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MIKHAIL KOSIBOROD, MDSaint Luke’s Mid America Heart Institute,
University of Missouri - Kansas City
On behalf of Henrik S. Rasmussen, Philip T. Lavin, Wajeh Qunibi, Bruce Spinowitz, David Packham, Simon Roger, Alex Yang, Edgar Lerma, Bhupinder Singh, and the HARMONIZE Study Group
Efficacy and Safety of ZS in Patients with Hyperkalemia: Results from the HyperkAlemia
RandoMized InterventiON multI-dose ZS maintEnance (HARMONIZE) clinical trial
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2Confidential and Proprietary |
Disclosures
This study was funded by:ZS Pharma, Inc., Coppell, Texas
Mikhail Kosiborod, MD:Consultant for ZS Pharma, Inc.Investigator in HARMONIZE Trial
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Background
Hyperkalemia
Common, and increasing in prevalence
Associated with poor outcomes in CVD and CKD1,2
Limits use of cardioprotective and renoprotective RAAS inhibitors3,4
May lead to life-threatening cardiac arrhythmias
Source: 1Jain et al, 2012; 2McMahon et al, 2012; 3Makani et al, 2013; 4Takaichi et al, 2007
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There is a clinical need for a hyperkalemia treatment that is effective, safe and well-tolerated
Current Treatment Options for Hyperkalemia are Limited
Most acute therapies do not remove excess potassium, and impractical in outpatient setting
– IV calcium, sodium bicarbonate, insulin and dextrose, nebulized beta-adrenergic agonists
Dietary potassium restriction met by non-adherence, limits healthy food choices
Sodium polystyrene sulfonate (SPS)– Uncertain efficacy - no rigorous clinical trials– Poorly tolerated– Reports of serious intestinal toxicity
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K+K+K+
First in class inorganic crystalline zirconium silicate compound
Exchanges K+ for H+ andNa+ in the intestine
Highly selective for K+
trapping (>125 times more than SPS)
Insoluble, stable, does not expand in water
Not systemically absorbed
Sodium Zirconium Cyclosilicate (ZS)
ZS CRYSTAL STRUCTURE
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Study Overview
HARMONIZE is a Phase 3, randomized, double blind,placebo controlled, international multicenter trial
Ambulatory patients with prior history or laboratory evidence of hyperkalemia were recruited from
44 nephrology, cardiology, general research sites:
US80%
South Africa12%
Australia8%
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Key Inclusion and Exclusion Criteria
Potassium values ≥ 5.1mEq/L, with no upper limit at entry
Ability to have repeated blood draws
Provision of written informed consent
INCLUSION CRITERIA
Dialysis requirement Cardiac arrhythmias
requiring immediate treatment
Active treatment with SPS Life expectancy < 3 months Pregnancy
EXCLUSION CRITERIA
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28 DayRandomized Phase
DOUBLE-BLIND, RANDOMIZED
ZS 10g QD
ZS 15g QD
Placebo QD
ZS 5g QD
7
4
4
4R
ando
miz
ed
::
:
STUDY DRUG DOSES
Study Design
OPEN-LABEL
48-HourOpen Label Phase
ZS DOSE
ZS 10g TID
Patients who achieve normokalemia
(K+ = 3.5 to 5.0 mEq/L) proceed to
Randomized Phase
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Study Endpoints
Primary endpoint was the comparison of mean serum potassium levels between placebo and each ZS treatment group during days 8-29 of the randomized phase
Prespecified secondary analyses included – In the open label phase: change from baseline in serum
potassium levels at all time intervals, proportion of patients achieving normokalemia by 24 and 48 hours, time to potassium normalization
– In the randomized phase: proportion of patients with mean potassium <5.1 mEq/L during days 8-29
Safety and tolerability
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RANDOMIZED DOUBLE
BLINDPHASE
(28 days)
85 were randomizedto placebo
258 enrolled and received 10g ZS
425 Patients were assessed for eligibility
Open Label Phase
(48 hours)
167 failed screening
14 did not enter randomized phase
45 were randomized
to 5g ZS
51 were randomizedto 10g ZS
56 were randomizedto 15g ZS
7 discontinued early
251 included in open label phase
237 into 28-day randomized phase
Study Population
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Open Label Randomized Phase10g
(n=258)Placebo(n=85)
5g(n=45)
10g(n=51)
15g(n=56)
