A Phase 1, Open-Label, Fixed Sequence Study to Investigate the Effect of Coadministration of Itraconazole on the Pharmacokinetics of CRD-740 in Healthy Adult Subjects

This is a Phase 1, single-site, open-label, fixed sequence crossover study to investigate the effect of coadministration of itraconazole on the pharmacokinetics of CRD-740 in healthy male and female subjects. Subjects will be admitted into the study site on Day -1 and will be confined to the study site until discharge on Day 16. Subjects will receive CRD-740 orally on Days 1 and 10. Itraconazole will be given once daily, orally, on Days 7 through 15.

开始日期2022-06-27

申办/合作机构

Cardurion Pharmaceuticals, Inc.初创企业

NCT05409183

/ Terminated临床2期

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Assess the Effectiveness of CRD-740 in Subjects With Chronic Heart Failure (CARDINAL-HF)

This is a study evaluating the effectiveness of CRD-740 in patients with either Heart Failure with Reduced Ejection Fraction (HFrEF) or Heart Failure with Preserved Ejection Fraction (HFpEF) after 12 weeks of treatment. The primary objective in Part A is to assess the effect of CRD-740 compared to placebo in plasma cGMP at Week 4 in HFrEF.
Part B of the study was not conducted in favor of redesigned new studies.

开始日期2022-05-26

申办/合作机构

Cardurion Pharmaceuticals, Inc.初创企业

100 项与 CRD-740 相关的临床结果

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100 项与 CRD-740 相关的转化医学

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100 项与 CRD-740 相关的专利（医药）

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项与 CRD-740 相关的文献（医药）

2024-11-01·MICROCIRCULATION

PDE9A Inhibition Improves Coronary Microvascular Rarefaction and Left Ventricular Diastolic Dysfunction in the ZSF1 Rat Model of HFpEF

Article

作者: Buncha, Vadym ; Hamdani, Nazha ; Hardell, Davis J. ; El‐Battrawy, Ibrahim ; Zhazykbayeva, Saltanat ; Pearson, William M. ; Fopiano, Katie Anne ; Bagi, Zsolt ; Lang, Liwei

ABSTRACT:

Objective:

Heart failure with preserved ejection fraction (HFpEF) commonly arises from comorbid diseases, such as hypertension, obesity, and diabetes mellitus. Selective inhibition of phosphodiesterase 9A (PDE9A) has emerged as a potential therapeutic approach for treating cardiometabolic diseases. Coronary microvascular disease (CMD) is one of the key mechanisms contributing to the development of left ventricular (LV) diastolic dysfunction in HFpEF. Our study aimed to investigate the mechanisms by which PDE9A inhibition could ameliorate CMD and improve LV diastolic function in HFpEF.

Methods and Results:

The obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat model of HFpEF was employed in which it was found that a progressively developing coronary microvascular rarefaction is associated with LV diastolic dysfunction when compared to lean, nondiabetic hypertensive controls. Obese ZSF1 rats had an increased cardiac expression of PDE9A. Treatment of obese ZSF1 rats with the selective PDE9A inhibitor, PF04447943 (3 mg/kg/day, oral gavage for 2 weeks), improved coronary microvascular rarefaction and LV diastolic dysfunction, which was accompanied by reduced levels of oxidative and nitrosative stress markers, hydrogen peroxide, and 3‐nitrotyrosine. Liquid chromatography–mass spectrometry (LC–MS) proteomic analysis identified peroxiredoxins (PRDX) as downregulated antioxidants in the heart of obese ZSF1 rats, whereas Western immunoblots showed that the protein level of PRDX5 was significantly increased by the PF04447943 treatment.

Conclusions:

Thus, in the ZSF1 rat model of human HFpEF, PDE9A inhibition improves coronary vascular rarefaction and LV diastolic dysfunction, demonstrating the usefulness of PDE9A inhibitors in ameliorating CMD and LV diastolic dysfunction through augmenting PRDX‐dependent antioxidant mechanisms.

