CytoSorbents Europe GmbH

Müggelseedamm 13112587 Berlin | Germany T +49 30 65 49 91 45 F +49 30 65 49 91 46 support@cytosorbents.com

CytoSorbents Switzerland GmbH

c/o MGM GmbH Wielandstrasse 5 | 4153 Reinach BL | Switzerland T +41 61 713 73 78F +41 61 713 73 79 support@cytosorbents.com CytoSorb Therapy – REGAIN CONTROL

With CytoSorb you can pursue these therapeutic targets:(supported by clinical and preclinical * data)

Organ protection (5,7,8,16,20)

Reduction in mortality (6,18)

Reduction in capillary leakage (19)

Stabilization in hemodynamics / shock reversal (3,5,6,18)

CytoSorb TherapyIntelligent Blood Purification in Systemic Hyperinflammation (SIRS) and Sepsis

• Current clinical data clearly points towards a rapid and pronounced stabilization in hemodynamics and organ function of intensive care patients with acute systemic hyperinflammation. (5,6,18)

• In these patients there is a high chance of success (shock reversal) possibly translating to survival benefits when the adsorber treatment is started in good time. (6,18)

• The safe use of CytoSorb therapy has been demonstrated in both the intraoperative cardiac surgery and the intensive care settings. (14,21)

• Proof of the removal of cytokines as well as other substances and metabolites (e.g. myoglobin, bilirubin, bile acids, bacterial toxins) has also been shown. (4,5,10,12)

The intelligent way of blood purificationCytoSorb Therapy

Easy and quick set up and safe application*

References (* preclinical data):1. Kellum JA et al. Crit Care Med. 2004 Mar;32(3):801-5 *2. Kellum JA et al. Crit Care Med. 2008 Jan;36(1):268-7 *3. Peng ZY et al. Crit Care Med. 2008 May;36(5):1573-7 *4. Linden K et al. Shock 2015 Nov;44(5):487-95. *5. Traeger K et al. Int J Artif Organs 2016 May 16;39(3):141-66. Kogelmann K et al. Crit Care 2017 Mar; 21:747. Peng ZY et al. Kidney Int. 2012 Feb;81(4):363-9 *8. Mikhova KM et al. J Thorac Cardiovasc Surg. 2013 Jan;145(1):215-24 *9. Faenza S et al. Crit Care 2016, 20(Suppl 2):P192 *10. Buttner S et al. Blood Purif 2017 44(1): 30-3111. Kuntsevich V. I. et al. Artif Cells Blood Substit Biotechnol 2009, 37(1):45-7 *

12. Gruda M et al. Crit Care 2016, 20(Suppl 2):P194 *13. Venkataraman R et al. Blood Purif 2004;22:143–149 *14. Bernardi MH et al. Crit Care 2016; 20(1): 9615. Traeger, K., et al. Int J Artif Organs 2017; May 1916. Peng ZY et al. Crit Care. 2014 Jul 3;18(4):R141 *17. Namas RA et al. Mol Med. 2012 Dec 20;18:1366-74 *18. Friesecke S et al. J Artif Organs 2017 epub19. David S et al. J Intensive Care 2017 5: 1220. Iskender I et al. J Heart Lung Transplant 2017 May 20 *21. Schädler D et al. 32nd ISICEM 2013, Brussels, Belgium: P6222. Becze Z et al. Int J Antimicrob Agents 2015; 46(1):13-1823. IFU CytoSorb® 300, ref. June 2017 *

Stand-alone therapy CytoSorb in CRRT, post dialyzer CytoSorb in CRRT, pre dialyzer

CytoSorb in CPB CytoSorb in ECMO

* Exemplary setup

• Whole blood perfusion without plasma separation

• Anticoagulation as usual (heparin, citrate)

• Blood flow 100-700 ml/min

• CE certified, class IIb, meets ISO 10993 standard

CytoSorb and CytoSorbents are trademarks of the CytoSorbents Corporation, USA. B1062R02EN2019 © Copyright 2019,

CytoSorbents Europe GmbH. All rights reserved.

www.cytosorb.com

CytoSorb should only be administered by personnel who have been properly trained in administration of extracorporeal therapies.

CytoSorb is not available for commercial sale in USA.

Life threatening organ dysfunction

SIRS

Sepsis

Multi Organ Dysfunction Syndrome

Section through adsorber Adsorber Bead Inner structure

Whole blood

IL-10

10 6030 4020 50 kDa

Aflato

xin

Bilirub

in

IL-8

C5α S100

-A8

IFN-γ

Myoglobin

IL-6

Staph.

aureu

s hem

olysin

HMGB1

Free h

emoglobin,

dimer

Staph.

aureu

s toxic

shock

toxin

Strep

t. pyo

genes

exoto

xin

TNF-α

, trim

er

Free h

emoglobin,

tetra

mer

Clostr. p

erfrin

gens t

oxin

Shiga-l

ike-to

xins

IL-1β

C3α

without CytoSorb

Overshooting Inflammatory Response

TimeInsult

Recovery

MOF / Death

Organ failure

Pro-Inflammatory

Cytokines

Anti-Inflammatory

Cytokines

with CytoSorb

Attenuated Inflammatory Response

Recovery

MOF /Death

InsultUse of CytoSorb

Time

Organ failure

Proprietary polymer technology • High-tech polymer

• Low flow resistance (23)

• Highest bio- and hemocompatibility

• No hemolysis

• Most efficient removal of cytokines and other hydrophobic middle sized molecules

• Acute treatment for 1-7 days, maximum of 24 hours per adsorber

Controlled and effective adsorption of numerous substances PAMPS (Pathogen Associated Molecular Patterns) e.g. enterotoxins (12)

DAMPS (Damage Associated Molecular Patterns) (12,13)

Cytokines (1,2,3,4,5)

Myoglobin (4,11)

Metabolites (e.g. Bilirubin, Bile acids, Ammonia) (9,10)

High level of safety • Size selectivity up to approx. 55 kDa

• No evidence of fibrinogen, coagulation inhibitors (ATIII/Prot C), immunoglobulins removal

• No clinically relevant reduction of albumin or platelets (9,14,21)

• No complete removal of physiologic mediators (concentration dependent elimination rate) (14,15)

Organ failure is often caused by inflammation (22)

• A dysregulated immune response in sepsis and other, non-infective insults can lead to organ failure: - Circulatory failure - ARDS - Liver failure - Renal failure - Encephalopathy

• Attenuation of the dysregulated reaction of the organism is an attractive adjunctive therapeutic option in systemic hyperin- flammation and sepsis

Modulation of the immune response can increase the chances of recovery

• Reduction in vasopressor need (5,6,18)

• Stabilization in fluid balance (16)

• Improvement in metabolic parameters (5,6,18)

• Recovery of organ functions (5,7,8)

• Effective reduction of excessive cytokine levels (3,16)

• Decreased de novo synthesis of inflammatory mediators (1,7)

• Controlled attenuation of the overshooting immune response (16,17)

• Re-targeting the cellular immune defense to the focus of infection (16,17)

Long lasting phases with high cytokine levels increase the risk of multi organ failure

(MOF) and death

Adsorption of overshooting levels of cytokines enables remodulation of the immune system

and can increase the chances of recovery