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Cyclosilicate (SZC) The image can then be scaled within
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SZC Crystal Structure

• Inorganic crystalline potassium binder;

not a polymer

• Exchanges H+ and Na+ for K+

K+ • Highly selective for K+; binding site width

and K+ ionic diameter are similar

• Insoluble, highly stable, and does not

expand in water

• Not systemically absorbed

Average Binding-Site Width:

3Å

SZC = sodium zirconium cyclosilicate.

Stavros F et al. PLoS One. 2014;9:e114686.
SZC Mechanism of Action
Highly Selective for K+
SZC preferentially captures for K+ in exchange for Na+ and H+,
even in the presence of Ca2+ and Mg2+
Relative Diameters of Major Cations*
Due to similar ionic diameters, K + and NH4+ fit best
in SZC pores, which are ~3 Å in size
3.5
2.98 2.96
3.0

Diameter (Å)
2.5 2.34 2.30
2.00
2.0
1.5 1.44

1.0
K+ NH4+ Na+ H3O+ Ca2+ Mg2+
0.5
0.0 K+ NH4 Na+ H3O+ Ca2 Mg2
Dehydrated Na+ and Ca2+ ions are too small to interact with the oxygen
For illustrative purposes only.
therefore entering the SZC pore is energetically unfavorable
No effect on serum Ca2+ and Mg2+ concentrations

Based on in vitro data, SZC may begin working immediately in the small intestine resulting in the early capture of K +

*Unhydrated.
SZC = sodium zirconium cyclosilicate.
Stavros F et al. PLoS One. 2014;9:e114686.
In Vitro, the Ion Affinity of SZC Has Been Shown to be K+ >> Na+, Ca2+
K+
Hydrated Ion SZC Pore Window • SZC pores utilize an energetically favorable size
selectivity filter
• K+ ion is more than balanced by the energy
regained by the interaction with oxygen
• Dehydrated Na+ and Ca2+ ions are too small to
interact with the oxygen

Na+ Ca2+
Hydrated Ion SZC Pore Window Hydrated Ion SZC Pore Window

Na+ Na+ Ca2+

Ca2+

SZC = sodium zirconium cyclosilicate.

Stavros F et al. PLoS One. 2014;9(12):e114686.
SZC Binds K+ Throughout the GI Tract
Small Intestine Large Intestine Exit

K+ Ca2+
Mg2+ K+ Mg2+
Ca 2+

Ca2+
K+ H
+
K+ K+ K K+
+
K+

H+ K+ K+
Mg2+
Mg Ca2+
K+
2+

Na+ K+ K+ K+ Na+
K+
K +

K+K K+ K+
+
K+K K+ K+
+
K+ K+ H+ K+ K+
H+ H+ H+
KKK++ KK++ K+
+
Na+ K+ Na+ KKK++ KK++ K+
+
Na+ Na+ Na+ K+ Na+

SZC SZC SZC SZC SZC SZC

• Based on in vitro data, SZC may begin working immediately in the small intestine to preferentially capture
K+
• K+ is exchanged for hydrogen and sodium

For illustrative purposes only.

GI = gastrointestinal; SZC = sodium zirconium cyclosilicate.
Stavros F et al. PLoS One. 2014;9(12):e114686.
SZC and SPS: Selectivity for K+
• In vitro studies were designed to examine the ion exchange capacities of SZC and SPS
• K+, Ca2+, and Mg2+ concentration ratio of 1:1:1
SZC Cation Bindinga Selectivity Ratio†
96%

• SZC displayed
25c 9.3x more K+ binding
2%b 2%b capacity than SPS
K+ Ca2+ Mg2+
K+ Ca2+ Mg
2+
• SZC was >125x more
selective for K+ than
SPS Cation Bindinga SPS
59%
• SPS was more
0.2
18% 24% selective for Mg2+ and
Ca2+ than K+
K++ Ca2+ Mg2+
K Ca 2+
Mg2+

aThe graph shows the ion exchange capacities in percentages which were calculated from mEq/g of SZC (2.7/0.05/0.05) and SPS (0.3/1.0/0.4 ) in a solution containing a 1:1:1 concentration ratio of K+, Ca2+, and Mg2+.These values are not representative of the K+ binding capacity of SZC or SPS in vivo; bSelectivity ratio = [K+] /

[Ca2+] + [Mg2+]; cExchange capacity of Ca2+ and Mg2+ was below the 0.05 detection limit; therefore, 0.05 was assumed for calculation purposes.