2024-06-02·EXPERT OPINION ON INVESTIGATIONAL DRUGS

The role of phosphodiesterase 9A inhibitors in heart failure

Review

作者: Foroshani, Saam ; Aronow, Wilbert S ; Lanier, Gregg M ; Karp, Avrohom

INTRODUCTION:

There are currently limited effective treatments available to improve lusitropy in patients suffering from heart failure with preserved ejection fraction. The role of PDE9A in diastolic dysfunction has been well-studied over recent years, with a special focus on its association with myocardial hypertrophy. Recent insights into PDE9A inhibition have brought to light the potential for reversal of cardiac remodeling, with multiple studies showing promising results in preclinical data.

AREAS COVERED:

This expert opinion provides an overview of the role of PDE9A in diastolic heart dysfunction along with the efficacy of PDE9A inhibitors in laboratory models of heart failure with preserved ejection fraction.

EXPERT OPINION:

The available data on PDE9A inhibition in preclinical studies suggest that there is potential for reversal of diastolic dysfunction and myocardial hypertrophy, however, conflicting data suggests that further studies are required before progressing to clinical trials.

2023-06-01·The European journal of neuroscience

Virtual screening and in vitro experiments highlight cannabidiol as a drug‐like phosphodiesterase 9 inhibitor

Article

作者: Bonini, Sara Anna ; Pellegrini‐Giampietro, Domenico E. ; Ribaudo, Giovanni ; Memo, Maurizio ; Landucci, Elisa ; Mazzantini, Costanza ; Maccarinelli, Giuseppina ; Giannangeli, Matteo ; Mastinu, Andrea ; Gianoncelli, Alessandra

Abstract:

The growing interest on the therapeutic potential against neurodegeneration of Cannabis sativa extracts, and of phytocannabinoids in particular, is paralleled by a limited understanding of the undergoing biochemical pathways in which these natural compounds may be involved. Computational tools are nowadays commonly enrolled in the drug discovery workflow and can guide the investigation of macromolecular targets for such molecules. In this contribution, in silico techniques have been applied to the study of C. sativa constituents at various extents, and a total of seven phytocannabinoids and four terpenes were considered. On the side of ligand‐based virtual screening, physico‐chemical descriptors were computed and evaluated, highlighting the phytocannabinoids possessing suitable drug‐like properties to potentially target the central nervous system. Our previous findings and literature data prompted us to investigate the interaction of these molecules with phosphodiesterases (PDEs), a family of enzymes being studied for the development of therapeutic agents against neurodegeneration. Among the compounds, structure‐based techniques such as docking and molecular dynamics (MD), highlighted cannabidiol (CBD) as a potential and selective PDE9 ligand, since a promising calculated binding energy value (−9.1 kcal/mol) and a stable interaction in the MD simulation timeframe were predicted.Additionally, PDE9 inhibition assay confirmed the computational results, and showed that CBD inhibits the enzyme in the nanomolar range in vitro, paving the way for further development of this phytocannabinoid as a therapeutic option against neurodegeneration.

