Challenges and Recommendations for Treating Hyperkalemia in Adults

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The prevalence of hyperkalemia is considerably greater in patients with chronic kidney disease (CKD) compared to the general population.¹  The ability to maintain normal serum potassium levels is reduced in patients with CKD due to decreasing capacity to excrete potassium.¹ There are some treatment options available to help patients reduce serum potassium levels and maintain normokalemia, but long-term data have been limited until recent years.

In 2018, the US Food and Drug Administration (FDA) approved LOKELMA^® (sodium zirconium cyclosilicate) 10 g for oral suspension, an oral potassium binder, which is indicated for the treatment of hyperkalemia in adults.² LOKELMA should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action.²

Kerry Cooper, MD, Vice President of US Medical Affairs, Renal at AstraZeneca, further discussed the unmet treatment need in the hyperkalemia market and the role of LOKELMA in this patient population.

See Important Safety Information for LOKELMA below.

Q: Hyperkalemia is garnering more attention. Can you describe the condition and the current treatment landscape?
A: Hyperkalemia is a chronic condition characterized by elevated potassium levels in the blood. The incidence of hyperkalemia in patients with advanced stages of CKD and presence of comorbidities can be as high as 40% to 50%.¹ If left untreated, hyperkalemia can worsen. Other causes of hyperkalemia include heart failure, diabetes, hypertension, and certain drugs, such as renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, which are used to treat patients with these conditions.¹ So, I think hyperkalemia is garnering more attention because there’s still a significant need to treat patients with CKD who have this complication.

Traditionally, chronic management of non-life threatening hyperkalemia has generally centered around reducing potassium intake through diet restrictions, reducing or eliminating exacerbating factors – such as guideline-recommended RAASi treatment that can cause hyperkalemia, or using agents that can remove potassium from the body, such as thiazide or loop diuretics.^3-5

Additionally, potassium binders, such as LOKELMA, are a treatment option that can also remove potassium from the body.

Q: Can you discuss the need for innovation in the treatment and management of hyperkalemia? What encouraged AstraZeneca to focus on this condition and advance more research and development in this space?
A: While hyperkalemia affects an estimated 3.7 million people in the US,⁶ awareness of the disease and its impact on CKD remains low.¹ Prior to additional treatment options being introduced in recent years, innovation in the treatment of hyperkalemia remained stagnant for decades. As an organization, we’re committed to continuing to address the unmet needs in this space.

Understanding the substantial consequences that can be associated with uncontrolled potassium levels, AstraZeneca recognized the importance of bringing new medicines to patients. For instance, in 2015, AstraZeneca acquired ZS Pharma, which gave us access to the potassium-binding compound ZS-9, now known as LOKELMA, which is approved in the United States for the treatment of hyperkalemia in adults.⁷

It’s AstraZeneca’s belief that driving increased awareness and diagnosis of high potassium, as well as advancing new treatments and standards of care, including LOKELMA, will help shed light on the risks of hyperkalemia.

Q: How can LOKELMA help patients with hyperkalemia lower their potassium levels, and what makes LOKELMA unique?
A: LOKELMA is an innovative, highly selective potassium binder that’s unique in that it has a crystal lattice structure, and it preferentially captures potassium and exchanges it for hydrogen and sodium.^2,8 In vitro, LOKELMA has a high affinity for potassium ions, even in the presence of other cations such as calcium and magnesium.²

Based on an in vitro study, LOKELMA has shown that it begins to capture potassium as early as the small intestines,⁸ where the majority of dietary potassium absorption occurs.⁹ LOKELMA is not a polymer. It is insoluble and does not expand in water, so it is not expected to swell within the GI tract.⁸

Q: Is LOKELMA currently being tested in other patient populations for the treatment of hyperkalemia?
A: AstraZeneca continues to invest in a robust clinical program for LOKELMA^® (sodium zirconium cyclosilicate) to assess its potential to treat a diverse range of patient populations.

“Understanding the substantial consequences that can be associated with uncontrolled potassium levels, AstraZeneca recognized the importance of bringing new medicines to patients.”

