for patients due to its aesthetic implications. To date, only finasteride and minoxidil compounds have been FDA approved for hair growth. Researchers from the Pusan National University conducted a study with the aim to synthesize and screen barbiturate and thiobarbiturate derivatives with the ability to stimulate hair growth. In vivo studies with hairless mice revealed five compounds that showed stimulatory activity on hair growth: MHY-511, MHY-681, MHY-684, MHY-694, and MHY-700. Among these five compounds, MHY-684, MHY-694 and MHY-700 were further evaluated in a C57BL/6 mouse model of hair loss. Their mechanism of action was investigated as well. All three compounds showed more effective hair growth stimulation than that observed with minoxidil, as well as a good cell proliferation rate in human dermal papilla cells, compared to other compounds in a library of almost 80 barbiturate and thiobarbiturate derivatives. These results show MHY-684, MHY-694, and MHY-700 to be good hair growth stimulants, which could awake interest in raw materials to be used as cosmetics (Kim, S.J. et al. 11th AFMC Int Med ChemSymp (AIMECS) (July 23-26, Melbourne) 2017, Abst).

皮肤病

2017年7月14日,FDA批准TREMFYA用于治疗中度至重度的斑块性银屑病

FDA批准了强生旗下Janssen Biotech公司的抗炎药Tremfya(guselkumab)用于适合系统疗法或光疗的中度至重度斑块型银屑病成人患者的治疗。Tremfya是首个也是唯一获批的针对白介素-23(IL-23)具有选择性阻断作用的生物疗法。IL-23是一种细胞因子,在斑块型银屑病中发挥了关键作用。据悉,强生使用了一张优先审评券加速了Tremfya的获批。该药获批得到了一项III期临床项目的支持,包括3个名为VOYAGE 1、VOYAGE 2和NAVIGATE的III期临床研究,共涉及超过2000例患者(ClinicalTrials.gov 编号NCT02207231,NCT02207244和NCT02203032)。该研究证实Tremfya对比安慰剂具有显著的疗效。在治疗的第16周,guselkumab治疗组至少70%的患者实现了至少90%皮肤清晰,超过80%的患者获得了清晰或几乎清晰的皮肤;同时治疗组在头皮部位的银屑病以及包括痒痛、疼痛、刺痛、灼热、皮肤紧实在内的斑块型银屑病症状也实现了显著改善。接近90%的患者在第28周实现PASI90缓解并且持续至第48周,证实guselkumab疗法可以维持持久的药效。在治疗的第24周,Tremfya治疗组超过70%的患者实现至少90%的皮肤清晰,对比Humira治疗组仅为40%。NAVIGATE试验证实了guselkumab对已上市抗炎药Stelara(ustekinumab)应答不足的患者也具有显著的疗效。在Stelara治疗的12周后随机继续Stelara治疗或切换至Tremfya治疗的第28周,Tremfya治疗组有31%的患者达到了皮肤清晰或几乎清晰,而Stelara治疗仅组为14%。(Janssen Biotech公司新闻稿)。

JUL 14, 2017
FDA APPROVES TREMFYA FOR MODERATE TO SEVERE PLAQUE PSORIASIS

The FDA has approved Janssen Biotech's Tremfya (guselkumab) for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Guselkumab is the first and only approved biologic therapy that selectively blocks only interleukin-23 (IL-23), a cytokine that plays a key role in plaque psoriasis. An expedited regulatory review followed application of an FDA priority review voucher. Approval was based on results from a clinical development program that included more than 2,000 patients in the phase III trials VOYAGE 1, VOYAGE 2 and NAVIGATE (respective ClinicalTrials.gov Identifiers NCT02207231, NCT02207244 and NCT02203032). Results demonstrated significant efficacy in patients with moderate to severe plaque psoriasis treated with guselkumab. In clinical studies, at 16 weeks, at least 7/10 guselkumab-treated patients achieved at least 90% clearer skin, and more than 80% demonstrated cleared or almost cleared skin. Improvements were also demonstrated with guselkumab in psoriasis involving the scalp and in symptoms of plaque psoriasis, including itch, pain, stinging, burning and skin tightness at week 16. Treatment with guselkumab resulted in clearer skin that lasted, as nearly 9/10 guselkumab-treated patients who achieved PASI 90 at week 28 maintained that response at week 48. Versus Humira, at week 24, more than 7/10 patients treated with guselkumab reported at least 90% clearer skin compared with more than 4/10 patients treated with Humira. NAVIGATE findings demonstrated the effectiveness of guselkumab in patients who had an inadequate response to treatment with Stelara (ustekinumab). At week 28, 31% of guselkumab-treated patients were considered cleared or almost cleared versus 14% of Stelara-treated patients 12 weeks after randomization to continue Stelara or transition to guselkumab (Janssen Biotech News Release).

