Summary Basis of Decision for Lokelma

 

Clinical Pharmacology

Lokelma (sodium zirconium cyclosilicate) is a non-absorbed, non-polymer inorganic powder with a uniform micropore structure that preferentially captures potassium in exchange for hydrogen and sodium cations. In vitro, sodium zirconium cyclosilicate is highly selective for potassium ions, even in the presence of other cations such as calcium and magnesium. Sodium zirconium cyclosilicate increases fecal potassium excretion through binding of potassium throughout the lumen of the gastrointestinal tract. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, which reduces potassium absorption and thus lowers serum potassium levels.

The clinical pharmacology program consisted of two studies ZS-006 and ZS-009. Study ZS-006 was conducted to examine the effect of Lokelma administered at 5 g or 10 g once daily for 4 days on sodium and potassium excretion in healthy subjects receiving a standardized diet. Dose-dependent reduction in serum potassium concentration and total urinary potassium excretion were accompanied by mean increases in fecal potassium excretion. No statistically significant changes in urinary sodium excretion were observed in this study. Moreover, the effect of sodium zirconium cyclosilicate on the pharmacokinetics of nine different drugs was assessed in healthy volunteers in the Study ZS-009. Lokelma can transiently increase gastric pH, resulting in changes in solubility and absorption kinetics of co-administered drugs with pH-dependent bioavailability. Therefore, oral medications with gastric pH-dependent bioavailability should be administered at least two hours before or two hours after the administration of Lokelma.

There is limited clinical trial experience regarding the use of Lokelma in patients with serum potassium concentrations greater than 6.5 mmol/L.

For further details, please refer to the Lokelma Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The potassium-lowering effects of Lokelma have been demonstrated in two randomized, double-blind, placebo-controlled trials (ZS-003 and ZS-004) in patients with hyperkalemia. The two studies tested the initial effect of Lokelma to correct hyperkalemia during a 48-hour period (correction phase) and then, to maintain normokalemia (maintenance phase). These studies included patients with chronic kidney disease (58%), heart failure (10%), diabetes mellitus (62%), and renin-angiotensin-aldosterone system inhibitor therapy (68%). Furthermore, two open-label studies (ZS-004E and ZS-005) tested the long-term safety of Lokelma.

Placebo-Controlled Studies

Study ZS-003: A Phase III Multicentre, Two-phase, Multi-dose, Prospective, Randomized, Double-blind, Placebo-controlled Study to Investigate the Safety and Efficacy of Sodium Zirconium Cyclosilicate (Microporous, Fractionated, Protonated Zirconium Silicate), an Oral Sorbent, in Subjects with Mild to Moderate Hyperkalemia

The aim of this study was to perform a controlled evaluation of the safety and efficacy of four different doses of sodium zirconium cyclosilicate administered three times daily (TID) for 48 hours in patients with mild to moderate hyperkalemia (serum potassium between 5.0-6.5 mmol/L) at baseline.

The primary efficacy endpoint was the difference in the exponential rate of change in serum potassium levels during the initial 48 hours of study drug treatment between the placebo-treated and Lokelma-treated patients.

A total of 753 patients with hyperkalemia were randomized equally to receive double-blind treatment with Lokelma (1.25 g, 2.5 g, 5 g, or 10 g) or a placebo administered TID for the initial 48 hours (acute phase). This was then followed by a randomized dose of Lokelma (1.25 g, 2.5 g, 5 g, and 10 g) or placebo administered once daily (QD) in the morning for 12 days (subacute phase). For the subacute phase, normokalemic patients who received Lokelma in the acute phase were randomized to receive either Lokelma at the same acute phase dose or placebo in a 1:1 ratio administered QD, whereas patients who received placebo in the acute phase were randomized to receive either 1.25 g or 2.5 g of Lokelma administered QD. During the acute phase (study days 1 and 2), all randomized patients received the study drug TID with meals. All patients who completed the acute phase and had i-STAT potassium values within the normal range (3.5 to 4.9 mmol/L) on the morning of study day 3 were to enter into the subacute phase (extended dosing) during which the study drug was to be administered QD with breakfast.

