Trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2-expressing salivary gland carcinoma: a pooled analysis of two phase I studies.

BACKGROUND: HER2-expressing salivary gland carcinoma (SGC) is associated with poor prognosis. Trastuzumab deruxtecan (T-DXd, DS-8201) has shown evidence of antitumor activity for several HER2-expressing solid tumors in multiple studies. This study aimed to present the efficacy and safety of T-DXd in patients with HER2-expressing SGC from a pooled analysis. METHODS: Patients with HER2-expressing SGC were pooled from two phase I, open-label studies of T-DXd: a two-phase, multiple-dose, first-in-human study (NCT02564900) and a single-sequence crossover drug-drug interaction study (NCT03383692). Endpoints included efficacy (objective response rate [ORR], duration of response [DoR] and progression-free survival [PFS]) and safety. RESULTS: This pooled analysis included 17 patients with SGC (median age: 57 years; male: 88.2%); median (range) follow-up duration was 12.0 (2.3-|34.8) months. Among these patients, 14 had received prior HER2-targeted agents and 13 had undergone prior radiotherapy. The investigator-assessed confirmed ORR was 58.8% (95% confidence interval [CI], 32.9-|81.6). The median (95% CI) DoR and PFS were 17.6 months (4.0 to not evaluable [NE]) and 20.5 months (11.1-NE), respectively. All 17 patients reported treatment-emergent adverse events (TEAEs); 76.5% reported TEAEs of grade ≥3. The most common TEAEs were decreased appetite (94.1%), nausea (88.2%) and neutrophil count decreased (76.5%). Of the 17 patients, five (29.4%) reported adjudicated drug-related interstitial lung disease (grade 1, n = 3; grade 2, n =1; grade 3, n = 1). CONCLUSION: The results of this pooled analysis provide evidence that clinical benefit is achievable with T-DXd in patients with HER2-expressing SGC. CLINICAL TRIAL INFORMATION: FIH study, NCT02564900; DDI study, NCT03383692.

Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer.

DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH-), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC.

Estimability study on the age of toddlers' gait development based on gait parameters.

In the first few years of toddlers' locomotion, various gait parameters improve gradually and dynamically with gait development. Therefore, in this study, we hypothesized that the age of gait development, or the level of gait development with age as its indicator, can be estimated from several gait parameters related to gait development, and investigated its estimability. In total, 97 healthy toddlers aged about 1-3 years participated in the study. All five selected gait parameters showed a moderate or higher correlation with age, but the duration with a large change and the strength of the association with gait development varied for each gait parameter. Multiple regression analysis was performed using age as the objective variable and five selected gait parameters as explanatory variables, and an estimation model (R2 = 0.683, adjusted R2 = 0.665) was created. The estimation model was verified using a test dataset separate from the training dataset (R2 = 0.82, p < 0.001). It was suggested that the age of gait development could be estimated from gait alone. Gait analysis based on empirical observations may reduce the need for skilled observers and their potential variability.

Factors Associated with the Antihypertensive Effect of Esaxerenone and Serum Potassium Elevation: A Pooled Analysis of Seven Phase III Studies.