项与 CRD-740 相关的新闻（医药）

2024-07-17

·Pharmaceutical Technology

Cardurion closes $260m in Series B to develop cardiovascular pipeline

Cardurion also plans to use the funding to expand the indications outlined for the two candidates and acquire additional assets for treating cardiovascular disorders. Image Credit: VectorMine / Shutterstock. US-based cardiology biotech Cardurion Pharmaceuticals has raised $260m in Series B financing to advance its drug pipeline. The proceeds will fund the late-stage trials for two of the company’s lead candidates, CRD-750, a phosphodiesterase 9 (PDE9) inhibitor for heart failure; and CRD-4730, a calmodulin-dependent protein kinase II (CaMKII) inhibitor for treating catecholaminergic polymorphic ventricular tachycardia. Both therapies are being evaluated in Phase II trials. The company also plans to use the fund to expand the number of indications being explored for the two candidates and acquire additional assets for treating cardiovascular disorders. The investors in the Series B round included Bain Capital, Ascenta Capital, and other US-based investment companies. CRD-750 is being evaluated in two Phase II trials (NCT06215586 and NCT06215911) to treat two types of heart failure – heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Both placebo-controlled trials are currently recruiting patients across multiple locations in the US and Canada. In May, the company presented positive data for another PDE9 inhibitor, CRD-740, in patients with heart failure. The CARDINAL-HF Phase IIa trial (NCT05409183) met its primary endpoint in patients with HFrEF by demonstrating a statistically significant median increase in plasma cyclic guanosine monophosphate (cGMP). See Also: Sumitomo Pharma’s DSP-5336 gains FDA fast track for AML AstraZeneca completes Amolyt Pharma acquisition CRD-4730 is being evaluated in a Phase II trial (NCT06005428) as a treatment for catecholaminergic polymorphic ventricular tachycardia—a rare genetic arrhythmic disease. The company also plans to develop CaMKII inhibitors to target additional cardiovascular indications. There has been an increased interest in developing novel cardiovascular therapies in recent months. In February, Novo Nordisk agreed to pay up to $1.46bn to license multiple molecular glue degraders for treating cardiometabolic disorders and rare diseases from Neomorph. As part of the agreement, Neomorph would bear discovery and preclinical research responsibilities while Novo Nordisk would have exclusive rights to further clinical development and commercialisation. Another approach that has emerged as a promising treatment in the cardiovascular space is drugs targeting the glucagon-like peptide-1 (GLP-1) receptor. Last year, Novo Nordisk reported that its GLP-1 therapy Wegovy (semaglutide) reduced the incidence of cardiovascular events in obese and overweight patients by 20% compared to placebo.

临床2期临床结果引进/卖出

2024-07-16

·BioPharmaDive

Cardurion raises another $260M to fuel heart drug pipeline

Dive Brief:Biotechnology startup Cardurion Pharmaceuticals on Tuesday raised a $260 million Series B round that will help it build its portfolio of heart disease drugs.Cardurion will use the funds to advance a pair of medicines into mid- and late-stage testing, run studies in newer indications and potentially acquire other assets for cardiovascular diseases. The round comes two months after the startup detailed datafrom a Phase 2 trial in heart failure.Ascenta Capital led the financing, which involved NEA, GV, Bain Capital Life Sciences and a handful of other investors. Bain has already invested heavily in Cardurion, having poured up to $300 million into the startup in 2021.Dive Insight:After years of being overlooked by investors, heart and metabolic disease startups are now getting closer attention,fueled in part by the spectacular success of obesity drugs as well as deals for companies working on cardiovascular research.Bristol Myers Squibb paid $13 billion in 2020 to buy MyoKardia and a drug the biotech had developed for a genetic heart condition, for example.Novartis spent $10 billion on a cholesterol drug from The Medicines Co. a year earlier. More recently, drugs like Wegovy and Zepbound have proven able to not only help people lose weight, but protect heart health as well, driving more interest in companies working in the field.Against that backdrop, Cardurion has been using its sizable bankroll to build a growing portfolio. The company was launched in 2017 with an alliance with Takeda, and has since advanced a group of medicines for heart failure and heart muscle dysfunctions. Its turned to deals to grow its pipeline too, in 2022 acquiring a medicine from now-defunct biotech Imara.In heart failure, Cardurion aims to improve upon standard care. Currently, about half of patients with the condition die within five years of their diagnosis. Though Novartis blockbuster medicine Entresto can reduce the risk of death or complications, there remains room for improvement.Cardurions drugs CRD-740 and CRD-750 block an enzyme called PDE9, a biological target thats been studied in other conditions like Alzheimers and sickle cell disease. In heart failure, PDE9 could prove beneficial because of its role regulating a molecule involved in the relaxation of heart muscles. Doing so could improve the hearts ability to pump blood, which is compromised in people with heart failure.Phase 2 data presented in May showed CRD-740 increased levels of that molecule, known as cGMP, after four weeks of treatment, meeting the studys primary goal.In a statement, the company said it is testing CRD-750 in two Phase 2 studies of people with heart failure. It will also use the funding to advance a second experimental drug targeting a protein linked to hyperactive muscle tissue. That drug will initially be tested in people with a rare condition called catecholaminergic polymorphic ventricular tachycardia. '

