Zs pharma ski ts a new class of agents with potential to enable advances in heart failure.
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Transcript of Zs pharma ski ts a new class of agents with potential to enable advances in heart failure.
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Selective Inorganic TrapsWith Potential to Enable Advances in Heart Failure
Henrik S. Rasmussen, MD, PhDZS Pharma Inc.
Coppell, TX, USA
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u ZS Pharma Incu Company founded in late 2008u Platform technology based on novel, highly selective ion trap
chemistry u Development of ZS-9
u Initial asset in is a selective K+ inorganic trap in development for hyperkalemia, a medical need
u Phase 2 and two Phase 3 studies met primary endpointsu Potential ancillary beneficial effects include decreased in
aldosterone and increased in bicarbonateu Clear regulatory guidance from the FDA and EMA u NDA submission 1H 2015, MAA submission 2H 2015
u Platform technology could be altered to be selective for other ions including sodium which is relevant for the HF community
ZS Pharma Corporate Overview
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Potent and Highly Selectiveu Large capacity for ion binding with high specificity for target
ions u Rapid onset of action and predictable effects with significant
changes in an hour
Additional Potential Benefitsu Significant dose-related serum aldosterone decrease u Significant dose-related serum bicarbonate increase
Tolerability Profileu Non-systemic and well tolerated with no drug related
serious adverse events
Selective K+ Inorganic Traps: An Investigational Treatment for Hyperkalemia
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Mechanism of ActionAcute Potassium EffectAdditional Potential BenefitsFuture Designs for Sodium Selectivity
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Cation Sizes Differ, Enabling Targeted Drug Therapy Design
*Stavros et al., submitted manuscriptSource: Stavros et al. PLoS One. 2014
CationCation Unhydrated Ionic DiameterUnhydrated Ionic Diameter Hydrated Ionic DiameterHydrated Ionic Diameter
H3O+
K+
NH4+
Na+
Ca2+
Mg2+
Zn2+
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Sodium Zirconium Cyclosilicate (ZS-9) is a Selective K+ Ion Trap
K+K+K+
ZS-9 Crystal Structure
Average Width of Micropore Opening 3Å
*Stavros et al., PLOSONE, 2015Abbreviations: GI, gastrointestinal
ZS-9 PROPERTIESu Unique microporous
zirconium silicate compound
u Designed with tiny (only 3Å in diameter) pore size to selectively trap K+ in the GI tract in exchange for hydrogen and sodium
u Insoluble and does not swell on contact with water
u Not systemically absorbed
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96
2** 2**
*Selectivity Ratio = [K+] / [Ca+2] + [Mg+2]**Exchange capacity of Ca2+ and Mg2+ was below the 0.05 detection limit; therefore, 0.05 assumed for calculation purposes.
KEY OBSERVATIONS
u ZS-9 has 9.3 times more K+ binding capacity than Sodium Polystyrene Sulfonate (SPS)
u ZS-9 is >125 times more selective for K+ than SPS
u SPS is more selective for Ca2+ than K+
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59
24
ZS-9 Ion Binding
SPS Ion Binding
Selectivity Ratio*
0.2
>25**
SOURCE: Stavros et al., PLOSONE. 2015.