INTRODUCTION: This study investigated factors associated with the antihypertensive effects of esaxerenone and the incidence of serum potassium elevation in patients with hypertension. METHODS: Using pooled data from seven phase III studies, the study analyzed factors associated with changes in office systolic (SBP) and diastolic (DBP) blood pressure from baseline to 12 weeks, and factors associated with incidence of serum potassium levels ≥ 5.5 mEq/L in esaxerenone-treated patients. RESULTS: Overall, 1466 and 1472 patients were included in the full analysis and safety analysis sets, respectively. Male sex (4.02/2.40 mmHg), weight ≥ 78.4 kg (4.62/2.09 mmHg), hypertension duration ≥ 10 years (2.66/1.71 mmHg), prior antihypertensive treatment (2.38/1.40 mmHg), plasma aldosterone concentration ≥ 120 pg/mL (1.66/1.17 mmHg), urinary albumin-to-creatinine ratio (UACR) ≥ 300 mg/gCr (8.94/4.85 mmHg) or 30-299 mg/gCr (5.17/4.15 mmHg), and smoking (2.62/1.27 mmHg) were associated with mean changes in SBP and DBP. Fasting blood glucose ≥ 126 mg/dL (- 2.73 mmHg) was associated with the mean change in SBP only, and older age (65-74 years, - 2.12 mmHg; and ≥ 75 years, - 3.06 mmHg) with mean change in DBP only. Factors significantly associated with incidence of serum potassium levels ≥ 5.5 mEq/L were higher baseline serum potassium (≥ 4.5 mEq/L, odds ratio [OR] 6.702); lower estimated glomerular filtration rate (≥ 90 mL/min/1.73 m2, OR 0.148; 60-89 mL/min/1.73 m2, OR 0.331 vs 30-59 mL/min/1.73 m2, respectively); higher UACR (30-299 mg/gCr, OR 7.317); higher DBP (≥ 100 mmHg, OR 3.248); and grade I hypertension (OR 2.168). CONCLUSION: Esaxerenone is effective in patients with a broad range of backgrounds, though some factors may predict increased benefit. Regarding elevated serum potassium, careful therapeutic management is recommended for patients with higher baseline serum potassium and reduced renal function. CLINICAL TRIAL REGISTRATION: UMIN000047026.

The renoprotective effect of esaxerenone independent of blood pressure lowering: a post hoc mediation analysis of the ESAX-DN trial.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are recommended as first-line drugs for hypertension with diabetic nephropathy owing to their renoprotective effect; however, their effect beyond lowering blood pressure (BP) has not been confirmed. Recent studies have shown that aldosterone plays a key role in causing renal injury; therefore, it is likely that mineralocorticoid receptor (MR) blockers inhibit aldosterone-induced renal damage in different ways from ACE inhibitors and ARBs. Therefore, we investigated the mechanism of the effect of an MR blocker on reducing the urinary albumin-to-creatinine ratio (UACR) using data from a randomized, double-blind, placebo-controlled phase 3 study (ESAX-DN) of a new nonsteroidal MR blocker, esaxerenone. This post hoc analysis used a novel statistical method to quantitatively estimate the effect of esaxerenone on UACR reduction mediated, or not mediated, by changes in systolic BP (SBP) and/or estimated glomerular filtration rate (eGFR). The proportion of the mediated effect by SBP changes to the total effect on UACR reduction was 9.8-10.7%; the UACR was reduced to 0.903-0.911 times the baseline at the end of treatment through the SBP-related pathway and to 0.422-0.426 times the baseline through the non-SBP-related pathway. Even considering both SBP and eGFR simultaneously, the proportion of the mediated effect was 21.9-28.1%. These results confirm that esaxerenone has a direct UACR-lowering effect independent of BP lowering and that its magnitude is much larger than that of the BP-dependent effect. Thus, esaxerenone could be a UACR-reducing treatment option for patients with diabetic nephropathy.

Reduction in the magnitude of serum potassium elevation in combination therapy with esaxerenone (CS-3150) and sodium-glucose cotransporter 2 inhibitor in patients with diabetic kidney disease: Subanalysis of two phase III studies.

