What changed in this filing

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Item 1. Business

2022-03-10 compared with 2021-03-09 · 378 added, 492 removed, 1231 unchanged (41% of the section changed)

We are a leader in critical care immunotherapy, investigating and commercializing our CytoSorb blood purification technology to reduce deadly uncontrolled inflammation in hospitalized patients around the world, with the goal of preventing or treating multiple organ failure in life-threatening illnesses and cardiac surgery.

Organ failure is the cause of nearly half of all deaths in the intensive care unit (“ICU”), with little to improve clinical outcome.

CytoSorb, our flagship product, is approved in the European Union (“EU”) as an effective extracorporeal cytokine filter and is designed to reduce the “cytokine storm” that could otherwise cause massive inflammation, organ failure and death in common critical illnesses such as sepsis, burn injury, trauma, lung injury, and pancreatitis.

These are conditions where the mortality is extremely high, yet no effective treatments exist.

We are a leader in the treatment of life-threatening conditions in the intensive care (“ICU”) and cardiac surgery using blood purification via our proprietary polymer adsorption technology.

We have a number of products commercialized and in development based on this technology platform.

Our flagship product, CytoSorb®, is already commercialized, and is being investigated to reduce deadly uncontrolled inflammation and dangerous substances in hospitalized patients around the world, with the goal of preventing or treating multiple organ failure, bleeding, and other potentially fatal complications.

Organ failure is the cause of nearly half of all deaths in the ICU, with little to improve clinical outcome.

CytoSorb, is approved in the European Union (“EU”) as an effective extracorporeal cytokine absorber, designed to reduce the “cytokine storm” or “cytokine release syndrome” that could otherwise cause massive inflammation, organ failure and death in common critical illnesses such as sepsis, burn injury, trauma, lung injury, cytokine release syndrome due to cancer immunotherapy, and pancreatitis.

These are conditions where the mortality is extremely high, yet few to no effective treatments exist.

In May 2018, we received a label expansion for CytoSorb covering use of the device for the removal of bilirubin and myoglobin in the treatment of liver disease and trauma, respectively.

In January 2020, we received CE-Mark label expansion for CytoSorb covering the use of the device for the removal of the anti-platelet agent, ticagrelor, in patients undergoing surgery requiring cardiopulmonary bypass.

In April 2020, the United States Food and Drug Administration (the “FDA”) granted Breakthrough Designation to CytoSorb for the removal of ticagrelor in a cardiopulmonary bypass circuit during emergent and urgent cardiothoracic surgery.

In April 2020, we announced that the FDA has granted Emergency Use Authorization (“EUA”) of CytoSorb for use in patients with COVID-19 infection.

In April 2020, the United States Food and Drug Administration (the “FDA”) granted Breakthrough Device Designation to CytoSorb for the removal of ticagrelor in a cardiopulmonary bypass circuit during emergent and urgent cardiothoracic surgery.

In April 2020, we announced that the U.S.

FDA has granted U.S.

Emergency Use Authorization (“EUA”) of CytoSorb for use in critically ill patients with COVID-19 infection and respiratory failure.

In May 2020, we received a CE-Mark label expansion for CytoSorb for the removal of rivaroxaban during cardiothoracic surgery requiring cardiopulmonary bypass.

CytoSorb is used during and after cardiac surgery to remove inflammatory mediators, such as cytokines, activated compliment and free hemoglobin that can lead to post-operative complications, such as acute kidney injury, lung injury, shock, and stroke.

We believe CytoSorb has the potential to be used in many other inflammatory conditions, including the treatment of autoimmune disease flares, cytokine release syndrome in cancer immunotherapy, and other applications in cancer, such as cancer cachexia.

CytoSorb has been used globally in more than 121,000 human treatments to date in critical illnesses and in cardiac surgery.

In August 2021, the Company announced that it was granted a second Breakthrough Device Designation for its DrugSorb-ATR Antithrombotic Removal System by the FDA to remove the direct oral anticoagulants, rivaroxaban and apixaban.

The Company has initiated two U.S.

clinical trials evaluating the use of DrugSorb-ATR during cardiothoracic surgery to remove ticagrelor, apixaban and rivaroxaban to prevent or reduce perioperative bleeding complications in pursuit of U.S.

FDA marketing approval.

We believe CytoSorb has the potential to be used in many other inflammatory conditions, including the treatment of autoimmune disease flares, and other applications in cancer, such as cancer cachexia.

