Label update is based on data from Phase IIIb DIALIZE trial
The National Medical Products Administration (NMPA) has approved a dosing label update in China for AstraZeneca’s Lokelma (sodium zirconium cyclosilicate) to include patients with hyperkalaemia on chronic haemodialysis.
The approval by the NMPA was based on data from the Phase IIIb DIALIZE trial, the first ever randomised, placebo-controlled trial to evaluate a potassium binder in patients on stable haemodialysis. The trial showed sustained potassium control pre-dialysis for more patients receiving Lokelma, compared with placebo.1
Lokelma was approved for the treatment of adult patients with hyperkalaemia in China by the NMPA in December 2019.
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “In China, more than 550,000 patients with chronic kidney disease on haemodialysis are at risk of developing hyperkalaemia,2 which can in turn lead to arrythmias and cardiac arrest. Today’s label update provides guidance to manage hyperkalaemia in this high-risk patient population, potentially enabling improved long-term treatment and overall kidney care.”
In DIALIZE, 41% of patients receiving Lokelma maintained pre-dialysis potassium levels on at least three out of four dialysis treatments after the long interdialytic interval and did not require urgent rescue therapy. This compared with 1% of patients receiving placebo, making it a statistically significant and clinically meaningful improvement (p<0.001). The safety profile of Lokelma observed in DIALIZE was consistent with previous trials.1
Lokelma is a highly selective, oral potassium-removing agent currently approved in a number of markets across the globe including the US, China, EU and Japan for the treatment of hyperkalaemia.
Earlier this year, the US Food and Drug Administration (FDA) and the European Commission (EC) approved label updates in the US and EU, respectively, to include a dosing regimen specifically to treat hyperkalaemia in patients with end-stage renal disease on chronic haemodialysis.
Hyperkalaemia
Hyperkalaemia is characterised by high levels of potassium in the blood, generally defined as greater than 5mmol/L.3 Many people living with chronic kidney disease (CKD) have hyperkalaemia despite being on haemodialysis and often experience fluctuations in their potassium levels.4,5 In Europe, approximately 300,000 patients with end-stage renal disease are undergoing haemodialysis, and more than 500,000 patients in the US are living with dialysis-dependent end-stage renal disease.6,7 Despite adequate haemodialysis, up to 25% of patients have serum potassium >5.5 mmol/L.8 Patients with high variability in potassium levels between dialysis sessions are at significant risk of arrhythmias, which can lead to cardiac arrest.4 Worldwide, there are an estimated 700 million and 64 million people living with CKD and HF respectively with hyperkalaemia occurring in 23 to 47% of patients with advanced CKD (stage 3-4) and/or HF.9-11
DIALIZE
DIALIZE is the first ever randomised, placebo-controlled trial to evaluate a potassium binder in patients on stable haemodialysis. The Phase IIIb, multicentre, double-blinded trial investigated the efficacy and safety of Lokelma versus placebo in 196 patients on haemodialysis with hyperkalaemia. Patients were randomised to receive Lokelma or placebo once daily on non-dialysis days for a treatment period of eight weeks. This included a four-week dose adjustment phase (starting at 5g and titrated weekly in 5g increments up to a maximum of 15g) and a four-week evaluation phase on stable dose.
The full results of the DIALIZE trial were published in September 2019 in the Journal of the American Society of Nephrology.
Lokelma
Lokelma (sodium zirconium cyclosilicate) is an insoluble, non-absorbed sodium zirconium silicate, formulated as a powder for oral suspension, that acts as a highly selective potassium-removing medicine. It is administered orally, is odourless, tasteless and stable at room temperature.12.13 It has been studied in three double-blinded, placebo-controlled trials and in one 12-month open label clinical trial in patients with hyperkalaemia.
AstraZeneca in CVRM
Cardiovascular, Renal and Metabolism (CVRM) together forms one of AstraZeneca’s three therapy 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 and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and cardiovascular health for millions of patients worldwide.
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References
1, Fishbane S et al. A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia. J Am Soc Nephrol 2019.
2. Wang F et al. Executive summary for the 2015 Annual Data Report of the China Kidney Disease Network (CK-NET). Kidney International 2019; 95(3):501–5.
3. Kovesdy CP. Management of hyperkalaemia in chronic kidney disease. Nat Rev Nephrol. Nov 2014;10:653-662.
4. Kovesdy CP. et al. Serum and Dialysate Potassium Concentrations and Survival in Hemodialysis Patients. Clin J Am Soc Nephrol. 2007:2:999-1007.
5. Evans KJ, Greenberg A. Hyperkalemia: A review. J Intensive Care Med. 2005;20:272-290.
6. Kramer A et al. The European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2016: A summary. Clinical Kidney Journal 2019; 12(5):702–20.
7. United States Renal Data System. 2018 Annual Data Report Volume 2: End-Stage Renal Disease Chapter 1: Incidence, Prevalence, Patient Characteristics, and Treatment Modalities. https://www.usrds.org/2018/view/v2_01.aspx. Published 2018. Accessed 1 May 2020.
8. Xu H et al. Prevalence of hyperkalemia in DOPPS: A real-world, international cohort of hemodialysis patients (MP371). presented at: ERA-EDTA Annual Congress 2017, 2019 Jun 3-6, Madrid, Spain..
9. 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 Lancet2017; 390(10100):1211–59.
10. James SL et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. The Lancet 2018; 392(10159):1789–858.
11. Latts LM et al. Hyperkalemia Is Prevalent in Patients with Cardiorenal Comorbidities. presented at: ISPOR 20th Annual International Meeting, 2015 May 16 - 20, Philadelphia PA.
12. LOKELMA® (sodium zirconium cyclosilicate) US Prescribing Information; last update: Oct 2020 [cited 23 Nov 2020]. Available from: URL: https://www.azpicentral.com/lokelma/lokelma.pdf.
13. 
Kosiborod M et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: The HARMONIZE randomized clinical trial. JAMA 2014; 312(21):2223–33.
Approval ID: Z4-29004 | Date of Preparation: November 2020