内分泌疾病

2017年7月11日,长效GLP-1类似物BPI-3016在临床前研究中显示有效

来自Betta Pharmaceuticals的研究人员发现了一个新的长效GLP-1类似物BPI-3016,并进行了针对II型糖尿病治疗的临床前研究。对hGLP-1进行结构优化而得到的BPI-3016被证实显著改善了hGLP-1的半衰期并提高了对DPP4切割的耐受性。在体外研究中,BPI-3016具备对GLP受体的亲和力并能够刺激cAMP的生成。数据表明,BPI-3016对GLP-1受体的亲和力(Ki = 19.4 nM)比GLP-1(Ki = 1.2 nM)稍低;它能够剂量依赖的刺激cAMP的生成(EC50 = 1.80 nM,GLP-1的EC50为0.10 nM)。在体内试验中,BPI-3016在ob/ob小鼠、db/db mice小鼠和自发性糖尿病猕猴模型中评价了对血糖控制,beta细胞数量和体重的影响。猕猴体内药代动力学研究显示BPI-3016的半衰期为95小时。此外,在单次给药后,BPI-3016能够减少禁食和餐后血糖水平并维持活性长达一周。该药也被证明具有降低体重指数和体脂以及改善葡萄糖耐受的能力,并在每周注射一次的七周内持续表现出促胰岛素分泌效应。上述临床前研究结论显示BPI-3016具备GLP-1的功能并具有更长效的作用,有望开发成每周使用一次的II型糖尿病治疗药物。(Ding, L. et al. Pharmacol Res 2017, 122: 130).

JUL 11, 2017
LONG-ACTING HUMAN GLP-1 ANALOGUE BPI-3016 DEMONSTRATES PROMISE IN PRECLINICAL STUDIES

Researchers from Betta Pharmaceuticals presented the discovery and preclinical characterization of a novel long-acting human glucagon-like peptide 1 (hGLP-1) analogue for the treatment of type 2 diabetes mellitus, BPI-3016. The long-acting hGLP-1(7-37) analogue BPI-3016 demonstrated significantly extended half-life and increased resistance to dipeptidyl peptidase 4 cleavage by structural modifications of hGLP-1. In vitro, BPI-3016 preserved receptor affinity to GLP receptors and was capable of stimulating cAMP production. The results indicated that BPI-3016 had a lower binding affinity (Ki = 19.4 nM) to GLP-1 receptors compared to that to GLP-1 (Ki = 1.2 nM). BPI-3016 also showed dose-dependent stimulatory effect on cAMP production with an EC50 at 1.80 nM and an EC50 for native GLP-1 of 0.10 nM. In vivo, the activity of BPI-3016 was evaluated in ob/ob mice, db/db mice, as well as in spontaneous diabetic cynomolgus monkeys, by investigating the drug candidate's effects on glycemic control, beta-cell mass and body weight. In pharmacokinetic studies in diabetic cynomolgus monkey models, the half-life of BPI-3016 was found to be 95 h after single dosing. Additionally, BPI-3016 reduced fasting and postprandial plasma glucose levels for up to 1 week after a single dose. The drug candidate also demonstrated the ability to reduce body mass index and body fat, improved glucose tolerance and it showed insulinotropic effects after once-weekly injections for 7 weeks. Overall, these preclinical findings demonstrate that BPI-3016 retains the effects of GLP-1 with significantly prolonged half-life, suggesting its potential as a promising new therapy for type 2 diabetes with once-weekly schedule in the clinic (Ding, L. et al. Pharmacol Res 2017, 122: 130).

