Lokelma Granted Fast Track Designation in the U.S. to Reduce Cardiovascular Outcomes in Patients on Chronic Hemodialysis With Hyperkalemia

November 19, 2021 — AstraZeneca has been granted Fast Track Designation in the United States (US) for the development of LOKELMA^® (sodium zirconium cyclosilicate) to reduce arrhythmia-related cardiovascular outcomes in patients on chronic hemodialysis with recurrent hyperkalemia (HK). The designation is based on the potential of LOKELMA to reduce serious adverse CV outcomes in this patient population, addressing a significant unmet medical need. This is being investigated in the ongoing Phase III DIALIZE-Outcomes trial.

HK is a prevalent condition in patients with chronic kidney disease (CKD) and heart failure (HF), affecting 24% to 48% of patients with moderate to advanced (stage 3-4) CKD and/or HF, and it remains a burden once patients are on chronic hemodialysis. In patients with end-stage renal disease (ESRD) receiving chronic hemodialysis, HK has been associated with an increased risk of all-cause and CV mortality, and hospitalizations.

The Food and Drug Administration’s (FDA) Fast Track program is designed to accelerate the development and review of new medicines for the treatment of serious conditions where there is an unmet treatment need.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca said: “The DIALIZE-Outcomes trial is the first ever cardiovascular outcomes trial with a potassium binder in hemodialysis and has the potential to transform standard of care for these patients. The FDA decision demonstrates the importance of this trial, which will offer important information on LOKELMA’s ability to reduce potentially deadly cardiovascular complications associated with hyperkalemia for patients on chronic hemodialysis.”

The DIALIZE-Outcomes trial is part of the CRYSTALIZE evidence program, which is comprised of over 50 clinical and real-world evidence studies researching the potential benefit of LOKELMA in the management of HK across the cardiorenal spectrum. The DIALIZE-Outcomes trial is currently underway with results expected in 2024. 

LOKELMA is a highly selective, oral potassium-removing agent currently approved in the US, EU, Canada, Hong Kong, China, Russia, Japan and other countries for the treatment of HK. In 2020, the FDA and the European Commission (EC) approved label updates in the US and EU, respectively, to include a dosing regimen specifically to treat HK in patients with ESRD on chronic hemodialysis.

IMPORTANT SAFETY INFORMATION FOR LOKELMA^® (sodium zirconium cyclosilicate)

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, but the extent of absorption by the patient is unknown. In clinical trials of LOKELMA^® in patients who were not on dialysis, edema was observed and 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
• In a clinical trial of LOKELMA^® in patients on chronic hemodialysis in which most patients were treated with doses of 5 g to 10 g once daily on non-dialysis days, there was no difference in the mean change from baseline in interdialytic weight gain (a measure of fluid retention) between the LOKELMA^® and placebo groups
• Hypokalemia in Patients on Hemodialysis: Patients on hemodialysis may be prone to acute illness that can increase the risk of hypokalemia on LOKELMA^® (eg, illnesses associated with decreased oral intake, diarrhea). Consider adjusting LOKELMA^® dose based on potassium levels in these settings
• Diagnostic Tests: LOKELMA^® has radio-opaque properties and, therefore, may give the appearance typical of an imaging agent during abdominal X-ray procedures

ADVERSE REACTIONS: The most common adverse reaction in non-dialysis patients 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 non-dialysis patients treated with 5 g, 10 g, and 15 g of LOKELMA once daily, respectively vs 2.4% of non-dialysis 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 READ FULL PRESCRIBING INFORMATION.

Notes

Hyperkalemia
Hyperkalemia is characterized by high levels of potassium in the blood, generally defined as greater than 5.0 meq/L. Many people living with chronic kidney disease (CKD) have hyperkalemia despite being on hemodialysis and often experience fluctuations in their potassium levels. More than 500,000 patients in the US are living with dialysis-dependent ESRD, and in Europe approximately 300,000 patients with ESRD are undergoing hemodialysis. Despite adequate hemodialysis, up to 25% of patients have serum potassium >5.5 meq/L. Patients with high variability in potassium levels between dialysis sessions are at significant risk of arrhythmias, which can lead to cardiac arrest. Worldwide, there are an estimated 850 million and 64 million people living with CKD and HF respectively with hyperkalemia occurring in an estimated 24% to 48% of patients with moderate to advanced (stage 3-4) CKD and/or HF.

DIALIZE-Outcomes
DIALIZE-Outcomes is a Phase III randomized, double-blind, placebo-controlled, multicenter

study evaluating the effect of LOKELMA on arrhythmia-related cardiovascular outcomes in patients on chronic hemodialysis with recurrent hyperkalemia. The study consists of a 4-week dose-titration period followed by patient visits every 3 months over an average of 2 years. This is an international study involving approximately 300 sites across the US, Canada, Russia, Europe, Asia, and South America.

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 odorless, tasteless and stable at room temperature. LOKELMA is indicated for the treatment of hyperkalemia in adults including patients on chronic hemodialysis.

AstraZeneca in CVRM
Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s three 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 and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection 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 CV health for millions of patients worldwide.

About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization 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. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.