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.

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