A Multi-Center, Parallel-Group, Randomized, Double Blind, Adaptive Study Investigating the Safety and Efficacy of THR-184 in Patients at Increased Risk of Developing Cardiac Surgery Associated-Acute Kidney Injury (CSA-AKI)

The purpose of this study is to determine whether THR-184 when administered around the time of cardiac surgery that requires cardiopulmonary bypass can prevent or ameliorate the development of acute kidney injury.

开始日期2013-05-01

申办/合作机构

Thrasos Therapeutics, Inc.

100 项与 THR-184 相关的临床结果

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100 项与 THR-184 相关的转化医学

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100 项与 THR-184 相关的专利（医药）

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项与 THR-184 相关的文献（医药）

2022-05-01·Biomedicine & Pharmacotherapy

BMP7-based peptide agonists of BMPR1A protect the left ventricle against pathological remodeling induced by pressure overload

Article

作者: Hurlé, María A ; Redondo, Juan M ; García, Raquel ; Expósito, Víctor ; Martínez, Fernando ; Gil, Aritz ; Salido-Medina, Ana B ; Nistal, J Francisco

Aortic stenosis (AS) exposes the left ventricle (LV) to pressure overload leading to detrimental LV remodeling and heart failure. In animal models of cardiac injury or hemodynamic stress, bone morphogenetic protein-7 (BMP7) protects LV against remodeling by counteracting TGF-β effects. BMP receptor 1A (BMPR1A) might mediate BMP7 antifibrotic effects. Herein we evaluated BMP7-based peptides, THR123 and THR184, agonists of BMPR1A, as cardioprotective drugs in a pressure overload model. We studied patients with AS, mice subjected to four-week transverse aortic constriction (TAC) and TAC release (de-TAC). The LV of AS patients and TAC mice featured Bmpr1a downregulation. Also, pSMAD1/5/(8)9 was reduced in TAC mice. Pre-emptive treatment of mice with THR123 and THR184, during the four-week TAC period, normalized pSMAD1/5/(8)9 levels in the LV, attenuated overexpression of remodeling-related genes (Col 1α1, β-MHC, BNP), palliated structural damage (hypertrophy and fibrosis) and alleviated LV dysfunction (systolic and diastolic). THR184 administration, starting fifteen days after TAC, halted the ongoing remodeling and partially reversed LV dysfunction. The reverse remodeling after pressure overload release was facilitated by THR184. Both peptides diminished the TGF-β1-induced hypertrophic gene program in cardiomyocytes, collagen transcriptional activation in fibroblasts, and differentiation of cardiac fibroblasts to myofibroblasts. Molecular docking suggests that both peptides bind with similar binding energies to the BMP7 binding domain at the BMPR1A. The present study results provide a preclinical proof-of-concept of potential therapeutic benefits of BMP7-based small peptides, which function as agonists of BMPR1A, against the pathological LV remodeling in the context of aortic stenosis.

2018-05-01·Pediatric Nephrology3区 · 医学

Acute kidney injury: emerging pharmacotherapies in current clinical trials

3区 · 医学

Review

作者: Devarajan, Prasad ; Benoit, Stefanie Woolridge

Acute kidney injury (AKI) is a significant source of morbidity and mortality in pediatric patients, affecting more than one quarter of critically ill children. Despite significant need, there are no targeted therapies to reliably prevent or treat AKI. Recent advances in our understanding of renal injury and repair signaling pathways have enabled the development of several targeted pharmaceuticals. Here we review emerging pharmacotherapies for AKI that are currently in clinical trials. Categorized by their general mechanism of action, the therapies discussed include anti-inflammatory agents (recAP, AB103, ABT-719), antioxidants (iron chelators, heme arginate), vasodilators (levosimendan), apoptosis inhibitors (QPI-1002), and repair agents (THR-184, BB-3, mesenchymal stem cells).

