阿格列扎(Aleglitazar) - 药物靶点：PPARα x PPARγ_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Aleglitazar (USAN)

+ [1]

靶点

PPARα x PPARγ

作用机制

PPARα激动剂(过氧化物酶体增长因子活化受体α激动剂)、PPARγ激动剂(过氧化物酶体增长因子活化受体γ激动剂)

治疗领域

心血管疾病遗传病与畸形内分泌与代谢疾病+ [1]

在研适应症-

非在研适应症

急性冠状动脉综合征心血管畸形心血管疾病+ [7]

原研机构

F. Hoffmann-La Roche Ltd.

在研机构-

非在研机构

Hoffmann-La Roche, Inc.F. Hoffmann-La Roche Ltd.

上海罗氏制药有限公司

最高研发阶段暂停临床3期

首次获批日期-

最高研发阶段(中国)暂停

特殊审评特殊审批 (中国)

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结构

分子式C24H23NO5S

InChIKeyDAYKLWSKQJBGCS-NRFANRHFSA-N

CAS号475479-34-6

关联

35

项与阿格列扎相关的临床试验

NCT01893242 / Withdrawn临床3期

A PHASE III RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE POTENTIAL OF ALEGLITAZAR TO REDUCE THE RISK OF END STAGE RENAL DISEASE AND CARDIOVASCULAR MORTALITY IN PATIENTS WITH TYPE 2 DIABETES AND CHRONIC KIDNEY DISEASE (ALERENAL STUDY)

This randomized, double-blind, placebo-controlled study will evaluate the potential of aleglitazar to reduce the risk of end stage renal disease and cardiovascular mortality in patients with type 2 diabetes mellitus and chronic kidney disease. Patients will be randomized to receive oral daily doses of aleglitazar or matching placebo. The anticipated time on study treatment is approximately 3 years.

开始日期2013-12-01

申办/合作机构

Hoffmann-La Roche, Inc.

CTR20130320 / Suspended临床3期

评价ALEGLITAZAR单药治疗与安慰剂相比较，对未经降糖药物治疗的2型糖尿病患者的疗效、安全性和耐受性

通过治疗26周后HbA1c的变化，评价Aleglitazar与安慰剂相比较，对未经降糖药物治疗的2型糖尿病患者血糖控制的疗效、安全性和耐受性

开始日期2013-06-17

申办/合作机构

F. Hoffmann-La Roche Ltd.

[+1]

NCT01871428 / Completed临床3期

A Multicenter, Randomized, Doubleblind, Placebo-Controlled, Phase III Study to Assess the Efficacy, Safety and Tolerability of Aleglitazar Monotherapy Compared With Placebo in Patients With Type 2 Diabetes Mellitus (T2D) Who Are Drug-Naïve to Antihyperglycemic Therapy

This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy, safety and tolerability of aleglitazar monotherapy in patients with Type 2 diabetes mellitus who are drug-naïve to anti-hyperglycemic therapy. Patients will be randomized to receive either aleglitazar 150 mcg orally daily or placebo for 26 weeks.

开始日期2013-06-01

申办/合作机构

Hoffmann-La Roche, Inc.

100 项与阿格列扎相关的临床结果

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100 项与阿格列扎相关的转化医学

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100 项与阿格列扎相关的专利（医药）

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51

项与阿格列扎相关的文献（医药）

2024-10-01·The American Journal of Pathology

Chronic Peroxisome Proliferator-Activated Receptor α/γ and Cannabinoid Receptor 2 Agonist Treatments Attenuated Visceral Adipose Tissue (VAT)–Derived Extracellular Vesicle–Related VAT and Intestinal Abnormalities in Nonalcoholic Steatohepatitis Mice

Article

作者: Su, Chien-Wei ; Yang, Ying-Ying ; Huang, Chia-Chang ; Wang, Ching-Hsiang ; Yang, Ching-Wen ; Hou, Ming-Chih ; Li, Tzu-Hao ; Lin, Han-Chieh ; Yeh, Hsiao-Yun ; Tsai, Hung-Cheng