SPS = sodium polystyrene sulfonate; SZC = sodium zirconium cyclosilicate.

Stavros F et al. PLoS One. 2014;9(12):e114686.

 Selected characteristics of potassium binders
Traditional Potassium Binder Novel Potassium Binder

Calcium polystyrene sulfonate (CPS) Sodium zirconium cyclosilicate (SZC)

Mechanism Nonspecific calcium cation-exchange resin1 Selective potassium binding in exchange for sodium and hydrogen 3

Action may be delayed for

Onset 1 hour4
1 to 2 days1
15 g orally 3 to 4 times daily2
10 g orally 3 times daily for a maximum of 72 hours (starting dose)4*
Dosing
5 g orally once daily (recommended starting maintenance dose) 4
30 g given as retention enema once daily 2

Treatment of HK associated with anuria or severe oliguria and treatment of Treatment of HK in adults; there is limited experience in patients with serum
Indication
HK in patients requiring dialysis5 K+ levels greater than 6.5 mmol/L4

Location Colon1 Entire intestinal tract3

Cases of intestinal necrosis, which may be fatal, and other serious GI

Adverse events Hypokalaemia and oedema-related events 4
adverse events have been reported2

Antacids, laxatives, digitalis, sorbitol, lithium, levothyroxine 2 Administer at least 2 hours before or 2 hours after oral medications with
Drug Interactions
Administer at least 3 hours before or 3 hours after other oral medications 2 clinically meaningful gastric pH–dependent bioavailability 4

*Dose differs for patients on haemodialysis- refer to SmPC for more information.4
References and abbreviations in slide notes.
FDA = US Food and Drug Administration; GI = gastrointestinal; HK = hyperkalaemia; SmPC = Summary of Product Characteristics.
1. Resonium calcium. Prescribing Information. Sanofi-Aventis Canada.
2. Calcium resonium. Summary of product characteristics. Sanofi.
3. Garimella PS, Jaber BL. Patiromer for hyperkalemia in diabetic CKD: a new kid on the block. Am J Kidney Dis. 2016;67(4):545-547. doi:10.1053/j.ajkd.2016.01.001
4. Lokelma. Product Information Indonesia. 2023
 Lokelma (Sodium Zirconium Cyclosilicate)
is indicated for the treatment of hyperkalaemia in adult patients

FOR ADULT (NON-DIALYSIS) PATIENTS

FOR HAEMODIALYSIS PATIENTS

Correction phase Maintenance phase RECOMMENDED STARTING DOSE

3× /daya,b 1× /daya,b 1× /non-dialysis days

10 g 5g 5g
for 24 to 72 hours for up to 1 year
To establish normokalaemia, the dose may be titrated up or down weekly based
until normokalemia is achieveda,b To establish minimum effective dose, LOKELMA on the predialysis serum K+ after the long interdialytic interval
may be titrated The dose could be adjusted at intervals of one week in increments of 5 g:
• Up to 10 g once daily or • Up to 15 g once daily on non-dialysis days
• Down to 5 g once every other day
It is recommended to monitor serum K + weekly while the dose is adjusted. To
No more than 10 g once daily should maintain normokalaemia, it is recommended to monitor serum K + regularly (e.g.,
be used for maintenance therapy monthly or more frequently based on clinical judgement)

