A Randomized, Double-blind, Parallel-group, Placebo and Active Comparator (Pioglitazone)-Controlled Clinical Study to Determine the Efficacy and Safety of Balaglitazone in Patients With Type 2 Diabetes on Stable Insulin Therapy

Type 2 diabetes mellitus is a metabolic disorder that is primarily characterized by insulin resistance, relative insulin deficiency, and hyperglycemia. People with type 2 diabetes are at high risk of many serious diabetic complications, including cardiovascular disease, blindness, nerve damage and kidney damage. Balaglitazone is a thiazolidinedione derivative that is being developed as an oral anti-diabetic drug to improve blood glucose control in patients with type 2 diabetes. The purpose of this study is to assess if additional treatment with balaglitazone in patients with type 2 diabetes on stable insulin treatment will improve blood glucose control and decrease the daily insulin dose compared to placebo, but with less impact on weight gain and oedema than pioglitazone (Actos®) 45 mg.

开始日期2007-07-01

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100 项与巴格列酮相关的专利（医药）

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项与巴格列酮相关的文献（医药）

2017-10-01·Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine

Balaglitazone reverses P-glycoprotein-mediated multidrug resistance via upregulation of PTEN in a PPARγ-dependent manner in leukemia cells

Article

作者: Azimi, Ako ; Yousefi, Bahman ; Badalzadeh, Reza ; Samadi, Nasser ; Majidinia, Maryam ; Baradaran, Behzad ; Shafiei-Irannejad, Vahid ; Zarghami, Nosratollah

Multidrug resistance in tumor cells is still a big challenge in cancer treatment. Therefore, identification ofsafe and effective multidrug resistance-reversing compounds with minimal side effects is an important approach in cancer treatment. Here, we investigated the role and potential mechanisms of peroxisome proliferator-activated receptor γ in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effect of doxorubicin on cell viability following treatment with balaglitazone, a peroxisome proliferator-activated receptor γ agonist, was evaluated using trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Rhodamine123 assay was used to determine the activity of two common drug efflux membrane transporters P-glycoprotein and multidrug resistance protein-1. P-glycoprotein, multidrug resistance protein-1, and phosphatase and tensin homolog deleted on chromosome 10 messenger RNA/protein expression levels were measured by quantitative reverse transcription polymerase chain reaction and western blot analyses. Annexin V/fluorescein isothiocyanate assay was also employed to investigate apoptosis. We showed that balaglitazone considerably enhanced the cytotoxicity of doxorubicin. Balaglitazone also significantly downregulated P-glycoprotein expression and activity in K562/DOX cells and reduced multidrug resistance through elevation of intracellular doxorubicin in cells. Furthermore, upon balaglitazone treatment, phosphatase and tensin homolog deleted on chromosome 10 expression could be restored in K562/DOX cells in a peroxisome proliferator-activated receptor γ-dependent manner. We concluded that peroxisome proliferator-activated receptor γ agonist, balaglitazone, could reverse multidrug resistance by inducing phosphatase and tensin homolog deleted on chromosome 10 and peroxisome proliferator-activated receptor/ phosphatase and tensin homolog deleted on chromosome 10 signaling pathway. These findings suggest that targeting peroxisome proliferator-activated receptor γ might serve as an effective approach for circumventing multidrug resistance in chemotherapy of cancerous patients.

2017-01-01·Diabetologia1区 · 医学

Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes

1区 · 医学

Article

作者: Genovese, Federica ; Riis, Bente J ; Nielsen, Mette J ; Byrjalsen, Inger ; Henriksen, Kim ; Schuppan, Detlef ; Leeming, Diana J ; Karsdal, Morten A ; Christiansen, Claus

AIMS/HYPOTHESIS:

The treatment of type 2 diabetes with full peroxisome proliferator-activated receptor gamma (PPARγ) agonists improves insulin sensitivity, but is associated with weight gain, heart failure, peripheral oedema and bone loss. Endotrophin, the C-terminal fragment of the α3 chain of procollagen type VI (also called Pro-C6), is involved in both adipose tissue matrix remodelling and metabolic control. We established a serum assay for endotrophin to assess if this novel adipokine could identify type 2 diabetic patients who respond optimally to PPARγ agonists, improving the risk-to-benefit ratio.

METHODS:

The BALLET trial (NCT00515632) compared the glucose-lowering effects and safety of the partial PPARγ agonist balaglitazone with those of pioglitazone in individuals with type 2 diabetes on stable insulin therapy. The per protocol population (n = 297) was stratified into tertiles based on baseline endotrophin levels. Participants were followed-up after 26 weeks, after which correlational analysis was carried out between endotrophin levels and measures of glucose control. This is a secondary post hoc analysis.

