Delving into the Latest Updates on Zibotentan with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Zibotentan (JAN/USAN/INN)

+ [2]

Target

ETA

Mechanism

ETA antagonists(Endothelin receptor type A antagonists)

Therapeutic Areas

Nervous System DiseasesCardiovascular DiseasesDigestive System Disorders+ [3]

Active Indication

FibrosisHypertension, PortalLiver Cirrhosis+ [4]

Inactive Indication

Advanced Malignant Solid NeoplasmBone metastasesBreast Cancer+ [10]

Originator Organization

AstraZeneca PLC

Active Organization

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

+ [1]

Inactive Organization

AstraZeneca (Wuxi) Trading Co., Ltd.

University College London

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC19H16N6O4S

InChIKeyFJHHZXWJVIEFGJ-UHFFFAOYSA-N

CAS Registry186497-07-4

A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase IIb Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Combination Compared to Zibotentan Monotherapy as well as Zibotentan/Dapagliflozin and Zibotentan Monotherapy Compared to Placebo in Participants with Cirrhosis - ZEAL-UNLOCK

Start Date15 May 2024

Sponsor / Collaborator

AstraZeneca AB

CTR20233552

/ RecruitingPhase 2

一项评估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在肝硬化伴门静脉高压特征受试者中的有效性、安全性和耐受性的两部分、多中心、随机、双盲、安慰剂对照、平行分组、剂量范围探索IIa/b期研究

[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]

100 Clinical Results associated with Zibotentan

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100 Translational Medicine associated with Zibotentan

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100 Patents (Medical) associated with Zibotentan

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94

Literatures (Medical) associated with Zibotentan

19 Nov 2024·Circulation

Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial

Article

Author: Sattar, Naveed ; Jolly, Lisa ; Morrow, Andrew ; Clesham, Gerald ; Rakhit, Roby ; Kennedy, Julie ; Kaski, Juan Carlos ; Padmanabhan, Sandosh ; Hoole, Stephen ; Davenport, Anthony ; Galasko, Gavin ; Kellman, Peter ; Perera, Divaka ; Greenwood, John P. ; Kotecha, Ashish ; Ferreira, Vanessa ; Macfarlane, Peter W. ; Weir, Robin A. ; Welsh, Paul ; McConnachie, Alex ; Arnold, Jayanth Ranjit ; Spyridopoulos, Ioakim ; Sinha, Aish ; Al-Lamee, Rasha ; Abraham, George R. ; Berry, Colin ; El Shibly, Mohamed ; Shanmuganathan, Mayooran ; Ford, Thomas J. ; Young, Robin

BACKGROUND: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene ( EDN1 ) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. METHODS: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. RESULTS: A total of 118 participants (mean±SD; years of age 63.5 [9.2]; 71 [60.2%] females; 25 [21.2%] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, −4.26 seconds [95% CI, −19.60 to 11.06] P =0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P <0.001). CONCLUSIONS:Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04097314.

01 Oct 2024·Journal of the American Society of Nephrology

Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD

Article

Author: Smeijer, J. David ; Górriz, José Luis ; Greasley, Peter J. ; Soler, Maria José ; Åstrand, Magnus ; Mercier, Anne-Kristina ; Heerspink, Hiddo J.L. ; Ambery, Phil ; Wasehuus, Victor S. ; Dhaun, Neeraj

Key Points

Increasing doses of the endothelin receptor antagonist zibotentan and lower eGFR were associated with a higher risk of fluid retention.

The higher risk of fluid retention could be attenuated by the combination of zibotentan with the sodium-glucose cotransporter 2 inhibitor dapagliflozin.