KERRY COOPER, MD

LOKELMA’s FDA approval was based on data from the safety and efficacy from three clinical trials.¹⁰

Study 1 Design: In the initial phase of a multicenter, 2-part, double-blind, randomized, placebo-controlled, phase 3 trial, 753 patients received LOKELMA (1.25, 2.5, 5, or 10 g) or placebo three times daily with meals for the initial 48 hours.² The study met its primary endpoint (difference in exponential rate of change in serum K⁺ levels during the initial 48 hours of LOKELMA [for the 2.5, 5, and 10 g dose groups] vs placebo), demonstrating a greater reduction in serum K⁺ levels for patients receiving LOKELMA compared to placebo (P<0.001).² Patients with a higher starting potassium level had a greater response to LOKELMA.² Reductions in serum potassium were observed as early as one hour after initiation and serum potassium concentrations continued to decline over the 48-hour treatment period.² LOKELMA effectively lowered potassium levels in patients with chronic kidney disease (CKD), heart failure, diabetes, and those taking RAASi therapy.²

Study 2 Design: In an open-label initial phase of a multicenter, 2-part, phase 3 trial, in which 258 patients received 10 g LOKELMA administered three times daily with meals for 48 hours, patients who achieved a K⁺ level between 3.5 and 5.0 mEq/L were randomized (4:4:4:7) to receive 5 g, 10 g, or 15 g LOKELMA^® (sodium zirconium cyclosilicate) or placebo once daily taken just before breakfast for 28 days in the withdrawal phase.² A total of 123 patients who completed the withdrawal phase participated in the 11-month, open-label extension study.² In the initial open-label phase of Study 2, 92% of patients achieved normal serum K⁺ levels within 48 hours from baseline.² The average serum K⁺ levels decreased from 5.6 mEq/L to 4.5 mEq/L (with LOKELMA 10 g three times daily for 48 hours with meals).² During the randomized withdrawal phase of Study 2, the study met its primary endpoint (mean serum K⁺ value over days 8-29), with LOKELMA 5 g, 10 g, and 15 g maintaining lower mean serum K⁺ levels than placebo (4.8 mEq/L, 4.5 mEq/L, and 4.4 mEq/L vs 5.1 mEq/L, respectively; p≤0.001 for all doses).² For patients who continued in the 11-month extension phase, the treatment effect on serum potassium was maintained with continued treatment.² The initial recommended treatment of hyperkalemia is 10 g administered three times a day for up to 48 hours. The approved recommended maintenance treatment dose of LOKELMA is 10 g once daily.² Serum potassium should be monitored and dose of LOKELMA adjusted at one-week intervals or longer in increments of 5 g dose based on the serum potassium level and the desired target range. The recommended maintenance dose range is from 5 g every other day to 15 g daily.²

In general, LOKELMA was shown to be well tolerated.² There are no GI side effects listed in the LOKELMA Prescribing Information; however, there were GI adverse events observed in the clinical studies.^2,11-14 In placebo-controlled trials in which patients were treated with once-daily doses of LOKELMA for up to 28 days, edema was reported in 4.4%, 5.9%, and 16.1% of patients receiving 5 g, 10 g, and 15 g LOKELMA, respectively, compared with 2.4% of patients receiving placebo.² In longer-term, uncontrolled trials, in which most patients were maintained on doses <15 g daily, edema (including edema, generalized edema, and peripheral edema) was reported in 8% to 11% of patients.²

IMPORTANT SAFETY INFORMATION FOR LOKELMA^® (sodium zirconium cyclosilicate) 10 g FOR ORAL SUSPENSION

WARNINGS AND PRECAUTIONS:

·Gastrointestinal Adverse Events in Patients with Motility Disorders: Avoid LOKELMA in patients with severe constipation, bowel obstruction or impaction, including abnormal post-operative bowel motility disorders. LOKELMA has not been studied in patients with these conditions and it may be ineffective and may worsen gastrointestinal conditions

·Edema: Each 5 g dose of LOKELMA contains approximately 400 mg of sodium. In clinical trials of LOKELMA, edema was generally mild to moderate in severity and was more commonly seen in patients treated with 15 g once daily. Monitor for signs of edema, particularly in patients who should restrict their sodium intake or are prone to fluid overload (eg., heart failure or renal disease). Advise patients to adjust dietary sodium, if appropriate. Increase the dose of diuretics as needed

ADVERSE REACTIONS: The most common adverse reaction with LOKELMA was mild to moderate edema. In placebo-controlled trials up to 28 days, edema was reported in 4.4%, 5.9%, 16.1% of patients treated with 5 g, 10 g and 15 g of LOKELMA once daily, respectively vs 2.4% of patients receiving placebo.

