Phase IIb/III Parallel-arm, Random., Active-controlled, Double-blind, Double-dummy, Multicenter, Non-inferiority Study in Patients With RVVC to Compare Efficacy, Safety and Tolerability of Topically Administered ProF-001 to Oral Fluconazole

This is a prospective, randomized, multi-center, active-controlled, double-blind, double-dummy, multicenter, non-inferiority study comparing the clinical efficacy, safety and tolerability of ProF-001 to fluconazole.

开始日期2019-10-01

申办/合作机构

ProFem

[+1]

NCT03115073 / Completed临床2/3期

A Phase IIa Randomized, Active-controlled, Double-blind, Dose-escalation Study in Patients With Vulvovaginal Candidiasis to Evaluate Dose Response Relationship of Clinical Efficacy, Safety and Tolerability of Topically Administered ProF-001

This is a multi-center, randomized, prospective, active-controlled, double-blind, dose-escalation study comparing dose response of clinical efficacy, safety, local tolerability of three different doses of ProF-001/Candiplus® (Candiplus® 0.2%, Candiplus® with 0.3%, Candiplus® with 0.4%) to 1% clotrimazole vaginal cream.
Patients with acute episode of vulvovaginal candidiasis (VVC) will be randomized to receive a daily dose of either 5 ml (intravaginal) of Candiplus® at three different doses for the first 3 days and 2.5 ml for the remaining 3 days or 5 ml (intravaginal) application of 1% clotrimazole cream over the first 3 days and 2.5 ml for the remaining 3 days according to the following scheme (with each application 2 cm of cream will be applied to the vulvar region):
Cohort 1: Candiplus® 0.2% versus clotrimazole mono Cohort 2: Candiplus® 0.3% versus clotrimazole mono Cohort 3: Candiplus® 0.4% versus clotrimazole mono Randomization into the cohorts will occur consecutively from the lowest dose to the highest dose, i.e. patients will be randomized first in cohort 1 and finally in cohort 3.
The proposed study is - after a pilot study to assess critical pharmacokinetic data - the second study within a clinical trial program with the objective to develop a new combination therapy for the treatment of vulvovaginal candidiasis.
The new combination consists of two registered drug substances.

开始日期2017-04-04

申办/合作机构

ProFem GmbH

EUCTR2016-004268-21-AT / Not yet recruiting临床2期

A phase IIa randomized, active-controlled, double-blind, dose-escalation study in patients with vulvovaginal candidiasis to evaluate clinical efficacy, safety and tolerability and dose response relationship of topically administered ProF-001

开始日期2017-03-23

申办/合作机构

ProFem GmbH

100 项与 CYP51A1 x COX 相关的临床结果

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100 项与 CYP51A1 x COX 相关的转化医学

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0 项与 CYP51A1 x COX 相关的专利（医药）

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项与 CYP51A1 x COX 相关的文献（医药）

2022-11-10·Journal of Medicinal Chemistry1区 · 医学

Novel Aryl Alkamidazole Derivatives as Multifunctional Antifungal Inhibitors: Design, Synthesis, and Biological Evaluation

1区 · 医学

Article

作者: Wang, Qingpeng ; Liu, Yating ; Yu, Shuai ; Liu, Min ; Sun, Bin ; Han, Jun ; Liu, Wenxia

Dual-target drug design was considered as the more reasonable antifungal strategy. In this study, three different series of novel compounds were designed using the skeleton screening and splicing method based on dual-target enzyme features, and their structures were synthesized and characterized. Among them, target compounds 5a-1-2, 14b-1-2, and 14c-2-1 with excellent antifungal activity (0.125-2.0 μg/mL) were selected for the subsequent mechanistic study. On the one hand, these compounds blocked the ergosterol biosynthesis pathway by inhibiting the core enzyme CYP51, which effectively induced rapid accumulation of reactive oxygen species, damaged the mitochondrial function, and eventually led to the occurrence of fungal apoptosis. On the other hand, these compounds also inhibited the inflammatory inducible enzyme cyclooxygenase-2, which further affected the expression of inflammatory factors and body's immune function. In conclusion, this study discovered potential target compounds, which could accelerate the rehabilitation process of the infected region.