内分泌疾病

2017年7月4日,MITSUBISHI TANABE PHARMA公司的CANALIA复方片剂在日本获批

Mitsubishi Tanabe Pharma公司获得了日本厚生省对旗下用于治疗II型糖尿病的复方药物Canalia(替格列汀/卡格列净)的生产和销售批准。Canalia是DPP-4抑制剂替格列汀(Tenelia)和SGLT2抑制剂卡格列净(Canaglu)组成的复方药物。替格列汀和卡格列净均是由Mitsubishi Tanabe Pharma公司在日本研发的治疗II型糖尿病的药物。Canalia复方每日服用一次,它结合两种药物并提供了两种不同的治疗机制:DPP-4抑制剂增加胰岛素的释放,SGLT2抑制剂则通过排尿控制血糖浓度。该药在接受Tenelia或Canaglu治疗后血糖水平控制不佳的日本II型糖尿病患者中开展了临床研究,研究数据证实了Canalia的疗效、安全性和耐受性。Canalia对于正在同时服用Tenelia和Canaglu并实现稳定控制血糖水平的II型糖尿病患者可提高服药便利性和治疗依从性;对于接受Tenelia或Canaglu单药治疗血糖水平控制不佳的II型糖尿病患者可更有效的控制血糖。目前,Tenelia由第一三共(Daiichi Sankyo)负责营销,Canaglu则由Mitsubishi Tanabe Pharma负责营销。此次批准的Canalia将由第一三共负责营销并两家公司共同推广。(Mitsubishi Tanabe Pharma公司新闻稿)。

图为替格列汀结构

图为卡格列净结构

JUL 04, 2017
MITSUBISHI TANABE PHARMA OBTAINS APPROVAL IN JAPAN FOR CANALIA COMBINATION TABLETS

Mitsubishi Tanabe Pharma has received manufacturing and sales approval for Canalia (teneligliptinhydrobromide/canagliflozin) combination tablets from the Japanese Ministry of Health, Labour and Welfare for the treatment of type 2 diabetes. Canalia combines the selective dipeptidyl peptidase IV (DPP-4) inhibitor Tenelia tablets (teneligliptin) and sodium/glucose cotransporter 2 (SGLT2) inhibitor Canaglu tablets (canagliflozin). Both Tenelia and Canaglu are agents for type 2 diabetes treatment originally discovered by Mitsubishi Tanabe Pharma in Japan. Canalia combination tablets consist of the combination of these two agents, formulated as a once-daily orally administered tablet that lowers blood-glucose levels based on two different mechanisms of action: inhibiting DPP-4 and thereby increasing insulin release according to blood glucose into urine. Results of clinical trials conducted in Japanese patients with type 2 diabetes who have inadequate glycemic control to Tenelia tablets or Canaglu tablets demonstrated efficacy, safety and good tolerability. Use of Canalia combination tablets by patients with type 2 diabetes whose blood glucose levels are stably controlled by concomitant treatment with Tenelia tablets and Canaglu tablets will enhance convenience and improve medication adherence. Use of Canalia combination tablets by type 2 diabetes patients who have inadequate glycemic control to monotherapy with Tenelia tablets or Canaglu tablets is also expected to result in improved blood glucose control. Currently, marketing of Tenelia tablets is conducted by Daiichi Sankyo, whereas marketing of Canaglu tablets is carried out by Mitsubishi Tanabe Pharma. Marketing of Canalia combination tablets will be conducted by Daiichi Sankyo, and both companies will co-promote the product, as is the case with Tenelia tablets and Canaglu tablets (Mitsubishi Tanabe Pharma News Release).