AIMS/INTRODUCTION: We evaluated the effect of co-administration of esaxerenone and a sodium-glucose cotransporter 2 (SGLT2) inhibitor on the magnitude of serum potassium elevation in Japanese patients with diabetic kidney disease. MATERIALS AND METHODS: We carried out a prespecified subanalysis of data from two phase III studies: a multicenter, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes and microalbuminuria (J308); and a multicenter, single-arm, open-label trial in patients with type 2 diabetes and macroalbuminuria (J309). Changes in serum potassium levels during the studies and other measures were evaluated according to SGLT2 inhibitor use. RESULTS: In both studies, time-course changes in serum potassium levels, and incidence rates of serum potassium elevation were lower in patients with co-administration of SGLT2 inhibitor in both the placebo and esaxerenone groups than those without the inhibitor. In contrast, time-course changes and mean percentage changes from baseline in urinary albumin-to-creatinine ratio, the proportion of patients with albuminuria remission and time-course changes in blood pressure did not change with or without SGLT2 inhibitor, whereas the albumin-to-creatinine ratio and blood pressure were reduced with esaxerenone. The blood glucose-lowering effect of SGLT2 inhibitor was not affected by esaxerenone. CONCLUSIONS: In Japanese patients with type 2 diabetes and albuminuria treated with esaxerenone, concomitant use of SGLT2 inhibitor reduced the magnitude of serum potassium elevation without any change of its antihypertensive and albuminuria-suppressing effects. Co-administration of esaxerenone and SGLT2 inhibitor might be a beneficial treatment option for patients with diabetic kidney disease.

Effect of esaxerenone on nocturnal blood pressure and natriuretic peptide in different dipping phenotypes.

There are limited data on the nighttime blood pressure (BP)-lowering effect of esaxerenone and its effect on N-terminal pro b-type natriuretic peptide (NT-proBNP), a predictor of cardiovascular risk, according to different dipping patterns of nocturnal BP. This was a post hoc analysis of a multicenter, open-label, long-term phase 3 study of esaxerenone, a new highly selective mineralocorticoid receptor blocker, in patients with essential hypertension. Patients were classified by dipping pattern (extreme dippers, dippers, non-dippers, risers). Mean changes in BP, changes in dipping pattern, mean NT-proBNP levels, and percentage of patients with normal NT-proBNP levels (<55 pg/mL) at baseline and Weeks 12 and 28 were evaluated. Nighttime systolic BP decreased in all dipping pattern groups at Week 28, with the riser group showing the greatest change (-25.5 mmHg). A significant shift in dipping pattern and riser/non-dipper pattern changes to dipper/extreme dipper pattern were found from baseline to Week 28 (p < 0.0001). The prevalence of the riser pattern decreased from 14.4% to 9.8%, and that of the non-dipper pattern from 44.7% to 39.2%. The decrease in NT-proBNP from baseline to Week 28 was statistically significant in risers, non-dippers, dippers, and extreme dippers (p < 0.001, respectively). At baseline, the proportion of patients with NT-proBNP <55 pg/mL was lowest in risers versus the other dipping pattern types, but after reductions in NT-proBNP in all groups to Week 28, these differences disappeared. Long-term administration of esaxerenone may be a useful treatment option for nocturnal hypertension, especially in patients with a riser pattern.

Effect of wearing diapers on toddler's gait.

Gait maturation in infants develops gradually through several phases. However, external factors such as childrearing practices, especially the wearing of diapers, may affect an infant's motor development. This study investigated the influence of different bulk stresses on the gait of toddlers wearing a disposable diaper. Twenty-six healthy toddlers (age: 19.2 ± 0.9 months) participated in this study. We measured the joint kinematics (pelvis angle and hip-joint angle) and spatiotemporal parameters (step length and step width) of the toddlers' gait under four dress conditions (wearing Type A_WET, Type A_DRY, and Type B_WET diapers and naked). Type B_WET had a higher bulk stress than Type A_WET, and Type A_DRY had lower stress than Type A _ WET. Our results indicate that the walk of toddlers when wearing a diaper differs from that when naked. This difference is due to the effect of the bulk of the diaper on the lower limb. A high bulk stress has a greater influence than that of a low bulk stress on joint dynamics and step width. Therefore, our findings suggest that wearing diapers with high bulk stress may inhibit the natural gait patterns of toddlers.

Effects of Repeated Oral Administration of Esaxerenone on the Pharmacokinetics of Midazolam in Healthy Japanese Males.

