[Translation] A two-part, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging Phase IIa/b study to evaluate the efficacy, safety, and tolerability of zibotentan plus dapagliflozin combination therapy and dapagliflozin monotherapy compared with placebo in subjects with cirrhosis and features of portal hypertension

评价zibotentan和达格列净联合治疗以及达格列净单药治疗与安慰剂相比的HVPG较基线的变化。

[Translation]

The change from baseline in HVPG was evaluated for the combination of zibotentan and dapagliflozin and dapagliflozin alone compared with placebo.

Start Date19 Apr 2024

Sponsor / Collaborator

AstraZeneca Global R&D (China) Co., Ltd.

[+2]

NCT06269484 / RecruitingPhase 2

A Multicentre, Randomised, Double-blind, Placebo-controlled Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Combination Compared to Zibotentan Monotherapy, Zibotentan/Dapagliflozin and Zibotentan Monotherapy Compared to Placebo in Participants With Cirrhosis

This is a Phase IIb multicentre, randomised, double-blind, parallel-group, placebo-controlled study to evaluate the safety of zibotentan/dapagliflozin in combination as compared to zibotentan monotherapy as well as zibotentan/dapagliflozin and zibotentan monotherapy as compared to placebo in patients with cirrhosis.

Start Date15 Feb 2024

Sponsor / Collaborator

AstraZeneca PLC

EUCTR2021-006577-30-BE / Unknown statusPhase 2

A Two Part Phase IIa/b Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Dose-ranging Study to Assess Efficacy, Safety, and Tolerability of the Combination of Zibotentan and Dapagliflozin, and Dapagliflozin Monotherapy Versus Placebo in Participants with Cirrhosis with Features of Portal Hypertension - ZEAL

Start Date14 Nov 2022

Sponsor / Collaborator

AstraZeneca AB

100 Clinical Results associated with Zibotentan

100 Translational Medicine associated with Zibotentan

100 Patents (Medical) associated with Zibotentan

Literatures (Medical) associated with Zibotentan

28 Feb 2024·Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

Efficacy and safety of zibotentan and dapagliflozin in patients with chronic kidney disease: study design and baseline characteristics of the ZENITH-CKD trial

Article

Author: Mercier, Anne-Kristina ; Wijkmark, Emma ; Althage, Magnus ; Ambery, Philip ; Heerspink, Hiddo J L ; Dwyer, Jamie P ; Sunnåker, Mikael ; Law, Gordon ; Turton, Michelle ; Ahlström, Christine ; Greasley, Peter J ; Wheeler, David C ; Lin, Min

ABSTRACT:

Background:

Sodium–glucose co-transporter 2 inhibitors (SGLT2is) are part of the standard of care for patients with chronic kidney disease (CKD), both with and without type 2 diabetes. Endothelin A (ETA) receptor antagonists have also been shown to slow progression of CKD. Differing mechanisms of action of SGLT2 and ETA receptor antagonists may enhance efficacy. We outline a study to evaluate the effect of combination zibotentan/dapagliflozin versus dapagliflozin alone on albuminuria and estimated glomerular filtration rate (eGFR).

Methods:

We are conducting a double-blind, active-controlled, Phase 2b study to evaluate the efficacy and safety of ETA receptor antagonist zibotentan and SGLT2i dapagliflozin in a planned 415 adults with CKD (Zibotentan and Dapagliflozin for the Treatment of CKD; ZENITH-CKD). Participants are being randomized (1:2:2) to zibotentan 0.25 mg/dapagliflozin 10 mg once daily (QD), zibotentan 1.5 mg/dapagliflozin 10 mg QD and dapagliflozin 10 mg QD alone, for 12 weeks followed by a 2-week off-treatment wash-out period. The primary endpoint is the change in log-transformed urinary albumin-to-creatinine ratio (UACR) from baseline to Week 12. Other outcomes include change in blood pressure from baseline to Week 12 and change in eGFR the study. The incidence of adverse events will be monitored. Study protocol–defined events of special interest include changes in fluid-related measures (weight gain or B-type natriuretic peptide).

Results:

A total of 447 patients were randomized and received treatment in placebo/dapagliflozin (n = 177), zibotentan 0.25 mg/dapagliflozin (n = 91) and zibotentan 1.5 mg/dapagliflozin (n = 179). The mean age was 62.8 years, 30.9% were female and 68.2% were white. At baseline, the mean eGFR of the enrolled population was 46.7 mL/min/1.73 m2 and the geometric mean UACR was 538.3 mg/g.