眼科疾病

2017年7月21日,欧盟批准了DOMPE公司的滴眼液CENEGERMIN用于治疗神经营养性角膜炎

欧盟委员会批准了意大利Dompe公司的滴眼液cenegermin用于治疗中度或重度神经营养性角膜炎。Cenegermin是一个重组的人体神经生长因子,可帮助恢复眼睛的正常愈合过程并修复角膜损伤。该药在2015年获得了孤儿药认证。Dompe已经向FDA提交了该药的BLA申请,并正在与日本药品与医疗器械管理局(PMDA)共同讨论其发展计划。

JUL 21, 2017
EUROPEAN COMMISSION APPROVES DOMPE'SCENEGERMIN EYE DROPS FOR NEUROTROPHIC KERATITIS

The European Commission has granted approval for Dompe's cenegermin eye drops for the treatment of moderate to severe neurotrophic keratitis. Cenegermin is a recombinant version of human nerve growth factor and is designed to restore the normal healing processes of the eye and repair corneal damage. The product was granted orphan drug designation in 2015. Dompe has started a rolling BLA submission in the U.S. and has begun discussions with Japan's Pharmaceuticals and Medical Devices Agency (PMDA) (Dompe News Release).

胃肠道功能疾病

2017年7月10日,PRAEVENTIX和TEMPLE UNIVERSITY发现了可用于治疗炎症性肠病5-HT7拮抗剂

根据5-HT7拮抗能抑制免疫反应、预防肠道炎症并阻碍炎症性肠病(IBD)进展的假说,来自Temple University和Praeventix公司的研究者们研究了一系列新颖的5-HT7拮抗剂,这项工作最近发表在2017年在费城举行的ACS MEDI-EFMC药化会议中。其中一个先导化合物PR-073显示出了高活性(Ki = 89 nM)和高选择性(> 10 mcM at 5-HT1-6),其小鼠口服生物利用度为17%,半衰期为3.4小时。在急性葡聚糖硫酸酯钠的小鼠IBD模型中,腹腔注射PR-073剂量10 mg/kg连续6天后可以有效降低炎症标志物浓度(髓过氧化物酶、白细胞介素-6、白细胞介素-1beta和TNF-alpha)和肠道损伤。在慢性IBD小鼠模型中,组织学和宏观评价均显示10 mg/kg 的PR-073腹腔注射6天后能够减轻肠道损伤并逆转慢性损伤,证实了之前的假说。对PR-073的进一步研究正在进行中,包括该化合物在脑组织和中枢神经系统中的分布和药效。(Canney, D. ACS MEDI-EFMC Med Chem Front (June 25-28, Philadelphia) 2017, Abst).

JUL 10, 2017
PRAEVENTIX, TEMPLE UNIVERSITY IDENTIFY 5-HT7 ANTAGONISTS FOR TREATING IBD

Acting on the hypothesis that serotonin 5-HT7 antagonism can inhibit immune responses, prevent intestinal inflammation and hinder the progression of inflammatory bowel disease (IBD), scientists at Temple University and Praeventix have sought novel 5-HT7 antagonists. Their work was presented at the ACS MEDI-EFMC Medicinal Chemistry Frontiers 2017 meeting in Philadelphia. A lead compound, PR-073, showed potency (Ki = 89 nM) and selectivity (> 10 mcM at 5-HT1-6) as well as oral bioavailability in the mouse (17%) with a 3.4 hour t1/2 after oral dosing. In an acute dextran sulfate sodium (DSS) model of IBD in mice, i.p. dosing of PR-073 at 10 mg/kg for 6 days reduced inflammatory markers (myeloperoxidase, interleukin-6, interleukin-1beta, TNF-alpha) and intestinal damage. In a chronic mouse DSS model of IBD, histologic and macroscopic scoring showed that PR-073 at 10 mg/kg i.p. for 6 days mitigated intestinal damage and reversed chronic damage, providing proof of concept. Continuing studies will further evaluate PR-073, among other things assessing its potential for brain penetration and CNS adverse effects (Canney, D. ACS MEDI-EFMC Med Chem Front (June 25-28, Philadelphia) 2017, Abst).