Serum K+ levels should be monitored regularly during treatment. Monitoring frequency will depend upon a variety of factors, including other medications, progression of CKD and dietary K+ intake. If severe hypokalaemia should occur,
LOKELMA should be discontinued and the patient is re-evaluated. LOKELMA should be administered at least 2 hours before or 2 hours after oral medications with clinically meaningful gastric pH-dependent bioavailability. Refer to full
Prescribing Information for more information including examples of such medicines.

a If normokalaemia is not achieved within 48 hours of treatment, the same regimen can be continued for an additional 24 hours. If normokalaemia is not achieved after 72 hours of treatment, other treatment approaches should be considered;
b Patients who miss a dose should be instructed to take the next usual dose at their normal time.
Lokelma Product Information Indonesia. 2023
 _______________________________

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SZC Clinical Trials (ZS-
004, ZS-004 E, ZS-005) The image can then be scaled within
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ZS-004 (HARMONIZE) + ZS-004E (Extension)
Study Designs
ZS-0041 ZS-004E (Extension)2
Phase III, multicenter, 2-phase prospective study in patients with Extension phase of patients who completed ZS-004 at 30 sites in US,
serum K+ ≥5.1 mmol/L at 44 nephrology, cardiology, general research South Africa, and Australia
sites in US, South Africa, and Australia

48-hR CORRECTION 28-day Maintenance 11-MONTH Maintenance

Open-Label Phase Double-blind Phase Open-Label Phase

Patients who achieved

Eligible patients†
normokalemia*

SZC 10 g QD
7: Placebo n=85

4: SZC 5 g QD
Randomization

SZC 10 g TID n=45 N=123

Ratio

N=258 4: SZC 10 g QD n=51 Titrated in 5 g QD increments or decrements

(maximum SZC 15 g QD; minimum SZC 5 QoD)
to maintain normokalemia (i-STAT K+ 3.5-5.0
4: SZC 15 g QD n=56 mmol/L)

Dose could be reduced to QoD for the remainder of the

study if serum K+ fell between 3.0-3.4 mmol/L at any time

*Proceeded to maintenance phase if patient achieved normokalemia (i-STAT K+ 3.5-5.0 mmol/L) by morning of study Day 3; †Two patients with i-STAT K+ >5.5 mmol/L at the end of ZS-004 entered the correction phase of ZS-004E where they received SZC 10 g TID and proceeded to the 11-month maintenance phase within 1
day once normokalemia (i-STAT K+ 3.5-5.0 mmol/L) was achieved. The remaining patients with i-STAT K+ 3.5-5.5 mmol/L at the end of ZS-004 immediately entered the 11-month maintenance phase to receive SZC 10 g QD.

QoD = every other day; SZC = sodium zirconium cyclosilicate; US = United States.

1. Kosiborod M et al. Article and protocol. JAMA. 2014;312:2223-2233; 2. Roger SD et al. Article and supplementary material. Am J Nephrol. 2019;50:473-480.
ZS-004 (HARMONIZE) + ZS-004E (Extension)
Key Inclusion and Exclusion Criteria

ZS-0041 ZS-004E2
• Completed ZS-004 randomized dosing phase or discontinued
• >18 years of age
due to hypo- or hyperkalemia and able to start ZS-004E
• Two consecutive i-STAT K+ values ≥5.1 mmol/L, with dosing within 2 days after last ZS-004 dose
no upper limit at entry • i-STAT K+ 3.5–6.2 mmol/L at ZS-004 study Day 29 visit, OR a
• Ability to have repeated blood draws mean i-STAT K+ 3.5–6.2 mmol/L for 2 consecutive
Key measurements at 0 and 60 minutes on correction phase Day
Inclusion 1/maintenance phase Day 1 if discontinued ZS-004 study due
Criteria to hypo- or hyperkalemia

• Dialysis
• Cardiac arrhythmia requiring immediate treatment
• Active treatment with resins (eg, SPS or sevelamer
• Dialysis
acetate), calcium acetate, calcium carbonate, or lanthanum
• Cardiac arrhythmia requiring immediate treatment
carbonate within 7 days
• Received alternative treatment for hyperkalemia during ZS-
• Treatment with lactulose, Xifaxan®, or other non-absorbed
Key 004 study
antibiotics for hyperammonemia within 7 days
• Diabetic ketoacidosis
Exclusion • Diabetic ketoacidosis
• Pseudohyperkalemia
Criteria • Pseudohyperkalemia

SPS = sodium polystyrene sulfonate.