BACKGROUND AND OBJECTIVE: Esaxerenone showed the potential to inhibit and induce activity against cytochrome P450 (CYP) 3A in in vitro studies. We investigated whether repeated administration of 5 mg/day esaxerenone for 14 days influences the pharmacokinetics of midazolam, a sensitive CYP3A substrate, in healthy Japanese males. METHODS: This single-centre, open-label, single-sequence study had two administration periods: period 1: single oral dose of 2 mg midazolam (day 0); period 2: repeated oral doses of 5 mg/day esaxerenone for 14 days, with a single oral dose of 2 mg midazolam on day 14. Full pharmacokinetic profiles of midazolam and 1-hydroxymidazolam on days 0 and 14 and safety data were obtained. Primary pharmacokinetic endpoints for midazolam were area under the plasma concentration-time curve (AUC) from zero to time of the last measurable concentration (AUClast), AUC from zero to infinity (AUCinf), and peak plasma concentration (Cmax). RESULTS: The study included 28 male subjects. One subject was withdrawn because of a mild adverse event (increased hepatic enzyme levels) that resolved without intervention. Repeated administration of esaxerenone increased midazolam AUClast, AUCinf, and Cmax by about 1.2-fold (1.201, 1.201, and 1.224, respectively) compared with administration of midazolam alone. However, repeated administration of esaxerenone did not affect the elimination half-life of midazolam (2.86 versus 2.63 h with and without esaxerenone). There were no safety concerns associated with concomitant administration of esaxerenone and midazolam. CONCLUSIONS: Esaxerenone 5 mg/day had no clinically significant effect on midazolam pharmacokinetics and was not associated with any safety issues. Esaxerenone can be concomitantly administered with drugs of CYP3A substrates without dose adjustments. CLINICAL TRIAL REGISTRATION: JapiCTI-152832.

Pharmacokinetics, Safety, and Efficacy of Trastuzumab Deruxtecan with Concomitant Ritonavir or Itraconazole in Patients with HER2-Expressing Advanced Solid Tumors.

PURPOSE: To evaluate drug-drug interactions between the human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd; DS-8201a) and the OATP1B/CYP3A inhibitor ritonavir or the strong CYP3A inhibitor itraconazole. PATIENTS AND METHODS: Patients with HER2-expressing advanced solid tumors were enrolled in this phase I, open-label, single-sequence crossover study (NCT03383692) and received i.v. T-DXd 5.4 mg/kg every 3 weeks. Patients received ritonavir (cohort 1) or itraconazole (cohort 2) from day 17 of cycle 2 through the end of cycle 3. Primary endpoints were maximum serum concentration (C max) and partial area under the concentration-time curve from beginning of cycle through day 17 (AUC17d) for T-DXd and deruxtecan (DXd) with (cycle 3) and without (cycle 2) ritonavir or itraconazole treatment. RESULTS: Forty patients were enrolled (cohort 1, n = 17; cohort 2, n = 23). T-DXd C max was similar whether combined with ritonavir [cohort 1, cycle 3/cycle 2; 90% confidence interval (CI): 1.05 (0.98-1.13)] or itraconazole [cohort 2, 1.03 (0.96-1.09)]. T-DXd AUC17d increased from cycle 2 to 3; however, the cycle 3/cycle 2 ratio upper CI bound remained at ≤1.25 for both cohorts. For DXd (cycle 3/cycle 2), C max ratio was 0.99 (90% CI, 0.85-1.14) for cohort 1 and 1.04 (0.92-1.18) for cohort 2; AUC17d ratio was 1.22 (1.08-1.37) and 1.18 (1.11-1.25), respectively. The safety profile of T-DXd plus ritonavir or itraconazole was consistent with previous studies of T-DXd monotherapy. T-DXd demonstrated promising antitumor activity across HER2-expressing solid-tumor types. CONCLUSIONS: T-DXd was safely combined with ritonavir or itraconazole without clinically meaningful impact on T-DXd or DXd pharmacokinetics.