血液及凝血功能疾病

2017年7月10日,FDA 批准 ENDARI 用于镰状细胞病的治疗

FDA批准了Emmaus Life Sciences公司的新药Endari(L-谷氨酰胺口服粉剂)用于 5 岁及以上年龄患有镰状细胞病的患者,用以减轻与该血液疾病相关的严重并发症。Endari可在镰状红细胞中增强烟酰胺腺嘌呤二核苷酸(NAD)的氧化还原电势从而降低氧化应激反应。Emmaus公司计划在今年第四季度将该药推向市场。Endari 的获批基于一项时长48周的有安慰剂对照的多中心随机双盲III期临床研究,共有230名镰状细胞病受试者入组(ClinicalTrials.gov编号NCT01179217)。该药被证实可以降低25%的镰状细胞病风险,并降低33%的住院治疗概率。此外,研究显示该药能够减少41%的住院治疗时间并降低超过60%的急性胸部综合症。Endari的安全性研究共有298名用药组患者和111位安慰剂受试者参加,研究证明该药对儿童和成人均有良好的耐受性,其最常见的不良反应(>10%)为便秘、恶心、头痛、腹痛、咳嗽、四肢疼痛、背部疼痛和胸痛(非心源性)。Endari获得了FDA的孤儿药认证。(FDA新闻稿;Emmaus Life Sciences公司新闻稿)。

图为L-谷氨酰胺结构

JUL 10, 2017
FDA APPROVES ENDARI FOR SICKLE CELL DISEASE

The FDA has approved Emmaus Life Sciences' Endari (L-glutamine) oral powder to reduce the severe complications of sickle cell disease in adult and pediatric patients age 5 years and older. Endari reduces oxidant damage to red blood cells by improving the redox potential of nicotinamide adenine dinucleotide (NAD), a coenzyme that has been identified as the primary regulator of oxidation. Emmaus plans to make the treatment available to patients as early as the fourth quarter of this year. FDA approval was supported by efficacy data from a 48-week, randomized, double-blind, placebo-controlled, multicenter phase III trial evaluating the effects of Endari, prescription grade L-glutamine, as compared to placebo in 230 adults and children with sickle cell disease (ClinicalTrials.gov Identifier NCT01179217). Endari was shown to reduce the frequency of sickle cell crises by 25% and hospitalizations by 33%. Additional findings showed a decrease in cumulative hospital days by 41% and lower incidence of acute chest syndrome by more than 60%. Endari's safety profile, established in 298 patients treated with L-glutamine and 111 patients treated with placebo in the phase II and phase III studies, was similar to placebo, being well tolerated in pediatric and adult patients. The most common adverse reactions occurring in greater than 10% of patients treated with Endari were constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain and chest pain (non-cardiac). Endari has orphan drug designation for this use (FDA News Release; Emmaus Life Sciences News Release).

抗感染药物

2017年7月31日,欧盟批准艾伯维的MAVIRET用于治疗慢性丙肝(基因型1-6)

欧盟批准艾伯维的Maviret(glecaprevir/pibrentasvir)每日一剂用于全部6种基因型(GT1-6)慢性丙型肝炎病毒(HCV)成人感染者的治疗。Maviret的批准经过了EMA的加速评审。该药对于没有发生肝硬化的丙肝初治患者仅需8周疗程。此外,Maviret也适用于具有特定治疗挑战的患者群体,如伴有代偿性肝硬化的慢性HCV患者以及目前治疗选择有限的患者,包括伴有严重慢性肾病以及基因型3型的HCV感染者。Maviret的获批基于共计8个已注册的临床试验的数据支持。该药在所有6个基因型HCV感染群体中治疗无肝硬化、初治患者群体在8周内取得了高达97.5%(n=779/799)的病毒学治愈率(SVR12)。Maviret在各类临床背景和病毒学特征的患者亚组中均取得了非常高的病毒学治愈率,包括患有慢性肾病的群体。在伴有肝硬化的患者中,Maviret的12周治愈率为98%(n=201/205)。在有或无代偿性肝硬化的基因型3丙肝患者中,Maviret 16周的治愈率为96%(n=66/69)。在所有注册研究中,该药的停药率少于0.1%,最常见的不良事件(发生率≥10%)为头痛和疲劳。其中,复方之一的Glecaprevir是由Enanta Pharmaceuticals公司发现的第二个蛋白酶抑制剂,由艾伯维开发和推向市场。(艾伯维公司新闻稿;Enanta Pharmaceuticals公司新闻稿)。