2022-09-22·Journal of Medicinal Chemistry1区 · 医学

Design, Synthesis, and Biological Evaluation of Dual-Target COX-2/CYP51 Inhibitors for the Treatment of Fungal Infectious Diseases

1区 · 医学

Article

作者: Fan, Haiyan ; Dong, Yue ; Han, Jun ; Liu, Wenxia ; An, Yunfei ; Liu, Yating ; Sun, Bin ; Liu, Min

The design of novel dual-target (COX-2/CYP51) inhibitors was proposed in the study, and three series of compounds were constructed though the pathway of skeleton screening and combination; their molecular structures were synthesized and evaluated. Most of the compounds exhibited significant antifungal ability. Among them, potential compounds (10a-2, 16b-3) with excellent antifungal and anti-drug-resistant fungal ability (MIC₅₀, 0.125-2.0 μg/mL) were selected for the subsequent mechanistic study. On the one hand, these compounds could block the ergosterol biosynthesis pathway by inhibiting CYP51 and influence the internal physiological function of fungal cells, which included the increase of the ROS level, the anomaly of ΔΨ_m, and the emergence of an apoptotic state. On the other hand, these compounds also effectively showed COX-2 inhibition ability, eliminated the inflammatory reaction of the infected region, and activated the body's immune function. In summary, this study not only provided a novel antifungal drug design pathway but also discovered excellent target compounds.

2003-01-01·Cytogenetic and Genome Research4区 · 生物学

Improving the comparative map of porcine chromosome 9 with respect to human chromosomes 1, 7 and 11

4区 · 生物学

Article

作者: Backofen, B. ; Chen, Y. ; Middleton, R. ; Aldenhoven, J. ; Moran, C.

Conserved segments have been identified by ZOO-FISH between pig chromosome 9 (SSC9) and human chromosomes 1, 7 and 11. To assist in the identification of positional candidate genes for QTL on SSC9, the comparative map was further developed. Primers were designed from porcine EST sequence homologous to genes in regions of human chromosomes 1, 7 and 11. Porcine ESTs were then physically assigned using the INRA somatic cell hybrid panel (INRASCHP) and the high-resolution radiation hybrid panel (IMpRH). Seventeen genes (PEPP3, RAB7L1, FNBP2, MAPKAPK2, GNAI1, ABCB1, STEAP, AKAP9, CYP51A1, SGCE, ROBO4, SIAT4C, GLUL, CACNA1E, PTGS2, C1orf16 and ETS1) were mapped to SSC9, while GUSB, CPSF4 and THG-1 were assigned to SSC3.

