Esaxerenone: First Global Approval

Drugs https://doi.org/10.1007/s40265-019-01073-5

ADISINSIGHT REPORT

Sean Duggan1

Abstract Esaxerenone (MINNEBRO™)—a novel oral, non-steroidal, selective mineralocorticoid receptor blocker—is being developed by Daiichi Sankyo for the treatment of hypertension and diabetic nephropathies. In January 2019, based on positive results from a phase III trial conducted in Japan in patients with essential hypertension, esaxerenone received marketing approval in Japan for the treatment of hypertension. This article summarizes the milestones in the development of esaxerenone leading to this frst global approval for the treatment of hypertension.

1 Introduction 1.1 Company Agreements

Daiichi Sankyo are developing esaxerenone (MINNE- In March 2006, Sankyo Co., Ltd, a subsidiary of Daiichi BRO™), a novel oral, non-steroidal, selective mineralocor- Sankyo, entered into a research collaboration agreement ticoid receptor blocker, for the treatment of hypertension and with Exelixis Inc. to develop and commercialise novel ther- diabetic nephropathies. Excessive mineralocorticoid recep- apies targeting the mineralocorticoid receptor [7]. Daiichi tor activation by endogenous ligands such as aldosterone has Sankyo obtained an exclusive, worldwide licence to certain been shown to play an important role in the development of intellectual property primarily relating to compounds that hypertension, as well as progression of nephropathy and car- modulate the mineralocorticoid receptor, including esaxer- diovascular disease [1–4]. Esaxerenone is thought to exert an enone [7, 8]. After completion of the research term, Sankyo antihypertensive efect by blocking mineralocorticoid recep- Co., Ltd has assumed responsibility for all further clinical tor activation. Esaxerenone was approved in Japan for the and regulatory development of the drug. In return, Exelixis treatment of hypertension on the 8th January 2019 [4, 5] on received a $US20 million upfront payment and will receive the basis of positive results from a phase III trial in Japa- research and development funding. nese patients with essential hypertension (NCT02890173; ESAX-HTN) [6]. The drug is available as 1.25, 2.5 and 5 mg tablets, with the recommended dosage of esaxerenone being 2 Scientifc Summary 2.5 mg once daily administered orally; if the efect is insuf- fcient, the dosage can be increased to 5 mg [4]. Clinical 2.1 Pharmacodynamics development of esaxerenone for the treatment of diabetic nephropathies is underway in Japan. Esaxerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has been shown to bind to mineralocorticoid receptors, thereby inhibiting aldosterone binding and activation of the receptor [4, 9]. In preclinical studies, esaxerenone inhibited the binding of aldosterone to the min- AdisInsight This profle has been extracted and modifed from the eralocorticoid receptor with greater potency than spirono- database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre- lactone and eplerenone (IC50 9.4, 36 and 713 nmol/L, clinical and clinical studies to market launch and beyond. respectively) [9]. Esaxerenone blocked aldosterone-induced transcriptional activation of human mineralocorticoid * Sean Duggan receptor with greater potency than eplerenone and spirono- [email protected] lactone (IC50 3.7 vs 66 and 970 nmol/L, respectively) in a 1 Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, cell-based assay [9]. Esaxerenone had no agonistic efect New Zealand

Vol.:(0123456789) S. Duggan

Positive top-line results from Phase III trial ESAX- HTN announced (Sep)

Phase I trials initiated (Dec 2010) NDA submitted in Japan (Feb) Approved in Japan for the Phase II trial in essential hypertension completed treatment of hypertension (NCT02345044; JapicCTI152772) [Aug] (Jan)

2015 2016 2017 2018 2019

NCT02722265 NCT02848170 NCT02890173 ESAX-HTN NCT02808026 Studies in essential hypertension NCT02807987 Studies in hypertension NCT02807974