上图为Glecaprevir结构

上图为Pibrentasvir结构

JUL 31, 2017
EUROPEAN COMMISSION APPROVES ABBVIE'SMAVIRET FOR CHRONIC HCV GENOTYPES 1-6

The European Commission has granted marketing authorization for AbbVie'sMaviret (glecaprevir/pibrentasvir), a once-daily, ribavirin-free treatment for adults with chronic hepatitis C virus (HCV) infection across all major genotypes (1-6). Maviret, which was reviewed under accelerated assessment by the EMA, is an 8-week treatment for patients without cirrhosis and new to treatment. The drug is also indicated for patients with specific treatment challenges, including those with compensated cirrhosis across all major HCV genotypes, and those who previously had limited treatment options, such as patients with severe chronic kidney disease or those with genotype 3 chronic HCV infection. Approval was supported by data from eight registrational studies. Trials showed a 97.5% (n = 779/799) cure rate (sustained virologic response at 12 weeks [SVR12]) post treatment with just 8 weeks of treatment in patients with genotypes 1-6 without cirrhosis and who were new to treatment. This cure rate was achieved in patients with varied patient and viral characteristics and including those with chronic kidney disease. For compensated cirrhotic patients, a 98% (n = 201/205) cure rate was achieved with 12 weeks of treatment. For genotype 3 treatment-experienced patients with or without compensated cirrhosis, a 96% (n = 66/69) cure rate was achieved with 16 weeks of treatment. In registrational studies, less than 0.1% of patients discontinued treatment due to adverse reactions. The most commonly reported adverse reactions (incidence 10% or greater) were headache and fatigue. Glecaprevir, one of the two new direct-acting antivirals in Maviret, is Enanta Pharmaceuticals' second protease inhibitor being developed and commercialized by AbbVie (AbbVie News Release; Enanta Pharmaceuticals News Release).

抗感染药物

2017年7月27日,VOSEVI在美国上市销售

吉利德的抗HCV新药Vosevi(sofosbuvir/velpatasvir/voxilaprevir三联方)目前已经在美国上市,由Diplomat Pharmacy负责销售。该复方片剂可用来治疗没有肝硬化或有代偿性肝硬化且以前接受过含NS5A抑制剂的治疗方案的成人慢性丙型肝炎病毒所有基因型造成的感染。Vosevi也可用于以往接受过含sofosbuvir但不含NS5A抑制剂治疗方案的基因型1a或3丙肝成人感染的治疗。(Diplomat Pharmacy公司新闻稿)。

JUL 27, 2017
VOSEVI NOW AVAILABLE IN U.S.

Vosevi (sofosbuvir/velpatasvir/voxilaprevir) is now available in the U.S., with Diplomat Pharmacy dispensing the newly approved treatment for hepatitis C virus infection. Gilead Sciences' fixed-dose combination tablet is used to treat all genotypes of chronic hepatitis C virus infection in adults without cirrhosis or with compensated cirrhosis who have previously been treated with a regimen containing an NS5A inhibitor. Vosevi is also indicated to treat chronic hepatitis C infection in patients with genotype 1a or 3 and previous treatment with a regimen containing Sovaldi (sofosbuvir) without an NS5A inhibitor (Diplomat Pharmacy News Release).

抗感染药物

2017年7月19日,FDA批准新药VOSEVI用于慢性丙型肝炎的再治疗

FDA批准了吉利德公司的新药Vosevi(索非布韦,sofosbuvir 400 mg/维帕他韦,velpatasvir 100 mg/和voxilaprevir 100 mg的复方制剂),用于治疗接受过含NS5A抑制剂方案治疗失败的全部6种基因型的丙肝成人感染者的再治疗和接受过含sofosbuvir但不含NS5A抑制剂方案治疗失败的基因型1a或3丙肝成人感染者的再治疗。FDA授予了该药优先评审资格和突破性疗法认证。该药的基于两个3期临床试验POLARIS-1(ClinicalTrials.gov编号NCT02607735)和POLARIS-4,研究评估了Vosevi 12周治疗方案对无肝硬化或有代偿性肝硬化患者的安全性和有效性。两项研究中共计353位Vosevi受试者中的340位达到了主要临床终点SVR12,即治疗结束后在12周内可维持体内病毒未检出状态。Vosevi带有一个安全性警告,指出HCV/HBV的合并感染患者需要注意HBV的复发风险。(Gilead Sciences公司新闻稿;FDA新闻稿)。

