Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as RDEA3170
Verinurad · 9 trials · 9 indications
Mean change from baseline in peak VO2 at Week 32 between the treatment groups was compared using change from baseline (i.e., week 32 value - baseline value) as the dependent variable, treatment as the independent variable and baseline peak VO2 included as covariate. H0: Difference in mean change from baseline in peak VO2 (verinurad + allopurinol vs placebo) = 0 Ha: Difference in mean change from baseline in peak VO2 (verinurad + allopurinol vs placebo) ≠ 0 A hierarchical test sequence was used for the confirmatory analysis of the primary and secondary objectives in order to address the issue of multiple testing and control the Type I error rate at an overall two-sided 0.05 level. Since this was the first test in the hierarchical test sequence and endpoint was not rejected at a two-sided 0.05 level, the testing sequence did not continue.
Analyses of change from baseline in uACR at 6 months (Visit 8) focused on: * High dose vs Placebo * High dose and Inter. dose combined vs Allopurinol alone * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo For High dose and Inter. dose combined the 2 categories merged forming 1 new temporary category.
Change from baseline in peak UA excretion during the first 8 hours on Day 7 of treatment to assess the effects of intensive UA lowering therapy with verinurad, febuxostat and dapagliflozin. Urine sample was collected in hourly intervals, and the highest amount of UA excreted in any interval was designated as peak UA excretion for each patient and treatment period.
Cmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
AUClast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
AUCτ assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
LS Mean Percentage Change (95% CI) from Baseline in UACR
LS Mean Percentage Change (90% CI) from Baseline in UACR Compared to Placebo
The primary objective of the study is to compare percent changes of serum uric acid levels from baseline levels after 16 weeks of dosing between RDEA3170 treatment groups and the placebo treatment group.
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad. Verinurad Cmax ratio of geometric mean of test treatment (verinurad+allopurinol with \[cyclosporine or rifampicin\], relative to reference treatment (verinurad+allopurinol alone) in each treatment period.
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad. Verinurad AUCinf ratio of geometric means of test treatment, relative to reference treatment in each treatment period.
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad. Verinurad AUClast ratio of geometric means of test treatment, relative to reference treatment in each treatment period.
Assessment of the effect of a single dose of verinurad given as either a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of International Council for Harmonisation Guideline E14 and associated Questions and Answers \[ICH E14 Q\&A\]), both in combination with allopurinol 300 mg, on the QTcF interval compared to placebo using a concentration-QTcF analysis. A linear mixed-effect concentration-QTcF model was used as the primary analysis. This is a result of the statistical model so it does not have values for every timepoint, it is just one set of numbers - summarizes data across all timepoints. No non-placebo-corrected QTcF data values were collected or could be obtained for each Arm/Group at Cmax of Verinurad.
To assess the safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess abnormal resting digital 12-lead electrocardiograms as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess abnormal pulse rate as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess white blood cell count (WBC), red blood cell count (RBC), neutrophils absolute count, lymphocytes absolute count, monocytes absolute count, eosinophils absolute count, basophils absolute count, platelets, and reticulocytes absolute count as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess abnormal blood pressure (systolic and diastolic) as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess safety and tolerability by assessment of the general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.
To assess serum level of sodium, potassium, calcium (total), and phosphate as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess Hb as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess hematocrit as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess MCV as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess MCH as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess MCHC as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
To assess the safety and tolerability profile of verinurad and allopurinol treatment in terms of the number of participants with abnormal clinical chemistry values. The laboratory variables to be measured are: bilirubin, creatinine, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), cystatin C, gamma glutamyl transpeptidase, urea and uric acid.
To assess the safety and tolerability profile of verinurad and allopurinol treatment in terms of the number of participants with abnormal urinalysis values. The laboratory variables to be measured are: protein, glucose, blood, uric acid, pH, sodium, creatinine, and cystatin C.
% change per treatment will be compared.
Timed urinary uric acid excretion per treatment will be compared
Renal clearance of uric acid will be calculated.