Key milestones in the development of esaxerenone, focusing on phase III trials in hypertension. NDA new drug application on the mineralocorticoid receptor and did not show any 2.2 Pharmacokinetics antagonistic or agonistic efect on glucocorticoid, androgen and progesterone receptors even at 5 μM, unlike eplerenone The pharmacokinetic properties of esaxerenone have been and spironolactone [9]. evaluated in phase I, double blind, sequential, dose-escalation Esaxerenone-induced mineralocorticoid receptor studies in healthy Japanese subjects [2]. Once-daily oral esax- antagonism has been evaluated in in vivo animal models erenone generally exhibited dose-proportional pharmacoki- using urinary sodium/potassium ratio concentrations as a netics following single (range 5–200 mg) [JapicCTI163473] biomarker for activity of the drug. In bilateral adrenalec- and multiple (10–100 mg/day for 10 days) [JapicCTI163476] tomized rats, administration of oral esaxerenone resulted dose regimens. Exposure reached steady state by day 4 in sub- in potent and long-lasting inhibition of an aldosterone- jects receiving oral esaxerenone 10–100 mg/day for 10 days; induced decrease in urinary sodium/potassium ratio [9]. the mean observed accumulation ratio was 1.36–1.98. Fol- Furthermore, esaxerenone dose-dependently increased the lowing a single oral administration of esaxerenone, the time urinary sodium/potassium concentration ratio in cynomol- to reach maximum plasma concentration was ≈ 3 h and the gus monkeys following a single-dose oral administration elimination half-life was ≈ 20 h; the pharmacokinetics of of the drug [4]. esaxerenone allow for a once-daily dosage regimen. In animal models of hypertension (DOCA/salt-induced The pharmacokinetics of esaxerenone are unafected by hypertensive rats and Dahl salt-sensitive hypertensive rats), food, with no diferences seen in Cmax and AUC following administration of esaxerenone resulted in dose-dependent a single oral esaxerenone 5 mg dose in healthy adult males and sustained antihypertensive efects [9–11], suppression of (n = 23) administered with or without a meal; the bioavail- renal injury development (e.g. proteinuria and renal hyper- ability of esaxerenone was 89% in those receiving esaxer- trophy) [10, 11] and inhibition of gene expression related to enone without food [4]. infammation, oxidative stress and fbrosis [10]. In healthy Japanese male subjects, administration of multiple doses of oral esaxerenone (10–100 mg/day HO for 10 days) resulted in dose-dependent changes in bio- O markers for the mineralocorticoid receptor in the plasma N HN S (increased plasma renin activity, active renin concentration and plasma aldosterone concentration), providing O supportive evidence for the pharmacological activity of O esaxerenone (JapicCTI163476). An increased urinary F sodium/potassium concentration ratio was also observed in these patients following a single-dose administration F of esaxerenone; however, no obvious dose-response was F seen for this parameter when multiple doses of the drug were administered [2]. Chemical structure of esaxerenone Esaxerenone: First Global Approval

Features and properties of esaxerenone

Alternative names CS-3150; MINNEBRO; XL-550 Class Antihypertensives, pyrroles, small molecules, sulfones Mechanism of action Mineralocorticoid receptor blocker Route of administration Oral

Pharmacodynamics Selectively binds to mineralocorticoid receptors (IC50 9.4 nmol/L), blocking aldosterone-induced transcriptional activation of the receptor (IC 50 3.7 nmol/L) Pharmacokinetics Dose proportional exposure; time to maximum plasma concentration ≈3 h; elimination half-life ≈ 20 h Adverse events Most frequent ↑ Serum potassium, ↑ blood uric acids, hyperuricaemia ATC codes WHO ATC code A10X (other drugs used in diabetes); A16A (other alimentary tract and metabolism products); C01E-B (other cardiac preparations); C02K (other antihypertensives) EphMRA ATC code A10X (other drugs used in diabetes); A16A (other alimentary tract and metabolism products); C1X (all other cardiac preparations); C2A [antihypertensives (of non-herbal origin) plain] Chemical name (5P)-1-(2-Hydroxyethyl)-N-[4-(methanesulfonyl)phenyl]-4-methyl-5-[2-(trifuoromethyl)phenyl]-1H-pyrrole-3-car- boxamide