1. Kosiborod M et al. Article and protocol. JAMA. 2014;312:2223-2233; 2. Roger SD et al. Supplementary material. Am J Nephrol. 2019;50:473-480.
 ZS-004 (HARMONIZE) + ZS-004E (Extension)
Mean Serum K+ Levels Across Correction, Maintenance, and Extension Phases
Correction Phase (48 hours) 1 Extension-MP (Days 1-337)2,‡
Maintenance Phase (Days 1-29) 1
SZC 10 g TID (n=258) (N=123)
5.8
K+ levels increased in
5.6 Placebo SZC 5 g† SZC 10 g† SZC 15 g†
Mean Serum K+ (mmol/L)

SZC titrated dose§ patients not

5.4 (n=82) (n=45) (n=50) (n=54) continuing on SZC
*
5.2 *
5.0 *
*
4.8
4.6 *
4.4
4.2
4.0 0 8 15 22 29 36 43 50 57 85 113 141 169 197 225 253 281 309 337 375
0 1 2 4 24 25 48 1 2 8 12 15 19 22 26 29 MP
BL
15 29 43 57 85 113 141 169 197 225 253 281 309 337
Off
Time (days) Drug
Time (hours) Time (days)
88% of patients receiving SZC maintained an average serum K + of
<5.1 mmol/L over 11 months
Mean decreases in serum K+ from HARMONIZE-CP BL
were observed at every time point during the Extension-MP,
ranging from –1.0 to –0.8 mmol/L (–17.8 to –14.4%; p ≤0.001 for all)

Note: Normokalemia defined as serum K+ 3.5–5.0 mmol/L. Error bars indicate 95% CI.
*p<0.001 vs. baseline; †p<0.001 vs. placebo during Days 8-29; ‡ITT population in Extension-MP consisted of patients who received ≥1 SZC dose with any post-Extension-CP BL safety data and
post-Extension-MP serum K+ measurements. Off-drug values were recorded at 7±1 days following the last dose of SZC; §Mean SZC doses to maintain normokalemia were 10 g QD in 73.2%,
>10 g QD in 13.0%, <10 g QD in 13.8% of patients.
BL = baseline; CP = correction phase; ITT = intent-to-treat; MP = maintenance phase; SZC = sodium zirconium cyclosilicate.
1. Kosiborod M et al. JAMA. 2014;312:2223-2233; 2. Roger SD et al. Article and supplementary material. Am J Nephrol. 2019;50:473-480.
ZS-004 (HARMONIZE)
Correction Phase: Mean Serum K+ Levels in Predefined Subgroups
SZC consistently reduced serum K+, regardless of comorbidities, use of RAASi therapy, or baseline K + level1-3

Mean Serum K+ Level With SZC 10 g TID at 0 and 48 Hours Across Prespecified Subgroups 1
6.2 6.2
Mean Serum K+ (mmol/L)

5.8 5.8

5.4 5.4

5.0 5.0

4.6 4.6

4.2 4.2

0 0
All CKD CKD HF* Diabetes Taking <5.5 5.5 to <6.0 ≥6.0
history* eGFR† mellitus* RAASi
Patient subgroups Baseline K+ level (mmol/L)
No. of patients: No. of patients:
Baseline 258 169 179 94 170 180 Baseline 119 100 39
48 hours 251 163 172 92 166 173 48 hours 115 99 37