Efficacy and safety of esaxerenone (CS-3150) in Japanese patients with type 2 diabetes and macroalbuminuria: a multicenter, single-arm, open-label phase III study.

BACKGROUND: Esaxerenone has potential renoprotective effects and reduces the urinary albumin-to-creatinine ratio (UACR) in patients with diabetic kidney disease and overt nephropathy. We investigated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes (T2D) and macroalbuminuria (UACR ≥ 300 mg/g creatinine). METHODS: We conducted a multicenter, single-arm, open-label phase III study in 56 patients with T2D and UACR ≥ 300 mg/g creatinine with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and treated with a renin-angiotensin system inhibitor. Patients received esaxerenone for 28 weeks at 1.25 mg/day initially with titration to 2.5 mg/day based on serum potassium (K+) monitoring. Efficacy was evaluated as the change in UACR from baseline to week 28. Safety endpoints included adverse events (AEs), incidence of serum K+ increase, and change in eGFR from baseline. RESULTS: UACR decreased by 54.6% (95% CI 46.9%, 61.3%) on average from baseline (544.1 mg/g creatinine) to the end of treatment (246.8 mg/g creatinine); 51.8% of patients showed improvement to early nephropathy. AE incidence was 69.6%. Three patients (5.4%) had serum K+ levels ≥ 6.0 mEq/L or ≥ 5.5 mEq/L on two consecutive occasions. Hyperkalemia in two patients was transient and resolved during the treatment period. One patient discontinued following two consecutive serum K+ values ≥ 5.5 mEq/L. The maximum change from baseline in eGFR was - 8.3 mL/min/1.73 m2 at week 24. CONCLUSIONS: Esaxerenone reduced UACR in Japanese patients with T2D and UACR ≥ 300 mg/g creatinine; more than half experienced a transition from UACR ≥ 300 mg/g creatinine to UACR < 300 mg/g creatinine. CLINICAL TRIAL REGISTRATION: JapicCTI-173696.

Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial.

BACKGROUND: HER2 amplification has been identified in 2-3% of patients with colorectal cancer, although there are currently no approved HER2-targeted therapies for colorectal cancer. We aimed to study the antitumour activity and safety of trastuzumab deruxtecan (an antibody-drug conjugate of humanised anti-HER2 antibody with topoisomerase I inhibitor payloads) in patients with HER2-expressing metastatic colorectal cancer. METHODS: DESTINY-CRC01 is an open-label, phase 2 study that recruited patients from 25 clinics and hospitals in Italy, Japan, Spain, the UK, and the USA. Eligible patients had centrally confirmed HER2-expressing metastatic colorectal cancer that had progressed on two or more previous regimens (HER2-targeted therapies other than trastuzumab deruxtecan permitted), were aged 18 years or older (≥20 years in Japan), had an Eastern Cooperative Oncology Group score of 0 or 1, and had RAS and BRAFV600E wild-type tumours. Patients were enrolled into one of three cohorts by HER2 expression level: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC2+ and in-situ hybridisation [ISH]-positive), cohort B (IHC2+ and ISH-negative), or cohort C (IHC1+). Patients received 6·4 mg/kg trastuzumab deruxtecan intravenously every 3 weeks until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate in cohort A by independent central review which was assessed in the full analysis set and safety was assessed in the safety analysis set. Both the full analysis set and the safety analysis set included all patients who received one or more doses of trastuzumab deruxtecan. This ongoing trial is registered with ClinicalTrials.gov, number NCT03384940. FINDINGS: Between Feb 23, 2018, and July 3, 2019, 78 patients were enrolled in the study (53 in cohort A, seven in cohort B, and 18 in cohort C), all of whom received at least one dose of study drug. For the 53 (68%) patients with HER2-positive tumours (cohort A), a confirmed objective response was reported in 24 (45·3%, 95% CI 31·6-59·6) patients after a median follow-up of 27·1 weeks (IQR 19·3-40·1). Grade 3 or worse treatment-emergent adverse events that occurred in at least 10% of all participants were decreased neutrophil count (17 [22%] of 78) and anaemia (11 [14%]). Five patients (6%) had adjudicated interstitial lung disease or pneumonitis (two grade 2; one grade 3; two grade 5, the only treatment-related deaths). INTERPRETATION: Trastuzumab deruxtecan showed promising and durable activity in HER2-positive metastatic colorectal cancer refractory to standard treatment, with a safety profile consistent with that reported in previous trastuzumab deruxtecan trials. Interstitial lung disease and pneumonitis are important risks requiring careful monitoring and prompt intervention. FUNDING: Daiichi Sankyo.

Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction.

Renin-angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin-angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m2, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: -18.5/-8.8 mmHg; add-on therapy: -17.8/-8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K+ level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K+ levels were transient, and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism.

Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca2+ channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] -17.7 [-20.6, -14.7] and -9.5 [-11.7, -7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K+ increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.

Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A Post Hoc Analysis of the ESAX-HTN Study.

BACKGROUND: Nocturnal hypertension is an important phenotype of abnormal diurnal blood pressure (BP) variability and a known risk marker for target organ damage and cardiovascular events. This study aimed to assess the differential BP-lowering effects of esaxerenone vs. eplerenone on nocturnal BP in hypertensive patients with different nocturnal dipping patterns. METHODS: This was a post hoc analysis of the "Esaxerenone (CS-3150) Compared to Eplerenone in Patients with Essential Hypertension" study (NCT02890173), which was a phase 3, multicenter, randomized, controlled, double-blind, parallel-group clinical study conducted in Japan. Ambulatory BP monitoring data were collected. RESULTS: Patients (n = 1,001) were randomized to esaxerenone 2.5 mg/day (n = 331) or 5 mg/day (n = 338), or eplerenone 50 mg/day (n = 332). Reductions in nighttime systolic BP (95% confidence interval) were significantly greater with 2.5 and 5 mg/day esaxerenone vs. eplerenone (-2.6 [-5.0, -0.2] and -6.4 mm Hg [-8.8, -4.0], respectively). Esaxerenone significantly reduced nighttime BP from baseline compared with eplerenone in non-dippers with previously uncontrolled BP. In addition, esaxerenone did not markedly alter nighttime BP in extreme dipper patients. In the esaxerenone 5 mg/day group, esaxerenone-induced decreases in nighttime BP were greater than eplerenone-induced decreases in older patients. CONCLUSIONS: Esaxerenone may be an effective treatment option for nocturnal hypertension, especially in older patients and those with a non-dipper pattern of nocturnal BP.

Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN): Phase 3 Randomized Controlled Clinical Trial.

