verinurad (RDEA3170) / AstraZeneca - LARVOL DELTA

Anti-inflammatory Treatment For Heart Failure With Reduced And Preserved Ejection Fraction: A Meta‑Analysis Of Randomized Controlled Trials (HFSA 2025) - "The anti-inflammatory treatment in the RCTs included colchicine, verinurad, mitiperstat, and anakinra. The anti-inflammatory treatment had a tendency toward improved clinical outcomes compared with placebo, which was consistent in the subgroup analysis of HFrEF and HFpEF. Further research is warranted to assess the efficacy of anti-inflammatory treatment for patients with heart failure."

Retrospective data • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation

Impact of Urate-Lowering Agents on Renal Outcomes in Chronic Kidney Disease: A Systematic Review. (PubMed, Cureus) - "Ten studies met the inclusion criteria, assessing allopurinol, febuxostat, verinurad, and topiroxostat. While febuxostat may slow CKD progression in select populations, evidence for allopurinol and combination therapies remains inconclusive. Heterogeneity in outcomes underscores the need for personalized treatment and further research to identify optimal candidates for ULA therapy."

Journal • Review • Chronic Kidney Disease • Nephrology • Renal Disease

Molecular mechanism of drug inhibition of URAT1. (PubMed, Nat Commun) - "Here, we present structures of the double-mutant rat homolog of URAT1 in complex with its substrate urate, and the clinical drugs benzbromarone, lesinurad, verinurad, and sulfinpyrazone. Additionally, critical interactions essential for its conformational transition are identified. These findings provide a molecular framework for understanding the physiological function of URAT1 and for developing more efficacious therapies to treat hyperuricemia."

Journal • 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

Structural Basis for Inhibition of Urate Reabsorption in URAT1. (PubMed, JACS Au) - "Here, we present cryoelectron microscopy structures of a humanized rat URAT1 bound with benzbromarone, lingdolinurad, and verinurad, elucidating the structural basis for drug recognition and inhibition. The three small molecules reside in the URAT1 central cavity with different binding modes, locking URAT1 in an inward-facing conformation. This study provides mechanistic insights into the drug modulation of URAT1 and sheds light on the rational design of potential URAT1-specific therapeutics for treating hyperuricemia."

Journal • Gout • Inflammatory Arthritis • Rheumatology

Mechanisms of urate transport and uricosuric drugs inhibition in human URAT1. (PubMed, Nat Commun) - "Structural comparison between different conformations of hURAT1 reveals the rocker-switch-like mechanism for urate transport. Benzbromarone and verinurad exert their inhibitory effect by blocking not only the binding of urate but also the structural isomerization of hURAT1."

Journal • Gout • Inflammation • Inflammatory Arthritis • Rheumatology

Crystal structure validation of verinurad via proton-detected ultra-fast MAS NMR and machine learning. (PubMed, Faraday Discuss) - "To do this, we take advantage of 1H resolution improvement at ultra-fast MAS and use solely 1H-detected experiments and machine learning methods to assign all the experimental proton and carbon chemical shifts. This framework provides a new tool for elucidating chemical information from crystalline samples with limited sample volume and yields remarkably faster acquisition times compared to 13C-detected experiments, without the need to employ dynamic nuclear polarization."

Journal • Machine learning

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

Verinurad Plus Allopurinol for Heart Failure With Preserved Ejection Fraction: The AMETHYST Randomized Clinical Trial. (PubMed, JAMA Cardiol) - P2 | "All patients received oral colchicine, 0.5 to 0.6 mg, daily for the first 12 weeks after randomization. Results of this randomized clinical trial show that despite substantial SUA lowering, verinurad plus allopurinol did not result in a significant improvement in peak VO2 or symptoms compared with allopurinol monotherapy or placebo in HFpEF. ClinicalTrials.gov Identifier: NCT04327024."

Clinical • Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Renal Disease

Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial. (PubMed, J Am Soc Nephrol) - No abstract available

Journal

Virtual screening and biological evaluation of natural products as urate transporter 1 (URAT1) inhibitors. (PubMed, J Biomol Struct Dyn) - "After molecular docking and conformational evaluation, four e-pharmacophoric models were constructed based on the complex structures of probenecid-URAT1, benzbromarone-URAT1, lesinurad-URAT1, and verinurad-URAT1. The results showed that the carbonyl group on C-4 and hydroxyl group on C-7, C-4', and C-5' in flavonoids were conducive for URAT1 inhibitory effects. This study facilitates the application of flavonoids in the development of URAT1 inhibitors.Communicated by Ramaswamy H. Sarma."