More than 162,000 cumulative CytoSorb devices have been utilized globally as of December 31, 2021 in critical illnesses and in cardiac surgery.

Our purification technologies are based on biocompatible, highly porous polymer beads that can actively remove toxic substances from blood and other bodily fluids by pore capture and surface adsorption.

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and internationally.

We have numerous product candidates under development based upon this unique blood purification technology, including HemoDefend, ContrastSorb, DrugSorb, and others.

In March 2011, CytoSorb was “CE Marked” in the EU as an extracorporeal cytokine filter indicated for use in clinical situations where cytokines are elevated, allowing for commercial marketing.

We have numerous product candidates under development based upon this unique blood purification technology, including CytoSorb XL, HemoDefend, ContrastSorb, DrugSorb, DrugSorb-ATR and others.

In March 2011, CytoSorb was “CE Marked” in the EU as an extracorporeal cytokine adsorber indicated for use in clinical situations where cytokines are elevated, allowing for commercial marketing.

The CE Mark demonstrates that a conformity assessment has been carried out and the product complies with the Medical Devices Directive.

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By replacing the function of failed organs, these supportive care therapies can initially help to keep patients alive, but do not help patients recover faster, and in many cases can increase the risk of dangerous complications.

Unlike these supportive care therapies, the goal of the CytoSorb cytokine filter is to proactively prevent or treat organ failure by reducing cytokine storm and reducing the maladaptive SIRS response.

In doing so, CytoSorb targets

the reduction in the severity of patient illness and the need for intensive care, while potentially improving clinical outcome and saving healthcare costs.

Unlike these supportive care therapies, the goal of the CytoSorb cytokine adsorber is to proactively prevent or treat organ failure by reducing cytokine storm and reducing the maladaptive SIRS response.

In doing so, CytoSorb targets the reduction in the severity of patient illness and the need for intensive care, while potentially improving clinical outcome and saving healthcare costs.

As part of the CE Mark approval process, we completed our randomized, controlled, European Sepsis Trial amongst 14 trial sites in Germany in 2011, with enrollment of 100 patients with sepsis and respiratory failure.

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Upon expanding our facility we quadrupled our manufacturing capacity and completed an audit upgrade from an ISO 13485:2003 certification to an ISO 13485:2016 certification.

In late June 2012, following the establishment of our European subsidiary, CytoSorbents Europe GmbH, a wholly-owned operating subsidiary of CytoSorbents Corporation, we began the commercial launch of CytoSorb in Germany with the hiring of Dr.

Christian Steiner as Vice President of Sales and Marketing and three additional sales representatives who joined us and completed their sales training during the third quarter of 2012.

The fourth quarter of 2012 represented the first quarter of direct sales with the full sales team in place.

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Fiscal year 2013 represented the first full year of CytoSorb commercialization.

We focused our direct sales efforts in Germany, Austria and Switzerland with four sales representatives.

The focus of the team was to encourage acceptance and usage by key opinion leaders (“KOLs”) throughout these countries.

We believe our relationships with KOLs are essential to drive adoption and recurrent usage of CytoSorb, facilitate purchases by hospital administration, arrange reimbursement, and generate data for papers and presentations.

As of the end of 2020, we had hundreds of KOLs in our commercialized territories worldwide in critical care, cardiac surgery, and blood purification, who were either using CytoSorb or supporting its use in clinical practice or clinical trials.

We focused our direct sales efforts in Germany, Austria and Switzerland.

In March 2016, we established CytoSorbents Switzerland GmbH, a wholly-owned subsidiary of CytoSorbents Europe GmbH, to conduct marketing and direct sales in Switzerland.

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On March 5, 2019, the Company announced the expansion of direct sales of CytoSorb for all applications to Poland and the Netherlands, and critical care applications to Sweden, Denmark and Norway.

In 2021, the Company expanded direct sales to include all indications in Sweden, Denmark and Norway.

As part of this effort, the Company established CytoSorbents Poland Sp.

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The EUA will be effective until a declaration is made that the circumstances justifying the EUA have terminated or until revoked by the FDA.

In April 2020, the Company also announced that the FDA had granted Breakthrough Designation to CytoSorb for the removal of ticagrelor in a cardiopulmonary bypass circuit during emergent and urgent cardiothoracic surgery.

The Breakthrough Devices

Program provides for more effective treatment of life-threatening or irreversibly debilitating disease or conditions, in this case the need to reverse the effects of ticagrelor in emergent or urgent cardiac surgery that can otherwise cause a high risk of serious or life-threatening bleeding.

