REG - AstraZeneca PLC - Discontinuation of two CRYSTALIZE evidence trials

AstraZenecaAnnouncement

01/12/2023 07:00

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RNS Number : 2716V  AstraZeneca PLC  01 December 2023

1 December 2023

Update on CRYSTALIZE evidence trials

Discontinuation of STABILIZE-CKD and DIALIZE-Outcomes Phase III trials

AstraZeneca has decided to discontinue the STABILIZE-CKD and DIALIZE-Outcomes
Phase III evidence trials for Lokelma (sodium zirconium cyclosilicate). The
decision was made due to substantially increased enrolment timelines and low
event rates, respectively, which made it prohibitive to deliver study results
within a timeframe to meaningfully advance clinical practice.

 

STABILIZE-CKD and DIALIZE-Outcomes trials are part of the CRYSTALIZE evidence
programme, which includes clinical and real-world evidence studies researching
the potential benefit of Lokelma in the management of hyperkalaemia (HK)
across the cardiorenal spectrum.

 

Sharon Barr, Executive Vice President, BioPharmaceuticals R&D said: "Our
ambitious CRYSTALIZE programme continues to generate evidence to improve the
current management of hyperkalaemia, which we believe leads to better outcomes
for cardiorenal patients when a potassium binder is included in their
treatment regimen. Lokelma is the leading branded potassium binder globally
and continues to benefit a broad hyperkalaemia patient population to achieve
rapid, sustained potassium control and is well tolerated."

 

The Company will work with investigators to ensure the necessary follow-up
with patients.

 

Lokelma is approved for the treatment of a broad HK patient population in 56
countries worldwide. The decision to discontinue the trials is not due to
safety concerns and the positive benefit-risk of Lokelma does not change in
the approved indication.

Notes

 

Hyperkalaemia
Hyperkalemia (HK) can be a chronic condition characterised by high levels of
potassium in the blood, generally defined as greater than 5 mmol/L.(1,2)
Patients with high potassium levels are at significant risk of cardiac
arrhythmias, which can lead to cardiac arrest.(3) Worldwide there are about
840 million and 64 million people living with CKD and HF respectively, who are
at an estimated two to three times higher risk of hyperkalemia.(4-7) RAASi
therapy is guideline-recommended to slow down CKD progression and reduce CV
events, but the dose is often lowered or therapy is discontinued when HK is
diagnosed.(8-11) This has been shown to negatively impact patient outcomes,
with mortality rates doubled for patients with CKD and HF whose RAASi had been
down-titrated or discontinued compared to patients on maximum RAASi dose.(12)

 

STABILIZE-CKD

STABILIZE-CKD is a Phase III randomised double-blind, placebo-controlled,
multicentre study evaluating the effect of Lokelma, as an adjunct to
optimised RAASi therapy (ACEi/ARB) on CKD progression in participants with
CKD and HK or at-risk of HK.(13) The study consists of a three-month
up-titration period with an ACEi/ARB to guideline-recommended doses while
taking Lokelma followed by a maintenance phase of two years with repeated
estimated glomerular filtration rate (eGFR) measurements, originally planned
to involve 1360 participants across the world.

DIALIZE-Outcomes
 DIALIZE-Outcomes is a Phase III randomised, double-blind, placebo-controlled, multicentre study evaluating the effect of Lokelma on arrhythmia-related cardiovascular outcomes in patients on chronic haemodialysis with recurrent HK.(14) The study involves approximately 2800 participants across the world.
Lokelma
 Lokelma (sodium zirconium cyclosilicate) is an anti-hyperkalaemia (HK) therapy that provides rapid potassium reduction and sustained potassium control.(15) It is indicated for the treatment of HK in adults, including patients with ESKD on chronic haemodialysis.(16) It is an insoluble, non-absorbed sodium zirconium silicate, formulated as a powder for oral suspension, that acts as a highly selective potassium-removing medicine.(16) It is administered orally and is odourless, tasteless, and stable at room temperature.(16-17) Lokelma has been approved in more than 56 countries including US, EU, China and Japan.(18)

 

AstraZeneca in CVRM
(https://www.astrazeneca.com/our-therapy-areas/cardiovascular-renal-and-metabolism.html)
 

Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms
one of AstraZeneca's main disease areas and is a key growth driver for the
Company. By following the science to understand more clearly the underlying
links between the heart, kidneys, liver and pancreas, AstraZeneca is investing
in a portfolio of medicines for organ protection by slowing or stopping
disease progression, and ultimately paving the way towards regenerative
therapies. The Company's ambition is to improve and save the lives of millions
of people, by better understanding the interconnections between CVRM diseases
and targeting the mechanisms that drive them, so we can detect, diagnose and
treat people earlier and more effectively.

