Delving into the Latest Updates on Imarikiren hydrochloride with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Imarikiren

+ [2]

Target

renin

Mechanism

renin inhibitors(Renin inhibitors)

Therapeutic Areas

Endocrinology and Metabolic DiseaseUrogenital DiseasesCardiovascular Diseases

Active Indication

Diabetic NephropathiesHypertension

Inactive Indication

AlbuminuriaDiabetes Mellitus, Type 2Liver Diseases

Originator Organization

Takeda Pharmaceutical Co., Ltd.

Active Organization

SCOHIA PHARMA, Inc.Startup

Inactive Organization

Takeda Pharmaceutical Co., Ltd.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC27H42ClN5O4

InChIKeyPUXOYQIZZIWCHH-NSLUPJTDSA-N

CAS Registry1202269-24-6

View All Structures (2)

The purpose of this study is to test the efficacy and safety on daily oral doses of TAK-272 5 mg, 20 mg, 40 mg and 80 mg in patients with type 2 diabetes mellitus and microalbuminuria by randomized, double-blind, placebo-controlled, parallel-group comparison in order to determine the clinical dose of TAK-272.

Start Date16 Oct 2014

Sponsor / Collaborator

Takeda Pharmaceutical Co., Ltd.

100 Clinical Results associated with Imarikiren hydrochloride

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100 Translational Medicine associated with Imarikiren hydrochloride

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100 Patents (Medical) associated with Imarikiren hydrochloride

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9

Literatures (Medical) associated with Imarikiren hydrochloride

01 May 2020·FEBS Open BioQ4 · BIOLOGY

Development of a novel murine heart failure model overexpressing human renin and angiotensinogen

Q4 · BIOLOGY

ArticleOA

Author: Nishimoto, Tomoyuki ; Takeyama, Michiyasu ; Kanagawa, Ray ; Yamamura, Takeshi ; Hara, Tomoya ; Murakami‐Asahina, Mirei ; Matsumoto, Hirokazu

Renin is the rate‐limiting enzyme of the renin–angiotensin system cascade, which drives the pathophysiological progression of heart failure. Species differences in the amino acid sequence of the catalytic domain of renin limit evaluations of the potency and efficacy of human renin inhibitors in animal models, and a high dose of inhibitors is usually needed to show its organ‐protective effects in rodents. In the present study, we developed a novel murine heart failure model (triple‐tg) to enable us to evaluate the cardioprotective effect of renin inhibitors at more relevant doses for humans, by cross‐breeding calsequestrin transgenic (CSQ‐tg) mice with human renin and human angiotensinogen double‐transgenic mice. The triple‐tg mice exhibited increased plasma renin activity, worsened cardiac hypertrophy, and higher mortality compared to CSQ‐tg mice. Triple‐tg mice treated with 10 mg·kg−1 of TAK‐272 (imarikiren/SCO‐272), an orally active direct renin inhibitor, exhibited improvements in heart failure phenotypes, such as cardiac hypertrophy and survival rate; however, a dose of 300 mg·kg−1 was required to improve symptoms in CSQ‐tg mice. Our results suggest that this newly generated triple‐tg heart failure model is useful to evaluate the cardioprotective effects of human renin inhibitors at clinically relevant doses, thereby minimizing the concerns of off‐target effects related to much higher drug exposure than that achieved in clinical study.