BACKGROUND AND OBJECTIVES: Diabetic kidney disease is an important complication of type 2 diabetes. In a phase 2b study, adding esaxerenone to renin-angiotensin system inhibitors dose dependently reduced the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and microalbuminuria. This 52-week phase 3 study further investigated the effects of esaxerenone on the urinary albumin-to-creatinine ratio in this patient group. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this multicenter, randomized, double-blind study, patients with type 2 diabetes and a urinary albumin-to-creatinine ratio of 45 to <300 mg/g creatinine treated with renin-angiotensin system inhibitors were randomized to esaxerenone or placebo for 52 weeks (n=455). Esaxerenone was initiated at 1.25 mg/d and titrated to 2.5 mg/d on the basis of serum potassium monitoring. The primary endpoint was the proportion of patients achieving urinary albumin-to-creatinine ratio remission (<30 mg/g creatinine and ≥30% reduction from baseline on two consecutive occasions). RESULTS: Overall, 49 (22%) and nine (4%) patients in the esaxerenone and placebo groups, respectively, achieved urinary albumin-to-creatinine ratio remission (absolute difference 18%; 95% confidence interval, 12% to 25%; P<0.001). The percent change in urinary albumin-to-creatinine ratio from baseline to end of treatment was significantly higher with esaxerenone versus placebo (-58% versus 8%; geometric least-squares mean ratio to placebo 0.38, 95% confidence interval, 0.33 to 0.44). There was a significant improvement with esaxerenone versus placebo in time to first remission (hazard ratio, 5.13; 95% confidence interval, 3.27 to 8.04) and time to first transition to urinary albumin-to-creatinine ratio ≥300 mg/g creatinine (hazard ratio, 0.23; 95% confidence interval, 0.11 to 0.48). More patients had a serum potassium level ≥6.0 or ≥5.5 mEq/L on two consecutive measurements in the esaxerenone group (20 [9%]) versus placebo (5 [2%]); these events were asymptomatic and resolved after dosage reduction or treatment discontinuation. CONCLUSIONS: Adding esaxerenone to existing renin-angiotensin system inhibitor therapy in patients with type 2 diabetes and microalbuminuria increased the likelihood of albuminuria returning to normal levels, and reduced progression of albuminuria to higher levels.

A Ruptured Blood Blister-Like Aneurysm Associated with Intraperitoneal Hemorrhage due to Segmental Arterial Mediolysis: A Case Report and Literature Review.

BACKGROUND: Segmental arterial mediolysis (SAM) is a rare non-atherosclerotic, noninflammatory vascular disease, characterized by mediolysis. We report an extremely rare case of subarachnoid hemorrhage (SAH) due to a ruptured blood blister-like aneurysm (BBA) of the internal carotid artery associated with SAM-related arteriopathy. CASE DESCRIPTION: We experienced a case of SAH followed by intraperitoneal hemorrhage that occurred 12 days after the SAH onset. SAH was caused by a ruptured BBA of the internal carotid artery, which was treated by trapping with high-flow bypass. Intraperitoneal hemorrhage was caused by a rupture of a posterior inferior pancreaticoduodenal artery (PIPDA) aneurysm, which induced hypovolemic shock resulting in death in spite of endovascular internal trapping. Postmortem pathologic examination revealed that the PIPDA pseudoaneurysm was due to SAM. CONCLUSIONS: We should pay attention to the association of SAM, which is a potentially life-threatening pathology when treating cerebral BBAs.

Double-Blind Randomized Phase 3 Study Comparing Esaxerenone (CS-3150) and Eplerenone in Patients With Essential Hypertension (ESAX-HTN Study).

Mineralocorticoid receptors (MRs) are implicated in the pathology of hypertension. MR blockers are recommended for the treatment of salt-sensitive or resistant hypertension. However, use of currently available MR blockers is limited by adverse events. This phase 3 multicenter, randomized, double-blind study compared the efficacy and safety of esaxerenone, a new selective nonsteroidal MR blocker, at 2.5 and 5 mg/day and eplerenone 50 mg/day in Japanese patients with essential hypertension. After a 4-week washout period, 1001 eligible adults with hypertension were randomized evenly to esaxerenone 2.5 or 5 mg/day or eplerenone 50 mg/day treatments, taken orally once daily for 12 weeks. Primary end points were changes in sitting systolic or diastolic blood pressure (BP) from baseline at the end of treatment. Esaxerenone 2.5 mg/day was noninferior to eplerenone for reductions in sitting and 24-hour BP. Reductions in BP with esaxerenone 5 mg/day were significantly greater than those with esaxerenone 2.5 mg/day. Changes in diurnal BP showed persistent 24-hour antihypertensive effects in all treatment groups. The proportions of patients achieving target sitting BP (<140/90 mm Hg) were 31.5%, 41.2%, and 27.5% with esaxerenone 2.5 and 5 mg/day and eplerenone 50 mg/day, respectively. Incidences of adverse events (all mild or moderate) were similar across treatment groups. These results indicate that esaxerenone is an effective and well-tolerated MR blocker in Japanese patients with essential hypertension, with BP-lowering activity at least equivalent to eplerenone. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT02890173.

