Enaroy (enarodustat) / Japan Tobacco, JW Pharma, Shenzhen Salubris - LARVOL DELTA

Lead Generation for a HIF Prolyl Hydroxylase Inhibitor: Discovery of (7-Hydroxy-[1,2,4]triazolo[1,5‑a]pyridine-8-carbonyl)glycine as a Lead Compound of Enarodustat. (PubMed, ACS Med Chem Lett) - "We successfully identified compound 21 bearing a [1,2,4]-triazolo-[4,3-a]-pyridine core as a lead compound. Structures of enarodustat and compound 21 differed only by the presence or absence of a phenethyl group, implying that the identification of a high-quality lead compound led to our success."

Journal • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Derivatives of the Clinically Used HIF Prolyl Hydroxylase Inhibitor Desidustat Are Efficient Inhibitors of Human γ-Butyrobetaine Hydroxylase. (PubMed, J Med Chem) - "We report that the clinically used hypoxia-inducible factor-α prolyl residue hydroxylase (PHD) inhibitors Desidustat, Enarodustat, and Vadadustat efficiently inhibit isolated recombinant BBOX, suggesting that BBOX inhibition by clinically used PHD inhibitors should be considered as a possible off-target effect. Structure-activity relationship studies on the Desidustat scaffold enabled development of potent BBOX inhibitors that manifest high levels of selectivity for BBOX inhibition over representative human 2OG oxygenases, including PHD2. The Desidustat derivatives will help to enable investigations into the biological roles of l-carnitine and the therapeutic potential of BBOX inhibition."

Journal • Cardiovascular

Pharmacokinetics, Pharmacodynamics, and Safety Evaluation of the Novel HIF-PH Inhibitor Enarodustat: An Open-Label Phase I Study in Healthy Chinese Participants. (PubMed, Clin Drug Investig) - "SAL-0951 was safe and well tolerated in healthy Chinese participants and had a linear pharmacokinetic profile. We found no ethnic differences in the pharmacokinetic characteristics of the drug between Chinese and Japanese populations."

Journal • P1 data • PK/PD data

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors for Anemia in Non-Dialysis Dependent Chronic Kidney Disease: Systematic Review and Meta-Analysis of Randomized Controlled Trials. (PubMed, Indian J Nephrol) - "The studies included roxadustat (n = 2), daprodustat (n = 3), molidustat (n = 3), vadadustat (n = 2), enarodustat (n = 1), and desidustat (n = 1). Broadly, HIF-PHI molecules exhibited little difference when compared to other alternatives like erythropoietin stimulating agents (ESAs), but the evidence is not of high certainty. Our meta-analysis provides evidence on the use of HIF-PHIs as an alternative to ESAs for anemia in NDD-CKDs."

Journal • Retrospective data • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors for Anemia in Dialysis-Dependent Chronic Kidney Disease: Systematic Review and Meta-Analysis of Randomized Controlled Trials. (PubMed, Indian J Nephrol) - "The studies included roxadustat (n = 9), daprodustat (n = 5), vadadustat (n = 2), molidustat (n = 2), enarodustat (n = 1), and desidustat (n = 1). Roxadustat increased treatment-emergent adverse events up to 6-52 weeks as compared to ESAs [OR: 1.45 (95% CI 1.08-1.96); p = 0.01; six studies; 1715 participants; moderate certainty evidence]. The study provided evidence on the use of HIF-PHIs for treating renal anemia in DD-CKD patients as an alternative to ESAs."

Journal • Retrospective data • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Enarodustat for the Treatment of Anemia in Chinese Patients with Non-Dialysis Chronic Kidney Disease: A Phase 3 Trial. (PubMed, Kidney Dis (Basel)) - "Its once-daily oral administration offers convenience that may enhance the adherence. Enarodustat shows the potential as a promising therapy for anemic patients with ND-CKD."

Journal • P3 data • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

EPO-Mimetic Peptide Pegmolesatide Therapy for Pure Red Cell Aplasia in a Patient with Non-dialysis-dependent Type 1 Diabetic Nephropathy: A Case Report. (PubMed, Kidney Med) - "Enarodustat and roxadustat were administered successively after discontinuation of EPO, but anemia did not improve, and the patient was maintained with weekly blood transfusions. Subsequently, the EPO-mimetic peptide pegmolesatide was administered, and the patient's hemoglobin started to increase after 1 week and increased from 50 g/L to 92 g/L over approximately 3 months. Based on these findings, we speculate that pegmolesatide can provide a safe, effective, and convenient therapeutic strategy for PRCA in Chinese patients with chronic kidney disease."

Journal • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Hematological Disorders • Nephrology • Renal Disease • Type 1 Diabetes Mellitus

Bioanalysis, Analysis, Chemistry, and Pharmacological Aspects of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors. (PubMed, Curr Top Med Chem) - "The development of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors (HIFPHIs), such as Roxadustat (ROX), Enarodustat (ENA), Desidustat (DES), Vadadustat (VAD), Molidustat (MOL), and Daprodustat (DAP), has significant effects on anemia in chronic kidney disease. Research indicates that most studies concentrate on hyphenated methodologies for drug estimation in various biological fluids. Consequently, this study assesses the biological efficacy of HIF-PHIs and elucidates the analytical methodologies currently employed for measurement across various matrices."

