Safety, Tolerability, and Pharmacokinetics of Valemetostat Tablets and the Effect of Food on Valemetostat Pharmacokinetics in Healthy Subjects: Two Phase 1 Studies.

Valemetostat is an oral, selective inhibitor of enhancer of zeste homolog-2 (EZH2) and EZH1. In a first-in-human phase-1 trial, valemetostat capsules were well tolerated and clinically active in patients with relapsed/refractory non-Hodgkin lymphoma. Subsequently, a film-coated tablet formulation was developed for future clinical trials and commercialization. We report outcomes from 2 phase 1 trials in healthy Japanese participants, assessing the safety, tolerability, and pharmacokinetics (PK) of valemetostat tablets at single ascending doses (50, 100, and 200-mg), the relative bioavailability between capsules and tablets, and the effect of food (high-fat or low-fat meals) on the PK of valemetostat tablets. In the ascending-dose study, valemetostat maximum plasma concentration (Cmax ) and area under the concentration-time curve (AUC) increased dose-proportionally. Valemetostat plasma PK parameters were similar between the capsule and tablet formulations following a single 200-mg dose. Administration of valemetostat, 200 mg after a meal, was associated with 50%-60% lower Cmax , 30%-50% lower AUC, and a median Tmax delay of 2.5-3 hours relative to fasted administration. Valemetostat was well tolerated in healthy subjects; treatment-emergent adverse events were mild (grade 1) in severity. Based on these trials, the tablet formulation of valemetostat is suitable for use in subsequent clinical trials and should be administered under fasted conditions to avoid a negative food effect.

Effect of itraconazole and fluconazole on the pharmacokinetics of valemetostat: An open-label, phase I study in healthy subjects.

Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 under investigation for the treatment of cancer, including non-Hodgkin's lymphomas and solid tumors. Itraconazole and fluconazole are antifungal medications often used as typical inhibitors of cytochrome P450 3A (CYP3A [itraconazole and fluconazole]) and P-glycoprotein (P-gp [itraconazole]) in drug-drug interaction studies. Valemetostat is a substrate of CYP3A and P-gp in vitro. This phase I, open-label, single-sequence crossover study (JapicCTI-183902) assessed the pharmacokinetics (PK) of valemetostat when co-administered with itraconazole (a strong CYP3A inhibitor and P-gp inhibitor) or fluconazole (a moderate CYP3A inhibitor) in healthy Japanese male participants 20-45 years of age. Participants were equally allocated to receive two doses of valemetostat 25 mg, once alone and once with either itraconazole or fluconazole (400-mg induction and 200-mg once daily maintenance). Valemetostat PK parameters with versus without itraconazole or fluconazole were compared using analysis of variance models. Overall, 32 participants were enrolled. Co-administration with itraconazole increased valemetostat peak concentration (Cmax ) by 2.9-fold and area under the plasma concentration-time curve extrapolated to infinity (AUCinf ) by 4.2-fold compared with valemetostat alone. When co-administered with fluconazole, the Cmax and AUCinf of valemetostat were each increased by 1.6-fold. No treatment-related or grade ≥3 adverse events were reported. Appropriate valemetostat dose reductions are warranted when used concomitantly with strong CYP3A and P-gp dual inhibitors.

Efficacy and Safety of Prasugrel vs Clopidogrel in Thrombotic Stroke Patients With Risk Factors for Ischemic Stroke Recurrence: A Double-blind, Phase III Study (PRASTRO-III).