Conclusion:

This study evaluates the UACR-lowering efficacy and safety of zibotentan with dapagliflozin as a potential new treatment for CKD. The study will provide information about an effective and safe zibotentan dose to be further investigated in a Phase 3 clinical outcome trial.

Clinical Trial Registration Number:

NCT04724837

21 Dec 2023·PNAS nexus

Conversion of raltegravir carrying a 1,3,4-oxadiazole ring to a hydrolysis product upon pH changes decreases its antiviral activity

Article

Author: Nakata, Hirotomo ; Sugiura, Masaharu ; Okumura, Mayu ; Nakamura, Tomofumi ; Hirotsu, Tatsunori ; Takamune, Nobutoki ; Yasunaga, Junichiro

Abstract:

Raltegravir (RAL), a human immunodeficiency virus (HIV)-1 integrase inhibitor, has been administered as part of antiretroviral therapy. Studies in patients with HIV-1 have shown high variability in the pharmacokinetics of RAL, and in healthy volunteers, coadministration of proton-pump inhibitors has been shown to increase the plasma RAL concentrations. Here, we found that RAL containing a 1,3,4-oxadiazole ring is converted to a hydrolysis product (H-RAL) with a cleaved 1,3,4-oxadiazole ring at pH 1.0 and 13.0 conditions in vitro, thereby reducing the anti-HIV activity of the drug. The inclusion of cyclodextrins (beta-cyclodextrin [βCD], random methyl-βCD [RAM-βCD], and hydroxypropyl-βCD [HP-βCD]) can protect RAL from pH-induced changes. The conversion of RAL to H-RAL was detected by using various mass spectrometry analyses. The chromatogram of H-RAL increased in a time-dependent manner similar to another 1,3,4-oxadiazole-containing drug, zibotentan, using high-performance liquid chromatography. Oral bioavailability and target protein interactions of H-RAL were predicted to be lower than those of RAL. Moreover, H-RAL exhibited significantly reduced anti-HIV-1 activity, whereas combinations with βCD, RAM-βCD, and HP-βCD attenuated this effect in cell-based assays. These findings suggest that βCDs can potentially protect against the conversion of RAL to H-RAL under acidic conditions in the stomach, thereby preserving the anti-HIV-1 effect of RAL. Although clinical trials are needed for evaluation, we anticipate that protective devices such as βCDs may improve the pharmacokinetics of RAL, leading to better treatment outcomes, including reduced dosing, long-term anti-HIV-1 activity, and deeper HIV-1 suppression.

01 Nov 2023·Lancet (London, England)Q1 · MEDICINE

Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial

Q1 · MEDICINE

Article

Author: Lin, Min ; Ueckert, Sebastian ; Wijkmark, Emma ; Carlson, Glenn ; Wheeler, David C ; Heerspink, Hiddo J L ; Ambery, Phil ; Greasley, Peter J ; Kiyosue, Arihiro ; Mercier, Anne-Kristina ; Åstrand, Magnus

BACKGROUND:

In patients with chronic kidney disease, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) can reduce albuminuria and glomerular filtration rate (GFR) decline. We assessed the albuminuria-lowering efficacy and safety of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin.

METHODS:

ZENITH-CKD was a multicentre, randomised, double-blind, active-controlled clinical trial, done in 170 clinical practice sites in 18 countries. Adults (≥18 to ≤90 years) with an estimated GFR (eGFR) of 20 mL/min per 1·73 m² or greater and a urinary albumin-to-creatinine ratio (UACR) of 150-5000 mg/g were randomly assigned (2:1:2) to 12 weeks of daily treatment with zibotentan 1·5 mg plus dapagliflozin 10 mg, zibotentan 0·25 mg plus dapagliflozin 10 mg, or dapagliflozin 10 mg plus placebo, as adjunct to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers if tolerated. The primary endpoint was a change from baseline in log-transformed UACR (zibotentan 1·5 mg plus dapagliflozin vs dapagliflozin plus placebo) at week 12. Fluid retention was an event of special interest, defined as an increase in bodyweight of at least 3% (at least 2·5% must have been from total body water) from baseline or an increase of at least 100% in B-type natriuretic peptide (BNP) and either a BNP concentration greater than 200 pg/mL if without atrial fibrillation or BNP greater than 400 pg/mL if with atrial fibrillation. This trial is registered with ClinicalTrials.gov, NCT04724837, and is completed.