04 May 2019·XenobioticaQ4 · MEDICINE

The effect of elevated α₁-acid glycoprotein on the pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, in rats

Q4 · MEDICINE

Article

Author: Ebihara, Takuya ; Higuchi, Tomoaki ; Tagawa, Yoshihiko ; Jinno, Fumihiro ; Yamamoto, Masami ; Shimizu, Hisao

The pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, was investigated in rats with subcutaneously injected turpentine oil, which was an inflammation animal model. Following intravenous administration of TAK-272 to the turpentine-treated rats, the systemic clearance and volume of distribution decreased with the elevated plasma α₁-acid glycoprotein (AGP) levels. The elevated plasma AGP levels were negatively correlated with the plasma unbound fraction of TAK-272 in the rats. Although the AUCs of total TAK-272 in the turpentine-treated rats were higher than those in the control rats after intravenous and oral administration, those of unbound TAK-272, which seem to directly contribute to the pharmacological effect and safety, were nearly equal between the turpentine-treated and control rats in the respective dose routes. TAK-272 has been shown to primarily bind to AGP in the human plasma. These results strongly suggested that the pharmacokinetic of TAK-272 in humans would also be affected by the variation in the plasma AGP levels and should be discussed with not only the total concentrations but also the unbound concentrations in the clinical trial for patients with elevated plasma AGP levels.

01 Mar 2019·Clinical Journal of the American Society of NephrologyQ1 · MEDICINE

Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria

Q1 · MEDICINE

Article

Author: Shimizu, Kohei ; Saiki, Takuya ; Umeda, Yuusuke ; Kuroda, Shingo ; Kagawa, Tomoya ; Sano, Yuhei ; Ito, Sadayoshi

BACKGROUND AND OBJECTIVESImarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSThis was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing.RESULTSChanges in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), -16% (imarikiren 5 mg), -27% (imarikiren 20 mg), -38% (imarikiren 40 mg), -39% (imarikiren 80 mg), and -31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo (P<0.001 each) as well as for candesartan cilexetil 8 mg versus placebo (P<0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated.CONCLUSIONSImarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.

100 Deals associated with Imarikiren hydrochloride

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetic Nephropathies	Phase 2	JP	SCOHIA PHARMA, Inc.Startup	-
Albuminuria	Phase 1	JP	Takeda Pharmaceutical Co., Ltd.	16 Oct 2014
Diabetes Mellitus, Type 2	Phase 1	JP	Takeda Pharmaceutical Co., Ltd.	16 Oct 2014
Hypertension	Phase 1	JP	SCOHIA PHARMA, Inc.Startup	-
Liver Diseases	Discovery	JP	Takeda Pharmaceutical Co., Ltd.	01 Mar 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02332824 (CTgov)	Phase 2	Diabetes Mellitus, Type 2 \| Albuminuria	415	Candesartan cilexetil Placebo (Placebo)	wvnetqndil(yiqiatsyho) = kpflrqapys yewxgpnrke (uncganfwln, mzccuzmjav - nltedkiuyw) View more	-	13 Aug 2018
				Candesartan cilexetil Placebo+TAK-272 (TAK-272 5 mg)	wvnetqndil(yiqiatsyho) = siplwjmewk yewxgpnrke (uncganfwln, psyghhyytd - zivjpmnqti) View more
NCT02367872 (CTgov)	Phase 1	Liver Diseases	48	TAK-272 (Cohort 1R: Normal Renal Function)	xngqfufifs(gxyxrzznbp) = qspunulvyv wvhbnsbhrg (yuhgkyiwey, hrgyxmzxac - wqcednybmz) View more	-	10 Aug 2017
				TAK-272 (Cohort 2R: Mild Renal Impairment)	xngqfufifs(gxyxrzznbp) = khquczttfv wvhbnsbhrg (yuhgkyiwey, yprqofxrif - jwvvhrmuby) View more
NCT02370615 (CTgov)	Phase 1	-	34	itraconazole+TAK-272 (Cohort 1: TAK-272 + Itraconazole)	shjjinxiyr(voagnpspob) = wwpaachaml btyyduirso (wfaeqeoynm, deduvwigdj - iwyxaarahj) View more	-	23 May 2016
				TAK-272+digoxin+midazolam (Cohort 2: Midazolam + Digoxin + TAK-272)	qvkvsthxfm(siswjgysiy) = ixuqfrycou gaiiieildt (ghwkjeiqgj, bwlzlxcnih - jypuzdkzdu) View more