临床2期

2024-05-13

·药明康德

潜在重磅疗法3期临床结果登NEJM，血友病长效疗法达2期主要终点……

▎药明康德内容团队编辑潜在重磅心肌病疗法3期临床结果发布，今年递交监管申请Cytokinetics公司今日宣布，在研疗法aficamten在治疗有症状的梗阻性肥厚型心肌病（HCM）患者的关键性3期临床试验SEQUOIA-HCM中达到主要终点和所有次要终点，快速和持久改善患者症状和功能。详细数据发表在《新英格兰医学杂志》（NEJM）上，并在由欧洲心脏病学会举办的2024年心力衰竭（Heart Failure 2024）国际会议上报告。这款创新疗法被行业媒体Evaluate列为值得关注的十大潜在重磅疗法之一。SEQUOIA-HCM的结果显示，与安慰剂相比，aficamten治疗24周显著改善了患者的运动能力，通过心肺运动测试（CPET）测量的最高氧气摄取量（pVO2）增加了1.74 mL/kg/min（95% CI：1.04-2.44，p=0.000002）。值得注意的是，在不同患者亚组中均一致观察到aficamten的积极影响。▲Aficamten达到SEQUOIA-HCM的主要终点（图片来源：参考资料[1]）Aficamten是一款选择性小分子心肌肌球蛋白抑制剂，通过减少每个心动周期中活性肌球蛋白产力横桥的数量，抑制与肥厚型心肌病相关的心肌过度收缩。Cytokinetics计划在今年晚些时候向美国和欧盟的监管机构递交监管申请。只需每周或每月一次，血友病A长效疗法2期临床结果积极诺和诺德（Novo Nordisk）公司今天宣布了长效血友病A疗法Mim8的2期临床试验FRONTIER 2的主要结果，该试验评估了每周一次或每月一次皮下注射Mim8与未接受预防治疗以及与之前的凝血因子预防治疗相比，在12岁及以上带有或不带有凝血因子抑制物的血友病A患者中的疗效和安全性。数据显示，与不进行预防治疗及之前的凝血因子预防治疗相比，每周一次和每月一次Mim8均能显著减少需要治疗的出血事件，达到试验的共同主要终点。在未接受预防治疗的人群中，每周一次和每月一次Mim8分别将需要治疗的出血事件减少97%和99%。在接受过凝血因子预防治疗的患者中，与之前的凝血因子预防治疗相比，每周一次和每月一次Mim8分别将需要治疗的出血事件减少48%和43%。Mim8是一种模拟凝血因子VIIIa的双特异性抗体，通过皮下注射给药，它通过连接凝血因子IXa和X，替代缺失的因子VIII，有效恢复身体的凝血酶生成能力，帮助血液凝固。基于与监管机构的沟通结果，诺和诺德计划在2024年年底递交Mim8的首个监管申请。创新心力衰竭疗法获概念验证Cardurion Pharmaceuticals公司今日宣布，在研磷酸二酯酶-9（PDE9）抑制剂CRD-740在概念验证2期临床试验CARDINAL-HF中获得积极结果。数据显示，CRD-740在射血分数降低型心力衰竭（HFrEF）患者中达到了主要终点，治疗四周后，中位血浆环状鸟苷酸（cGMP）水平显著提高。血浆cGMP是细胞内cGMP的生物标志物，其水平反映了保护性心肌利钠肽（NP）信号通路的活性，该通路在心力衰竭中已证明具有临床益处。基于这一2a期临床试验的结果，Cardurion公司已启动两项总计包含640名患者的2期临床试验，其中一项在HFrEF中进行剂量探索，另一项将评估CRD-740治疗射血分数保留型心力衰竭患者的效果。▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Cytokinetics Announces Primary Results From SEQUOIA-HCM Presented in Late Breaking Clinical Trial Session at the European Society of Cardiology Heart Failure 2024 Congress and Published in the New England Journal of Medicine. Retrieved May 13, 2024, from https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-primary-results-sequoia-hcm-presented[2] Novo Nordisk A/S: Once-weekly and once-monthly Mim8 demonstrate superior reduction of treated bleeding episodes compared to on-demand and prior prophylaxis treatment in people with haemophilia A in the Frontier 2 trial. Retrieved May 13, 2024, from https://www.globenewswire.com/news-release/2024/05/13/2880715/0/en/Novo-Nordisk-A-S-Once-weekly-and-once-monthly-Mim8-demonstrate-superior-reduction-of-treated-bleeding-episodes-compared-to-on-demand-and-prior-prophylaxis-treatment-in-people-with-.html[3] Cardurion Pharmaceuticals Presents Positive Clinical Results from CARDINAL‑HF Phase 2a Clinical Trial of PDE9 Inhibitor in Patients With Heart Failure. Retrieved May 13, 2024, from https://www.businesswire.com/news/home/20240511287537/en/Cardurion-Pharmaceuticals-Presents-Positive-Clinical-Results-from-CARDINAL%E2%80%91HF-Phase-2a-Clinical-Trial-of-PDE9-Inhibitor-in-Patients-With-Heart-Failure免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床2期临床3期临床结果引进/卖出