项与 CYP51A1 x COX 相关的新闻（医药）

2022-05-16

·医药观澜

迈入全球医药研发TOP25！一文盘点恒瑞医药创新药研发管线

近日，恒瑞医药发布新闻稿称，在Informa Pharma Intelligence按照临床研发规模评选出的全球医药企业TOP25中，恒瑞医药因一年来研发管线数量大幅增加，排名从37位跃升至16位，首次进入TOP25榜单。新闻稿还表示，截至目前，该公司已有10款创新药获批上市，另有60余个创新药正在临床开发，250多项临床试验在海内外开展。在国际化进展方面，恒瑞医药开展近20项国际临床试验，其中国际多中心3期项目有7项，并有10余项研究处于准备阶段。那么，恒瑞医药创新药管线重点有哪些？近期有哪些重要进展？未来还有哪些值得期待？新药获批数量增至10款！根据公开资料，截至目前，恒瑞医药在中国获批上市的创新药数量已有10款。其中有3款产品于2021年首次获得中国国家药监局（NMPA）批准，分别是TPOR激动剂海曲泊帕乙醇胺、CDK4/6抑制剂羟乙磺酸达尔西利（SHR6390）和SGLT-2抑制剂脯氨酸恒格列净。其中，海曲泊帕乙醇胺获得NMPA批准用于特定慢性原发免疫性血小板减少症（ITP）成人患者，以及对免疫抑制治疗疗效不佳的重型再生障碍性贫血（SAA）成人患者；达尔西利获得NMPA批准用于特定激素受体阳性（HR+）、人表皮生长因子受体2阴性（HER2-）的复发或转移性乳腺癌患者；恒格列净获得NMPA批准用于改善成人2型糖尿病患者的血糖控制。另外，恒瑞医药还有其它7款新药已于2021年以前在中国获批上市，分别是：选择性COX-2抑制剂艾瑞昔布、VEGFR-2酪氨酸激酶抑制剂（TKI）甲磺酸阿帕替尼、第二代长效粒细胞集落刺激因子（G-CSF）硫培非格司亭、HER2抑制剂马来酸吡咯替尼、PD-1抑制剂卡瑞利珠单抗、短效GABAa受体激动剂甲苯磺酸瑞马唑仑、PARP抑制剂氟唑帕利。其中，部分新药自去年以来又陆续收获了新的适应症。例如，抗肿瘤新药卡瑞利珠单抗4个新适应症相继获批，分别是一线鳞状非小细胞肺癌、一线食管鳞癌、二线及以上鼻咽癌、一线鼻咽癌，这使得该新药获批适应症总数达8个。再如，创新药氟唑帕利获批第二个适应症，用于铂敏感复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗。还有麻醉镇静新药瑞马唑仑获批第三个适应症，用于全身麻醉的诱导和维持。抗PD-L1单抗、新型抗真菌药等递交上市申请除了已获批上市的新药，恒瑞医药在研管线中还有多款产品已进入后期开发阶段，适应症涵盖肿瘤、自身免疫性疾病、干眼病、痛风及术后镇痛等。其中，DPP-4抑制剂、新一代AR抑制剂、抗真菌新药、抗PD-L1单抗等已相继在中国申报上市。 2021年10月，恒瑞医药新一代AR拮抗剂SHR3680在中国递交上市申请并获得中国国家药监局药品审评中心（CDE）受理，并以“纳入突破性治疗药物程序的药品”纳入优先审评，拟开发适应症为：治疗高瘤负荷的转移性激素敏感性前列腺癌（mHSPC）患者。根据恒瑞医药早前发布的新闻稿，相较于第一代AR抑制剂，SHR3680具有更强的AR抑制作用，且无激动作用。 2022年1月，恒瑞医药在中国提交1类新药SHR8008胶囊的新药上市申请并获得受理，拟用于治疗急性外阴阴道假丝酵母菌病（VVC，也称霉菌性阴道炎）。SHR8008是Mycovia公司开发的一种新型口服唑类抗真菌药物，可高度特异性抑制真菌CYP51酶。2019年6月，恒瑞医药与Mycovia公司达成超1亿美元的合作，获得了该药在大中华区的独家权益。值得注意的是，该产品已于今年4月获得美国FDA批准，用于在不具有生殖潜力的女性中，降低复发性外阴阴道假丝酵母菌病（RVVC）的复发几率。同月，恒瑞医药1类新药抗PD-L1单抗阿得贝利单抗注射液（SHR-1316）的上市申请也获得CDE受理，拟用于联合化疗一线治疗广泛期小细胞肺癌适应症。