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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

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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

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-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