Results from this study demonstrated that Lokelma showed dose-dependent reductions in serum potassium at the 2.5 g, 5 g, and 10 g doses compared to a placebo. Mean serum potassium reduction was 0.7 mmol/L and 86% of patients had normal potassium values within 48 hours at the 10 g dose TID. Patients with higher baseline potassium levels had a greater response to Lokelma. In the maintenance phase, the analysis demonstrated statistically significant superiority of the Lokelma 5 g and 10 g doses compared with placebo. The number of normokalemic days (i.e., serum potassium levels between 3.5 and 5.0 mmol/L) were statistically significantly greater with Lokelma 10 g QD, 5 g QD, and 2.5 g QD compared to a placebo.

Study ZS-004: A Phase III Multicentre, Multi-phase, Multi-dose, Prospective, Randomized, Double-blind, Placebo-controlled Maintenance Study to Investigate the Safety and Efficacy of Sodium Zirconium Cyclosilicate, an Oral Sorbent, in Subjects with Hyperkalemia

The aim of this study was to evaluate the efficacy and safety of three different doses of sodium zirconium cyclosilicate administered QD for 28 days in maintaining normokalemia (serum potassium between 3.5 - 4.9 mmol/L, inclusive) in patients with hyperkalemia (i-STAT potassium level ≥5.0 mmol/L) at baseline and who achieved normokalemia within 2 days of acute therapy.

The primary efficacy endpoint was the number of days patients remained normokalemic during the 28-day double-blind randomized maintenance phase.

A total of 258 patients with hyperkalemia received 10 g of Lokelma administered TID for 24 to 72 hours (open-label acute phase). Patients who achieved normokalemia (i-STAT potassium values from 3.5 to 4.9 mmol/L, inclusive) on the morning of Study Day 2 (after 3 doses of 10 g Lokelma), Study Day 3 (after 6 doses of 10 g Lokelma) or Study Day 4 (after 9 doses of 10 g Lokelma) were then, in a double-blind fashion, randomized in a 4:4:4:7 ratio to receive one of three doses of Lokelma (2.5 g, 5 g, and 10 g) or a placebo control QD for the following 28 days (double-blind randomized maintenance phase).

Results from this study demonstrated that reductions in potassium were observed 1 hour after the first 10 g dose of Lokelma. Median time to normokalemia was 2.2 hours, with 66% of patients achieving normokalemia within 24 hours and 88% within 48 hours. Of these 258 patients, 237 patients (92%) achieved normokalemia at end of the correction phase and were then randomized in a double-blind fashion to one of three doses of Lokelma (5 g, 10 g, or 15 g) or a placebo QD for 28 days. In this maintenance phase, the primary endpoint was the mean serum potassium values obtained from study Day 8 to Day 29. Administration of the Lokelma 5 g, 10 g, and 15 g QD doses resulted in mean serum potassium levels of 4.8, 4.5, and 4.4 mmol/L, respectively, versus 5.1 mmol/L reported with placebo (p≤0.0001 for all doses). The proportion of patients with average serum potassium <5.1 mmol/L from study Day 8 to Day 29 was statistically significantly higher with Lokelma (i.e., 80%, 90%, and 94% for the 5 g, 10 g and 15 g QD doses, respectively), compared with placebo (46%) and the analysis of normokalemic patients showed consistent results. One hundred and twenty-three patients who completed the ZS-004 28-day maintenance phase on Lokelma, entered the 11-month open-label extension phase (Study ZS-004E). During the study Day 8 to Day 337, the proportion of patients with mean serum potassium ≤5.1 mmol/L was 88% with a mean serum potassium level of 4.66 mmol/L. Eighty percent of patients were considered normokalemic and less than 1% had levels below 3.5 mmol/L.

Long-Term Clinical Studies

Study ZS-004E: A Phase III Multicentre, Multi-phase, Multi-dose, Prospective, Randomized, Double-blind, Placebo-controlled Maintenance Study to Investigate the Safety and Efficacy of Sodium Zirconium Cyclosilicate, an Oral Sorbent, in Subjects with Hyperkalemia

The aim of this study was to generate open-label, long-term safety, tolerability, and efficacy follow-up data in patients with hyperkalemia who participated in Study ZS-004, evaluating Lokelma doses from 5 g every other day (QOD) to 15 g QD.