Through Breakthrough Designation, the FDA intends to work with CytoSorbents to expedite the development, assessment, and regulatory review of CytoSorb for the removal of ticagrelor, while maintaining statutory standards of regulatory approval (e.g., 510(k), de novo 510(k) or premarket approval) consistent with the FDA’s mission to protect and promote public health.

In April 2020, the Company also announced that the FDA had granted Breakthrough Device Designation to CytoSorb for the removal of ticagrelor in a cardiopulmonary bypass circuit during emergent and urgent cardiothoracic surgery.

The Breakthrough Devices Program provides for more effective treatment of life-threatening or irreversibly debilitating disease or conditions, in this case the need to reverse the effects of ticagrelor in emergent or urgent cardiac surgery that can otherwise cause a high risk of serious or life-threatening bleeding.

Through Breakthrough Designation, the FDA intends to work with CytoSorbents to expedite the development, assessment, and regulatory review of the Company’s proprietary polymer adsorption technology for the removal of ticagrelor, while maintaining statutory standards of regulatory approval (e.g., 510(k), de novo 510(k) or premarket approval) consistent with the FDA’s mission to protect and promote public health.

In July 2021, the Company received full approval of its Investigational Device Exemption (“IDE”) by the FDA to conduct the pivotal STAR-T (Safe and Timely Antithrombotic Removal – Ticagrelor) double-blind, randomized control trial (“RCT”) for up to 120 patients in the United States to support FDA marketing approval of DrugSorb-ATR, which is based on the same proprietary polymer technology as CytoSorb.

In May 2020, we received CE-Mark label expansion approving the use of CytoSorb for the removal of rivaroxaban, a widely-used Factor Xa inhibitor and novel oral anticoagulant, during cardiothoracic surgery requiring cardiopulmonary bypass.

With this announcement, and the E.U.

approval earlier this year to remove ticagrelor , for the same indication, CytoSorb is providing cardiac surgeons and perfusionists an easy-to-use and rapid new treatment option to help reduce the risk of serious and potentially fatal perioperative bleeding complications caused by these two drugs, in separate categories of blood thinners .

In addition, we now have more than 50 investigator-initiated studies and additional Company sponsored trials that are currently planned, enrolling or completed in Europe and elsewhere outside of the United States.

We believe that these trials, which are conducted and supported by what we believe to be well-known university hospitals and KOLs, are the equivalent of Phase 3 and Phase 4 clinical studies.

We believe they will provide invaluable information regarding the success of the device in the treatment of sepsis, cardio-pulmonary bypass surgery, liver failure, and many other indications, and if successful, may be integral in helping to drive additional usage and adoption of CytoSorb.

approval in January 2020 to remove ticagrelor, for the same indication, CytoSorb is providing cardiac surgeons and perfusionists an easy-to-use and rapid new treatment option to help reduce the risk of serious and potentially fatal perioperative bleeding complications caused by these two drugs, in separate categories of blood thinners.

In October 2020, we announced the E.U.

approval of the ECOS-300CY cartridge for the removal of inflammatory mediators during ex vivo organ perfusion under CE Mark designation, with the goal of helping to preserve or improve the health and quality of solid organs to be transplanted.

CytoSorbents also announced a partnership with Aferetica srl to provide the ECOS-300CY cartridge under the exclusive trade name, PerSorb™, that is compatible with Aferetica’s PerLife™ ex vivo organ perfusion system, recently approved in the E.U.

In 2021, commercialization of PerSorb™ and Aferetica’s PerLife™ ex vivo organ perfusion system commenced in Italy.

In June 2021, we began construction on the Company’s new global headquarters and state-of-the-art manufacturing facility following the lease of a 48,500 square foot mixed-use facility in Princeton, New Jersey.

The new production facility was designed to support annual sales of up to $400 million while improving product gross margins and allowing space for future product line expansions.

We expect to complete the certification audit in the first half of 2022, and commercial production of CytoSorb is expected to commence in the second half of 2022.

In August 2021, the Company announced that it was granted a second Breakthrough Device designation for its DrugSorb-ATR Antithrombotic Removal System by the U.S.

Food and Drug Administration (FDA).

This Breakthrough Device designation covers the removal of the Direct Oral Anticoagulants (DOACs) apixaban and rivaroxaban in a cardiopulmonary bypass circuit to reduce the likelihood of serious perioperative bleeding during urgent cardiothoracic surgery.