Note: Normokalemia defined as serum K+ 3.5–5.0 mmol/L. Error bars indicate 95% CI.
*The definitions used to identify subjects with baseline comorbid conditions (across the ZS Pharma clinical development program) were based on custom lists of preferred terms. AstraZeneca has elected to use more recognized
definitions that are based on the standardized Medical Dictionary for Regulatory Activities query (narrow) for each comorbid condition. For example, in the original HF population (n=94), the mean change from baseline in K + was -1.173
mmol/L at 48 hours. Based on the AstraZeneca re-analysis, the percentage of patients with HF is 11% (28/251) with a mean change in K + of -1.196 mmol/L at 48 hours; 3 †Baseline eGFR <60 mL/min/1.73 m 2.1
CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; HF = heart failure; RAASi = renin–angiotensin–aldosterone system inhibitor; SZC = sodium zirconium cyclosilicate.
1. Kosiborod M et al. JAMA. 2014;312:2223-2233; 2. LOKELMA Product Information Indonesia. 2023; 3. In House Data, AstraZeneca Pharmaceuticals LP. LOKELMA (sodium zirconium cyclosilicate) oral suspension. Subgroups based on
comorbid conditions at baseline in ZS clinical studies. Doc ID-003819479. April 4, 2018.
ZS-004 Analysis in Baseline Serum K+ ≥6.5 mmol/L
Changes in K+ From Study Baseline Over 48 Hours
Reductions after
one SZC 10 g dose
7.0 • Serum K+ declined significantly by 0.7
and 0.9 mmol/L by 1 and 2 hours,
6.5 respectively
-0.7
Mean Serum K+ (mmol/L)

-0.9 • Higher K+ reductions were observed

* -1.2 for patients with higher baseline
6.0 serum K+
* -1.8

* • Median time to serum

5.5
K+ <6.0 mmol/L was 1.1 hour

5.0 *

Baseline SZC 10 g
4.5
0 1 2 24 48
Time, hours
n= 9 9 9 8 8

Note: Serum K+ concentration measured at 1, 2, 24 and 48 hours. Absolute reduction in serum K+ and median time to serum K+ <6.0 mmol/L was calculated. Error bars indicate 95% CI.
*p<0.01.
SZC = sodium zirconium cyclosilicate.
Levy P et al. Presented at: ACEP Scientific Assembly; October 26-29, 2015; Boston, MA.
ZS-004 (HARMONIZE)
Adverse Events
Correction Phase Maintenance Phase

Adverse Events SZC 10 g TID Placebo QD SZC 5 g QD SZC 10 g QD SZC 15 g QD

Occurring in ≥5% of Patients, n (%) (n=258) (n=85) (n=45) (n=51) (n=56)
Any event 20 (7.8) 27 (31.8) 24 (53.3) 15 (29.4) 25 (44.6)
Blood and lymphatic system disorders
Anemia 0 0 0 0 3 (5.4)
Gastrointestinal disorders*
Constipation 2 (0.8) 6 (7.1) 0 1 (2.0) 1 (1.8)
General disorders and administration-site conditions
Edema† 0 2 (2.4) 1 (2.2) 3 (5.9) 8 (14.3)
Metabolism and nutrition disorders
Hypokalemia (<3.5 mmol/L)‡ 0 0 0 5 (9.8) 6 (10.7)
Hypokalemia (reported as AE) 0 0 0 0 1 (1.8)
Infections and infestations
Nasopharyngitis 0 1 (1.2) 0 0 3 (5.4)
Upper respiratory tract infection 1 (0.4) 1 (1.2) 3 (6.7) 1 (2.0) 1 (1.8)

• No clinically relevant changes in serum electrolytes (Na+, Mg2+, or Ca2+), vital signs, blood pressure, heart rate, or body weight
• No dose-dependent increase in urinary sodium excretion

*Gastrointestinal adverse events were reported in 14% (12/85) in placebo group, 7% (3/45) in SZC 5 g group, 2% (1/51) in SZC 10 g group, and 9% (5/56) in SZC 15 g group;
†
Included terms edema, generalized edema, or peripheral edema as treatment-emergent adverse event. Of the 14 patients who developed edema, 5 patients in the SZC 15 g
group required change in therapy; ‡All cases of hypokalemia were mild (3.0–3.4 mmol/L) and resolved after dose reduction.
AE = adverse event; SZC = sodium zirconium cyclosilicate.
Kosiborod M et al. JAMA. 2014;312:2223-2233.
ZS-004 (HARMONIZE) + ZS-004E (Extension)
Summary