The primary efficacy endpoint was the proportion of patients with average serum potassium ≤5.1 mmol/L during the extended dosing phase, study Days 8 to 337 inclusively.

This study was conducted on an outpatient basis at 30 global sites. All patients who completed the Study ZS-004 extended dosing phase study Day 29, had i-STAT potassium values between 3.5 and 5.5 mmol/L, and who continued into the open-label extension study, entered into the extended dosing phase and started on open-label Lokelma at a dose of 10 g QD. All patients with i-STAT potassium values >5.5 mmol/L at the Study ZS-004 extended dosing phase study Day 29 Visit who continued into the open-label extension study underwent an acute phase, where they received Lokelma 10 g TID for 24 (3 doses) or 48 hours (6 doses), depending on their daily i-STAT potassium measurement.

For patients who discontinued treatment during Study ZS-004 due to hypo- or hyperkalemia, a baseline potassium value was determined within 1 day of taking the first dose of Lokelma by taking two potassium measurements (i-STAT and central laboratory) at 0 and 60 minutes (±10 minutes). If the mean i-STAT value was between 3.5 and 5.5 mmol/L, inclusive, patients entered the extended dosing phase and received Lokelma 10 g QD. If the mean i-STAT potassium value was >5.5 mmol/L, patients entered the acute phase.

Patients entering the acute phase received the study drug TID with meals for either 1 day (3 doses) or 2 days (6 doses), depending on the i-STAT potassium values. Patients who attained normokalemia (i-STAT potassium between 3.5 and 5.0 mmol/L, inclusive) after either 24 or 48 hours of treatment entered the extended dosing phase. Any patient whose i-STAT potassium level was not within the normal range (i-STAT potassium between 3.5 and 5.0 mmol/L, inclusive) on the morning of acute phase study Day 3 exited from the study and did not progress into the extended dosing phase.

Patients who entered into the extended dosing phase took the first dose of study drug in the clinic (extended dosing phase study Day 1) and thereafter took the study drug at home, in the morning just before breakfast, except on days with scheduled clinic visits, when study drug was taken in the clinic. Patients received up to 11 months (336 days) of additional treatment with open-label Lokelma and returned to the clinic on extended dosing phase study Days 8, 15, 22, 29, 36, 43, 50, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337 and 7 (± 1) days after the last dose of study drug for an end of study visit.

If a patient's i-STAT potassium value increased above 5.5 mmol/L during the extended dosing phase treatment at 10 g QD, the dose could be increased to 15 g QD. Conversely, if the i-STAT potassium value decreased to between 3.0 and 3.4 mmol/L, inclusive, the dose of Lokelma could be decreased in 5 g QD decrements. If a patient was on a 5 g QD dose and still developed i-STAT potassium values between 3.0 and 3.4 mmol/L, inclusive, the dose could be reduced to QD. Any time the Lokelma dose was adjusted or a renin-angiotensin-aldosterone system inhibitor or diuretic dose was adjusted or initiated, the patient returned to the site 7 (±1) days later for a potassium measurement and recording of adverse events and concomitant medications.

Results from this study demonstrated that during the study days 8 to 337, the proportion of patients with mean serum potassium ≤5.1 mmol/L was 88%. The mean serum potassium level was 4.66 mmol/L. The proportion of patients with mean serum potassium measurements between 3.5 and 5.0 mmol/L was 80% (range from 70.3% to 84.3%); below 3.5 mmol/L was less than 1%.

Study ZS-005: A Phase III Multicentre, Multi-dose, Open-label, Maintenance Study to Investigate the Long-term Safety and Efficacy of Sodium Zirconium Cyclosilicate (Microporous, Fractionated, Protonated Zirconium Silicate), an Oral Sorbent, in Subjects with Hyperkalemia

The aim of this study was to generate open-label, long-term (up to 12 months) safety and tolerability data for Lokelma in patients with hyperkalemia (serum potassium ≥5.1 mmol/L).

