Urece (dotinurad) / Fuji Yakuhin, Mochida, Fortress, Eisai - LARVOL DELTA

Changes in Uric Acid Levels and Effects on Renal Function After Switching From Febuxostat to Dotinurad in Patients With Chronic Kidney Disease: A Retrospective Study. (PubMed, Cureus) - "In CKD patients with hyperuricemia, the change from febuxostat to dotinurad did not cause a significant change in UA levels. The eGFR slope tended to slow with the change to dotinurad, although the difference was not statistically significant."

Journal • Retrospective data • Chronic Kidney Disease • Nephrology • Renal Disease

Efficacy and safety of dotinurad versus febuxostat for the treatment of gout: a randomised, multicentre, double-blind, phase 3 trial in China. (PubMed, Arthritis Rheumatol) - "Dotinurad 4 mg/day was superior to febuxostat 40 mg/day in achieving serum urate levels ≤6.0 mg/dL at week 24 and was well tolerated in Chinese patients with gout."

Journal • P3 data • Gout • Inflammatory Arthritis • Rheumatology

Molecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs. (PubMed, Cell Discov) - "Pharmacological inhibition of hURAT1 with drugs such as dotinurad, benzbromarone, lesinurad, and verinurad promotes urate excretion and alleviates gout symptoms. Complemented by mutagenesis and cell-based assays, these structures reveal the mechanisms of urate reabsorption and hURAT1 inhibition. Our findings elucidate the molecular basis of urate transport and anti-gout medication action and provide a structural framework for the rational design of next-generation therapies for hyperuricemia and gout."

Journal • Gout • Inflammatory Arthritis • Pain • Rheumatology

Comparative assessment of the effects of dotinurad and febuxostat on the renal function in chronic kidney disease patients with hyperuricemia. (PubMed, Sci Rep) - "No change was observed after febuxostat treatment (33.4 ± 19.6 to 34.1 ± 21.6 mL/min/1.73 m2). Renal function improved only with dotinurad, thus highlighting its renoprotective effects beyond the reduction of serum UA."

Clinical • Journal • Retrospective data • Chronic Kidney Disease • Nephrology • Renal Disease

DIANA-NEXT: Effect of Dotinurad in Hyperuricemia with Hypertension (clinicaltrials.gov) - P4 | N=360 | Recruiting | Sponsor: Saga University | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Gout • Hypertension • Inflammatory Arthritis • Rheumatology

DIANA-NEXT: Effect of Dotinurad in Hyperuricemia With Hypertension: a Randomized Study With Febuxostat (clinicaltrials.gov) - P4 | N=360 | Not yet recruiting | Sponsor: Saga University

New P4 trial • Cardiovascular • Gout • Hypertension • Inflammatory Arthritis • Rheumatology

Open Label PK, PD and DDI of Dotinurad and Allopurinol in Gout Patients with Hyperuricemia (clinicaltrials.gov) - P1/2 | N=20 | Completed | Sponsor: Urica Therapeutics Inc. | Recruiting ➔ Completed | Phase classification: P1b ➔ P1/2 | Trial completion date: Nov 2023 ➔ Jul 2024 | Trial primary completion date: Nov 2023 ➔ Jun 2024

Phase classification • Trial completion • Trial completion date • Trial primary completion date • Gout • Inflammatory Arthritis • Rheumatology

Optimizing Gout Treatment: A Comprehensive Review of Current and Emerging Uricosurics. (PubMed, Joint Bone Spine) - "ULTs include xanthine oxidoreductase inhibitors, uricosurics, less commonly used in the US but widely used in Europe and Asia, including benzbromarone, dotinurad, and probenecid (the only US Food and Drug Administration (FDA) approved uricosuric in the US), and uricases, including rasburicase and pegloticase (available only in the US). Any drug that increases renal excretion of uric acid, independently of the mechanism through which it exerts its effect, may be considered a uricosuric drug. This review discusses drugs that increase renal excretion of uric acid, either approved or in development, as well as off-label drugs with uricosuric properties."

