A Phase 3 Study of Enarodustat (JTZ-951) in Japanese Hemodialysis Patients for Treatment of Anemia in Chronic Kidney Disease: SYMPHONY HD Study.

INTRODUCTION: Enarodustat (JTZ-951) is a new oral hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). We conducted a phase 3 study to compare the efficacy and safety of enarodustat with darbepoetin alfa (DA) in Japanese anemic patients with CKD receiving maintenance hemodialysis. METHODS: Subjects receiving maintenance hemodialysis were randomly assigned at a 1:1 ratio to receive oral enarodustat once daily or intravenous DA every week for 24 weeks with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within a target range (≥10.0 to <12.0 g/dL). The primary efficacy endpoint was difference in mean Hb level between arms during the evaluation period defined as weeks 20-24 (noninferiority margin: -1.0 g/dL). Intravenous iron preparations were prohibited during the screening period and during weeks 0-4. RESULTS: The mean Hb level of each arm during the evaluation period was 10.73 g/dL (95% confidence interval [CI]: 10.56, 10.91) in the enarodustat arm and 10.85 g/dL (95% CI: 10.72, 10.98) in the DA arm. The difference in the mean Hb level between arms was -0.12 g/dL (95% CI: -0.33, 0.10), confirming the noninferiority of enarodustat to DA. The mean Hb level of each arm was maintained within the target range during the treatment period. Increased total iron-binding capacity and serum iron and decreased hepcidin were observed through week 4 in the enarodustat arm albeit after switching from erythropoiesis-stimulating agents. No apparent safety concerns of enarodustat were observed compared with DA. DISCUSSION/CONCLUSION: Enarodustat was noninferior to DA for the treatment of anemia in CKD patients receiving maintenance hemodialysis and was generally well tolerated over 24 weeks.

A Phase 3 Study of Enarodustat in Anemic Patients with CKD not Requiring Dialysis: The SYMPHONY ND Study.

INTRODUCTION: Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that might be a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy (noninferiority to darbepoetin alfa [DA]) and safety of enarodustat in Japanese anemic patients with CKD not requiring dialysis. METHODS: Erythropoiesis-stimulating agent (ESA)-naïve patients and ESA-treated patients were randomized at a 1:1 ratio to receive enarodustat orally once daily or DA subcutaneously every 2 or 4 weeks for 24 weeks, respectively. Subjects in each arm had dose adjustments every 4 weeks to maintain their hemoglobin (Hb) level within the target range (10 to 12 g/dl). The primary endpoint was the difference in the mean Hb level between arms during the evaluation period defined as weeks 20 to 24 (noninferiority margin: -0.75 g/dl). RESULTS: The mean Hb level during the evaluation period in the enarodustat arm was 10.96 g/dl (95% confidence interval [CI]: 10.84 to 11.07 g/dl) with a difference of 0.09 g/dl (95% CI: -0.07 to 0.26 g/dl) between arms, establishing its noninferiority to DA. Nearly 90% of subjects in both arms maintained a mean Hb level within the target range. Compared with DA, enarodustat was associated with decreased hepcidin and ferritin, and increased total iron-binding capacity. There were no apparent differences in the incidence of adverse events between arms (65.4% [enarodustat], 82.6% [DA]). CONCLUSIONS: The efficacy of enarodustat was comparable to DA in anemic patients with CKD not requiring dialysis. No new safety concerns were identified compared with DA.

Catalytic Hydrolysis of Phosphate Monoester by Supramolecular Complexes Formed by the Self-Assembly of a Hydrophobic Bis(Zn2+-cyclen) Complex, Copper, and Barbital Units That Are Functionalized with Amino Acids in a Two-Phase Solvent System.

We previously reported on the preparation of supramolecular complexes by the 2:2:2 assembly of a dinuclear Zn2+-cyclen (cyclen = 1,4,7,10-tetraazacyclododecane) complex having a 2,2'-bipyridyl linker equipped with 0~2 long alkyl chains (Zn2L1~Zn2L3), 5,5-diethylbarbituric acid (Bar) derivatives, and a copper(II) ion (Cu2+) in aqueous solution and two-phase solvent systems and their phosphatase activities for the hydrolysis of mono(4-nitrophenyl) phosphate (MNP). These supermolecules contain Cu2(µ-OH)2 core that mimics the active site of alkaline phosphatase (AP), and one of the ethyl groups of the barbital moiety is located in close proximity to the Cu2(µ-OH)2 core. The generally accepted knowledge that the amino acids around the metal center in the active site of AP play important roles in its hydrolytic activity inspired us to modify the side chain of Bar with various functional groups in an attempt to mimic the active site of AP in the artificial system, especially in two-phase solvent system. In this paper, we report on the design and synthesis of new supramolecular complexes that are prepared by the combined use of bis(Zn2+-cyclen) complexes (Zn2L1, Zn2L2, and Zn2L3), Cu2+, and Bar derivatives containing amino acid residues. We present successful formation of these artificial AP mimics with respect to the kinetics of the MNP hydrolysis obeying Michaelis-Menten scheme in aqueous solution and a two-phase solvent system and to the mode of the product inhibition by inorganic phosphate.

Enarodustat, Conversion and Maintenance Therapy for Anemia in Hemodialysis Patients: A Randomized, Placebo-Controlled Phase 2b Trial Followed by Long-Term Trial.