Median Age years 65 66 64 65 65Male % 58 52 60 53 71
White % 83 86 80 86 82Black % 14 12 18 10 16
BL Serum K+ <5.5 mEq/L % 46 51 51 37 43BL Serum K+ 5.5-<6.0 mEq/L % 39 35 38 45 46
BL Serum K+ ≥6.0 mEq/L % 15 14 11 18 11RAAS inhibitors % 70 72 73 71 59
Heart Failure % 36 31 40 35 45Diabetes Mellitus % 66 64 58 75 70
Baseline eGFR <60 % 69 61 69 75 73Brain Natriuretic Peptide pg/mL 126 101 175 101 152
Baseline Characteristics
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4.4
4.6
4.8
5.0
5.2
5.4
5.6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (hr)
ZS DOSES:
KEY OBSERVATIONS
Mean starting K+ of 5.55 mEq/L
0.2, 0.4, & 0.5 mEq/L potassium decline at 1, 2, & 4 hours respectively (p<0.001)
Median time to K+ normalization 2.2 hours
84% of patients normalized by 24 hrs
98% of patients normalized by 48 hrs
**
*
**
*
Results: Open-Label PhaseM
ean
Pota
ssiu
m (m
Eq/L
)
*P value <0.001
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4.4
4.6
4.8
5.0
5.2
5.4
5.6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (hr)
ZS DOSES:
KEY OBSERVATIONS
Mean starting K+ of 5.55 mEq/L
0.2, 0.4, & 0.5 mEq/L potassium decline at 1, 2, & 4 hours respectively (p<0.001)
Median time to K+ normalization 2.2 hours
84% of patients normalized by 24 hrs
98% of patients normalized by 48 hrs
**
*
**
*
Results: Open-Label PhaseM
ean
Pota
ssiu
m (m
Eq/L
)
*P value <0.001
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4.4
4.6
4.8
5.0
5.2
5.4
5.6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (hr)
ZS DOSES:
KEY OBSERVATIONS
Mean starting K+ of 5.55 mEq/L
0.2, 0.4, & 0.5 mEq/L potassium decline at 1, 2, & 4 hours respectively (p<0.001)
Median time to K+ normalization 2.2 hours
84% of patients normalized by 24 hrs
98% of patients normalized by 48 hrs
**
*
**
*
Results: Open-Label PhaseM
ean
Pota
ssiu
m (m
Eq/L
)
*P value <0.001
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15Confidential and Proprietary |
4.4
4.6
4.8
5.0
5.2
5.4
5.6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (hr)
ZS DOSES:
KEY OBSERVATIONS
Mean starting K+ of 5.55 mEq/L
0.2, 0.4, & 0.5 mEq/L potassium decline at 1, 2, & 4 hours respectively (p<0.001)
Median time to K+ normalization 2.2 hours
84% of patients normalized by 24 hrs
98% of patients normalized by 48 hrs
**
*
**
*
Results: Open-Label PhaseM
ean
Pota
ssiu
m (m
Eq/L
)
*P value <0.001
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16Confidential and Proprietary |
4.4
4.6
4.8
5.0
5.2
5.4
5.6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (hr)
ZS DOSES:
KEY OBSERVATIONS
Mean starting K+ of 5.55 mEq/L
0.2, 0.4, & 0.5 mEq/L potassium decline at 1, 2, & 4 hours respectively (p<0.001)
Median time to K+ normalization 2.2 hours
84% of patients normalized by 24 hrs
98% of patients normalized by 48 hrs
**
*
**
*
Results: Open-Label PhaseM
ean
Pota
ssiu
m (m
Eq/L
)
*P value <0.001
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17Confidential and Proprietary |
4.4
4.6
4.8
5.0
5.2
5.4
5.6
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (hr)
ZS DOSES:
KEY OBSERVATIONS
Mean starting K+ of 5.55 mEq/L
0.2, 0.4, & 0.5 mEq/L potassium decline at 1, 2, & 4 hours respectively (p<0.001)
Median time to K+ normalization 2.2 hours
84% of patients normalized by 24 hrs
98% of patients normalized by 48 hrs
**
*
**
*
Results: Open-Label PhaseM
ean
Pota
ssiu
m (m
Eq/L
)
*P value <0.001
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18Confidential and Proprietary |
4.2
4.6
5.0
5.4
5.8
6.2
6.6
All CKD(GFR<60)
HF DM On RAASi <5.5 5.5-<6.0 ≥6.0
10g ZS (0 Hr) 10g ZS (48 Hr)
Open Label Phase:Consistent Efficacy in All Subgroups
Baseline S-K (mEq/L)
* * * * * * **-0.8
-1.5
Mea
n Po
tass
ium
(mEq
/L)
*P value <0.0001
Error bars represent ±95 confidence intervals
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5.06
4.75
4.51
4.37
4.0
4.2
4.4
4.6
4.8
5.0
5.2
5.4
Placebo ZS 5 g ZS 10 g ZS 15 g
**
*
*p-value <0.001*p-value <0.001
*p-value <0.001
Achieves Primary Endpoint, Mean K+
Maintenance on Days 8-29 for All Doses M
ean
Pota
ssiu
m (m
Eq/L
)
Baseline K+ (mEq/L) 5.55 5.53 5.58 5.55
Study Group:
Error bars represent ±95 confidence intervals
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4.2
4.4
4.6
4.8
5.0
5.2
5.4
5.6
3 5 7 9 11 13 15 17 19 21 23 25 27 29 31
Placebo (n=82) 5 g ZS (n=45)10 g ZS (n=50) 15 g ZS (n=54)
*
Time (Day)
**
*
*