FINDINGS:

Between April 28, 2021, and Jan 17, 2023, we assessed 1492 participants for eligibility. For the main analysis, we randomly assigned 449 (30%) participants, 447 (99%) of whom (mean age 62·8 years [SD 12·1], 138 [31%] female, 309 [69%] male, 305 [68%] White, mean eGFR 46·7 mL/min per 1·73 m² [SD 22·4], and median UACR 565·5 mg/g [IQR 243·0-1212·6]) received treatment with zibotentan 1·5 mg plus dapagliflozin (n=179 [40%]), zibotentan 0·25 mg plus dapagliflozin (n=91 [20%]), or dapagliflozin plus placebo (n=177 [40%]). Zibotentan 1·5 mg plus dapagliflozin and zibotentan 0·25 mg plus dapagliflozin reduced UACR versus dapagliflozin plus placebo throughout the treatment period of the study. At week 12, the difference in UACR versus dapagliflozin plus placebo was -33·7% (90% CI -42·5 to -23·5; p<0·0001) for zibotentan 1·5 mg plus dapagliflozin and -27·0% (90% CI -38·4 to -13·6; p=0·0022) for zibotentan 0·25 mg plus dapagliflozin. Fluid-retention events were observed in 33 (18%) of 179 participants in the zibotentan 1·5 mg plus dapagliflozin group, eight (9%) of 91 in the zibotentan 0·25 mg plus dapagliflozin group, and 14 (8%) of 177 in the dapagliflozin plus placebo group.

INTERPRETATION:

Zibotentan combined with dapagliflozin reduced albuminuria with an acceptable tolerability and safety profile and is an option to reduce chronic kidney disease progression in patients already receiving currently recommended therapy.

FUNDING:

AstraZeneca.

News (Medical) associated with Zibotentan

26 Jun 2024

·www.fiercepharma.com

New CKD drugs are promising, but need stronger efficacy data, kidney docs say: GlobalData

In total, the chronic kidney disease market is forecast to balloon in size from $2.2 billion last year to $13.5 billion by 2033, during which time a range of new treatments are on track to make their debuts. Though a host of drugs currently under development are poised to massively expand the existing market for chronic kidney disease (CKD) treatments, they’ll need to go further to win the support of doctors, according to a new report. The segment is expected to expand at a compound annual growth rate of nearly 20% over the course of a decade, according to GlobalData’s estimates. The report comprises the seven major markets of the U.S., France, Germany, Italy, Spain, the U.K. and Japan, though GlobalData noted that the U.S. will be a disproportionately large contributor to that growth, thanks to its higher prevalence of CKD and costs of prescription medications. In total, the CKD market is forecast to balloon in size from $2.2 billion last year to $13.5 billion by 2033, during which time a range of new treatments are on track to make their debuts. Among those now in development are ProKidney’s cell therapy rilparencel, also known as React, and AstraZeneca’s combinations of zibotentan and dapagliflozin, and balcinrenone and dapagliflozin—all of which are currently in clinical trials. Meanwhile, Novo Nordisk is also exploring a potential expanded indication for Ozempic in CKD. Just last month, Novo shared results from its FLOW study of once-weekly Ozempic’s ability to reduce the risk of major kidney disease events in patients with both CKD and Type 2 diabetes. With a median follow-up period of nearly three and a half years, the study found that participants treated with the GLP-1 had an average 24% risk reduction compared to those assigned to the placebo group, and their rate of kidney function decline was “significantly slower.” Additionally, semaglutide was shown to reduce the risk of major cardiovascular events by 18% and all-cause mortality by 20%. Following that data drop, Novo confirmed that it will pursue expanded approvals for Ozempic in the U.S. and Europe by the end of this year. Despite the promising results from the studies of those and other potential new CKD therapeutics so far, according to GlobalData, many kidney doctors have yet to be convinced to shake up their existing CKD treatment standards and have “mixed views” about tacking on another drug to their patients’ current regimens. “It will be easier for new drug entrants to capture CKD market share if they offer a novel mechanism of action or help to improve compliance,” Kajal Jaddoo, senior pharma analyst at GlobalData, said in the report. “Overall, nephrologists surveyed by GlobalData have indicated that the pipeline for CKD is somewhat promising, but a significant improvement in efficacy would have to be demonstrated by any therapy for it to become either a replacement or add-on to the existing therapies.”