ZS-0041 ZS-004E2
• Mean serum K+ levels were significantly reduced • Over Days 8-337, 88.3% of patients treated with
with one SZC dose at 1 hour vs. baseline (p<0.001) SZC maintained mean serum K+ levels of
• Over Days 8-29: ≤5.1 mmol/L
• Significant reductions in mean serum K+ levels were
observed in all SZC groups vs. placebo
Efficacy • SZC 5 g, 10 g, and 15 g QD maintained serum K+ <5.1
mmol/L in 80%, 90%, and 94% of patients,
respectively (p<0.001 vs. placebo)
• SZC consistently reduced serum K+ regardless of
comorbidities (CKD, HF, and DM), RAASi therapy, or
baseline K+ level

• The most common AE in SZC-treated patients was • SZC was generally well tolerated
edema (2.2% in SZC 5 g, 5.9% in
SZC 10 g, and 14.3% in SZC 15 g vs. 2.4% in placebo) • The most common AEs (occurring in ≥5% of
Safety
patients) were hypertension, UTI, peripheral
edema, and constipation

Note: Normokalemia defined as serum K+ 3.5–5.0 mmol/L.

AE = adverse event; CKD = chronic kidney disease; DM = diabetes mellitus; HF = heart failure; RAASi = renin–angiotensin–aldosterone system inhibitor; UTI = urinary tract infection; SZC =
sodium zirconium cyclosilicate.
1. Kosiborod M et al. JAMA. 2014;312:2223-2233; 2. Roger SD et al. Article and supplementary material. Am J Nephrol. 2019;50:473-480.
ZS-005
Study Design
• Phase III, prospective, international, multicenter, open-label, single-arm, trial in patients with 2 consecutive i-STAT K + levels ≥5.1
mmol/L at entry and no protocol-mandated restrictions on diet
• 56 investigational sites: US, Australia, Europe, South Africa

DAY 1–3 12-Month Primary Efficacy Endpoints

• Correction phase:
Correction Phase Maintenance Phase • Proportion of patients who achieved
serum K+ of 3.5 to ≤5.0 mmol/L
• Maintenance phase (over Months 3-12):
Patients who achieved • Proportion of patients who maintained
normokalemia* mean serum
N=751 N=746 K+ ≤5.1 mmol/L and ≤5.5 mmol/L

Key Secondary Efficacy Endpoints

• Proportion of patients with mean serum K+
3.5-5.5 mmol/L over Months 3-12
5 g QD to start, then 5 g QoD or
SZC 10 g TID 5 g QD/10 g QD/15 g QD based on i-STAT K+ value
• Changes in serum K+ at other time points

*Patients who achieved normokalemia (i-STAT K+ 3.5–5.0 mmol/L) at any point during the correction phase were eligible to enter the subsequent 12-month maintenance phase.
QoD = every other day; SZC = sodium zirconium cyclosilicate; US = United States.
Spinowitz BS et al. Article and supplemental material. Clin J Am Soc Nephrol. 2019;14:798-809.
ZS-005
Key Inclusion and Exclusion Criteria

Key Key
Inclusion Exclusion
Criteria Criteria

• ≥18 years of age • Pseudohyperkalemia

• Two consecutive i-STAT K+ values, measured • Documented GFR <15 mL/min/1.73 m2
60 (±15) minutes apart, both ≥5.1 mmol/L within 90 days before study entry
within 1 day before first SZC dose on • Undergoing dialysis
correction phase Day 1 (both ≥5.1 mmol/L • Cardiac arrhythmias requiring immediate
and ≤6.5 mmol/L for patients in Germany) treatment
• Ability to have repeated blood draws or • Diabetic ketoacidosis
effective venous catheterization • Treatment with SPS or CPS within the
previous 3 days
• Treatment with lactulose, rifaximin, or
other non-absorbed antibiotics for
hyperammonemia within the previous
7 days