上图为Sofosbuvir结构

上图为Velpatasvir结构

上图为Voxilaprevir结构

JUL 19, 2017
FDA APPROVES VOSEVI FOR RE-TREATMENT OF CHRONIC HCV INFECTION

The FDA has approved Gilead Sciences' Vosevi (sofosbuvir 400 mg/velpatasvir 100 mg/ voxilaprevir 100 mg), a single-tablet regimen for the re-treatment of chronic hepatitis C virus (HCV) infection in adults with genotypes 1, 2, 3, 4, 5 or 6 previously treated with an NS5A inhibitor-containing regimen, or with genotype 1a or 3 previously treated with a sofosbuvir-containing regimen without an NS5A inhibitor. The FDA granted priority review and breakthrough therapy designations to this application. Approval was based on data from the phase III POLARIS-1 (ClinicalTrials.gov Identifier NCT02607735) and POLARIS-4 studies, which evaluated 12 weeks of Vosevi in direct-acting antiviral-experienced chronic HCV-infected patients without cirrhosis or with compensated cirrhosis. In these populations across the two studies, 340 of the 353 patients treated with Vosevi (96%) achieved the primary endpoint of SVR12, defined as maintaining undetectable viral load 12 weeks after completing therapy. Vosevi has a boxed warning in its product label regarding the risk of hepatitis B virus (HBV) reactivation in HCV/HBV coinfected patients (Gilead Sciences News Release; FDA News Release).

抗感染药物

2017年7月5日,治疗带状疱疹的药物AMENALIEF在日本获批

日本厚生省批准了Maruho公司的新药Amenalief(amenamevir,200mg片剂)用于治疗带状疱疹。. Amenalief是由AstellasPharma公司研发的具有新颖作用机制的抗疱疹病毒药物。它通过抑制病毒复制过程中的关键步骤—螺旋酶复合物的活性,从而阻断病毒的增殖。Maruho公司自2012年起从 Astellas公司获得授权,对Amenalief进行了后续的开发并成功的将其推向日本市场。(Maruho公司新闻稿)。

图为Amenamevir结构

JUL 05, 2017
AMENALIEF APPROVED IN JAPAN TO TREAT HERPES ZOSTER

Maruho has received manufacturing and marketing approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for Amenalief (amenamevir) tablets 200 mg for the treatment of herpes zoster (shingles) in Japan. Amenalief is an anti-herpes virus agent with a novel mechanism of action created by AstellasPharma. It has been shown to inhibit the proliferation of the varicella-zoster virus by inhibiting the activity of the helicase-primase complex, which is essential for viral DNA replication. Maruho has advanced the development of Amenalief under a 2012 license agreement with Astellas for the development and commercialization of the product in Japan (Maruho News Release).

肌肉骨骼和结缔组织疾病

2017年7月13日,韩国首先批准了INVOSSA-K细胞和基因疗法用于退行性关节炎

TissueGene公司宣布其在韩国的合作伙伴Kolon Life Science公司获得了韩国药监局对Invossa-K(tonogenchoncel-L)的上市批准,这是一种针对退行性关节炎的同种异体细胞的基因疗法。该药的批准得到了一项临床III期研究的支持,结论证实了经过一次关节注射后,患者的减轻疼痛,关节的活动性增加且关节结构得到了改善。(TissueGene公司新闻稿)。

JUL 13, 2017
KOREA FIRST TO APPROVE INVOSSA-K CELL AND GENE THERAPY FOR DEGENERATIVE ARTHRITIS

TissueGene said Korean partner Kolon Life Science received marketing approval for Invossa-K (tonogenchoncel-L), an allogeneic cell and gene therapy for degenerative arthritis, from the Korea Ministry of Food and Drug Safety. Approval was based on results from phase III trials testing the therapy as a single intra-articular injection, which demonstrated pain relief, increased mobility and improvements in joint structure (TissueGene News Release).

 

      ----转自:CLARIVATE ANALYTICS

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