Clinical ResultDrug ApprovalCell Therapy

20 Feb 2024

·www.biospace.com

AstraZeneca Looks to Differentiate in Kidney Disease Space Despite Setback: GlobalData

Pictured: AstraZeneca building/iStock, Sundry Photography AstraZeneca announced in its recent quarterly update that it discontinued a Phase IIb trial for its investigational drug tozorakimab for the treatment of diabetic kidney disease due to efficacy. However, a new report from analytics firm GlobalData is bullish on the potential prospects of the pharma’s pipeline drug zibotentan, if it gets approval. Despite removing tozorakimab from its Phase II pipeline for diabetic kidney disease (DKD), zibotentan could be “an optimal treatment of choice” for patients and “of high value” for physicians trying to find treatments for the disease. “According to key opinion leaders (KOLs) interviewed by GlobalData, unmet needs in the kidney disease space include next-generation therapies with alternate mechanisms of action and enhanced clinical pro ” Kajal Jaddoo, senior pharma analyst at GlobalData, said in a statement. Tozorakimab, which acts by blocking endothelin receptors and binds to the ET-A receptor, made it to a Phase IIb DKD study in 2019, with GlobalData stating that there was evidence that increased inflammation is associated with deterioration in renal function. The trial’s hypothesis was that the drug may be “beneficial” for DKD patients on standard of care (SOC) who have inflammation as well. But that promise was not realized. “AstraZeneca has a strong commercial position and is well known in both the metabolic and cardiovascular markets. KOLs further emphasized that until further clinical data solidifies the superior or non-inferior safety and efficacy of monoclonal antibodies in combination with SOC, physicians will not substantially change their prescribing patterns,” Jaddoo said. Zibotentan acts by blocking growth receptors called endothelin receptors, binding selectively to the ET-A receptor and inhibiting endothelin-mediated mechanisms that promote cell proliferation, according to GlobalData. However, zibotentan has not seen success in other verticals, such as cancer. In 2010, zibotentan failed to improve survival in a late-phase trial in prostate cancer, while a year later a Phase III study in prostate cancer was stopped as it was unlikely to reach the endpoints of overall and progression-free survival. Still, in 2023, a combination of zibotentan and dapagliflozin showed statistically significant results in the urinary albumin-to-creatinine ratio (UACR) to asses albuminuria, with the UACR difference being down over 33% and earning a p-value of p<0.001. AstraZeneca saw a 90% plummet in its COVID-19 business in 2023 but still managed to secure 6% in total growth for the year and an 8% growth rate in the fourth quarter of last year. Areas such as cardiovascular, rare disease, oncology, and metabolism were significant growth factors for the pharma and executives are confident the company is poised for more growth in 2024. Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.

Phase 2Phase 3Clinical Result

06 Nov 2023

·endpts.com

AstraZeneca, Eledon and Alpine spell out kidney program successes: ASN roundup

Over the past few days, Big Pharma and biotech companies alike presented results at the American Society of Nephrology’s annual kidney week. Endpoints News sifted through the data to highlight several key readouts, including those that triggered notable stock reactions or pushed forward a new mechanism. On Friday, AstraZeneca unveiled positive data from the Phase IIb ZENITH-CKD study of its investigational ETA receptor antagonist, zibotentan, in combination with SGLT2 inhibitor Farxiga in chronic kidney disease. The pharma major plans to advance the combination to a Phase III trial with 1,500 people, set to start in the first quarter of 2024. You’ll get access to free articles each month, plus you can customize what newsletters get delivered to your inbox each week, including breaking news.

Phase 2Clinical Result

100 Deals associated with Zibotentan

External Link

KEGG	Wiki	ATC	Drug Bank
D07741	Zibotentan	-	DB06629

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Prostatic Cancer	Phase 3	EU	AstraZeneca PLC	-
Prostatic Cancer	Phase 3	-	AstraZeneca PLC	-
Prostatic Cancer	Phase 3	-	AstraZeneca PLC	-
Prostatic Cancer	Phase 3	-	AstraZeneca PLC	-
Fibrosis	Phase 2	US	AstraZeneca PLC	15 Feb 2024
Fibrosis	Phase 2	JP	AstraZeneca PLC	15 Feb 2024
Fibrosis	Phase 2	AU	AstraZeneca PLC	15 Feb 2024
Fibrosis	Phase 2	BE	AstraZeneca PLC	15 Feb 2024
Fibrosis	Phase 2	CZ	AstraZeneca PLC	15 Feb 2024
Fibrosis	Phase 2	DE	AstraZeneca PLC	15 Feb 2024