In October 2021, the Company also received full FDA approval of an IDE application to conduct a double-blind, randomized, controlled clinical study for up to 120 patients entitled, “Safe and Timely Antithrombotic Removal – Direct Oral Anticoagulants (STAR-D),” in the United States to support FDA marketing approval.

In addition, there are many investigator-initiated and additional Company sponsored trials that are currently planned, enrolling, or completed in Europe and in other countries abroad, using our blood purification technology that may provide valuable information regarding the use of the device in the treatment of different conditions such as sepsis, cardio-pulmonary bypass surgery, liver failure, COVID-19, organ transplant and many others.

If successful, these studies may help to drive additional usage and adoption of our blood purification technologies.

As of March 1, 2022, our European commercialization team included 107 people.

We have complemented our direct sales efforts with sales to distributors and/or strategic corporate partners.

For more information regarding our distributors and strategic partners, refer to the Sales and Marketing section in item 1 of this report.

We continuously evaluate other potential distributor and strategic partner networks in other countries where we are approved to market the device.

Overall, we have established either direct sales or distribution (via distributors or strategic partners) of CytoSorb in 67 countries worldwide.

For more information regarding our distributors and strategic partners, refer to the Sales and Marketing section in Iitem 1 of this Report.

Overall, we have established either direct sales or distribution (via distributors or strategic partners) of CytoSorb in more than 70 countries worldwide.

Registration of CytoSorb is typically required in each of these countries prior to active commercialization.

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We cannot generally predict the timing of these registrations, and there can be no guarantee that we will ultimately achieve registration in countries where we have established distribution.

For example, in August 2014 we announced exclusive distribution of CytoSorb in Taiwan with Hemoscien Corporation.

However, in March 2015, due to the complexity we encountered with Taiwanese product registration, we elected to terminate our agreement with Hemoscien.

Outside of the EU, CytoSorb has distribution in Turkey, India, Sri Lanka, Australia, New Zealand, Russia, Serbia, Norway, Vietnam, Malaysia, Hong Kong, Chile, Panama, Costa Rica, Colombia, Brazil, Mexico, Argentina, Perú, Guatemala, Ecuador, Bolivia, the Dominican Republic, El Salvador, Iceland, Israel, UAE, Iran, Saudi Arabia and other Middle Eastern countries, and South Korea.

Outside of the EU, CytoSorb has distribution in Turkey, India, Sri Lanka, Australia, New Zealand, Russia, Serbia, Vietnam, Malaysia, Hong Kong, Chile, Panama, Costa Rica, Colombia, Brazil, Mexico, Argentina, Perú, Guatemala, Ecuador, Bolivia, the Dominican Republic, El Salvador, Iceland, Israel, UAE, Iran, Saudi Arabia and other Middle Eastern countries, and South Korea.

We cannot guarantee that we will generate meaningful sales in the countries where we have established registration, due to other factors such as market adoption and reimbursement.

For example, in December 2019, we discontinued our distributor relationship with Dr.

Reddy’s in South Africa due to lack of market adoption.

We continuously evaluate other potential distributor and strategic partner networks in other countries that accept CE Mark approval.

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CytoSorbents donated the initial CytoSorb devices and provided product, training, and support to CMS to introduce CytoSorb initially into four hospitals in the Wuhan, China area.

The therapy was used and will be evaluated in severe COVID-19 coronavirus patients with a systemic inflammatory response being treated with either continuous renal replacement therapy (CRRT) or extracorporeal membrane oxygenation (ECMO).

The therapy was used in severe COVID-19 coronavirus patients with a systemic inflammatory response being treated with either continuous renal replacement therapy (CRRT) or extracorporeal membrane oxygenation (ECMO).

The use of CytoSorb for the treatment of patients with severe COVID-19 coronavirus infection is considered exploratory in nature in China and is currently not yet approved for commercial purposes in mainland China.

In addition to our direct and distributor commercial channels, we have a number of strategic partners to market and distribute CytoSorb.

In addition to our direct and distributor commercial channels, we have a number of strategic partners to market and/or distribute CytoSorb.

These partners include Biocon Biologics Limited, Fresenius Medical Care AG, B.

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This study also provided additional treatment options for CytoSorb, helped to support the positive clinical data from our first European Sepsis Trial, and helped to shape the trial protocol for a pivotal sepsis study.

In addition to the dosing study, we plan to use data generated and published in the more than 50 investigator-initiated studies and trials sponsored by us currently planned, enrolling or completed in Europe and abroad.