BackgroundEndothelin receptor antagonists (ERAs) reduce albuminuria but are limited by fluid retention risk, particularly in patients with CKD. Combining ERAs with sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have diuretic effects, offers a promising strategy to mitigate fluid retention. In this post hoc analysis of the Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD) trial, we assessed fluid dynamics in patients with CKD treated with the ERA zibotentan alone and in combination with the SGLT2 inhibitor dapagliflozin.MethodsIn the ZENITH-CKD trial, 508 patients with CKD (eGFR ≥20 ml/min per 1.73 m2 and a urinary albumin-creatinine ratio of 150–5000 mg/g) were randomized to treatment with placebo, dapagliflozin 10 mg plus placebo, zibotentan (0.25, 1.5, or 5 mg) plus dapagliflozin 10 mg, and zibotentan 5 mg plus placebo. We evaluated correlations between changes in fluid retention markers and bioimpedance-measured extracellular fluid in response to zibotentan treatment. We used Cox proportional hazards regression to assess the association between zibotentan/dapagliflozin treatment, baseline characteristics, and fluid retention and the relationship between zibotentan plasma exposure and fluid retention.ResultsAfter 3 weeks of treatment with zibotentan 0.25, 1.5, or 5 mg plus dapagliflozin 10 mg, changes in body weight (β=0.36 [95% confidence interval (CI), 0.26 to 0.45]) per kg, B-type natriuretic peptide (β=0.38 [95% CI, 0.22 to 0.54]) per doubling, and hemoglobin (β=−0.29 [95% CI, −0.48 to −0.10]) per g/dl were independently associated with changes in extracellular fluid. Higher doses of zibotentan were associated with significantly higher risk of fluid retention compared with dapagliflozin alone (zibotentan 5 mg hazard ratio (HR) 8.50 [95% CI, 3.40 to 21.30]). The HR attenuated when zibotentan was combined with dapagliflozin (zibotentan/dapagliflozin 5/10 mg HR 3.09 [95% CI, 1.08 to 8.80], zibotentan/dapagliflozin 1.5/10 mg 2.70 [95% CI, 1.44 to 5.07], and zibotentan/dapagliflozin 0.25/10 mg HR 1.21 [95% CI, 0.50 to 2.91]). The risk of fluid retention was higher with higher zibotentan exposure and lower eGFR.ConclusionsHigh doses of zibotentan were associated with a higher risk of fluid retention, which was attenuated with lower doses and the addition of dapagliflozin.Clinical Trial registry name and registration number:ZENITH-CKD Trial, NCT04724837.

01 Sep 2024·Clinical Pharmacology & Therapeutics

From Plan to Pivot: How Model‐Informed Drug Development Shaped the Dose Strategy of the Zibotentan/Dapagliflozin ZENITH Trials

Article

Author: Sunnåker, Mikael ; Åstrand, Magnus ; Ueckert, Sebastian ; Ambery, Phil ; Mercier, Anne‐Kristina ; Greasley, Peter J. ; Hamrén, Bengt

Getting the dose right is a key challenge in drug development; model‐informed drug development (MIDD) provides powerful tools to shape dose strategies and inform decision making. In this tutorial, the case study of the ZENITH trials showcases how a set of clinical pharmacology and MIDD approaches informed an impactful dose strategy. The endothelin A receptor antagonist zibotentan, combined with the sodium‐glucose co‐transporter‐2 inhibitor dapagliflozin, has yielded a robust and significant albuminuria reduction in the Phase IIb trial ZENITH‐CKD and is being investigated for reduction of kidney function decline in a high‐risk chronic kidney disease population in the Phase III trial ZENITH High Proteinuria. Endothelin antagonist treatment has, until now, been limited by the class effect fluid retention. ZENITH‐CKD investigated a wide range of zibotentan doses based on pharmacokinetics in renal impairment, competitor‐data exposure–response modeling, and clinical trial simulations. Recruitment delays reduced interim analysis data availability; here, supportive dose–response modeling recovered decision‐making confidence. At trial completion, the low‐dose arm enabled Phase III dose selection between Phase IIb doses. Dose–response modeling of efficacy and Kaplan–Meier analyses of tolerability identified a kidney‐function‐based low‐dose strategy of 0.25 or 0.75 mg zibotentan (with 10 mg dapagliflozin) to balance benefit/risk in ZENITH High Proteinuria. The applied clinical pharmacology and MIDD principles enabled successful Phase IIb dose finding, rationalized and built confidence in the innovative Phase III dosing strategy and identified a potential therapeutic window for zibotentan/dapagliflozin, providing the opportunity for a significant improvement in the treatment of chronic kidney disease with high proteinuria.