In this open-label maintenance study, long-term effects of Lokelma were assessed in 751 patients with hyperkalmia. The open-label maintenance study consisted of two phases, an acute phase and long-term maintenance phase. Patients who had 2 consecutive i-STAT potassium values ≥5.1 mmol/L entered the acute phase and received Lokelma 10 g TID for 24 to 72 hours, based on potassium values. Patients who achieved normokalemia within 72 hours (number of patients [n] = 746; 99%) entered the maintenance phase of the study. All patients in the maintenance phase received Lokelma at a starting dose of 5 g QD (minimum dose) which could be titrated to a maximum dose of 15 g QD, based on the patient's serum potassium levels. The duration of the long-term maintenance phase was Days 8 to 365.

Results from this study demonstrated that during the maintenance phase (Days 8 to 365), 75.6% of patients maintained normokalemia and the proportion of patients with a mean serum potassium ≤5.1 mmol/L was 88% (95% confidence interval 0.857, 0.908). The mean serum potassium levels increased following discontinuation of treatment.

Indication

The New Drug Submission for Lokelma was filed by the sponsor with the following indication, which Health Canada subsequently approved:

• Lokelma (sodium zirconium cyclosilicate) is indicated for the treatment of hyperkalemia in adult patients.

Overall Analysis of Efficacy

Overall, the efficacy of Lokelma for lowering the serum potassium levels has been demonstrated. In the placebo-controlled studies, Lokelma 10 g TID was proven to effectively reduce serum potassium to the normokalemic range within 48 hours (correction phase) in patients with hyperkalemia. This effect was observed regardless of baseline serum potassium levels, although the extent of reduction observed was greater in patients with higher baseline levels. The majority of patients maintained normokalemia thereafter when Lokelma was administered as a single daily dose in both placebo-controlled and long-term studies (maintenance phase). Lokelma reduced serum potassium and maintained normal serum potassium levels regardless of age, sex, race, comorbid disease (chronic kidney disease, heart failure or diabetes mellitus) or concomitant use of renin-angiotensin-aldosterone system inhibitors.

 

For more information, refer to the Lokelma Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

Clinical Safety

The primary evaluation of safety of Lokelma is based on the data accumulated from the two clinical studies previously described in the Clinical Efficacy section along with their open-label extensions. Additionally, safety data were also collected from several Phase II and Phase III clinical studies which supported the clinical development program. As a result, safety data have been collected in over 1,760 hyperkalemic patients including 507 patients exposed for at least one year.

 

Lokelma has high selectivity for potassium and therefore, does not have clinically significant effects on serum calcium and magnesium. Each 5 g of Lokelma contains approximately 400 mg of sodium and this drug preferentially captures potassium in exchange for hydrogen and sodium cations. Therefore, treatment with Lokelma increases the risk of edema which was reported as the most common adverse reaction in placebo-controlled studies, with an overall incidence of 5.7% with Lokelma versus 1.7 % with placebo. Most (53%) edema events were managed by initiating a diuretic or adjusting a diuretic dose; the remainder did not require treatment. Monitor for signs of edema, particularly in patients who need to restrict their sodium or are prone to fluid overload associated with comorbidities (e.g., heart failure or renal disease). In clinical studies, 4.1% of Lokelma-treated patients developed hypokalemia.

 

Gastrointestinal disorders such as constipation and nausea were also common adverse reactions. Other less common (<1%) adverse drug reactions include congestive cardiac failure, diarrhea, vomiting and gastroenteritis. The assessment of long-term safety and efficacy of Lokelma based on a study with an open-label design did not show new or significant safety signals after up to 12 months of treatment.

 

During correction of hyperkalemia, dose-dependent QTc prolongation was observed in both placebo-controlled and open-label long-term studies, as anticipated following changes in serum potassium. No case of serious cardiac arrhythmia, including Torsades de pointes, ventricular tachycardia, or sudden unexpected cardiac death were reported.

 

A total of 10 deaths was reported in patients treated with Lokelma in the placebo-controlled and open-label long-term clinical trials. All deaths were considered related to underlying diseases rather than to Lokelma.

 

Overall, edema and gastrointestinal disorders were the most commonly reported adverse reactions in clinical studies. Dose-related increases in the incidence of hypokalemia and QTc prolongation were observed. No clinically meaningful changes in serum calcium, magnesium, or phosphate were reported with Lokelma compared to placebo.

 

For more information, refer to the Lokelma Product Monograph, approved by Health Canada and available through the Drug Product Database.