Journal • Review • Gout • Immunology • Inflammation • Inflammatory Arthritis • Rheumatology

Transport mechanism and structural pharmacology of human urate transporter URAT1. (PubMed, Cell Res) - "To uncover the mechanisms of urate transport and drug inhibition, we determined cryo-EM structures of human URAT1 with urate, counter anion pyrazinoate, or anti-gout drugs of different chemotypes - lesinurad, verinurad, and dotinurad. In addition, we found that while all three drugs compete with substrates and halt the transport cycle, verinurad and dotinurad further hijack gating residues to achieve high potency. These insights advance our understanding of organic anion transport and provide a foundation for designing improved gout therapeutics."

Journal • Gout • Immunology • Inflammatory Arthritis • Pain • Rheumatology

Effect of Dotinurad on Serum Uric Acid Concentration in Chronic Kidney Disease Patients Treated with Febuxostat. (PubMed, J Nippon Med Sch) - "This study is the first to show the effect of combining dotinurad with febuxostat in lowering sUA levels in G3 and G4 patients. Additional research is required in order to clarify the pharmacological mechanisms of dotinurad in patients with CKD."

Biomarker • Journal • Retrospective data • Chronic Kidney Disease • Nephrology • Renal Disease

A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PHASE 3 STUDY COMPARING EFFICACY OF DOTINURAD AND FEBUXOSTAT FOR THE TREATMENT OF GOUT IN CHINESE SUBJECTS (EULAR 2024) - P3 | "Dotinurad 4 mg demonstrated superiority to febuxostat 40 mg in lowering SUA and dotinurad 2 mg was non-inferior to febuxostat 40mg in Chinese subjects with gout. Dotinurad was well tolerated."

Clinical • P3 data • Gout • Infectious Disease • Inflammatory Arthritis • Novel Coronavirus Disease • Rheumatology

Safety and Efficacy of Dotinurad on Uric Acid in Patients With Chronic Kidney Disease With Estimated Glomerular Filtration Rate Below 25 mL/Min/1.73 m². (PubMed, Cureus) - "Additionally, no serious adverse effects were identified in any of the patients throughout the observation period. Conclusion Although the sample size in this study was small, our findings demonstrate the efficacy of dotinurad in individuals with advanced CKD who have an eGFR lower than 25 mL/min/1.73 m2."

Journal • Chronic Kidney Disease • Nephrology • Renal Disease

Unique Binding Sites of Uricosuric Agent Dotinurad for Selective Inhibition of Renal Uric Acid Reabsorptive Transporter URAT1. (PubMed, J Pharmacol Exp Ther) - "Mutations in these residues reduce affinity of dotinurad for URAT1, confirming their role in conferring selective inhibition. Additionally, the interaction between dotinurad and URAT1 involving H142 was found to mediate hydrogen bonding."

Journal

Dotinurad restores exacerbated kidney dysfunction in hyperuricemic patients with chronic kidney disease. (PubMed, BMC Nephrol) - "Dotinurad administration to patients with CKD and HUA appears to be beneficial in restoring kidney function. Dotinurad may represent a potential medication for the prevention of kidney function decline caused by HUA."

Journal • Chronic Kidney Disease • Nephrology • Renal Disease

A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease. (PubMed, Cells) - "OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • ABCG2

Pipeline Therapies for Gout. (PubMed, Curr Rheumatol Rep) - "Dotinurad may function in the setting of decreased renal function. Arhalofenate has anti-URAT-1 activity and may also blunt gout flares. A new xanthine oxidase inhibitor (XOI), tigulixostat, is under study...Dapansutrile, an oral agent under investigation, inhibits activation of the NLRP3 inflammasome and may be an effective anti-inflammatory. New treatments for gout that are under study may work in the setting of comorbidities, simplify management, utilize new mechanisms, or have reduced side effects."

Journal • Review • Gout • Inflammatory Arthritis • Nephrology • Renal Calculi • Renal Disease • Rheumatology • IL1B • NLRP3

Dotinurad, a Potent and Selective Uricosuric Agent, Exhibited Promising Pharmacokinetics and Pharmacodynamic Profiles to Significantly Reduce Serum Urate Levels Following Once Daily Dosing in Healthy U.S. Subjects in a Phase 1 Clinical Trial (ACR Convergence 2023) - "Following 4 consecutive once-daily treatments, dotinurad has exhibited a pharmacokinetic profile, in western healthy subjects, comparable to that from Japanese healthy men. All tested doses of dotinurad (1, 2, 4 & 8 mg QD) significantly reduced serum urate levels. These results support the potential application of dotinurad as a once-daily treatment for hyperuricemia in western population."