7

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

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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
Bone metastases	Discovery	DE	AstraZeneca PLC	01 Nov 2007
Bone metastases	Discovery	PL	AstraZeneca PLC	01 Nov 2007
Bone metastases	Discovery	FR	AstraZeneca PLC	01 Nov 2007
Bone metastases	Discovery	BR	AstraZeneca PLC	01 Nov 2007
Bone metastases	Discovery	MX	AstraZeneca PLC	01 Nov 2007
Bone metastases	Discovery	BE	AstraZeneca PLC	01 Nov 2007
Bone metastases	Discovery	GB	AstraZeneca PLC	01 Nov 2007
Bone metastases	Discovery	CA	AstraZeneca PLC	01 Nov 2007
Bone metastases	Discovery	IN	AstraZeneca PLC	01 Nov 2007
Bone metastases	Discovery	US	AstraZeneca PLC	01 Nov 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04724837 (ZENITH-CKD, Pubmed \| J Am Soc Nephrol)	Phase 2	Chronic Kidney Diseases	508	Zibotentan 0.25 mg	(vxcudyflfo) = rfnjlulrxr dmjxcwdzbn (brhbihjoch, 0.26 - 0.45)	Positive	01 Oct 2024
				Zibotentan 1.5 mg	(vxcudyflfo) = firzrsqzqd dmjxcwdzbn (brhbihjoch, 0.26 - 0.45)
ESC2024	Not Applicable	Microvascular Angina	-	Zibotentan 10 mg	wizdbodukz(oihndydyif) = Adverse events were more common during the zibotentan period (60.2%) compared to placebo (14.4%, p<0.001) qvcsviuruv (twarhsleia )	-	01 Sep 2024
NCT04724837 (ZENITH-CKD, ASN2023) Manual	Phase 2	Chronic Kidney Diseases	447	Zibotentan 0.25 mg+dapagliflozin 10 mg	(dlmmozvhwz) = wxqwwamlvn bthmcqpyzp (pcarlgauvg, -38.4% - -13.6%) View more	Positive	03 Nov 2023
				Zibotentan 1.5 mg+dapagliflozin 10 mg	(dlmmozvhwz) = mkrgxymtty bthmcqpyzp (pcarlgauvg, -42.5% - -23.5%) View more
NCT04724837 (ZENITH-CKD, Pubmed \| Lancet)	Phase 2	Chronic Kidney Diseases	449	Zibotentan 1.5 mg plus dapagliflozin 10 mg	xcnexyoknm(vzivnegrhi) = 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. gudeqwhwcn (gdsvllejic )	Positive	01 Nov 2023
				Zibotentan 0.25 mg plus dapagliflozin 10 mg
NCT00617669 (ENTHUSE M1C, ASCO_GU 12021 \| ASCO_GU 22021) Manual	Phase 3	Prostatic Cancer	466	zibotentan+docetaxel (lean)	(wzzwrevmgy) = ltsuiwpzym gofjydykqz (ymuekeclak ) View more	Positive	20 Feb 2021
				zibotentan+docetaxel (overweight)	(wzzwrevmgy) = pmngganloh gofjydykqz (ymuekeclak ) View more
NCT02047708 (ZEBRA-1, ACR2019)	Phase 2	Chronic Kidney Diseases	16	Zibotentan 10 mg/day	xzrwylllba(yzbuymuaux) = 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) prvwxelbeh (xfipogqylj )	Positive	10 Nov 2019
				Placebo
NCT02047708 (ZEBRA-1, ASN2019)	Phase 2	Scleroderma, Systemic eGFR \| urinary MCP-1	16	Zibotentan 10 mg/day	vypwstypaa(zprnbarwmb) = There were 46 reported adverse events (26 placebo and 20 zibotentan) with 6 serious adverse events (3 in each arm) snrwlmwruf (nrtwdzozbn )	Positive	05 Nov 2019
				Placebo
NCT00929162 (AGO-OVAR 2.14, Pubmed \| Gynecol Oncol)	Phase 2	Platinum-Sensitive Ovarian Carcinoma Second line	120	Zibotentan 10mg	(iujaetbcnn) = riokthyedl velrexpkcp (hdfgateepl )	Negative	01 Jul 2013
				Placebo	(iujaetbcnn) = bzmbjyvboa velrexpkcp (hdfgateepl )
NCT00626548 (Pubmed \| Prostate Cancer Prostatic Dis) Manual	Phase 3	Castration-Resistant Prostatic Cancer	1,421	zibotentan	(qxtqfjxcuy): 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 \| J Clin Oncol) Manual	Phase 3	Metastatic castration-resistant prostate cancer	1,052	docetaxel+zibotentan	(yjfygkacob) = There was no difference in OS for patients receiving docetaxel-zibotentan compared with those receiving docetaxel-placebo rraykkbdmx (jajopypgvq ) View more	Negative	10 May 2013
				docetaxel+Placebo