RESULTS:

Endotrophin was significantly associated with therapeutic response to balaglitazone and pioglitazone. At week 26, only individuals in the upper two tertiles showed significant reductions in HbA_1c and fasting serum glucose compared with baseline. The OR for a 1% and a 0.5% reduction in HbA_1c for individuals in the upper two tertiles were 3.83 (95% CI 1.62, 9.04) p < 0.01, and 3.85 (95% CI 1.94, 7.61) p < 0.001, respectively. Endotrophin levels correlated with adipose tissue mass, insulin resistance and fatty liver index. Notably, PPARγ-associated adverse effects, such as moderate-to-severe lower extremity oedema, only occurred in the lower tertile.

CONCLUSIONS/INTERPRETATION:

Elevated endotrophin serum levels predict response to two insulin sensitisers and reduce the risk of associated adverse effects, thereby, identifying patients with type 2 diabetes who may profit from PPARγ agonist treatment.

2016-12-01·AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY

Fibrogenesis assessed by serological type III collagen formation identifies patients with progressive liver fibrosis and responders to a potential antifibrotic therapy.

Article

作者: Patel, Keyur ; Byrjalsen, Inger ; Schuppan, Detlef ; Goodman, Zachary ; Krag, Aleksander ; Henriksen, Kim ; Christiansen, Claus ; Leeming, Diana J ; Gardner, Stephen ; Nielsen, Mette Juul ; Karsdal, Morten A

There are no approved treatments for liver fibrosis. To aid development of antifibrotic therapies, noninvasive biomarkers that can identify patients with progressive fibrosis and that permit monitoring of the response to antifibrotic therapy are much needed. Samples from a phase II antifibrotic trial of the glitazone farglitazar in patients with advanced hepatitis C, with matched follow-up liver biopsies, and from a phase III study of balaglitazone in patients with late-stage Type 2 diabetes (BALLET study) were analyzed for serological Pro-C3 levels in conjunction with other disease parameters. In the farglitazar study, a predefined cutoff value for Pro-C3 as a selection criterion led to the identification of subjects who 1) progressed by histological scores and 2) responded to therapy, as documented by attenuated fibrosis in liver biopsies. In the BALLET trial, subjects with the highest tertile of Pro-C3 levels responded to balaglitazone with reductions in levels of alanine aminotransferase and Pro-C3, as well as improved insulin sensitivity and lipid profile. Elevated Pro-C3 levels are indicative of active fibrogenesis and structural progression of fibrosis, and it can potentially identify patients most likely to benefit from antimetabolic and antifibrotic treatments. Serum Pro-C3 may facilitate patient selection and could help to speed up antifibrotic drug development and validation.