DRUG INTERACTIONS: LOKELMA can transiently increase gastric pH. In general, oral medications with pH-dependent solubility should be administered at least 2 hours before or 2 hours after LOKELMA. Spacing is not needed if it has been determined the concomitant medication does not exhibit pH-dependent solubility.

INDICATION AND LIMITATION OF USE
LOKELMA is indicated for the treatment of hyperkalemia in adults.
LOKELMA should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action.

Please see full Prescribing Information for LOKELMA.

Q: What is AstraZeneca’s ambition in kidney care?
A: AstraZeneca’s efforts are focused on helping patients better navigate and manage the complexities associated with renal care. Our patient-centric approach drives our research and development to investigate treatment options that will help address patients’ unmet needs, and it is our ambition that one day we will be able to modify or potentially halt the natural course of renal disease.

Kerry Cooper, MD, is the Vice President of US Medical Affairs, Renal at AstraZeneca. He has more than 30 years of experience in nephrology and has held several leadership roles, most notably as an executive medical director at Amgen. Prior to Amgen, Dr Cooper served as the dialysis unit medical director at Scottsdale Nephrology, as well as Arizona Kidney Disease & Hypertension Center. Dr Cooper’s expertise lies in the development of medical strategy, engagement, and communication within the healthcare community, including supporting the value proposition of renal-cardio therapies to enable access for appropriate patients. Dr Cooper received his Doctor of Medicine degree at the Yale School of Medicine in 1979.

References

1. National Kidney Foundation. Clinical update on hyperkalemia. Published 2014.
2. LOKELMA^® (sodium zirconium cyclosilicate) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018.
3. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-221. doi: 10.1056/ NEJMoa1410853.
4. Kovesdy CP. Epidemiology of hyperkalemia: an update. Kidney Int Suppl. 2016;6(1):3-6. doi: 10.1016/j.kisu.2016.01.002.
5. American Heart Association. Types of blood pressure medication. https://www.heart.org/en/health-topics/high-blood-pressure/changes-you-can-make-to-manage-high-blood-pressure/types-of-blood-pressure-medications. Published 2017.
6. Betts KA, Woolley JM, Mu F, McDonald E, Tang W, Wu EQ. The prevalence of hyperkalemia in the United States. Curr Med Res Opin. 2018;34(6):971-978. doi: 10.1080/03007995.2018.
7. AstraZeneca. AstraZeneca completes acquisition of ZS Pharma. https://www.astrazeneca.com/media-centre/press-releases/2015/AstraZeneca-completes-acquisition-of-ZS-Pharma-17122015.html#. Accessed November 6, 2019.
8. Stavros F, Yang A, Leon A, Nuttall M, Rasmussen HS. Characterization of structure and function of ZS-9, a K+ selective ion trap. PLoS One. 2014;9(12):e114686. doi: 10.1371/ journal.pone.0114686.
9. Demigné C, Sabboh H, Rémésy C, Meneton P. Protective effects of high dietary potassium: nutritional and metabolic aspects. J Nutr. 2004;134(11):2903-2906. https://doi. org/10.1093/jn/134.11.2903.
10. AstraZeneca. LOKELMA^™ approved in the US for the treatment of adults with hyperkalemia. https://www.astrazeneca-us.com/media/press-releases/2018/lokelma-approved-in-the-us-for-the-treatment-of-adults-with-hyperkalemia-05182018.html. Published May 18, 2018. Accessed December 5, 2019.
11. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. [article and supplementary material]. N Engl J Med. 2015;372(3):222-231. doi:10.1056/ NEJMoa1411487. Accessed January 8, 2020.
12. Kosiborod M, Rasmussen HS, Lavin P, 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):2223-2233. doi: 10.1001/jama.2014.15688.
13. Spinowitz BS, Fishbane S, Pergola PE, et al. Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: a 12-Month Phase 3 Study. Clin J Am Soc Nephrol. 2019;14(6):798-809. doi: 10.2215/CJN.12651018.
14. Roger SD, Spinowitz BS, Lerma EV, et al. Efficacy and Safety of Sodium Zirconium Cyclosilicate for Treatment of Hyperkalemia: An 11-Month Open-Label Extension of HARMONIZE. Am J Nephrol. 2019;50(6):473-480. doi: 10.1159/000504078.

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