In pharmacokinetic studies in healthy male subjects receiv- trough sSBP from baseline to the end of the treatment period ing a single oral dose of [14C]esaxerenone 20 mg (n = 6), the of − 13.7 and − 16.9 mmHg, respectively, compared with most abundant moiety in plasma was esaxerenone (40.8%) − 12.1 mmHg in eplerenone 50 mg/day recipients (n = 316); followed by metabolites O-glucuronide (M4) and acyl-glu- corresponding changes in trough sDBP from baseline were curonide of hydrolysate (M11) [21.4 and 8.0%, respectively]; − 6.8 and − 8.4 versus − 6.1 mmHg (primary endpoint anal- detection of several oxidized forms of metabolites in urine ysis) [4, 6]. According to noninferiority analyses, esaxer- and faeces suggest that multiple metabolic pathways exist for enone 2.5 mg/day was noninferior to eplerenone 50 mg/day esaxerenone, i.e. oxidation, glucuronidation, and hydrolysis in terms of the primary endpoint of change in trough sSBP/ [12]. In vitro metabolism studies demonstrated esaxerenone sDBP from baseline in the per protocol population [6]. Esax- is metabolized by CYP3A4, CYP3A5 and multiple UDP- erenone 5 mg/day was superior to esaxerenone 2.5 mg/day in glucuronosyltransferase isoforms. The total excretion rate of terms of the primary endpoint, as assessed in the full analy- esaxerenone was 92.5%, with 54.0% and 38.5% excreted in sis set (p < 0.001) [6]. The primary objective of the study the faeces and urine, respectively; the excretion rate of the was to confrm noninferiority of esaxerenone 2.5 mg once unchanged drug via these routes was 18.7% and 1.6%. daily compared with eplerenone 50 mg once daily in terms The pharmacokinetics of esaxerenone are not altered of antihypertensive efcacy. Patients underwent a 4-week to a clinically signifcant extent by moderate renal impair- washout period before the 12-week treatment period began. ment (eGFR 30 to 60 mL/min/1.73 m2) or mild or moderate According to results from a number of Japanese phase hepatic impairment (Child-Pugh A and B, respectively); the III trials reported in the Japanese prescribing informa- efect of severe renal or hepatic impairment on the pharma- tion, a stable antihypertensive efect with esaxerenone has cokinetics of esaxerenone is currently unknown [4]. also been obtained across diferent patient populations; this includes patients with severe hypertension (grade 2.3 Therapeutic Trials III; sSBP ≥ 180 mmHg or sDBP ≥ 110 mmHg, n = 20) [NCT02808026], hypertensive patients (sSBP ≥ 140 mmHg 2.3.1 Phase III Studies to < 180 mmHg and sDBP ≥ 80 mmHg to < 110 mmHg) with moderate renal impairment (eGFR ≥ 30 to < 60 mL/ Esaxerenone demonstrated antihypertensive efects in a min/1.73 m2; n = 44) [NCT02807987] or type 2 diabetes pivotal randomised, double-blind, parallel-group, compara- mellitus and albuminuria (urine albumin-to-creatinine ratio tive phase III trial in Japanese patients with essential hyper- ≥ 30 to < 1000 mg/g; n = 51) [NCT02807974] and in pri- tension [sitting systolic BP (sSBP) 140 to < 180 mmHg; mary aldosteronism (n = 58) [NCT02885662] [4]. A stable sitting diastolic BP (sDBP) 90 to < 110 mmHg; 24-h BP antihypertensive efect was also obtained with longer-term > 130/80 mmHg] (NCT02890173; ESAX-HTN) [4, 6]. esaxerenone therapy, alone or in combination with an ARB Treatment with esaxerenone 2.5 mg/day (n = 306) and or ACE inhibitor, for 28–52 weeks in patients with essential 5.0 mg/day (n = 322) for 12 weeks resulted in changes in hypertension (n = 368) [NCT02722265] [4]. S. Duggan