CPS = calcium polystyrene sulfonate; GFR = glomerular filtration rate; SPS = sodium polystyrene sulfonate; SZC = sodium zirconium cyclosilicate.
Spinowitz BS et al. Supplemental material. Clin J Am Soc Nephrol. 2019;14:798-809.
ZS-005
Mean Serum K+ Over Time in the Maintenance Phase (ITT Population)
CP (24-72 hours)
SZC 10 g TID Maximum SZC doses to
Maintenance Phase maintain normokalemia
5 g QD in 47%
Mean Serum K+ (mmol/L)

10 g QD in 41%
p<0.001 vs. CP baseline at all
15 g QD in 12%
5.5 SZC-titrated dose points

5.0

4.5

4.0
0 29 57 85 113 141 176 211 239 267 295 330 365 Off-
drug*
Time (days)

Day
1 8 15 22 29 57 85 113 141 176 211 239 267 295 330 365 OD
n 734 733 713 705 701 674 645 620 602 588 559 546 524 508 495 439 597
Nominal ∆, mmol/L -0.85 -0.79 -0.78 -0.81 -0.83 -0.87 -0.91 -0.88 -0.88 -0.96 -0.90 -0.87 -0.99 -0.93 -0.94 -1.00 -0.63
Percent ∆, % -15 -14 -14 -14 -15 -15 -16 -15 -15 -17 -16 -15 -17 -16 -17 -18 -11

Note: Normokalemia defined as K+ 3.5-5.0 mmol/L. Error bars indicate 95% CI. The ITT population included all participants who received SZC and had any postbaseline
K+ values measured during the study phase.
*Off-drug values were recorded at 7±1 days following the last dose of SZC.
CP = correction phase; ITT = intention-to-treat; SZC = sodium zirconium cyclosilicate.
Spinowitz BS et al. Clin J Am Soc Nephrol. 2019;14:798-809.
ZS-005
Vital Signs and Laboratory Parameters in the Maintenance Phase
Mean (95% CI) Change from
Correction Phase Baseline
Mean (95% CI) at Correction Phase Day 29 Day 365 (End of Study)†
Baseline (N=746)* (n=701) (n=731)
Systolic BP, mm Hg 135.6 (134.2–137.0) –1.1 (–2.4 to 0.2) 0.0 (–1.4 to 1.4)
Diastolic BP, mm Hg 77.1 (76.3–77.8) –0.3 (–1.0 to 0.4) –0.6 (–1.4 to 0.2)
Pulse rate, beats/min 69.0 (68.2–69.8) 0.1 (–0.6 to 0.7) 1.3 (0.5–2.0)
Weight‡, kg 86.25 (84.66–87.84) 0.28 (–0.06 to 0.62) 0.32 (–0.10 to 0.74)

Laboratory Parameter, mmol/L§

Magnesium 0.81 (0.80–0.82) –0.01 (–0.01 to 0.00) 0.01 (0.00–0.01)
Calcium 2.31 (2.30–2.33) 0.02 (0.01–0.04) –0.01 (–0.02 to 0.01)
Sodium 138.4 (138.1–138.7) 0.7 (0.4–1.0) 0.2 (–0.1 to 0.5)
Phosphate 1.18 (1.16–1.20) 0.03 (0.02–0.05) 0.07 (0.05–0.09)