Journal

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

"【#HeartFailure2023】AMETHYST試験より、血清尿酸値の高いLVEFの保たれた心不全（HFpEF）患者において、URAT1阻害薬であるVerinuradとアロプリノールの併用は、アロプリノール単剤、及びプラセボと比較して尿酸値を顕著に低下させたもの、peakVO2、QOL… ( 続きはリンクへ ) https://t.co/g0iqx3jIV6" (@tcross_news)

Cardiovascular • Congestive Heart Failure • Dyslipidemia • Heart Failure

Verinurad plus allopurinol for heart failure with preserved ejection fraction: results from the AMETHYST randomized controlled trial (HEART FAILURE 2023) - No abstract available

Clinical • Late-breaking abstract • Cardiovascular • Congestive Heart Failure • Heart Failure

Pharmacological evaluation of a novel skeleton compound isobavachin (4',7-dihydroxy-8-prenylflavanone) as a hypouricemic agent: Dual actions of URAT1/GLUT9 and xanthine oxidase inhibitory activity. (PubMed, Bioorg Chem) - "In vivo, isobavachin exhibited powerful urate-lowering and uricosuric effects at 5-20 mg/kg compared with the positive drugs morin (20 mg/kg) and RDEA3170 (10 mg/kg)...A pharmacokinetic study in SD rats indicated isobavachin had lower bioavailability (12.84 ± 5.13 %) but long half-time (7.04 ± 2.68 h) to maintain a continuous plasma concentration. Collectively, these results indicate that isobavachin deserves further investigation as a candidate anti-hyperuricemic drug with a novel mechanism of action: selective urate reabsorption inhibitor (URAT1/GLUT9) with a moderate inhibitory effect on XOD."

Journal • Gout • Hepatology • Inflammatory Arthritis • Rheumatology • ABCG2

Verinurad does not prolong QTc interval: A thorough QT study using concentration-QTc modelling. (PubMed, Br J Clin Pharmacol) - P1 | "As the effect on ΔΔQTcF was below the threshold for regulatory concern (10 msec) at the supratherapeutic exposure, it can be concluded that verinurad and allopurinol treatment does not induce QTcF prolongation at the highest clinically relevant exposures."

Journal

Considerations for Choosing First-Line Urate-Lowering Treatment in Older Patients with Comorbid Conditions. (PubMed, Drugs Aging) - "The large-scale randomized controlled trials (RCTs) directly investigating gout patients regarding cardiovascular (CV) safety have only recently been introduced; CARES and FAST compared the CV safety of the two xanthine oxidase inhibitors (XOis), febuxostat versus allopurinol, in patients with gout. The combination therapy of a novel uricosuric, verinurad, plus febuxostat reduced albuminuria in hyperuricemic patients with type 2 diabetes and CKD in a phase 2a trial, and further RCTs are awaited. Finally, the sodium-glucose cotransporter-2 inhibitor class of oral hypoglycemic agents, known to exert beneficial CV and renal effects independent of glycemic control, have shown a uricosuric effect and could be used as adjunctive therapy in older patients with cardiorenal comorbidities."

Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Gout • Immunology • Inflammatory Arthritis • Metabolic Disorders • Nephrology • Renal Disease • Rheumatology • Type 2 Diabetes Mellitus

Urate Regulates Mitochondrial Function in a URAT1 Dependent Manner in Renal Epithelial Cells (KIDNEY WEEK 2022) - "Further, the application of probenecid, a general anion transporter blocker with affinity for URAT1, or verinurad, a specific URAT1 inhibitor, abolished the effects of extracellular urate on lactate levels, though URAT1 inhibition alone had no effect. Both effects were abolished in the presence 0.5μM of verinurad. Conclusion We conclude that increased tubular urate alters intracellular lactate levels and mitochondrial function in a URAT1 dependent manner, providing mechanistic evidence that urate alters cell metabolism in the proximal tubule and may contribute to kidney disease progression."