Clinical • P1 data • PK/PD data • Cardiovascular • Gout • Inflammatory Arthritis • Rheumatology

The Efficacy and Safety of Dotinurad on Uric Acid and Renal Function in Patients with Hyperuricemia and Advanced Chronic Kidney Disease: A Single Center, Retrospective Analysis. (PubMed, Drug Des Devel Ther) - "With the 12-month dotinurad treatment, the annual change in the patients' eGFR was significantly improved from -6.0 ± 12.9 mL/min/1.73 m/year to -0.9 ± 4.6 mL/min/1.73 m/year (p<0.05), but there was no change in the control group. Dotinurad can decrease UA levels and might attenuate renal function decline in individuals with hyperuricemia and advanced CKD."

Journal • Metastases • Retrospective data • Chronic Kidney Disease • Dyslipidemia • Nephrology • Renal Disease

Systematic review and model-based analysis to identify whether renal safety risks of URAT1 inhibitors are fully determined by uric acid-lowering efficacies. (PubMed, Semin Arthritis Rheum) - "Uric acid-lowering efficacy is not an independent factor for the renal safety risk of different URAT1 inhibitors, and structural differences could be responsible for the difference. The adverse renal effects of URAT1 inhibitors are dose-dependent, and the combination with high doses of XOIs can significantly reduce the renal safety risk by reducing uric acid excretion by the kidneys."

Journal • Review

Efficacy of dotinurad in patients with severe renal dysfunction. (PubMed, Clin Exp Nephrol) - "Dotinurad may have UA-lowering effects and the potential to improve kidney function in patients with severe renal dysfunction."

Journal • Chronic Kidney Disease • Nephrology • Renal Disease

Open Label PK, PD and DDI of Dotinurad and Allopurinol in Gout Patients With Hyperuricemia (clinicaltrials.gov) - P1b | N=20 | Recruiting | Sponsor: Urica Therapeutics Inc.

New P1 trial • Gout • Inflammatory Arthritis • Rheumatology

URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease. (PubMed, iScience) - "Intriguingly, among various factors related to the pathophysiology of diet-induced obesity, palmitic acid significantly increased URAT1 expression in NRCMs and subsequently induced apoptosis, oxidative stress, and inflammatory responses via MAPK pathway, all of which were reduced by dotinurad. These results indicate that URAT1 is a potential therapeutic target for metabolic heart disease."

Journal • Cardiovascular • Fibrosis • Genetic Disorders • Heart Failure • Immunology • Inflammation • Obesity

Potentiation of the Uricosuric Effect of Dotinurad by Trans-Inhibition of the Uric Acid Reabsorptive Transporter URAT1. (PubMed, Drug Metab Dispos) - "Probenecid and benzbromarone have been used as uricosuric agents, while dotinurad was recently approved in Japan. Trans-inhibition was due to the attenuation of monocarboxylates efflux via URAT1, which is a driving force for URAT1-mediated exchange transport of uric acid. Overall, this is the first study to experimentally demonstrate trans-inhibition mechanism of URAT1."

Journal

Inhibition of the uric acid efflux transporter ABCG2 enhances stimulating effect of soluble uric acid on IL-1β production in murine macrophage-like J774.1 cells. (PubMed, Hypertens Res) - "An ABCG2 inhibitor, febuxostat, but not a urate reabsorption inhibitor, dotinurad, enhanced IL-1β production in cells pretreated with soluble UA. In conclusion, genetic and pharmacological inhibition of ABCG2 enhanced IL-1β production especially under hyperuricemic conditions by increasing intracellularly accumulated soluble UA that activates the NLRP3 inflammasome and pro-IL-1β transcription in macrophage-like J774.1 cells."

Journal • Preclinical • ABCG2 • IL1B • NLRP3

Changes in Urinary Uric Acid Concentration after Dotinurad Administration to Patients with Hyperuricemia: A Post Hoc Analysis of Two Clinical Trials in Japan. (PubMed, Clin Pharmacol Drug Dev) - "An inverse correlation was observed between urine volume and urinary uric acid concentration. This study highlights the significance of adequately managing urinary uric acid concentrations by increasing urine volume and alkalinizing urine to prevent uric acid crystallization during dotinurad administration."

Journal • Retrospective data • Gout • Inflammatory Arthritis • Rheumatology