AIM: To examine the efficacy and safety of prasugrel vs clopidogrel in thrombotic stroke patients at risk of ischemic stroke. METHODS: This multicenter, active-controlled, randomized, double-blind, double-dummy, parallel group study enrolled thrombotic stroke patients aged ≥ 50 years at risk of ischemic stroke. Patients received prasugrel (3.75 mg/day) or clopidogrel (75 or 50 mg/day) for 24-48 weeks; other antiplatelet drugs were prohibited. The primary efficacy endpoint was the composite incidence of ischemic stroke, myocardial infarction (MI), and death from other vascular causes from the start to 1 day after treatment completion or discontinuation. Secondary efficacy endpoints included the incidences of ischemic stroke, MI, death from other vascular causes, ischemic stroke and transient ischemic attack, and stroke. Safety endpoints included bleeding events and adverse events (AEs). RESULTS: In the prasugrel (N=118) and clopidogrel (N=112; all received 75 mg) groups, the primary efficacy endpoint composite incidence (95% confidence interval) was 6.8% (3.0%-12.9%) and 7.1% (3.1%-13.6%), respectively. The risk ratio (prasugrel/clopidogrel) was 0.949 (0.369-2.443). Secondary efficacy endpoints followed a similar trend. The combined incidences of life-threatening, major, and clinically relevant bleeding were 5.0% and 3.5% in the prasugrel and clopidogrel groups, respectively. The incidences of all bleeding events and AEs were 19.2% and 24.6% and 76.7% and 82.5% in the prasugrel and clopidogrel groups, respectively. No serious AEs were causally related to prasugrel. CONCLUSIONS: We observed a risk reduction of 5% with prasugrel vs clopidogrel, indicating comparable efficacy. There were no major safety issues for prasugrel.

Antihypertensive Effect of Long-Term Monotherapy with Esaxerenone in Patients with Essential Hypertension: Relationship Between Baseline Urinary Sodium Excretion and Its Antihypertensive Effect.

INTRODUCTION: The blood pressure (BP) control mechanism for mineralocorticoid receptor blockers is unclear, and analysis of their use as a single agent in the clinical setting is required to resolve this uncertainty. There is a paucity of data on esaxerenone monotherapy assessing its long-term antihypertensive effect and urinary biomarkers. METHODS: This post hoc exploratory substudy of a long-term phase 3 study evaluated the effect of esaxerenone monotherapy (2.5 or 5 mg/day) in treatment-naïve patients who continued the therapy during the 52-week study period (n = 25). In addition to blood biomarkers, urinary biomarkers were also assessed in 24-h urine collection samples. RESULTS: Esaxerenone monotherapy was associated with consistent reductions in systolic/diastolic BP in the substudy population (- 23.5/- 13.1 mmHg at week 52, p < 0.001 vs baseline). Plasma aldosterone concentrations and plasma renin activity significantly increased during esaxerenone monotherapy at all time points. On the basis of the observations that both urine volume and urinary sodium excretion also decreased up to the end of the study, and were significantly lower at 12 weeks, patients were further categorized into higher/lower urinary sodium excretion subgroups according to whether their baseline values were above or below the median. In the group with higher baseline urinary sodium excretion, esaxerenone exhibited a significantly greater decrease in systolic/diastolic BP compared to the lower baseline group. CONCLUSION: Esaxerenone exhibited sustained and stable antihypertensive activity even when administered as a single agent for 52 weeks in patients with essential hypertension. The additional urinary biomarker analysis suggests that the BP-lowering effects of esaxerenone may be partly exerted via mechanisms related to salt and water retention, and that the effect is particularly pronounced in patients with hypertension and higher baseline urinary sodium excretion, which may reflect a state of excessive salt intake. TRIAL REGISTRATION: NCT02722265.

Bioequivalence of Esaxerenone Conventional Tablet and Orally Disintegrating Tablet: Two Single-Dose Crossover Studies in Healthy Japanese Men.

We assessed the bioequivalence of a single dose of 5-mg of esaxerenone administered as an orally disintegrating tablet (ODT) with the conventional oral tablet in healthy Japanese men. This single-center, open-label, randomized, two-drug, two-stage crossover, single-dose study was conducted in two parts. In study 1, both formulations were taken with water. In study 2, only the ODT formulation was taken without water. The primary outcome was the evaluation of bioequivalence of the ODT and conventional tablet using the pharmacokinetic (PK) parameters maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve to the last quantifiable time (AUClast ). Plasma concentrations were measured using a validated liquid chromatography/mass spectrometry method and PK parameters were calculated by noncompartmental analysis. The ratios of the geometric least-squares mean (2-sided 90% confidence intervals [90%CIs]) for ODT with (study 1) and without (study 2) water to the conventional tablet were 1.03 (1.00-1.07) and 1.01 (0.96-1.06) for Cmax and 1.03 (1.00-1.07) and 0.96 (0.94-0.98) for AUClast , respectively. The 90%CIs fell within the predefined bioequivalence range of 0.80-1.25. Treatment-emergent adverse events were similar between both formulations. In conclusion, esaxerenone 5-mg ODT taken with or without water was bioequivalent to a single 5-mg conventional oral tablet.