Chronic Kidney Disease • Nephrology • Renal Disease

Comparative efficacy and safety of uricosuric agents in the treatment of gout or hyperuricemia: a systematic review and network meta-analysis. (PubMed, Clin Rheumatol) - "This network meta-analysis demonstrated an important absolute benefit of dotinurad 4 mg once daily to achieve target serum uric acid and low risk of adverse events for drug treatment of gout or hyperuricemia patients. Additionally, verinurad might be used as an alternative uricosuric therapeutic option to dotinurad. These findings provided further comprehensive insight into the treatment value of current uricosuric agents for gout or hyperuricemia. Key Points 1. This is the first systematic review and network meta-analysis examining the efficacy and safety of currently available uricosuric agents in gout or hyperuricemia patients. 2. Recommended doses of dotinurad 4mg once daily used for the treatment of gout or hyperuricemia patients can significantly decrease serum uric acid levels. 3. The present findings will provide further comprehensive insight into the treatment value of certain uricosuric agents for gout or hyperuricemia."

Journal • Retrospective data • Review • Gout • Inflammatory Arthritis • Rheumatology

UHPLC-MS/MS-based method for quantification of verinurad in rat plasma and its application in a bioavailability study. (PubMed, Biomed Chromatogr) - "Lesinurad was used as an internal standard (IS) and simple protein precipitation was utilized to prepare the analytes from the matrix. The pharmacokinetic study revealed that verinurad showed high clearance and high bioavailability (78.1%). To the best of our knowledge, this is the first report of the bioavailability study of verinurad."

Journal • Preclinical

Characterization of the uric acid transporter URAT1 (SLC22A12) in platelets and megakaryocytes (ISTH 2022) - "Platelet aggregation in response to classical platelet agonists (collagen, arachidonic acid, ADP and thrombin receptor activating peptide (TRAP)), in the presence or absence of pharmacological URAT1 inhibitors (lesinurad and verinurad) was verified by light transmission aggregometry in washed platelets prepared from whole blood of healthy male and female volunteers. URAT1 immunoreactivity was detected on the surface of and within platelets and MEG-01 cells, at the expected molecular weight of 65 kD. Cell fractionation experiments were consistent with flow cytometry results. Incubation of washed platelets with uric acid (50-100 µg/ml) did not induce spontaneous platelet aggregation, nor did it induce synergistic effects in the presence of low concentrations of classical platelet agonists."

Cardiovascular • Hematological Disorders • Immunology • Inflammatory Arthritis • Nephrology • Renal Calculi • Rheumatology • Thrombosis

AMETHYST: Study of Verinurad in Heart Failure With Preserved Ejection Fraction (clinicaltrials.gov) - P2 | N=159 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Congestive Heart Failure • Heart Failure

Pharmacokinetics, pharmacodynamics, and safety of verinurad with and without allopurinol in healthy Asian, Chinese, and non-Asian participants. (PubMed, Pharmacol Res Perspect) - P1 | "When accounting for dose, the steady-state pharmacokinetics of verinurad following multiple dosing were comparable between healthy Asian and Chinese participants and healthy non-Asian participants. Verinurad treatments were well tolerated, including at higher verinurad exposures than previously evaluated after repeated dosing."

Journal • PK/PD data

SAPPHIRE: A Study of Verinurad and Allopurinol in Patients With Chronic Kidney Disease and Hyperuricaemia (clinicaltrials.gov) - P2b; N=861; Completed; Sponsor: AstraZeneca; Active, not recruiting ➔ Completed

Clinical • Trial completion • Chronic Kidney Disease • Nephrology • Renal Disease • CST3

Discovery of novel verinurad analogs as dual inhibitors of URAT1 and GLUT9 with improved Druggability for the treatment of hyperuricemia. (PubMed, Eur J Med Chem) - "Moreover, KPH2f presented benign safety profiles without causing hERG toxicity, cytotoxicity in vitro (lower than verinurad), and renal damage in vivo. Collectively, these results suggest that KPH2f represents a novel, safe and effective dual URAT1/GLUT9 inhibitor with improved druggabilities and is worthy of further investigation as an anti-hyperuricemic drug candidate."

Journal • Gout • Inflammatory Arthritis • Rheumatology • ABCG2