Clinical Result

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04724837 (ZENITH-CKD, ASN2023) Manual	Phase 2	Chronic Kidney Diseases	447	Zibotentan 0.25 mg+dapagliflozin 10 mg	lfotgptuqw(awchhlrzoe) = sfusgryrmn siyaxnbejj (bgfpcwzuwa, -38.4% - -13.6%) View more	Positive	03 Nov 2023
				Zibotentan 1.5 mg+dapagliflozin 10 mg	lfotgptuqw(awchhlrzoe) = uczijrormj siyaxnbejj (bgfpcwzuwa, -42.5% - -23.5%) View more
NCT00617669 (ENTHUSE M1C, ASCO_GU2021) Manual	Phase 3	Prostatic Cancer	466	zibotentan+docetaxel (lean)	qnbygavmav(nomwymvpkp) = amlntrjmxu oyezqelhsg (uecpkbozym ) View more	Positive	20 Feb 2021
				zibotentan+docetaxel (overweight)	qnbygavmav(nomwymvpkp) = tcuqursjku oyezqelhsg (uecpkbozym ) View more
NCT02047708 (ZEBRA-1, ACR2019)	Phase 2	Chronic Kidney Diseases	16	Zibotentan 10 mg/day	ldvxbxtpoo(gtdbyuvifb) = There were 46 reported adverse events (AE) (26 placebo and 20 active treatment) in ZEBRA-1 in 11 patients (6 placebo and 5 zibotentan). Of the 46 reported AE, 6 were serious (3 in each arm) rnaatxtcus (xqppiykzkt )	Positive	10 Nov 2019
				Placebo
NCT02047708 (ZEBRA-1, ASN2019)	Phase 2	Scleroderma, Systemic eGFR \| urinary MCP-1	16	Zibotentan 10 mg/day	jbmfdjpqsw(befauagnum) = There were 46 reported adverse events (26 placebo and 20 zibotentan) with 6 serious adverse events (3 in each arm) fomlbrofyg (bitnojtpds )	Positive	05 Nov 2019
				Placebo
NCT00929162 (AGO-OVAR 2.14, Pubmed \| Obstet Gynecol Surv)	Phase 2	Platinum-Sensitive Ovarian Carcinoma Second line	120	Zibotentan 10mg	uuefgatiqm(eljmharqdf) = vhwwqhckxl mfgqoapetv (zjrvdrlldp )	Negative	01 Jul 2013
				Placebo	uuefgatiqm(eljmharqdf) = poysicesjy mfgqoapetv (zjrvdrlldp )
NCT00626548 (Pubmed \| Prostate Cancer Prostatic Dis) Manual	Phase 3	Castration-Resistant Prostatic Cancer	1,421	zibotentan	kvyvgknaef(pbqtjdegvc): HR = 1.13 (95% CI, 0.73 - 1.76), P-Value = 0.589 View more	Negative	01 Jun 2013
				Placebo
NCT00617669 (ENTHUSE M1C, Pubmed \| J Urol) Manual	Phase 3	Metastatic castration-resistant prostate cancer	1,052	docetaxel+zibotentan	aylxwkxrhj(dgjyungyhw) = There was no difference in OS for patients receiving docetaxel-zibotentan compared with those receiving docetaxel-placebo imdpovuezp (fsqwcmsqds ) View more	Negative	10 May 2013
				docetaxel+Placebo
NCT01119118 (CTgov)	Phase 2	Prostatic cancer metastatic	6	ZD4054	mrlvhemmen(ydnrchfmxi) = rscraxhhdv mhjnvsetus (urjcpmrswx, ryktirhsiz - dttycfaorq) View more	-	29 Apr 2013
ISRCTN73199181 (FOLFERA, ASCO_GI2013)	Phase 2	Metastatic Colorectal Carcinoma	111	FOLFIRI + Zibotentan	rllgpfdbzg(btetovryvk) = ajtjhqwdau fclqxspqtc (tpjgcmnbch )	Negative	01 Feb 2013
				FOLFIRI + Placebo	rllgpfdbzg(btetovryvk) = autyovhciy fclqxspqtc (tpjgcmnbch )
NCT00090363 (CTgov)	Phase 2	Pain \| Prostatic Cancer \| Bone metastases	447	Placebo (Placebo)	ktahwghrxv(otgtylfblm) = muyvgestve oxtvbankli (xsmkchcecf, apydomgffk - hrvpwjhsrp) View more	-	03 Sep 2012
				ZD4054 10 mg (ZD4054 10 mg)	ktahwghrxv(otgtylfblm) = rbjecjbtse oxtvbankli (xsmkchcecf, mlncgldluk - mkleyofqrg) View more

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