This study explores the mechanisms and combined effects of chronic peroxisome proliferator-activated receptor (PPAR)α/γ and cannabinoid receptor 2 (CB₂R) agonists on visceral adipose tissue (VAT)-derived extracellular vesicle (EV) release and associated systemic/VAT inflammation, decreased VAT capillary density/fibrosis, and intestinal inflammation/hyperpermeability in nonalcoholic steatohepatitis (NASH) mice. NASH mice received 1 month of PPARα/γ agonist aleglitazar (10 mg/kg per day) or CB₂R agonist JWH015 (3 mg/kg per day) alone or combined. High EV release from VAT of NASH mice was associated with severe systemic/VAT/intestinal inflammation, reduced capillary network of VAT, and intestinal hyperpermeability. Combined JWH015 with aleglitazar treatment significantly suppressed high-fat diet-induced obesity/adiposity, inhibited VAT expansion, reduced VAT inflammation/fibrosis, normalized VAT capillary network, and attenuated intestinal mucosal injury, inflammation, and hyperpermeability in NASH + aleglitazar + JWH015 mice. The inhibition of AT-derived EV release and hypoxia-inducible factor (HIF)1α levels in AT-derived EV, normalization of CB₂R, PPARα, PPARγ, PPARγ1, PPARγ2, tight junction proteins, vascular endothelial growth factor/CD31 expression, and down-regulation of HIF1α, monocyte chemoattractant protein-1, and transforming growth factor-β1 were observed in the VAT and intestine of the NASH + aleglitazar + jwh015 group. In vitro experiments revealed that PPARα/γ and CB₂R activation attenuated NASH AT-derived EV-induced pathogenic changes in the J774/SVEC4-10/Caco2/3T3-L1 cell system. This study suggested that VAT-derived EVs contribute to the pathogenesis of nonalcoholic fatty liver disease and that combined PPARα/γ and CB₂R agonist treatment reduces VAT-released EV release and HIF1/monocyte chemoattractant protein-1 signals to ameliorate hepatic steatosis and VAT/intestine abnormalities of NASH mice.

2024-02-01·Diabetes Research and Clinical Practice

Impact of age on the predictive value of NT-proBNP in patients with diabetes mellitus stabilised after an acute coronary syndrome

Article

作者: Angeli, Fabio ; Grobbee, Diederick E ; Stähli, Barbara E ; Tardif, Jean-Claude ; Schwartz, Gregory G ; Heerspink, Hiddo J L ; Cavallini, Claudio ; Pancani, Silvia ; Savonitto, Stefano ; Perrone Filardi, Pasquale ; Lincoff, A Michael ; Mannini, Andrea ; Morici, Nuccia ; Nozza, Anna ; Cosentino, Francesco

AIMSTo assess the impact of age on the prognostic value of NT-proBNP concentration in patients with type-2 diabetes mellitus (T2DM) stabilised after an Acute Coronary Syndrome (ACS).METHODSThe AleCardio study compared aleglitazar with placebo in 7226 patients with T2DM and recent ACS. Patients with heart failure were excluded. Median follow-up was 104 weeks. Baseline NT-proBNP plasma concentration was measured centrally. Multivariable Cox regression was used to determine the mortality predictive information provided by NT-proBNP across age groups.RESULTSMedian age was 61y (IQR 54, 67). NT-proBNP concentration increased by quartile (Q) of age (median 264, 318, 391, and 588 pg/ml). Compared to Q1, patients in Q4 of NT-proBNP had higher (p < 0.001) adjusted HR for all-cause (aHR 6.9; 95 % CI 4.0-12) and cardiovascular (11; 5.4-23) death. Within each age Q, baseline NT-proBNP in patients who died was 3 times higher than in survivors (all p < 0.001). When age and NT-proBNP levels were modeled as continuous variables, their interaction term was nonsignificant. The relative prognostic information provided by NT-proBNP (percent of total X²) increased from 38 % in age Q1 to 75 % in age Q4 for mortality, and from 50 % to 88 % for CV death.CONCLUSIONSAmong patients with T2DM stabilised after an ACS, NT-proBNP level predicts death irrespective of age.

2020-01-01·Diabetes, Obesity and Metabolism2区 · 医学

Exposure and response analysis of aleglitazar on cardiovascular risk markers and safety outcomes: An analysis of the AleCardio trial

2区 · 医学

Article

作者: Schwartz, Gregory G. ; Stevens, Jasper ; Svensson, Anders ; Weichert, Arlette ; Wedel, Hans ; Grobbee, Diederick E. ; Schrieks, Ilse C. ; Heerspink, Hiddo J. L. ; Nicholls, Stephen J. ; Koomen, Jeroen V. ; Lincoff, A. Michael

AbstractAimsThe AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator‐activated receptor‐αγ agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar.Materials and MethodsThe AleCardio trial enrolled 7226 patients to receive aleglitazar 150 μg or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population.ResultsConcomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma‐concentration‐time curve (AUC0–24) of 174.7 ng h/mL (SD: ±112.9 ng h/mL) versus 142.2 ng h/mL (SD: ±92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002, <0.001 and < 0.001, respectively).ConclusionsConcomitant use of clopidogrel was identified as a covariate that explained interindividual variability in exposure to aleglitazar. Patients using clopidogrel showed an additional lowering of HbA1c, at the expense of an additional decrease in haemoglobin, and an increase in serum creatinine and adiponectin. Clopidogrel is a moderate inhibitor of CYP2C8. Because aleglitazar is metabolized by CYP2C8, a pharmacokinetic interaction could explain differences in exposure and response to aleglitazar.