2.3.2 Phase II Studies 2.4 Adverse Events

Esaxerenone dose-dependently lowered trough sSBP/ In a pooled analysis of Japanese clinical trials (n = 1250), sDBP from baseline in patients with essential hyperten- adverse events were observed in 13.0% (n = 162) of patients sion (n = 400), according to a randomised, double-blind, receiving esaxerenone [4]. The most commonly observed placebo-controlled, open-label dose-ranging phase II study adverse events reported with esaxerenone were increased (NCT02345044) [4, 13]. Reductions in sSBP and sDBP from levels of serum potassium (4.1%; n = 51) and blood uric baseline reached statistical signifcance in patients receiving acid (1.4%; n = 17), and hyperuricaemia (1.0%; n = 13). The esaxerenone 2.5 and 5 mg/day (all p < 0.001) [13]. Changes frequency of serious adverse events with esaxerenone was from baseline in trough sSBP with esaxerenone 1.25, 2.5 low, with the most commonly reported being hyperkalaemia and 5 mg/day were − 10.7, − 14.3 and − 20.6 mmHg, (1.7%). respectively, compared with − 7.0 mmHg for placebo; cor- In the pivotal phase III trial in patients with essential responding changes in sDBP were − 5.0, − 7.6, − 10.4 and hypertension (NCT02890173), treatment with esaxerenone − 3.8 mmHg [4]. A dose-dependent decrease from baseline 2.5 and 5 mg once daily for 12 weeks was generally well tol- in 24-h BP was also observed with esaxerenone, with sig- erated [6]. No-dose dependent hyperkalaemia (≥ 5.5 mEq/L) nifcant decreases from baseline in 24-h BP reported in esax- was observed in the esaxerenone treatment groups. erenone 1.25 (p < 0.05), 2.5 and 5 mg/day (all p < 0.0001) treatment groups compared with placebo [13]. Patients were 2.5 Ongoing Clinical Trials randomised to esaxerenone 1.25, 2.5 or 5 mg/day or placebo (n = 82, 84, 88 and 85, respectively) for a treatment period There are a number of phase II and III Japanese clini- of 12 weeks, following a washout period of 4 weeks. An cal trials listed as complete but for which results are not open-label treatment arm evaluating eplerenone 50–100 mg/ yet available, including in patients with essential hyper- day was also included, although results for this arm have not tension (NCT02848170; JapicCTI163324 and Japi- yet been presented. cCTI121921), hypertension and moderate renal impairment (NCT02448628; JapicCTI152883), as well as in patients with diabetic nephropathies (NCT02345057;

Key clinical trials of esaxerenone (Daiichi Sankyo; conducted in Japan) Drug(s) Condition or disease Phase Status Identifer

Esaxerenone; Essential hypertension III Completed NCT02890173; JapicCTI163348; ESAX-HTN eplerenone Esaxerenone Essential hypertension III Completed NCT02722265; JapicCTI163176 Esaxerenone; Essential hypertension III Completed NCT02848170; JapicCTI163324 olmesartan medoxomil Esaxerenone Hypertension III Completed NCT02808026; JapicCTI163287 Esaxerenone Hypertension with moderate renal impair- III Completed NCT02807987; JapicCTI163288 ment Esaxerenone, Hypertension with type 2 diabetes and III Completed NCT02807974; JapicCTI163293 albuminuria Esaxerenone Hypertension with primary aldosteronism III Completed NCT02885662; JapicCTI163349 Esaxerenone Diabetic nephropathies III Completed JapicCTI173696 Esaxerenone Diabetic nephropathies III Ongoing JapicCTI173695; ESAX-DN Esaxerenone; Essential hypertension II Completed NCT02345044; JapicCTI152772 eplerenone Esaxerenone Essential hypertension II Completed JapicCTI121921 Esaxerenone Hypertension with moderate renal impair- II Completed NCT02448628; JapicCTI152883 ment Esaxerenone Diabetic nephropathies II Completed NCT02345057; JapicCTI152774 Esaxerenone Diabetic nephropathies II Completed JapicCTI122018 Esaxerenone: First Global Approval