Long-term phase 3 study of esaxerenone as mono or combination therapy with other antihypertensive drugs in patients with essential hypertension.

This study investigated the long-term antihypertensive effects of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker, alone or in combination with a calcium channel blocker (CCB) or a renin-angiotensin system (RAS) inhibitor, in Japanese patients with essential hypertension. Patients were treated with esaxerenone starting at 2.5 mg/day increasing to 5 mg/day if required to achieve blood pressure (BP) targets as a monotherapy or with a CCB or RAS inhibitor. After the first 12 weeks of treatment, an additional antihypertensive agent could be added if required to achieve the target BP; the total treatment period was 28 or 52 weeks. The primary endpoint was a change from baseline in sitting BP. Of the 368 enrolled patients, 245 received monotherapy, and 59 and 64, respectively, took a CCB or RAS inhibitor concurrently. Mean changes from baseline in sitting systolic/diastolic BP (95% confidence intervals) at weeks 12, 28 and 52 were -16.1 (-17.3, -14.9)/-7.7 (-8.4, -6.9), -18.9 (-20.2, -17.7)/-9.9 (-10.7, -9.2), and -23.1 (-25.0, -21.1)/-12.5 (-13.6, -11.3) mmHg, respectively (all P < 0.0001 vs baseline). Similar BP reductions at these weeks were observed between all patient subgroups stratified by age, and the observed decreases in 24-h ambulatory BP were consistent with the efficacy observed in sitting BP. Esaxerenone was also well-tolerated with a rate of hyperkalemia at 5.4% (serum potassium ≥5.5 mEq/L), indicating a good safety profile for treatment over the long-term or in combination with a CCB or RAS inhibitor. In conclusion, esaxerenone may be a promising treatment option for patients with hypertension.

Efficacy and safety of dosage-escalation of low-dosage esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes and albuminuria: a single-arm, open-label study.

The stimulation of mineralocorticoid receptors is linked to the development of hypertension and cardiovascular or renal damage in patients with diabetes, and the blockade of these receptors may be an effective treatment option. This open-label study with a 12-week treatment period assessed the antihypertensive (primary) and antialbuminuric (secondary) efficacy and safety of esaxerenone as an add-on therapy to a renin-angiotensin system inhibitor in hypertensive patients with type 2 diabetes and albuminuria (urinary albumin-creatinine ratio 30 to <1000 mg/g•Cr). Esaxerenone was administered over 12 weeks at a starting dosage of 1.25 mg/day, which was gradually titrated to 2.5 mg/day and 5 mg/day at weeks 4, 6, or 8 according to the dosage-escalation criteria based on serum K+ levels, the estimated glomerular filtration rate, and the likelihood/occurrence of hypotension. Of the 51 patients enrolled, 44 (86.3%) reached an esaxerenone dosage of 2.5 or 5 mg/day. The changes from the baseline in sitting systolic and diastolic blood pressures were -13.7 mmHg (p < 0.05) and -6.2 mmHg (p < 0.05), respectively. Significant decreases in blood pressure occurred regardless of age, baseline systolic blood pressure, glycated hemoglobin level, and estimated glomerular filtration rate. The urinary albumin-creatinine ratio decreased by 32.4% from the baseline (p < 0.05). Two consecutive serum K+ measurements ≥ 5.5 mEq/L occurred in one patient but resolved after dosage reduction. Esaxerenone showed antihypertensive and antialbuminuric effects and a low risk of hyperkalemia with dosage titration from 1.25 mg in Japanese hypertensive patients with type 2 diabetes and albuminuria receiving a renin-angiotensin system inhibitor.