 

AstraZeneca (https://www.astrazeneca.com/)

AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical
company that focuses on the discovery, development, and commercialisation of
prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals,
including Cardiovascular, Renal & Metabolism, and Respiratory &
Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries
and its innovative medicines are used by millions of patients worldwide.
Please visit astrazeneca.com (http://www.astrazeneca.com/) and follow the
Company on social media @AstraZeneca.
(https://gateway.zscalertwo.net/auD?origurl=https:%2f%2fwww.linkedin.com%2fcompany%2fastrazeneca&_ordtok=Mkk3WV5DBDPmQrD4F5MGdGDMZR)

Contacts

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.

 

References

1.   Thomsen RW et al. Elevated Potassium levels in patients with chronic
kidney disease; occurrence, risk factors and clinical outcomes - a Danish
population-based cohort study. J Am Heart Assoc. 2018;7:e008912

2.   Kovesdy CP, et al.Management of hyperkalaemia in chronic kidney
disease. Nat Rev Nephrol. Nov 2014;10:653-662

3.   Kovesdy CP, et al. Serum and Dialysate Potassium Concentrations and
Survival in Hemodialysis Patients. Clin J Am Soc Nephrol. 2007:2:999-1007.

4.   Jain N, et al. Predictors of hyperkalemia and death in patients with
cardiac and renal disease. Am J Cardiol. 2012;109(10):1510-1513.

5.   Sarwar, et al. Hyperkalemia in Heart Failure. J Am Coll Cardiol.
2016;68(14):1575-1589.

6.   Jager KJ, et al. A Single Number for Advocacy and
Communication-Worldwide More than 850 Million Individuals Have Kidney
Diseases. Nephrol Dial Transplant. 2019;34(11):1803-5.

7.   Vos T, et al. Global, regional, and national incidence, prevalence, and
years lived with disability for 328 diseases and injuries for 195 countries,
1990-2016: A systematic analysis for the Global Burden of Disease Study 2016.
The Lancet 2017; 390(10100):1211-59.

8.   McDonagh TA, et al. 2021 ESC guidelines for the diagnosis and treatment
of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726.

9.   Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA
Guideline for the Management of Heart Failure: A Report of the American
College of Cardiology/American Heart Association Joint Committee on Clinical
Practice Guidelines. J Am Coll Cardiol. 2022;79(17):e263-e421.

10.  Collins AJ, et al. Association of serum potassium with all-cause
mortality in patients with and without heart failure, chronic kidney disease,
and/or diabetes. Am J Nephrol. 2017;46(3):213-221.

11.  Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group.
Kidney Int. 2022;102(5S): S1-S127.

12.  Epstein et al. Evaluation of the Treatment Gap Between Clinical
Guidelines and the Utilization of Renin-Angiotensin Aldosterone System
Inhibitors. Am J Manag Care. 2015;21(11 suppl): S212-S220.

13.  ClinicalTrials.Gov: A Study to Evaluate the Effect of Sodium Zirconium
Cyclosilicate on Chronic Kidney Disease (CKD) Progression in Participants With
CKD and Hyperkalaemia or at Risk of Hyperkalaemia (STABILIZE-CKD). Available
at: https://clinicaltrials.gov/study/NCT05056727?intr=lokelma&rank=7
(https://clinicaltrials.gov/study/NCT05056727?intr=lokelma&rank=7) . Last
accessed November 2023.

14.  ClinicalTrials.Gov: Effect of Sodium Zirconium Cyclosilicate on
Arrythmia-related Cardiovascular Outcomes in Participants on Chronic
Hemodialysis With Recurrent Hyperkalemia (DIALIZE-Outcomes). Available at:
https://clinicaltrials.gov/study/NCT04847232?intr=lokelma&rank=6
(https://clinicaltrials.gov/study/NCT04847232?intr=lokelma&rank=6) . Last
accessed November 2023.

15.  Kosiborod M, et al.  Effect of sodium zirconium cyclosilicate on
potassium lowering for 28 days among outpatients with hyperkalemia: the
HARMONIZE randomized clinical trial [article and protocol]. JAMA.
2014;312:2223-2233.

16.  European Medicines Agency  Internet  Lokelma (sodium zirconium
cyclosilicate). Summary of Product Characteristics; [cited 12 Oct 2023].
Available at:
https://www.ema.europa.eu/en/documents/product-information/lokelma-epar-product-information_en.pdf
(https://www.ema.europa.eu/en/documents/product-information/lokelma-epar-product-information_en.pdf)
. Last accessed November 2023

17.  Lokelma® (sodium zirconium cyclosilicate) for oral suspension
 Internet . US prescribing information. Wilmington (DE): AstraZeneca
Pharmaceuticals LP; [cited 12 Oct 2023]. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207078s003lbl.pdf
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207078s003lbl.pdf)
. Last accessed November 2023.

18.  AstraZeneca. Data on file.  REF-198643 

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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