Approximately 20 of these studies are currently enrolling.

These trials, which are funded and supported by well-known university hospitals and KOLs, are the equivalent of Phase 2 clinical studies.

They will provide invaluable information regarding the success of the device in the treatment of sepsis, cardio-pulmonary bypass surgery, trauma, and many other indications, and if successful, will be integral in helping to drive additional usage and adoption of CytoSorb.

In addition to sepsis and other critical care applications, cardiac surgery is an important application for CytoSorb in the European market.

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and EU combined including, for example, coronary artery bypass graft surgery, valve replacement surgery, heart and lung transplant, congenital heart defect repair, aortic reconstruction, and left ventricular assist device (“LVAD”) implantation.

Cardiac surgery can result in inflammation and the production of high levels of inflammatory cytokines, as activation of complement, and cause hemolysis, leading to the release of toxic plasma free hemoglobin.

Cardiac surgery can result in inflammation and the production of high levels of inflammatory cytokines, activation of complement, and cause hemolysis, leading to the release of toxic plasma free hemoglobin.

These can lead to post-operative complications such as respiratory failure, circulatory failure, and acute kidney injury.

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Direct cytokine and hemoglobin removal with CytoSorb enables it to replace the former market for leukoreduction filters in cardiac surgery that attempt to indirectly reduce cytokines by capturing cytokine-producing leukocytes – an inefficient and suboptimal approach.

A more recent application is the use of CytoSorb during cardiothoracic surgery to prevent or reduce perioperative bleeding by removing the blood thinners ticagrelor and rivaroxaban.

The Company is currently conducting the following clinical trials:

United States

REFRESH 2-AKI

Post-Cardiac Surgery AKI

Ticagrelor Removal During Cardiac Surgery

United States

Direct Anticoagulants Removal During Cardiac Surgery

United States

Real world outcomes in COVID-19 patients under the EUA

Ticagrelor Removal During Cardiac Surgery

United Kingdom

Ticagrelor Removal During Cardiac Surgery

Evaluation of Patients Suffering From Acute Liver Failure

STAR Registry

Real world outcomes in antithrombotic removal

The Company is also providing an update on the following investigator initiated clinical trial:

Infective Endocarditis

COSMOS Registry

Real world outcomes across multiple critical care applications

For further detailed information regarding our clinical trial strategy, see the section entitled “Clinical Studies” of this Item 1 of this Report.

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or approval in any other country or jurisdiction.

Because of the limited studies we have conducted, we are subject to substantial risk that our technology will have little or no effect on the treatment of any indications that we have targeted.

We have been successful in obtaining technology development contracts from agencies in the U.S.

We have been successful in obtaining technology development contracts from multiple U.S.

governmental agencies, such as the National Institutes of Health and the U.S.

Department of Defense, including the Defense Advanced Research Projects Agency (“DARPA”), the U.S.

Army, the U.S.

Air Force, as well as the National Institutes of Health.

Air Force, Special Operations Command, and Joint Program Executive Office (JPEO).

See the section entitled “Government Research Grants” of this Item 1 of this Report for information regarding the specific grants.

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The Company completed the Offering pursuant to the terms of an Underwriting Agreement, dated as of July 21, 2020, by and among the Company and Cowen and Company, LLC and SVB Leerink LLC, as representatives of the several underwriters named therein.

The Company received gross proceeds of approximately $57.5 million from the Offering.

After deducting the underwriting discounts and commissions and fees and expenses payable by the Company in connection with the Offering, the Company received net proceeds of approximately $53.8 million.

The Company received gross proceeds of approximately $57.5 million from the Offering and after deducting the underwriting discounts and commissions and fees and expenses payable by the Company in connection with the Offering, the Company received net proceeds of approximately $53.8 million.

Shelf Registration

On July 26, 2018, the Company filed a registration statement on Form S-3 with the SEC (as amended, the “2018 Shelf”).

The 2018 Shelf, which was declared effective on August 7, 2018, enables the Company to offer and sell, in one or more offerings, any combination of common stock, preferred stock, senior or subordinated debt securities, warrants and units, up to a total dollar amount of $150 million.

The 2018 Shelf, which was declared effective on August 7, 2018, enabled the Company to offer and sell, in one or more offerings, any combination of common stock, preferred stock, senior or subordinated debt securities, warrants and units, up to a total dollar amount of $150 million.

The 2018 Shelf terminated automatically upon the 2021 Shelf (as defined below) being declared effective on July 27, 2021.