100 项与阿格列扎相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D08845	阿格列扎	-	DB08915

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
2型糖尿病	临床3期	印度	F. Hoffmann-La Roche Ltd.	2010-01-05
2型糖尿病	临床3期	泰国	上海罗氏制药有限公司	2010-01-05
2型糖尿病	临床3期	韩国	F. Hoffmann-La Roche Ltd.	2010-01-05
2型糖尿病	临床3期	韩国	F. Hoffmann-La Roche Ltd.	2010-01-05
2型糖尿病	临床3期	瑞典	上海罗氏制药有限公司	2010-01-05
2型糖尿病	临床3期	印度	F. Hoffmann-La Roche Ltd.	2010-01-05
2型糖尿病	临床3期	韩国	F. Hoffmann-La Roche Ltd.	2010-01-05
2型糖尿病	临床3期	印度	F. Hoffmann-La Roche Ltd.	2010-01-05
2型糖尿病	临床3期	瑞典	上海罗氏制药有限公司	2010-01-05
2型糖尿病	临床3期	瑞典	上海罗氏制药有限公司	2010-01-05

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01197911 (CTgov)	临床1期	-	38	aleglitazar (Normal Hepatic Function)	壓鹹選選廠醖獵顧齋鬱(窪獵鑰鹹簾選觸範淵鏇) = 願廠糧構鏇範遞網壓願淵壓鹹築獵選壓願憲顧 (夢願憲製憲糧衊齋壓觸, 鹹淵艱簾網鑰壓觸積齋 ~ 選淵醖鏇網壓餘獵願顧) 更多	-	2015-12-24
				aleglitazar (Mild Hepatic Impairment)	壓鹹選選廠醖獵顧齋鬱(窪獵鑰鹹簾選觸範淵鏇) = 壓鑰壓齋鹽鏇願簾壓範淵壓鹹築獵選壓願憲顧 (夢願憲製憲糧衊齋壓觸, 淵網廠淵選製齋鬱獵簾 ~ 網醖網壓遞範襯構糧網) 更多
NCT01715818 (ALEPREVENT, Pubmed \| Am Heart J) 人工标引	临床3期	2型糖尿病 \| 糖尿病前期	1,996	aleglitazar	(積壓簾簾顧獵鑰願簾鬱) = Despite the brief duration of treatment, aleglitazar induced favorable changes in glycosylated hemoglobin and blood lipids, similar for participants with T2D or prediabetes. 蓋築鹹壓壓襯鹽簾壓範 (積繭獵鹽壓構構鹹遞齋 ) 更多	不佳	2015-07-01
				Placebo
NCT01691846 \| NCT01691989 \| NCT01691755 (Pubmed \| Diabetes Obes Metab) 人工标引	临床3期	2型糖尿病	591	aleglitazar	(壓範廠夢醖襯網廠鏇膚) = Reductions in HbA1c concentration from baseline to week 26 were statistically significantly greater with aleglitazar than with placebo. 簾衊艱鹹積築積構夢觸 (簾窪醖鏇鏇鹹鏇顧築製 )	积极	2015-06-01
				Placebo
NCT01043029 (AleNephro, Pubmed \| BMC Nephrol)	临床2期	2型糖尿病 \| 慢性肾病	302	Aleglitazar 150 μg/day	構觸製齋觸衊齋遞衊簾(淵糧鬱餘憲鬱繭窪鏇鹹) = Superior improvements in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, with similar effects on glycosylated hemoglobin were observed with aleglitazar versus pioglitazone 顧憲繭醖窪範膚顧夢蓋 (獵網觸築壓繭獵製蓋膚 )	-	2014-11-18
				Pioglitazone 45 mg/day
NCT01042769 (AleCardio, Pubmed \| J Coll Physicians Surg Pak)	临床3期	2型糖尿病 \| 急性冠状动脉综合征	7,226	Aleglitazar 150 µg	(襯觸遞網糧膚製餘憲鏇) = 築壓淵蓋醖製製遞蓋醖艱繭築鹽鏇顧積構範蓋 (膚夢網築鬱鏇齋鹹襯製 )	不佳	2014-04-16
				Placebo	(襯觸遞網糧膚製餘憲鏇) = 夢鏇衊淵觸醖憲製鬱顧艱繭築鹽鏇顧積構範蓋 (膚夢網築鬱鏇齋鹹襯製 )
NCT00388518 (SYNCHRONY, Pubmed \| Lancet)	临床2期	2型糖尿病	332	Aleglitazar 50 mug	鹹選齋鹹齋簾鑰遞選蓋(鏇鹽糧壓衊鑰範廠選鬱) = 構鏇夢顧鑰鑰獵糧糧醖範餘繭膚遞範鹹繭艱網 (淵餘構選製淵憲淵壓鹹, 0.00 ~ -0.70)	-	2009-07-11
				Aleglitazar 150 mug	鹹選齋鹹齋簾鑰遞選蓋(鏇鹽糧壓衊鑰範廠選鬱) = 觸憲醖範範糧鏇築鏇鬱範餘繭膚遞範鹹繭艱網 (淵餘構選製淵憲淵壓鹹, -0.99 ~ -1.70) 更多