**
***
***
*
*
*
**
*** * ***
ZS DOSES:
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29
Randomized Phase:Mean Potassium Levels Over Time
Mea
n Po
tass
ium
(mEq
/L)
* Two-sample t-test p-value <0.05
Primary Endpoint
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0
10
20
30
40
50
60
70
80
90
100
Placebo 5 g ZS 10 g ZS 15 g ZS
Study Group
(38/82)
(36/45)
(45/50)(51/54)
46%
90%*80%*
94%*
Randomized Phase: Proportion of Patients with Mean K <5.1 mEq/L during Days 8-29
Perc
ent o
f Stu
dy G
roup
*P value <0.001
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Randomized Phase:Efficacy Consistent in All Subgroups
4.0
4.2
4.4
4.6
4.8
5.0
5.2
5.4
All CKD HF DM On RAASi
Placebo 10g ZS
* * ** *
Error bars represent ±95 confidence intervals
Mea
n Po
tass
ium
(mEq
/L)
*P value <0.001
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Tolerability profile comparable to placebo No treatment-related serious adverse events Numerically lower rates of GI AEs with ZS vs. placebo
Edema numerically higher in ZS 15 g dose
7 out of 14 edema patients did not require treatment 13 of 14 edema patients had peripheral edema only and successfully
completed the study Hypokalemia higher in ZS 10g and 15g dose groups
All cases mild (3.0 to 3.4 mEq/L) and resolved with dose adjustments
PBO ZS 5g ZS 10g ZS 15g12 (14%) 3 (7%) 1 (2%) 5 (9%)
PBO ZS 5g ZS 10g ZS 15gReported AE 2 (2%) 1 (2%) 3 (6%) 8 (14%)
Needed Treatment Adjustment 2/2 0/1 0/3 5/8
PBO ZS 5g ZS 10g ZS 15gHypokalemia 0 (0%) 0 (0%) 5 (10%) 6 (11%)
Adverse Event 0 (0%) 0 (0%) 0 (0%) 1 (2%)
Safety and Tolerability
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No changes in serum sodium, magnesium, and calcium
No increase in urinary sodium excretion
No differences in heart rate or blood pressure
No difference in body weight
No cardiac arrhythmias or EKG changes
Other Safety Data of Interest
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Study Limitations
Hospitalized patients Patients with life-threatening arrhythmias Patients on dialysis (however 36% of patients had
advanced CKD [Stage IV/V])
Due to focus on outpatient management of hyperkalemia,certain patient subgroups not included:
Focus on potassium levels; not powered formortality and other clinical events
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Conclusions
Open Label: ZS rapidly lowered serum potassium to normal range in patients with hyperkalemia Significant reduction in K+ by 1 hr; median time to normalization 2.2 hrs 84% patients normokalemic by 24 hrs, 98% by 48 hrs Greater absolute declines in K+ among patients with higher K+ at baseline
Randomized Phase: Compared with placebo, all 3 doses of ZS resulted in Significantly lower serum potassium Higher proportion of patients with normal potassium for up to 4 weeks
Results consistent across all patient subgroups including HF, CKD, DM, RAASi
Tolerability profile comparable to placebo
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Further studies are planned to evaluate theefficacy and safety of ZS over longer time periods
and in additional patient populations
Future Directions
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jamanetwork.com
Available at jama.com and on The JAMA Network Reader at
mobile.jamanetwork.com
M. Kosiborod and coauthors
Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia: The HARMONIZE Randomized Clinical Trial
Published online November 17, 2014
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Appendix
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Potassium Measurements
All potassium levels were measured– in whole blood with a point-of-care device (i-STAT; Abbott
Laboratories) – in serum via central laboratory
Eligibility for enrollment, randomization and treatment decision were based on i-STAT values
All statistical analysis based on central lab values Potassium measured at 1, 2, 4, 24, and 48 hours during open
label phase Day 1, 2, 8, 12, 15, 19, 22, 26, 29 during randomized phase
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Statistical Analysis
Samples size of 232 patients in the randomized phase at 90% power, 0.3 mEq/L mean difference in potassium levels during days 8-29 for each ZS dose versus placebo
Longitudinal generalized estimated equation (GEE) model was used to simultaneously compare each ZS dose (highest to lowest) versus placebo with mean day 8-29 potassium value