JapicCTI152774, JapicCTI173696 and JapicCTI122018). 4. Daiichi Sankyo. Esaxerenone (Minnebro): Japanese prescribing There is one ongoing phase III study of esaxerenone for the information; 2019. http://www.pmda.go.jp/PmdaSearch/iyaku Detail/430574_21490B6F1026_1_02#CONTRAINDICATIO treatment of patients with diabetic nephropathies in Japan NS. Accessed 15 Jan 2019. (JapicCTI173695). 5. Daiichi Sankyo. Daiichi Sankyo announces approval of MINNE- BRO™ tablets for the treatment of hypertension in Japan [media release]. 8 Jan 2019. https://www.daiichisankyo.com. 3 Current Status 6. Ito S, Ito H, Rakugi H, et al. A double blind phase III study of esaxerenone (CS-3150) compared to eplerenone in patients with essential hypertension (ESAX-HTN study). J Hypertens. Esaxerenone received its frst global approval in January 2018;36(Suppl 1):e239. 2019 in Japan for the treatment of hypertension. 7. Daiichi Sankyo. Sankyo and Exelixis sign joint research agreement [media release]. 23 Mar 2016. https://www.sec.gov/Archi ves/edgar/data/1340156/000119312506061375/dex991.htm. Compliance with Ethical Standards 8. Exelixis. Exelixis announces frst quarter 2006 fnancial results [media release]. 9 May 2006. http://www.exelixis.com. Funding The preparation of this review was not supported by any 9. Arai K, Homma T, Morikawa Y, et al. Pharmacological pro- external funding. fle of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist. Eur J Pharmacol. Conflict of interest 2015;761:226–34. During the peer review process the manufacturer 10. Arai K, Morikawa Y, Ubukata N, et al. CS-3150, a novel non- of the agent under review was ofered an opportunity to comment on steroidal mineralocorticoid receptor antagonist, shows preventive the article. Changes resulting from any comments received were made and therapeutic efects on renal injury in deoxycorticosterone by the authors on the basis of scientifc completeness and accuracy. acetate/salt-induced hypertensive rats. J Pharmacol Exp Ther. Sean Duggan is a salaried employee of Adis/Springer, is responsible 2016;358(3):548–57. for the article content and declares no relevant conficts of interest. 11. Arai K, Tsuruoka H, Homma T. CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats. Eur J References Pharmacol. 2015;769:266–73. 12. Yamada M, Mendell J, Takakusa H, et al. Pharmacokinetics, metabolism, and excretion of [14C]esaxerenone, a novel miner- 1. Mulatero P, Milan A, Williams TA, et al. Mineralocorticoid recep- alocorticoid receptor blocker in humans. Drug Metab Dispos. tor blockade in the protection of target organ damage. Cardiovasc 2019;47(3):340–9. Hematol Agents Med Chem. 2006;4(1):75–91. 13. Ito S, Ito H, Rakugi H, et al. Treatment with esaxerenone (CS- 2. Kato M, Furuie H, Shimizu T, et al. Single- and multiple-dose 3150) is associated with a signifcant dose dependent antihy- escalation study to assess pharmacokinetics, pharmacodynamics pertensive efect in essential hypertensive patients [abstract no. and safety of oral esaxerenone in healthy Japanese subjects. Br J BP.02.01]. J Hypertens. 2017;35(Suppl 2):e173. Clin Pharmacol. 2018;84(8):1821–9. 3. Shibata S, Ishizawa K, Uchida S. Mineralocorticoid receptor as a therapeutic target in chronic kidney disease and hypertension. Hypertens Res. 2017;40(3):221–5. 本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

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