Journal • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

CANNON: Correction of Anemia with Enarodustat in Non-dialysis Dependent Chronic Kidney Disease (clinicaltrials.gov) - P4 | N=1670 | Not yet recruiting | Sponsor: Shanghai Zhongshan Hospital

New P4 trial • Anemia • Chronic Kidney Disease • Congestive Heart Failure • Hematological Disorders • Nephrology • Renal Disease

SAL-0951 in the Treatment of Chemotherapy-induced Anemia in Patients With Non-myeloid Malignancies (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Shenzhen Salubris Pharmaceuticals Co., Ltd.

New P2 trial • Anemia • Chemotherapy-Induced Anemia • Hematological Disorders • Oncology

Efficacy and Safety Study of SAL-0951 in the Treatment of Renal Anemia in Patients Receiving Peritoneal Dialysis (clinicaltrials.gov) - P3 | N=37 | Completed | Sponsor: Shenzhen Salubris Pharmaceuticals Co., Ltd.

New P3 trial • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Study of SAL-0951 Compared to Recombinant Human Erythropoietin in Anemic Patients Receiving Maintenance Hemodialysis (clinicaltrials.gov) - P3 | N=100 | Completed | Sponsor: Shenzhen Salubris Pharmaceuticals Co., Ltd.

New P3 trial • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Metabolomic Insights into Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors' Kidney Protection in Contrast-Induced Nephropathy (KIDNEY WEEK 2024) - "This study has clarified the biochemical changes from contrast medium and enarodustat's modulation. Enarodustat appeared to promote a metabolic shift aiding renal recovery post-CIN. Elevated metabolites related to energy and repair in Nx-E suggested enhanced AKI protection."

Acute Kidney Injury • Nephrology • Renal Disease • HIF1A

Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat. (PubMed, ChemMedChem) - "We obtained crystal structures of Desidustat and Enarodustat in complex with the human 2OG oxygenase factor inhibiting hypoxia-inducible factor-α (FIH), which, together with modelling studies, inform on the binding modes of Desidustat and Enarodustat to active site Fe(II) in 2OG oxygenases, including PHD1-3. The results will help in the design of selective inhibitors of both the PHDs and other 2OG oxygenases, which are of medicinal interest due to their involvement inter alia in metabolic regulation, epigenetic signalling, DNA-damage repair, and agrochemical resistance."

Journal • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease • Targeted Protein Degradation

A national, multicenter, prospective study of the efficacy and safety of enarodustat in anemic patients with CKD not requiring dialysis (ChiCTR) - P=N/A | N=160 | Recruiting | Sponsor: The First Affiliated Hospital of Wenzhou Medical University; The First Affiliated Hospital of Wenzhou Medical University

New trial • Anemia • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Hypertension • Renal Disease

Changes in Iron Markers and D-dimer Levels during Enarodustat Treatment Depends on Different Iron Prescription Patterns in Hemodialysis Patients (ERA-EDTA 2024) - "We divided the subjects into three groups according to practice patterns of iron administration: subjects who did not receive iron at all during the enarodustat administration period (Non-Iron Group), subjects who received intravenous iron at least once (IV Iron Group), and subjects who continuously received oral iron-containing preparations including ferric citrate (Oral Iron Group). These findings suggest the superiority of continuous oral iron supplementation over intermittent IV iron supplementation or no iron supplementation during HIF-PH inhibitor administration in terms of preventing thrombosis through maintaining TSAT levels. The association between iron- related parameters and the occurrence of thrombosis needs to be analyzed."

Clinical • Anemia • Cardiovascular • Hematological Disorders • Renal Disease

The comparison of four hypoxia-inducible factor prolyl hydroxylase inhibitors on drug potency and cost for treatment in patients with renal anemia. (PubMed, Clin Exp Nephrol) - "The difference in dose escalation for anemia treatment among HIF-PHIs is due to differences in drug potency, where the HPI significantly differs among HIF-PHIs. The disparity between the HPI and the cost of the initial dose accounts for the variance in the daily costs of renal anemia treatment among HIF-PHIs."

Journal • Anemia • Hematological Disorders

Consensus commentary and position of the Italian Society of Nephrology on KDIGO controversies conference on novel anemia therapies in chronic kidney disease. (PubMed, J Nephrol) - "This class of drugs stimulates endogenous erythropoietin production and, at the same time, improves iron absorption and mobilization of iron stores (less evident with daprodustat, vadadustat and enarodustat). Kidney Disease: Improving Global Outcomes (KDIGO) recently reported the conclusions of the Controversies Conference on HIF-PHIs held in 2021. The goal of the present position paper endorsed by the Italian Society of Nephrology is to better adapt the conclusions of the latest KDIGO Conference on HIF-PHIs to the Italian context by reviewing the efficacy and safety of HIF-PHIs as well as their use in subpopulations of interest as emerged from more recent publications not discussed during the KDIGO Conference."