Potassium, Calcium, and Magnesium Concentration Ratio (1:1:1)
ZS-9 Highly Selective for Potassium Ion
K+ Ca2+
Mg2+
K+ Ca2+
Mg2+
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Mechanism of ActionAcute Potassium EffectAdditional Potential BenefitsFuture Designs for Sodium Selectivity
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Mea
n Po
tass
ium
(mm
ol/L
)
*P value <0.001
-0.2 -0.4 -0.5-0.7
-1.0
**
**
*
N = 153 151 151151
Time (hr)
152
Results: ZS003 and ZS004 Combined Open-Label Phase – Heart Failure Subgroup
KEY OBSERVATIONS
u Mean starting K+ of 5.47 mmol/L, n=153
u 0.2, 0.4, & 0.5 mmol/L potassium decline at 1, 2, & 4 hours respectively (p<0.001)
u Median time to K+ normalization 2.0 hours
u 90% of patients normalized by 24 hrs
u 99% of patients normalized by 48 hrs
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Mea
n Po
tass
ium
(mm
ol/L
)
*P value <0.001
-0.4-0.6 -0.7
-0.9
-1.5
** *
*
*
N = 45 44 4344
Time (hr)
43
KEY OBSERVATIONS
u Mean starting K+ of 6.27 mmol/L
u 0.4, 0.6, 0.7, 0.9, 1.0, & 1.5 mmol/L potassium decline at 1, 2, 4, 24, 25 & 48 hours respectively (p<0.001)
u ZS004, Median time to K+ <6.0 mmol/L is 1.1 hours
u ZS004, Median time to K+ <5.5 mmol/L is 4.0 hours
Results: ZS003 and ZS004 Combined Open-Label Phase – Pts with ≥6.0 mmol/L
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Mechanism of ActionAcute Potassium EffectAdditional Potential BenefitsFuture Designs for Sodium Selectivity
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Percent Change from Baseline to Day 29 Aldosterone in HF Patients
Study 004 Aldosterone Percent Change from Baseline to Day 29
7
-32
-44 -46
Placebo (n=18) ZS 5 g (n=14) ZS 10 g (n=12) ZS 15 g (n=13)
* P-value <0.05Study Group
* *
BL S-Aldo (nq/dL) 7.02 12.57 9.32 9.18
*Perc
ent
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Significant Serum Bicarbonate Increase with Once Daily 10g and 15g ZS-9
Study 004 Mean Serum Bicarb Chg from Acute BL (MP): 5g, 10g and 15g vs PBO
* P-value <0.05
0.4 0.5
1.0 0.9
3.0
2.42.6 2.6
Day 15 Day 29(ITT)
Placebo 5g ZS 10g ZS 15g ZS
mm
ol/L
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Percentage of Patients with Bicarbonate <22 mmol/L Over Course of Study
Study 004 Proportion of Patients with Bicarbonate <22 mmol/L
KEY OBSERVATIONS
uRapid Normal Serum Bicarbonate
uNo change seen in Placebo
uDose dependent drop in ZS-9
u98% of Patients on 15g ZS-9 achieved normal Bicarbonate by end of study
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17
11
22
1617 17
9 10
2
10g TID(n=258)
Placebo(n=85)
5g ZS (n=45)
10g ZS (n=51)
15g ZS (n=56)
0
5
10
15
20
25
30
35 Baseline
Perc
ent
Open Label Phase
Randomized Phase
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Potential Benefits of Aldosterone Reduction
u Less cardiac and renal fibrosis
Potential Benefits of Increased Bicarbonate
u Reduced CKD progression
u Improved insulin sensitivity
u Less renal osteo-dystrophia
Summary of Additional Potential Benefits
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Mechanism of ActionAcute Potassium EffectAdditional Potential BenefitsFuture Designs for Sodium Selectivity
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Potential For A Selective Sodium Ion Trap
K+K+Na+
Crystalline Structure
Average Width of Micropore Opening
~2.4Å
Abbreviations: GI, gastrointestinal
POTENTIAL PROPERTIESu Unique microporous
zirconium silicate compound
u Potential to be designed with a pore size to selectively trap Na+ in the GI tract
u Insoluble and does not swell on contact with water
u Not systemically absorbed
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K+
OO
H
H
H
HO
OH
H
H
H
K+K+
O
H
H
OH
H
Na+
O H
H
O
H
H
K+Ca2+
O
HH
O
H H
O
H
H
O
H
H K+K+Ca2+
Pore/WindowHydrated Ion ILLUSTRATIVE
Na+
Energy to dehydrate the ion is more than balanced by the energy regained by the interaction with carbonyl oxygens
With a pore designed for Na+, other ions will be too small to interact with the oxygens, entering the pore/window is energetically unfavorable
Na+
Pores/Windows Mimic Physiologic Ion Channel Selectivity With Potential to Trap Sodium
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Selective Ion Traps Can be Designed to Be Specific for the Ionic Size of Na+
Source: Stavros et al. PLoS One. 2015
CationCation Unhydrated Ionic DiameterUnhydrated Ionic Diameter Hydrated Ionic DiameterHydrated Ionic Diameter
H3O+
K+
NH4+
Na+
Ca2+
Mg2+
Zn2+
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Selective K+ Ion Traps rapidly lowered serum potassium to normal range in patients with hyperkalemiau Significant reduction in K+ by 1 hr in patients with K+ of greater
than or equal to 6.0 mmol/Lu In patients with HF, 99% of patients normalized in 48 hours with a
median time to normalization of 2 hrs
Potential to be specific for other ionsu The technology can be modified to potentially target other ions
such as sodiumu An oral, non-absorbed, medication with comparable tolerability to
Placebo, to remove sodium could be useful in Heart Failure
Potent and highly-specificu High selectivity and large capacity for potassium bindingu Rapid onset of action and predictable effects
Conclusions