On July 14, 2021, the Company filed a registration statement on Form S-3 with the SEC, which was amended on July 20, 2021 and declared effective by the SEC on July 27, 2021 (as amended, the “2021 Shelf”).

The 2021 Shelf enables the Company to offer and sell, in one or more offerings, any combination of common stock, preferred stock, senior or subordinated debt securities, warrants and units, up to a total dollar amount of $150 million.

Open Market Sale Agreement with Jefferies LLC and B.

Riley FBR, Inc.

On July 9, 2019, the Company entered into an Open Market Sale Agreement (the “New Sale Agreement”) with Jefferies LLC and B.

On July 9, 2019, the Company entered into an Open Market Sale Agreement (the “Sale Agreement”) with Jefferies LLC and B.

Riley FBR, Inc.

(each an “Agent” and, together, the “Agents”), pursuant to which the Company may sell, from time to time, at its option, shares of the Company’s common stock having an aggregate offering price of up to $25,000,000 through the Agents, as the Company’s sales agents.

All shares of the Company’s common stock offered and sold, or to be offered and sold under the New Sale Agreement were or will be issued and sold pursuant to the Company’s 2018 Shelf by methods deemed to be an “at the market offering” as defined in Rule 415(a)(4) promulgated under the Securities Act of 1933, as amended, in block transactions or if specified by the Company, in privately negotiated transactions.

On April 20, 2020, the Company and the Agents entered into an amendment to the New Sale Agreement (the “Amendment”) to provide for an increase in the aggregate offering amount under the New Sales Agreement, such that as of April 20, 2020, the Company may offer and sell Shares having an additional aggregate offering price of up to $50 million under the New Sale Agreement, as amended by the Amendment (the “Amended Sale Agreement”).

Subject to the terms of the Amended Sales Agreement, the Agents are required to use their commercially reasonable efforts consistent with their normal sales and trading practices to sell the shares of the Company’s common stock from time to time, based upon the Company’s instructions (including any price, time or size limits or other customary parameters or conditions the Company may impose).

The Company is required to pay the Agents a commission of up to 3.0% of the gross proceeds from the sale of the shares of the Company’s common stock sold thereunder, if any.

(each an “Agent” and, together, the “Agents”), pursuant to which the Company could sell, from time to time, at its option, shares of the Company’s common stock having an aggregate offering price of up to $25 million through the Agents, as the Company’s sales agents.

All shares of the Company’s common stock offered and sold, or to be offered and sold under the Sale Agreement would have been issued and sold pursuant to the Company’s 2018 Shelf by methods deemed to be an “at the market offering” as defined in Rule 415(a)(4) promulgated under the Securities Act of 1933, as amended, in block transactions or if specified by the Company, in privately negotiated transactions.

On April 20, 2020, the Company and the Agents entered into an amendment to the Sale Agreement (the "Amendment") to provide for an increase in the aggregate offering amount under the Sales Agreement, such that as of April 20, 2020, the Company could offer and sell Shares having an additional aggregate offering price of up to $50 million under the Sale Agreement, as amended by the Amendment (the "Amended Sale Agreement").

Subject to the terms of the Amended Sales Agreement, the Agents were required to use their commercially reasonable efforts consistent with their normal sales and trading practices to sell the shares of the Company’s common stock from time to time, based upon the Company’s instructions (including any price, time or size limits or other customary parameters or conditions the Company may impose).

The Company was required to pay the Agents a commission of up to 3.0% of the gross proceeds from the sale of the shares of the Company’s common stock sold thereunder, if any.

The Company has also agreed to provide the Agents with customary indemnification rights.

The offering of the shares of the Company’s common stock under the Amended Sales Agreement will terminate upon the earliest of (a) the sale of the maximum number or amount of the shares of the Company’s stock permitted to be sold under the Amended Sale Agreement and (b) the termination of the Amended Sale Agreement by the parties thereto.

During the year ended December 31, 2019, the Company sold 191,244 shares pursuant to the Amended Sale Agreement, at an average selling price of $4.11 per share, generating net proceeds of approximately $762,000.

During the year ended December 31, 2020, the Company sold 4,110,625 shares pursuant to the Amended Sale Agreement, at an average selling price of $6.64 per share, generating net proceeds of approximately $26,476,000.

In the aggregate, the Company has sold 4,301,869 shares pursuant to the Amended Sale Agreement, at an average selling price of $6.53 per share, generating net proceeds of approximately $27,238,000.