项与巴格列酮相关的新闻（医药）

2024-06-28

·药通社

仿制药企终点？

2024 CMC（CRO&MAH&CMO）博览会，将于8月15-16日在苏州国际博览中心C、D、E馆召开，内容涵盖前沿法规政策、MAH、改良型新药、吸入制剂、透皮制剂、中药、缓控释制剂、注射剂、原料药、辅料领域热点话题。如何做出海外认可的药品质量?海外临床试验之项目管理有何重点？欢迎报名CMC大会！见证破局点一键报名 · 见证合作！国内做制剂出海的常规思路是什么样的？在中国做注册之后，再去各个国家做申报注册。时不我待。第九批集采的平均降价幅度达到了58%，部分产品降幅甚至超过90%；注射剂型占比约六成，是历次集采中注射剂占比最大的一次。宏观数据上的1个百分点，降落到企业身上就是沉重的负担。而即将到来的第十批也呼之欲出，涵盖13个治疗大类、144个未被国采的品种引颈待割，集采规则渐趋稳定，大品种无路可逃。本日次条文章《药企和猪企，其实都是朝阳产业》一文写道：一个价格治理、联动挂网、VBP就把价格击穿，低价基本上永褒青春，价格倒查追溯，活跃区+非活跨跃区，差比+比价，只有更低没有最低，没有循环往复，虽然有个别接续项目价格还有弹性，但总体来看，药品价格只有持续向低。同时，集采的利好逐渐被消磨殆尽。2023年第一批和第二批集采的合同期相继到期，原国家集采中选品种的同品种占比已然大大回落。图 | 各批集采中选品钟在品种层面的市场份额占比情况数据来源：中国医药工业信息中心整理，其中2023年截至第三季度出海吗？前人的螃蟹印度也走过同样的路。举个例子。90年代初期，Reddy和其它的印度制药公司一样，也在拼命的“吹嘘”自己的仿制药品。但Reddy的女婿G.V. Prasad认为印度想要加入世界贸易组织（WTO），政府可能在国际制药公司的压力下会重新认可药物的专利，加之印度制药行业激烈的竞争，生产仿制药品几乎已经无利可图，公司必须在战略上转变。 1992年，Dr. Reddy建立了新药研发实验室，在90年代先后合成了Balaglitazone和Ragaglitazar两大产品，不过这两个产品最终都未获得FDA的批准。新药研发并不是Dr. Reddy的擅长，也无法在短时间内为公司带来业绩的改变。在竞争日益加剧的背景之下，该公司不得不复制原料出海的成功经验，开启了制剂出海的道路。虽然此时的Ranboxy（曾经印度第一的制药公司）在制剂出海上已经积累了丰富的经验而在印度国内名声大噪，但Reddy并没有一味地复制Ranboxy的模式，Reddy所瞄准的是“高附加值”的仿制药品。 2001-2010年是美国仿制药市场快速发展的黄金时期，为了抓住市场机遇，Dr. Reddy大幅增加了ANDA申报量。到2010年时，该公司已经申报了180余个ANDA，其中103个获得了FDA批准。由于在氟西汀上吃到了甜头，Dr. Reddy的paragraph 4类申请一直比较活跃，挑战专利申报数占总申报数的55.8%，昂丹司琼和舒马曲坦分别在2006年和2008年获得180天的市场独占期，分别为Dr. Reddy带来28.9亿和78.9亿卢比的销售额增长。 2000年以后，欧洲国家也在大力推行仿制药替代。为了抓住欧洲市场快速增长所带来的机遇，Dr. Reddy迅速在欧洲布局，收购了多家欧洲仿制药公司，并于2006年，吞并了德国第四大仿制药企业Betapharm。随着Betapharm的并入，欧洲业务迅速打破了僵局，为该公司奉献了高达20%的销售额。因为销售额的暴涨，Dr. Reddy还成功超越了Ranbaxy，成为印度第一大仿制药巨头。中国制药企业此时面临的困境，与彼时面临出海的印度企业类似。如何出海？今天举两个原料药企出海做制剂的例子，不具名。一家企业和南美的国家政府达成了合作，搭建政商关系，形成良好的合作闭环。第二家直接长期驻扎在海外，收购当地的药店及其它渠道，深度绑定经销商；还有将品种委托给代理商，由对方进行销售。还有第三种思路吗？在非专利的国家进行产品申报，比如尼泊尔、老挝市场等等。印度目前由于专利制度的推行，不少企业将品种放在尼泊尔，并在当地建立工厂；也有部分欧洲企业在塞浦路斯建厂、收购药企。药融圈某总此次在老挝考察时发现，老挝市场背后也有很多中国人在运作，然后再通过各类渠道将产品分销到国内市场。除此之外，在撒哈拉以南非洲进口药品市场，印度药品“一骑绝尘”。根据中国医药保健品进出口商会数据，当前非洲面临多种疾病负担，包括艾滋病、疟疾、结核病等传染病，同时慢性病（如心血管疾病、糖尿病）也在逐渐增加，对相关进口药品的需求也将持续增加。在药品进口方面，印度仿制药企体现出较强的国际化能力，占非洲药品进口额的29.8%，来自中国的份额为6.8%，位于药品进口来源国的第6位，未来仍有较大上升空间。很多印度仿制药也已打造出品牌优势，形成了强大的产品和品牌组合群，如Strides在神经病变、疟疾和贫血等治疗领域建立了多个品牌。但中国企业在开拓非洲市场方面还未成建制，布局上鲜有能够渗透到非洲当地整个产业链的，也未能像印度企业那样在非洲形成产业生态，缺少体系协同。本文的结论是什么？如今，中国市场的群体都要开始转变思维，不要等国内品种出来再苦苦寻求销售战略，整合国际资源，再根据各个市场填补空缺。换一个思维，就会觉得这个世界很不一样。参考文献：《中国仿制药发展报告（2023版）》张廷杰《挖一挖仿制药出海的秘密》国泰君安《中国医药出海投资图谱：把握个体出海阶段的积极变化》药事纵横《印度仿制药出海模式的开拓者——瑞迪博士》海证《从非洲市场看中印制药企业国际化差异》推荐阅读

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