Fractional excretion and renal clearance of uric acid will be calculated.
| Arm | Type | Description |
|---|---|---|
| Verinurad 12 + allopurinol | EXPERIMENTAL | Dose \[mg\] verinurad/allopurinol: Step 1 - titration\_3/100 Step 2 - titration\_7.5/200 Step 3 - target dose 12/300 |
| Allopurinol alone | EXPERIMENTAL | Dose \[mg\] verinurad/allopurinol: Step 1 - titration\_0/100 Step 2 - titration\_0/200 Step 3 - target dose 0/300 |
| Placebo | PLACEBO_COMPARATOR | Placebo \[mg\] in 3 steps 0/0 |
| High Dose | EXPERIMENTAL | High Dose (mg) (verinurad/allopurinol) Step 1 - titration\_ 3/100 Step 2 - titration\_ 7.5/200 Step 3 - target dose\_ 12/300 |
| Intermediate Dose | EXPERIMENTAL | Intermediate Dose (mg) verinurad/allopurinol Step 1 - titration\_ 3/100 Step 2 - titration\_ 7.5/200 Step 3 - target dose\_ 7.5/300 |
| Low Dose | EXPERIMENTAL | Low Dose (mg) verinurad/allopurinol Step 1 - titration\_3/100 Step 2 - titration\_3/200 Step 3 - target dose\_3/300. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at Visit 9. |
| Allopurinol alone (0/300 mg) | EXPERIMENTAL | Step 1 - titration\_0/100 Step 2 - titration\_0/200 Step 3 - target dose\_0/300 |
| Placebo (0/0 mg) | PLACEBO_COMPARATOR | Placebo (mg) in 3 steps\_0/0 |
| Treatment A | EXPERIMENTAL | Randomized patients will receive orally once daily fixed dose of the following drugs: verinurad + febuxostat + dapagliflozin; |
| Treatment B | EXPERIMENTAL | Randomized patients will receive orally once daily fixed dose of the following drugs: verinurad + febuxostat + dapagliflozin matched placebo |
| Verinurad 9 mg+Febuxostat 80 mg | EXPERIMENTAL | Capsule administered orally, once daily for 24 weeks |
| RDEA3170 1 | EXPERIMENTAL | RDEA3170 5mg followed by RDEA3170 7.5mg |
| RDEA3170 2 | EXPERIMENTAL | RDEA3170 10mg followed by RDEA3170 12.5mg |
| RDEA3170 3 | EXPERIMENTAL | RDEA3170 12.5mg followed by RDEA3170 15mg |
| RDEA3170 4 | PLACEBO_COMPARATOR | RDEA3170 Placebo |
| Allopurinol | OTHER | Allopurinol 200mg |
| Verinurad + allopurinol | EXPERIMENTAL | The subjects will receive single oral dose of verinurad 7.5 mg and allopurinol 300 mg under fasted condition. |
| Verinurad + allopurinol + cyclosporine | EXPERIMENTAL | The subjects will receive single oral dose of verinurad 7.5 mg, allopurinol 300 mg and cyclosporine 600 mg under fasted condition. |
| Verinurad + allopurinol + rifampicin | EXPERIMENTAL | The subjects will receive single oral dose of verinurad 7.5 mg, allopurinol 300 mg and rifampicin 600 mg under fasted condition. |
| Treatment ABC | EXPERIMENTAL | Subjects will receive a single dose of all 3 treatments (A, B, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration. |
| Treatment BCA | EXPERIMENTAL | Subjects will receive a single dose of all 3 treatments (B, C, and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration. |
| Treatment CAB | EXPERIMENTAL | Subjects will receive a single dose of all 3 treatments (C, A, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration. |
| Treatment ACB | EXPERIMENTAL | Subjects will receive a single dose of all 3 treatments (A, C, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration. |
| Treatment BAC | EXPERIMENTAL | Subjects will receive a single dose of all 3 treatments (B, A, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration. |
| Treatment CBA | EXPERIMENTAL | Subjects will receive a single dose of all 3 treatments (C, B and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration. |
| 24 mg Verinurad+300 mg allopurinol | EXPERIMENTAL | During Run-in Period, participants will be dosed with 300 mg of allopurinol from Day -7 to Day -1. During the Treatment Period, participants will be administered 24 mg verinurad with 300 mg allopurinol once daily on Days 1 to 7. |
| 12 mg Verinurad+300 mg allopurinol | EXPERIMENTAL | During Run-in Period, participants will be dosed with 300 mg of allopurinol once daily from Day -7 to Day -1. During Treatment Period, participants will receive a single dose of 12 mg verinurad and 300 mg allopurinol on Day 1. No dosing will be done on Day 2. Participants will continue dosing on Day 3 and will be dosed once daily until Day 9. |
| Cohort 1 | EXPERIMENTAL | The half of patients randomized to this cohort will be dosed in the order of Febuxostat 10mg, RDEA3170 2.5 mg + Febuxostat 10mg, RDEA3170 2.5 mg + Febuxostat 20mg, and Febuxostat 20mg. The other half will be dosed in the reverse order. |
| Cohort 2 | EXPERIMENTAL | The half of patients randomized to this cohort will be dosed in the order of Febuxostat 10mg, RDEA3170 5 mg + Febuxostat 10mg, RDEA3170 5 mg + Febuxostat 20mg, and Febuxostat 20mg. The other half will be dosed in the reverse order. |