In addition, during the year ended December 31, 2020, the Company paid approximately $49,000 in expenses related to the Amended Sale Agreement.

There were no sales pursuant to the Amended Sale Agreement during the year ended December 31, 2021.

In the aggregate, the Company has sold 4,301,869 shares pursuant to the Amended Sale Agreement, at an average selling price of $6.53 per share, generating net proceeds of approximately $27.2 million.

The Company may no longer offer and sell additional shares of the Company’s common stock under the Amended Sale Agreement following the declaration of effectiveness of the 2021 Shelf on July 27, 2021.

Open Market Sale Agreement with Jefferies LLC

On December 30, 2021, the Company entered into an Open Market Sale Agreement (the “Sale Agreement”) with Jefferies LLC (the “Agent”), pursuant to which the Company could sell, from time to time, at its option, shares of the Company’s common stock having an aggregate offering price of up to $25 million through the Agent, as the Company’s sales agent.

All shares of the Company’s common stock offered and sold, or to be offered and sold under the Sale Agreement would have been issued and sold pursuant to the Company’s 2021 Shelf by methods deemed to be an “at the market offering” as defined in Rule 415(a)(4) promulgated under the Securities Act of 1933, as amended, in block transactions or if specified by the Company, in privately negotiated transactions.

Subject to the terms of the Sales Agreement, the Agent is required to use their commercially reasonable efforts consistent with their normal sales and trading practices to sell the shares of the Company’s common stock from time to time, based upon the Company’s instructions (including any price, time or size limits or other customary parameters or conditions the Company may impose).

The Company is required to pay the Agent a commission of up to 3.0% of the gross proceeds from the sale of the shares of the Company’s common stock sold thereunder, if any.

There were no sales pursuant to the Sale Agreement during the year ended December 31, 2021.

Research and Development

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$1.5M Phase II SBIR;

$3.0M Bridge SBIR), the Joint Program Executive Office – Chemical and Biological Defense, (JPEO-CBD), ($150K Phase I and Phase I option, $1.0M Phase II), the

Army Peritoneal dialysis/mesh packing for hyperkalemia ($150K Phase I SBIR, $1.0M Phase II), Universal Plasma ($150K Phase I and 1.0M Phase II STTR;

$3.0M Bridge SBIR), the Joint Program Executive Office – Chemical and Biological Defense, (JPEO-CBD), ($150K Phase I and Phase I option, $1.0M Phase II), the U.S.

Army Peritoneal dialysis/mesh packing for hyperkalemia ($150K Phase I SBIR, $1.0M Phase II, $1.5 M 2 nd Phase II), Universal Plasma ($150K Phase I and 1.0M Phase II STTR;

$2.9M Defense Health Agency, US Army and CDMRP Phase III STTR;

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Our polymer adsorbent technology can remove drugs, bioactive lipids, inflammatory mediators such as cytokines, free hemoglobin, toxins, and immunoglobulin from blood and physiologic fluids depending on the polymer construct.

It is believed that the technology may have many applications in the treatment of common, chronic and acute healthcare conditions including, but not limited to, the adjunctive treatment and/or prevention of sepsis;

the treatment of other critical care illnesses such as severe burn injury, trauma, acute respiratory distress syndrome and pancreatitis;

The technology has been used in a wide variety of acute healthcare applications including, but not limited to, the adjunctive treatment and/or prevention of sepsis;

the treatment of other critical care illnesses such as severe burn injury, trauma, acute respiratory distress syndrome, liver failure, and pancreatitis;

the prevention of post-operative complications of cardiopulmonary bypass surgery;

the treatment of cancer cachexia;

the treatment of cytokine release syndrome in cancer immunotherapy, the prevention of damage to organs donated by brain-dead donors prior to organ harvest;

the prevention of transfusion reactions caused by contaminants in transfused blood products;

the prevention of contrast induced nephropathy, the treatment of drug overdose, and the treatment of chronic kidney failure.

These applications vary by cause and complexity as well as by severity but share a common characteristic, i.e., high concentrations of inflammatory mediators and toxins in the circulating blood.

Our flagship product, CytoSorb, animal-targeted VetResQ, ECOS-300CY, and other product candidates under development, including CytoSorb XL, BetaSorb, ContrastSorb, DrugSorb, HemoDefend-RBC, HemoDefend-BGA, K + ontrol,and others consist of a cartridge containing adsorbent, porous polymer beads, although the polymers used in these devices are physically different.

the removal of non-infectious contaminants in transfused blood products;

the treatment of drug overdose, and the removal of antithrombotic drugs during cardiothoracic surgery that could otherwise cause severe perioperative bleeding.