100 项与 CRD-740 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
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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
射血分数保留型心力衰竭	临床2期	美国	Cardurion Pharmaceuticals, Inc.初创企业	2022-05-26
射血分数保留型心力衰竭	临床2期	加拿大	Cardurion Pharmaceuticals, Inc.初创企业	2022-05-26
射血分数保留型心力衰竭	临床2期	以色列	Cardurion Pharmaceuticals, Inc.初创企业	2022-05-26
射血分数保留型心力衰竭	临床2期	英国	Cardurion Pharmaceuticals, Inc.初创企业	2022-05-26
射血分数降低的心力衰竭	临床2期	美国	Cardurion Pharmaceuticals, Inc.初创企业	2022-05-26
射血分数降低的心力衰竭	临床2期	加拿大	Cardurion Pharmaceuticals, Inc.初创企业	2022-05-26
射血分数降低的心力衰竭	临床2期	以色列	Cardurion Pharmaceuticals, Inc.初创企业	2022-05-26
射血分数降低的心力衰竭	临床2期	英国	Cardurion Pharmaceuticals, Inc.初创企业	2022-05-26

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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


NCT05409183 (CARDINAL‑HF \| CARDINAL-HF, CTgov)	临床2期	射血分数保留型心力衰竭 \| 射血分数降低的心力衰竭	60	CRD-740 (CRD-740)	願鏇襯窪衊鏇夢醖願網(襯夢製築鏇構憲膚遞遞) = 觸繭築獵壓襯夢繭網鑰築齋艱鑰齋蓋構簾網夢 (齋築觸築鏇製簾餘築範, 糧襯蓋膚壓膚鹽遞廠鹽 ~ 艱艱廠繭艱積鑰壓襯鹽)	-	2024-12-19
				Placebo (Placebo)	願鏇襯窪衊鏇夢醖願網(襯夢製築鏇構憲膚遞遞) = 遞繭選顧鑰繭夢範獵鑰築齋艱鑰齋蓋構簾網夢 (齋築觸築鏇製簾餘築範, 網積範廠築衊選衊淵醖 ~ 鬱膚鹹艱夢鬱積襯鬱醖)
NCT05409183 (CARDINAL‑HF, Company_Website) 人工标引	临床2期	射血分数降低的心力衰竭	60	CRD-740	艱遞簾夢範遞艱繭衊積(願餘鹹鏇夢願獵艱糧膚) = achieved statistically significant median increases in plasma cGMP at four weeks, compared to placebo 鬱鹹淵憲鹽壓壓範積遞 (獵製夢鏇觸構餘襯願遞 ) 达到更多	积极	2024-05-13
				Placebo