Journal • Anemia • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Nephrology • Oncology • Renal Disease

The drug-specific properties of hypoxia-inducible factor-prolyl hydroxylase inhibitors in mice reveal a significant contribution of the kidney compared to the liver to erythropoietin induction. (PubMed, Life Sci) - "Renal EPO induction is the major target of HIF-PH inhibitors for their therapeutic effects on erythropoiesis. Additionally, the drug-specific properties of HIF-PH inhibitors in EPO induction and iron metabolism have been shown in mice, providing useful information for selecting the proper HIF-PH inhibitor for each renal anemia patient."

Journal • Preclinical • Hematological Disorders • Nephrology • Renal Disease • EPO • ERFE

Low molecular weight acids and OATP1B mediated hepatic clearance: In vitro and in vivo evaluation using novel hypoxia-inducible factor prolyl hydroxylase inhibitors (Dustats). (PubMed, Drug Metab Dispos) - "Five acid dustats, namely daprodustat, desidustat, enarodustat, roxadustat and vadadustat, showed specific transport by OATP1B1/1B3 in transporter-transfected HEK293 cells...Hepatic clearance (non-renal) was about 4-fold (vadadustat) to >11-fod (daprodustat and roxadustat) higher in control group compared to rifampin-treated subjects...Significant active uptake mechanisms are not apparent for the neutral compound, molidustat. Characterization of uptake mechanisms is therefore important in predicting human pharmacokinetics and evaluating drug-drug interactions for low MW acids."

Journal • Preclinical • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Untargeted Detection of HIF Stabilizers in Doping Samples: Activity-Based Screening with a Stable In Vitro Bioassay. (PubMed, Anal Chem) - "Improved pharmacological characterization was established by the stable cell-based formats, and broad specificity was demonstrated by pharmacologically characterizing a diverse set of HIF stabilizers (including enarodustat, IOX2, IOX4, MK-8617, JNJ-42041935). In a practical context, a urinary limit of detection of 1.15 μg/mL (95% detection rate) was determined, confirming the matrix-dependent detectability of roxadustat in urine. Pending optimization of a universal sample preparation strategy and/or a methodology to correct for the matrix effects, this untargeted approach may serve as a complementing method in antidoping control, as theoretically, it would be capable of detecting any unknown substance with HIF stabilizing activity."

Journal • Preclinical • HIF1A

New Therapeutic Strategies in the Treatment of CKD Anemia: Hypoxia-Induced Factor Prolyl-Hydroxylase Inhibitors (PubMed, G Ital Nefrol) - "The drugs currently produced are roxadustat, daprodustat, vadadustat, molidustat, desidustat, and enarodustat; among these only roxadustat is currently approved and usable in Italy. The possibility of oral intake, pleiotropic activity on martial and lipidic metabolism, and the non-inferiority compared to erythropoietins make these drugs a valid alternative to the treatment of anemia associated with chronic kidney disease in the nephrologist practice."

Journal • Anemia • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Effect of the Phosphate Binder Sevelamer Carbonate on the Bioavailability of Enarodustat, an Oral Erythropoiesis Stimulating Agent. (PubMed, Clin Pharmacol Drug Dev) - "However, the interaction was substantially mitigated by staggering the administration of enarodustat and sevelamer carbonate. Administration of 4 single oral doses of enarodustat 25 mg, with or without sevelamer carbonate, were safe and well tolerated in this study."

Journal • Chronic Kidney Disease • Hematological Disorders • Metabolic Disorders • Nephrology • Renal Disease

A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Enarodustat for the Treatment of Renal Anemia in Chinese Non-Dialysis CKD Patients (KIDNEY WEEK 2023) - P3 | "Enarodustat was more effective in treating anemia in ESA-Naïve Chinese ND-CKD patients than placebo. Meanwhile, it had a similar safety profile with the placebo."

Clinical • Late-breaking abstract • P3 data • Anemia • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease

Hypoxia-Inducible Factor-Prolyl Hydroxylase (HIF-PHD) Inhibitor Accelerates Liver Cyst Growth in Autosomal Dominant Polycystic Kidney Disease (KIDNEY WEEK 2023) - "Both cystic and non-cystic mice were randomly assigned to vehicle-only and enarodustat-treated groups (non-Cystic (CT), non-Cystic (Ena), Cystic (CT) and Cystic (Ena) group)... HIF-PHD inhibitor accelerated liver cyst formation via proliferation of cyst lining cells by activating the MAPK pathway and mTOR pathway."

Autosomal Dominant Polycystic Kidney Disease • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Nephrology • Polycystic Kidney Disease • Renal Disease • PCNA • PKD1 • PRKD1