根据近日发表在《柳叶刀-肿瘤学》（The Lancet Oncology）的多中心的3期临床研究数据，阿得贝利单抗联合化疗用于上述适应症可以显著延长患者总生存期（OS）至15.3个月。恒瑞医药曾在新闻稿指出，这项结果刷新了现有免疫药物一线治疗广泛期小细胞肺癌的总生存纪录。另外，恒瑞医药自主研发的1类新药磷酸瑞格列汀治疗2型糖尿病的新药上市申请正在CDE审评审批中。该产品为二肽基肽酶Ⅳ（DPP-4）抑制剂，是一款可促进胰岛β细胞释放胰岛素并抑制胰岛α细胞分泌胰高血糖素的口服类降糖药。除此之外，恒瑞医药还有多款重要产品已进入3期临床研发阶段，下面列举部分产品做介绍：多靶点酪氨酸激酶抑制剂/抗肿瘤苹果酸法米替尼，正在开发用于联合卡瑞利珠治疗宫颈癌、肺癌、肾细胞癌等多种实体瘤治疗，其中宫颈癌适应症还被CDE纳入突破性治疗品种；以JAK1为作用靶点的JAK抑制剂SHR0302片，针对类风湿关节炎、强直性脊柱炎、银屑病关节炎、特应性皮炎等适应症均已处于3期开发阶段，且特应性皮炎适应症已被CDE纳入突破性治疗品种；靶向PD-L1和TGF-β双靶点的双特异性抗体SHR-1701，正在开展针对晚期结直肠癌、胃癌等多项3期临床研究；高选择性、强效尿酸重吸收转运子1（URAT1）抑制剂SHR4640，拟用于治疗痛风和高尿酸血症；人源化的IgG1抗IL-17A单克隆抗体药物SHR-1314，拟用于成人中重度慢性斑块型银屑病、强直性脊柱炎；抗PCSK9单抗SHR-1209，拟用于治疗高胆固醇血症；偏向性的MOR激动剂SHR8554，拟用于术后镇痛；外周KOR具有高度选择性SHR0410，拟用于术后镇痛；单一组分全氟己基辛烷（F6H8）的无菌滴眼液SHR8058，拟用于睑板腺功能障碍相关干眼病SHR8058；透明的环孢素A眼用溶液SHR8028，拟用于干眼病。小结根据恒瑞医药财报，该公司近年来在研发上的投入逐年增加。2017年、2018年、2019年、2020年，该公司累计投入的研发资金分别为17.59亿元、26.70亿元、38.96亿元、49.89亿元。到2021年，恒瑞医药累计研发投入已达62.03亿元，比上年增长24.34%，研发投入占营收比重达23.95%，创历史新高。除了上述已经获批上市或者进入后期开发阶段的产品，恒瑞医药在研管线仍在不断扩展。截至目前，该公司有60余个创新药正在临床开发，250多项临床试验在海内外开展。今年以来，该公司已有新型口服小分子GnRH受体拮抗剂SHR7280、白细胞介素-15（IL-15）融合蛋白SHR-1501、HER2抗体偶联药物（ADC）SHR-A1811等创新候选药先后在中国获批临床。值得注意的是，恒瑞医药在研管线中多个创新产品的研究成果已先后发表在《自然-医学》（Nature Medicine）、《美国医学会杂志》（JAMA）、《柳叶刀》（The Lancet）子刊等国际知名学术杂志，或者登上美国临床肿瘤学会（ASCO）、欧洲肺癌大会（ELCC）等专业产业盛会。希望恒瑞医药这些在研产品在后续临床开发中进展顺利，早日为中国乃至全球患者带来更多新药、好药。参考资料： [1] 恒瑞医药首入全球医药研发TOP25，排名16位创中国药企新高！Retrieved May 12，2022. From https://mp.weixin.qq.com/s/BSNBqVUBlSztW_-MWoYkFQ [2] 600276:恒瑞医药2021年年度报告. Retrieved Apr 23， 2022, from https://pdf.dfcfw.com/pdf/H2_AN202204221560905081_1.pdf?1650655520000.pdf [3] 恒瑞医药新闻稿及公告内容来源于网络，如有侵权，请联系删除，谢谢。

药物审批创新药免疫疗法抗体财报优先审批