BACKGROUND: Enarodustat (JTZ-951) is an orally available hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin levels in the treatment of anemia associated with chronic kidney disease (CKD). OBJECTIVE: A phase 2b study of enarodustat to assess the hemoglobin (Hb) response, safety, and maintenance dosage was conducted in Japanese anemic patients with hemodialysis-dependent CKD. METHODS: Subjects receiving a stable dose of an erythropoiesis-stimulating agent were randomized to receive once-daily enarodustat at a dose of 2, 4, or 6 mg or placebo in a double-blind manner for 6 weeks (Period 1) followed by 24-week open treatment with enarodustat, adjusted in the range of 2-8 mg to maintain Hb within a target range (10.0-12.0 g/dL; Period 2). RESULTS: Change in Hb from baseline increased with enarodustat dose in Period 1. In Period 2, the proportion of subjects who maintained their Hb level within the target range at the end of treatment was 65.1%. To maintain Hb levels within the target range over the course of Period 2, approximately 80% of subjects required 2 dose adjustments or fewer. Enarodustat decreased hepcidin and ferritin levels, increased total iron-binding capacity, and was generally well tolerated. CONCLUSIONS: Enarodustat corrected and maintained Hb levels in anemic patients with hemodialysis-dependent CKD. Phase 3 studies of enarodustat are currently ongoing.

Catalytic Hydrolysis of Phosphate Monoester by Supramolecular Phosphatases Formed from a Monoalkylated Dizinc(II) Complex, Cyclic Diimide Units, and Copper(II) in Two-Phase Solvent System.

Design and synthesis of enzyme mimic with programmed molecular interaction among several building blocks including metal complexes and metal chelators is of intellectual and practical significance. The preparation of artificial enzymes that mimic the natural enzymes such as hydrolases, phosphatases, etc. remains a great challenge in the field of supramolecular chemistry. Herein we report on the design and synthesis of asymmetric (nonsymmetric) supermolecules by the 2:2:2 self-assembly of an amphiphilic zinc(II)-cyclen complex containing a 2,2'-bipyridyl linker and one long alkyl chain (Zn2L3), barbital analogues, and Cu2+ as model compounds of an enzyme alkaline phosphatase that catalyzes the hydrolysis of phosphate monoesters such as mono(4-nitrophenyl)phosphate at neutral pH in two-phase solvent system (H2O/CHCl3) in pH 7.4 and 37 °C. Hydrolytic activity of these complexes was found to be catalytic, and their catalytic turnover numbers are 3-4. The mechanistic studies based on the UV/vis and emission spectra of the H2O and CHCl3 phases of the reaction mixtures suggest that the hydrophilicity/hydrophobicity balance of the supramolecular catalysts is an important factor for catalytic activity.

Supramolecular Complexes Formed by the Self-assembly of Hydrophobic Bis(Zn(2+)-cyclen) Complexes, Copper, and Di- or Triimide Units for the Hydrolysis of Phosphate Mono- and Diesters in Two-Phase Solvent Systems (Cyclen=1,4,7,10-Tetraazacyclododecane).

We previously reported on supramolecular complexes 4 and 5, formed by the 4 : 4 : 4 or 2 : 2 : 2 assembly of a dimeric zinc(II) complex (Zn2L(1)) having 2,2'-bipyridyl linker, dianion of cyanuric acid (CA) or 5,5-diethylbarbituric acid (Bar), and copper(II) ion (Cu(2+)) in an aqueous solution. The supermolecule 4 possesses Cu2(µ-OH)2 centers and catalyzes hydrolysis of phosphate monoester dianion, mono(4-nitrophenyl)phosphate (MNP), at neutral pH. In this manuscript, we report on design and synthesis of hydrophobic supermolecules 9 and 10 by 4 : 4 : 4 and 2 : 2 : 2 self-assembly of hydrophobic Zn2L(2) and Zn2L(3) containing long alkyl chains, CA or Bar, and Cu(2+) and their phosphatase activity for the hydrolysis of MNP and bis(4-nitrophenyl)phosphate (BNP) in two-phase solvent systems. We assumed that the Cu2(µ-OH)2 active sites of 9 and 10 would be more stable in organic solvent than in aqueous solution and that product inhibition of the supermolecules might be avoided by the release of HPO4(2-) into the aqueous layer. The findings indicate that 9 and 10 exhibit phosphatase activity in the two-phase solvent system, although catalytic turnover was not observed. Furthermore, the hydrolysis of BNP catalyzed by the hydrophobic 2 : 2 : 2 supermolecules in the two-phase solvent system is described.

Supramolecular phosphatases formed by the self-assembly of the bis(Zn²âº-cyclen) complex, copper(II), and barbital derivatives in water.

In our previous paper, we reported that a dimeric Zn(2+) complex with a 2,2'-bipyridyl linker (Zn2L(1)), cyanuric acid (CA), and a Cu(2+) ion automatically assemble in aqueous solution to form 4:4:4 complex 3, which selectively catalyzes the hydrolysis of mono(4-nitrophenyl)phosphate (MNP) at neutral pH. Herein, we report that the use of barbital (Bar) instead of CA for the self-assembly with Zn2L(1) and Cu(2+) induces 2:2:2 complexation of these components, and not the 4:4:4 complex, to form supramolecular complex 6 a, the structure and equilibrium characteristics of which were studied by analytical and physical measurements. The finding show that 6 a also accelerates the hydrolysis of MNP, similarly to 3. Moreover, inspired by the crystal structure of 6 a, we prepared barbital units that contain functional groups on their side chains in an attempt to produce supramolecular phosphatases that possess functional groups near the Cu2(µ-OH)2 catalytic core so as to mimic the catalytic center of alkaline phosphatase (AP).