| Cohort 3 | EXPERIMENTAL | The half of patients randomized to this cohort will be dosed in the order of Febuxostat 20mg, RDEA3170 5 mg + Febuxostat 20mg, RDEA3170 5 mg + Febuxostat 40mg, and Febuxostat 40mg. The other half will be dosed in the reverse order. |
| Cohort 4 | EXPERIMENTAL | The half of patients randomized to this cohort will be dosed in the order of Febuxostat 20mg, RDEA3170 10 mg + Febuxostat 20mg, RDEA3170 10 mg + Febuxostat 40mg, and Febuxostat 40mg. The other half will be dosed in the reverse order. |
| Cohort 5 | EXPERIMENTAL | RDEA3170 2.5mg, RDEA3170 5mg, RDEA3170 10mg, RDEA3170 15mg |
| Cohort 6 | EXPERIMENTAL | The half of patients randomized to this cohort will be dosed in the order of Benzbromarone 50 mg, Febuxostat 10mg+RDEA3170 2.5 mg, then Febuxostat 20mg+RDEA3170 5 mg. The other half will be dosed in the order of Febuxostat 10mg+RDEA3170 2.5 mg, Febuxostat 20mg+RDEA3170 5 mg, then Benzbromarone 50mg. |
| Name | Type | Description |
|---|---|---|
| Verinurad | DRUG | The treatment will be titrated in 3 steps for target low dose (3 mg), intermediate dose (7.5 mg) and high dose (12mg) of verinurad. Drug: Allopurinol The treatment will be titrated in 3 steps. Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol. |
| Allopurinol | DRUG | Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol |
| Placebo for verinurad | DRUG | Matching Capsule |
| Placebo for allopurinol | DRUG | Matching tablet |
| Febuxostat | DRUG | Randomized patients will receive orally once daily fixed dose of febuxostat in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo |
| Dapagliflozin | DRUG | Randomized patients will receive orally once daily fixed dose of dapagliflozin in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo |
| Dapagliflozin matched placebo | OTHER | Randomized patients will receive orally once daily fixed dose of dapagliflozin matched placebo in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo |
| Verinurad 9 mg+Febuxostat 80 mg | DRUG | Capsule administered orally, once daily for 24 weeks |
| Placebo | DRUG | Capsule administered orally, once daily for 24 weeks |
| RDEA3170 | DRUG | Oral Treatment |
| Cyclosporine | DRUG | The subjects will receive single oral dose of soft capsule cyclosporine 600 mg on Day 1 of treatment period 2 under fasted condition. |
| Rifampicin | DRUG | The subjects will receive single oral dose of film coated tablets rifampicin 600 mg on Day 1 of treatment period 3 under fasted condition. |
| Benzbromarone | DRUG | Oral Treatment |
Inclusion Criteria: * Patient must be ≥ 40 years of age at the time of signing the ICF * Patients with hyperuricaemia defined as sUA level of \> 6 mg/dL. * Patients with documented diagnosis of symptomatic HFpEF according to all of the following criteria: 1. Have NYHA functional class II-III at ...
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Verinurad is an investigational small molecule being studied for hyperuricemia, including asymptomatic hyperuricemia, and for chronic kidney disease and heart failure with preserved ejection fraction (HFpEF). It has been evaluated both as a single agent and in fixed-dose combinations with allopurinol or febuxostat. It is not approved and remains in clinical development.
Verinurad targets SLC22A12, also known as URAT1, a urate transporter in the kidney. Verinurad acts as an inhibitor of this transporter, which is the mechanism under investigation for lowering serum uric acid in hyperuricemia and related conditions such as chronic kidney disease.
Verinurad is being developed by AstraZeneca PLC, which trades under the ticker AZN. AstraZeneca has sponsored the clinical trial program evaluating verinurad alone and in combination with allopurinol or febuxostat across hyperuricemia, chronic kidney disease, and HFpEF.
Verinurad is in Phase 2 clinical development and is investigational. Four trials have been completed, including two Phase 2 studies and two Phase 1 studies, with no active trials currently listed. The completed program enrolled 905 participants in total, and the trials were randomized, double-blind, and controlled.
Completed trials include NCT03990363, a Phase 2 study of verinurad and allopurinol in chronic kidney disease and hyperuricaemia with 861 participants, and NCT04327024, a Phase 2 study in heart failure with preserved ejection fraction with 159 participants. Phase 1 trials NCT04532918 and NCT04256629 evaluated drug interactions and cardiac electrical activity.