2018-02-01·Journal of the American Society of Nephrology1区 · 医学

Perioperative THR-184 and AKI after Cardiac Surgery

1区 · 医学

Article

作者: Dagenais, François ; Shaw, Andrew D ; Rossert, Jerome ; Mesana, Thierry ; Cortville, David ; Brown, Craig ; de Varennes, Benoit ; Tardif, Jean-Claude ; Chertow, Glenn M ; Fontes, Manuel ; Himmelfarb, Jonathan ; Sundt, Thoralf M ; McCullough, Peter A

AKI after cardiac surgery is associated with mortality, prolonged hospital length of stay, use of dialysis, and subsequent CKD. We evaluated the effects of THR-184, a bone morphogenetic protein-7 agonist, in patients at high risk for AKI after cardiac surgery. We conducted a randomized, double-blind, placebo-controlled, multidose comparison of the safety and efficacy of perioperative THR-184 using a two-stage seamless adaptive design in 452 patients between 18 and 85 years of age who were scheduled for nonemergent cardiac surgery requiring cardiopulmonary bypass and had recognized risk factors for AKI. The primary efficacy end point was the proportion of patients who developed AKI according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. The proportion of patients who developed AKI within 7 days of surgery was similar in THR-184 treatment groups and placebo groups (range, 74%-79%; P=0.43). Prespecified secondary end point analysis did not show significant differences in the severity of AKI stage (P=0.53) or the total duration of AKI (P=0.44). A composite of death, dialysis, or sustained impaired renal function by day 30 after surgery did not differ between groups (range, 11%-20%; P=0.46). Safety-related outcomes were similar across all treatment groups. In conclusion, compared with placebo, administration of perioperative THR-184 through a range of dose exposures failed to reduce the incidence, severity, or duration of AKI after cardiac surgery in high-risk patients.

100 项与 THR-184 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
急性肾损伤	临床2期	加拿大	Thrasos Therapeutics, Inc.	2013-05-01
急性肾损伤	临床2期	美国	Thrasos Therapeutics, Inc.	2013-05-01
科凯恩氏综合症	临床2期	美国	Thrasos Therapeutics, Inc.	2013-05-01
科凯恩氏综合症	临床2期	加拿大	Thrasos Therapeutics, Inc.	2013-05-01

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临床结果

适应症

分期

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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


ESC2022	N/A	BMPR1A \| pSMAD1/5/(8)9	-	THR184	顧衊窪顧繭網淵蓋選選(醖衊餘築廠顧選選積觸) = 築窪觸膚網壓遞糧壓鑰膚獵廠鬱憲憲餘鹹構鏇 (獵鬱觸襯鏇鹹糧鬱齋網 )	-	2022-04-30
				Saline	顧衊窪顧繭網淵蓋選選(醖衊餘築廠顧選選積觸) = 積築淵窪簾壓顧製壓糧膚獵廠鬱憲憲餘鹹構鏇 (獵鬱觸襯鏇鹹糧鬱齋網 )
NCT01830920 (CTgov)	临床2期	急性肾损伤 \| 科凯恩氏综合症	452	Placebo (Placebo)	醖膚鹹鹽膚遞積鬱獵獵(鏇鹽壓鹽廠獵糧構範醖) = 憲糧窪築積繭獵選壓鹹獵醖襯顧觸選繭壓觸網 (淵製廠鑰範選願選積齋, 鏇艱範窪膚蓋壓觸夢壓 ~ 餘夢襯艱鹹製艱鬱鏇簾) 更多	-	2017-04-20
				THR-184 (THR-184 Dose 1)	醖膚鹹鹽膚遞積鬱獵獵(鏇鹽壓鹽廠獵糧構範醖) = 餘積繭餘鬱積獵簾淵糧獵醖襯顧觸選繭壓觸網 (淵製廠鑰範選願選積齋, 夢鏇鹽鑰繭蓋遞鬱淵選 ~ 鏇顧壓鬱觸網簾願獵鬱) 更多
THR-184 (ASN2011)	N/A	急性肾损伤 \| 缺血 \| 慢性肾病	-	THR-184	(積製繭構範製構獵淵鹹) = 鬱鏇鏇鏇積築衊築窪餘夢窪築淵醖範襯鬱廠鑰 (鹽鬱繭顧鬱廠鬱鹽簾淵 ) 更多	积极	2011-11-08