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Also known as Zibotentan
Zibotentan/Dapagliflozin · 6 trials · 5 indications
To determine whether zibotentan and dapagliflozin in fixed dose combination is superior to dapagliflozin alone to slow decline in kidney function
To estimate the efficacy of zibotentan and dapagliflozin in FDC versus dapagliflozin alone in reducing albuminuria
The effect of zibotentan 1.5/dapagliflozin 10 mg versus dapagliflozin 10 mg on UACR was assessed.
To characterize the single-dose plasma PK of orally administered zibotentan in healthy non-Asian and Japanese participants.
To characterize the single-dose plasma PK of orally administered zibotentan in healthy non-Asian and Japanese participants.
To characterize the single-dose plasma PK of orally administered zibotentan in healthy non-Asian and Japanese participants
To assess the PK of a single oral dose of zibotentan in participants with moderate hepatic impairment and moderate renal impairment compared to a group of healthy matched controls
To assess the PK of a single oral dose of zibotentan in participants with moderate hepatic impairment and moderate renal impairment compared to a group of healthy matched controls
To assess the PK of a single oral dose of zibotentan in participants with moderate hepatic impairment and moderate renal impairment compared to a group of healthy matched controls
Plasma sample will be collected to understand the PK profiling of zibotentan metabolites and to meet the regulatory requirements.
Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
| Arm | Type | Description |
|---|---|---|
| Zibotentan/Dapagliflozin dose A or Zibotentan/Dapagliflozin dose B | EXPERIMENTAL | Drug dose (dose A or B) are determined based on eGFR values. Participants will receive daily oral dose of zibotentan/dapagliflozin in fixed dose combination. |
| Dapagliflozin alone | ACTIVE_COMPARATOR | Participants will receive daily oral dose of dapagliflozin. |
| Zibotentan Dose A + Dapagliflozin | EXPERIMENTAL | Participants will receive once daily oral dose A of zibotentan and 10 mg dapagliflozin for 12 weeks. |
| Zibotentan Dose B + Dapagliflozin | EXPERIMENTAL | Participants will receive once daily oral dose B of zibotentan and 10 mg dapagliflozin for 12 weeks. |
| Placebo + Dapagliflozin | EXPERIMENTAL | Participants will receive once daily oral dose of dapagliflozin 10 mg and placebo for 12 weeks. |
| Treatment sequence ABCD: Zibotentan | EXPERIMENTAL | Participants will receive single dose of Zibotentan in 4 occassions with first Treatment A, followed by Treatment B, Treatment C and then Treatment D with each dose separated by 3 washout periods. |
| Treatment sequence BDAC: Zibotentan | EXPERIMENTAL | Participants will receive single dose of Zibotentan in 4 occassions with first Treatment B, followed by Treatment D, Treatment A and then Treatment C with each dose separated by 3 washout periods |
| Treatment sequence CADB: Zibotentan | EXPERIMENTAL | Participants will receive single dose of Zibotentan in 4 occassions with first Treatment C, followed by Treatment A, Treatment D and then Treatment B with each dose separated by 3 washout periods. |
| Treatment sequence DCBA: Zibotentan | EXPERIMENTAL | Participants will receive single dose of Zibotentan in 4 occassions with first Treatment D, followed by Treatment C, Treatment B and then Treatment A with each dose separated by 3 washout periods. |
| Cohort 1: Participants with moderate hepatic impairment and moderate renal impairment | EXPERIMENTAL | Participants will receive a single oral dose of zibotentan under fasted conditions. |
| Cohort 2: Healthy participants | EXPERIMENTAL | Participants will receive a single oral dose of zibotentan under fasted conditions. |
| Part 1 | EXPERIMENTAL | Participants will be administered with zibotentan once daily for 5 days. |
| Part 2: Treatment Sequence ABC | EXPERIMENTAL | Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment A; Treatment B; Treatment C) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. |
| Part 2: Treatment Sequence BCA | EXPERIMENTAL | Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment B; Treatment C; Treatment A) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. |
| Part 2: Treatment Sequence CAB | EXPERIMENTAL | Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment C; Treatment A; Treatment B) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. |
| Name | Type | Description |
|---|---|---|
| Zibotentan/Dapagliflozin | DRUG | Participants will receive zibotentan/dapagliflozin in fixed-dose combination as per the arms they are randomized to |
| Dapagliflozin | DRUG | Participants will receive dapagliflozin as per the arms they are randomized to |
| Zibotentan | DRUG | Participants will receive zibotentan as per the arms they are randomized. |
| Placebo | DRUG | Participants will receive placebo as per the arms they are randomized to. |
| Zibotentan (Treatment A) | DRUG | Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2. |
| Dapagliflozin (Treatment A) | DRUG | Dapagliflozin tablet will be administered orally as single dose in Part 2. |
| Zibotentan/Dapagliflozin - Formulation 1 (Treatment B) | DRUG | Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2. |
| Zibotentan/Dapagliflozin - Formulation 2 (Treatment C) | DRUG | Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2. |
Inclusion Criteria: 1. Participant must be ≥ 18 years of age and of legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent. 2. Diagnosis of CKD, defined as eGFR ≥ 20 and \< 90 mL/min/1.73 m2 and UACR \> 700 mg/g (\> 79 mg/mmol) or UP...
Zibotentan/Dapagliflozin is an investigational fixed-dose combination of zibotentan and dapagliflozin being developed by AstraZeneca for chronic kidney disease with high proteinuria. It pairs an endothelin receptor antagonist with an SGLT2 inhibitor in a single oral regimen. The combination is in Phase 2 and Phase 3 clinical development.
Zibotentan/Dapagliflozin combines two mechanisms. Zibotentan is an antagonist of EDNRA, the endothelin receptor type A, while dapagliflozin is an SGLT2 inhibitor. Blocking EDNRA reduces endothelin-driven vasoconstriction and proteinuria, and SGLT2 inhibition supports kidney and cardiometabolic protection. Both components are small molecules given orally.
AstraZeneca PLC, which trades under the ticker AZN, is developing Zibotentan/Dapagliflozin. The company sponsors the clinical program evaluating the fixed-dose combination in chronic kidney disease with high proteinuria, as well as studies of zibotentan alone in hepatic and renal impairment.
Zibotentan/Dapagliflozin is investigational and has not been approved. The combination has been studied in a Phase 2 trial in chronic kidney disease with high proteinuria, and a Phase 3 trial, ZENITH High Proteinuria, is active but not recruiting. Zibotentan alone has also been evaluated in Phase 1 pharmacokinetic studies.
The Phase 3 ZENITH High Proteinuria trial, NCT06087835, compares Zibotentan/Dapagliflozin with dapagliflozin alone in adults with chronic kidney disease and high proteinuria and enrolled 1,835 participants across many countries. A Phase 2 study, NCT06942910, tested the combination versus dapagliflozin alone in 224 participants in Russia. Phase 1 studies NCT06715670 and NCT05112419 assessed zibotentan pharmacokinetics.
No. Zibotentan/Dapagliflozin is a fixed-dose combination product, sometimes listed as Zibotentan/Dapagliflozin FDC, containing both zibotentan and dapagliflozin. Zibotentan, also called Treatment A in some study records, is the endothelin receptor antagonist component studied on its own in Phase 1 pharmacokinetic trials.