• No clinically meaningful changes were observed in vital signs, and only minimal changes in serum and urinary parameters
• Hypokalemia: No patients had severe hypokalemia (serum K+ <2.5 mmol/L), 9 patients had serum K+ 2.5–2.9 mmol/L
(1 event each), 34 patients had with serum K+ 3.0–3.4 mmol/L
*The safety population comprised all participants who received ≥1 dose of SZC during the given study phase and had any post-baseline follow-up for safety; †Last scheduled study visit day
(± 1 day) while on study drug; ‡The number of participants with available weight measure was; 743, 690, and 426 for correction phase baseline, and Day 29, and Day 365/end of study of
the maintenance phase, respectively; §References values: Magnesium (low <0.37 mmol/L; high >1.64 mmol/L); calcium (low <1.75 mmol/L; high >2.75 mmol/L); sodium (low <120 mmol/L;
high >160 mmol/L); phosphate (low<0.65 mmol/L; high >2.10 mmol/L).
BP = blood pressure; MedDRA = Medical Dictionary for Regulatory Activities; SZC = sodium zirconium cyclosilicate.
Spinowitz BS et al. Article and supplemental material. Clin J Am Soc Nephrol. 2019;14:798-809.
ZS-005
Summary

Efficacy Safety

• SZC corrected elevated K+ into the normal • Safety data were consistent with the
range (within 1 to 3 days) and maintained established safety profile from shorter-term
serum K+ ≤5.1 mmol/L in 88% of patients controlled studies
over Months 3-12
• These findings support the use of SZC for
outpatient treatment of hyperkalemia and
maintenance of normokalemia for up to 12
months without dietary or RAASi medication
restrictions

RAASi = renin–angiotensin–aldosterone system inhibitor; SZC = sodium zirconium cyclosilicate.

Spinowitz BS et al. Clin J Am Soc Nephrol. 2019;14:798-809.
 Majority of Patients Continued RAASi Therapy While Taking
SZC for Hyperkalemia
ZS-005 (Phase III)1,a OPTIMIZE I (Real-world Evidence)2,c

Of the 483 patients who received RAASi therapy at the start of CP: Of the 589 patients who initiated SZC while on RAASi therapy:

Maintained same
RAASi dose 74% 70%

Increased
RAASi dose 13%b 8%

Decreased
RAASi dose 14%b 87% of patients continued 5% 83% of patients had new or
RAASi use while taking SZC refilled RAASi prescriptiond
following SZC initiation3
Discontinued
RAASi therapy 11% 17%

Note: RAASi includes ACEi, ARB, and MRA in the ZS-005 study1 and ACEi, ARB, ARNI, MRA, and direct renin inhibitor in the OPTIMIZE I study.3
a
A prespecified exploratory analysis of a Phase III, open-label, single-arm, 12-month study in adult outpatients with hyperkalemia (i-STAT K+ ≥5.1 mmol/L) who are not on dialysis;1 bNonmutually
exclusive; cA retrospective, noncomparative cohort study utilizing US insurance claims data in adult outpatients with a hyperkalemia diagnosis who initiated SZC in an outpatient setting (index
date), while receiving RAASi therapy between January 2018 and June 2020.2 Hyperkalemia was diagnosed using the ICD-10-CM diagnosis code E87.5;4 dNew or refilled RAASi prescription was
defined as different fill or refill of same RAASi within 90 days of ending their index RAASi.3
Abbreviations and references in slide notes.
SZC is generally well tolerated and has limited drug interactions

Safety Pharmacology and Drug interactions

patients were evaluated in clinical trials to SZC does not affect serum Ca2+ or Mg2+
1760 establish SZC safety profile; 507 patients concentrations or urinary Na+ excretion
received SZC for at least 1 year

SZC is not absorbed or metabolized by the body

of patients reported edema that was generally and there are no expected effects of other
5.7% mild to moderate in severitya medicinal products on the pharmacologic action of
SZC

SZC can transiently increase gastric pH and

4.1% of patients reported hypokalemia (serum K + less should be administered at least 2 hours before or 2
than 3.5 mmol/L) that resolved with SZC dose hours after oral medications with clinically
K+ adjustment or discontinuation meaningful gastric pH dependent bioavailability

aIn up to 47% of patients, edema resolved without treatment. The remainder were managed with diuretic initiation or diuretic dose adjustment.

SZC = sodium zirconium cyclosilicate.

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