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28-DAY RANDOMIZED MAINTENANCE PHASE
425 Patients were assessed for eligibility
48-HOUR OPEN-LABEL PHASE
167 failed screening160 due to potassium values <5.1 mEq/L1 due to prior randomization in ZS-9 study2 withdrew consent1 due to inability to have repeated blood draws or
effective venous catheterization1 hospitalized prior to randomization1 due to participant compliance1 due to Investigator’s decision
7 Discontinued early5 withdrew consent2 due to hyperkalemia
a ECG withdrawal criteria included significant increase in PR interval (>250 msec in the absence of pre-existing atrioventricular block), or widening of the QRS complex (>140msec in the absence of pre-existing bundle branch block) or peaked T-wave or an increase in QTc interval >25msec to more than 500msec or >25msec in somebody with a baseline QTc of >500msec
b due to having no follow-up potassium measurements after the maintenance phase baseline
14 did not enter randomized phase1 met ECG withdrawal criteriaa
1 withdrew consent1 due to Investigator’s decision9 due to hyperkalemia2 due to hypokalemia
251 included in 48-hour open-label phase intent-to-treat population
237 randomized into 28-day randomized phase
85 randomizedto placebo
45 randomizedto 5g ZS-9
51 randomizedto 10g ZS-9
56 randomizedto 15g ZS-9
82 included in the randomized phase intent-to-treat population
45 included in the randomized phase intent-to-treat population
50 included in the randomized phase intent-to-treat population
54 included in the randomized phase intent-to-treat population
258 enrolled and received 10g ZS-9 (safety population)
10 Discontinued early2 withdrew consent1 due to participant
compliance2 due to unconfirmed
eligibility3 due to
hyperkalemia2 for other reasons
5 Discontinued early3 due to adverse event1 met ECG withdrawal
criteriaa
1 for other reason
7 Discontinued early2 due to unconfirmed
eligibility3 due to
hypokalemia2 for other reasons
7 Discontinued early1 due to adverse event1 due to Investigator’s
decision1 due to hypokalemia2 met ECG withdrawal
criteria1 due to unconfirmed
eligibility1 for other reason
3 not included in the intent-to-treat populationb
1 not included in the intent-to-treat populationb
2 not included in the intent-to-treat populationb
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34Confidential and Proprietary |
* * ** *
4.0
4.2
4.4
4.6
4.8
5.0
5.2
5.4
All CKD HF DM On RAASi
Placebo 5g ZS-9
Seru
m P
otas
sium
(mEq
/L)
*P value <0.001
Maintenance of Potassium AcrossAll Subgroups on ZS – 5g
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35Confidential and Proprietary |
**
* * *
4.0
4.2
4.4
4.6
4.8
5.0
5.2
5.4
All CKD HF DM On RAASi
Placebo 15g ZS-9
Seru
m P
otas
sium
(mEq
/L)
*P value <0.001
Maintenance of Potassium AcrossAll Subgroups on ZS – 15g
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36Confidential and Proprietary |
4.24.44.64.85.05.25.45.65.86.06.26.4
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
<5.5 (n=119) 5.5-6.0 (n=100) ≥6.0 (n=39)
Study 004 Mean s-K+ (Acute, All K+ ranges) – 10gSerum Potassium (mEq/L)
Dose
SOURCE: 14.2.1.2.7-9
Time (hr)
DOSES:
Biostats Review and QC pending
ZS004 Mean K+ for all K+ ranges
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37Confidential and Proprietary |
All ZS-004 Hypokalemia Cases Transient, With No Arrhythmias, and No Need for K+ Supplements
StudyTotal
Hypokalemic Instances
# of Exposure
Days*
Hypokalemic Instances/Exp
osure Days
Patients with Hypokalemia
# of Patients
Patients with Hypokalemia
/Total Patients
ZS-002 2 120 0.2% 2 60 3.3%
ZS-003 2 8,330 <0.1% 2 595 0.3%
ZS-004 11 4,560 0.2% 11 152 7.2%
TOTAL 15 13,010 0.1% 15 807 1.8%
0 of 807 ZS Patients With Serum K+ <3.0 mEq/L
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14
55
75
Black Patients in StudyPopulation
Black Patients inHypokalemic Population
Black Patients inHypokalemic PopulationThat Discontinued Study
Black Patients are at a Greater Risk for Developing Hypokalemia than Non BlackProportion of Total Patients that are BlackPercentage of Patients
*Hypokalemia was determined by two subsequent [separated by 10 minutes] Cenetron values of S-K < 3.5mmol/l**Discontinuation from study was determined by I-STAT S-K < 3.0mmol/l
n = 257 11 4
14%
55%
75%