These applications vary by cause and complexity as well as by severity but share a common characteristic, i.e., high concentrations of inflammatory mediators,toxins, or drugs in the circulating blood.

Our flagship product, CytoSorb, animal-targeted VetResQ, DrugSorb-ATR, ECOS-300CY, and other product candidates under development, including CytoSorb XL, BetaSorb, ContrastSorb, DrugSorb, HemoDefend-RBC, HemoDefend-BGA, K + ontrol, and others consist of a cartridge containing adsorbent, porous polymer beads, although the polymers used in these devices are physically different.

The cartridges incorporate industry standard connectors at either end of the device, which connect directly to the extracorporeal circuit (bloodlines) in series with a dialyzer as a standalone device.

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The patient’s blood is accessed through a catheter inserted into his or her veins.

The catheter is connected to the extra-corporeal circuit and the blood pump draws blood from the patient, pumps it through the cartridge and returns it back to the patient in a closed loop system.

The catheter is connected to the extracorporeal circuit and the blood pump draws blood from the patient, pumps it through the cartridge and returns it back to the patient in a closed loop system.

All of these devices are expected to be compatible with standard blood pumps or hemodialysis machines used commonly in hospitals and will therefore not require hospitals to purchase additional expensive equipment and will require minimal training.

The polymer beads designed for the HemoDefend platform are intended to be used in multiple configurations, including a point-of-transfusion in-line filter between the blood bag and the patient, as well as a patent-pending “Beads in a Bag” configuration, where the beads are placed directly into a blood storage bag.

We are a critical care focused immunotherapy company.

Immunotherapy is the ability to control the immune response to fight disease.

CytoSorb, through its ability to bind mediators that regulate inflammation, is a critical care-focused immunotherapy.

Critical care medicine includes the treatment of patients with serious or life-threatening conditions who require comprehensive care in the ICU, with highly skilled physicians and nurses and advanced technologies to support critical organ function to keep patients alive.

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Unfortunately, most supportive care therapies only help to keep patients alive by supporting organ function but do not help reverse the underlying causes of organ failure and do not help patients recover more quickly.

Because of this, the treatment course is often poorly defined and highly variable, leading to lengthy ICU stays, a higher risk of adverse outcomes from hospital acquired infections, medical errors, and

other factors, as well as exorbitant costs.

There is an urgent need for more effective “active” therapies that can help to reverse or prevent organ failure.

Our main product, CytoSorb, is a unique cytokine filter designed to try to address this void, by reducing “cytokine storm” and working to reduce the subsequent deadly inflammation that can lead to organ failure and death.

Our main product, CytoSorb, is a unique cytokine adsorber designed to try to address this void, by reducing “cytokine storm” and working to reduce the subsequent deadly inflammation that can lead to organ failure and death.

In May 2018, the approved indications for use of CytoSorb in the EU were expanded to include the removal of bilirubin in liver disease, and the removal of myoglobin in trauma.

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Intra-operatively, CytoSorb is either used to help stabilize patients with serious conditions such as infective endocarditis, or to prevent post-operative complications such as acute kidney injury, vasoplegia, respiratory failure, infection, and others.

CytoSorb is also used intra-operatively to remove blood thinners to prevent or reduce bleeding and associated complications during cardiothoracic surgery.

Post-operatively, CytoSorb is used in the intensive care unit to treat the post-operative systemic inflammatory response syndrome (post-op SIRS), sepsis, and other complications.

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CytoSorb has been evaluated in the randomized, controlled European Sepsis Trial in 100 patients in Germany with predominantly septic shock and acute respiratory distress syndrome or acute lung injury.

The therapy was safe in more than 300 human treatments and generally well-tolerated.

CytoSorb demonstrated the ability to reduce a broad range of cytokines from the blood of critically-ill patients.

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In October 2011, following its PROWESS SHOCK trial that demonstrated no benefit in mortality in septic shock patients, Lilly voluntarily withdrew Xigris from all markets worldwide, and is no longer available as a treatment.

Development of many experimental therapies has been discontinued, including Eritoran from Eisai, CytoFab from BTG/Astra Zeneca, Talactoferrin from Agennix, tranexemic acid from Leading Biosciences, and others.

For more information regarding our competitor’s clinical trials, see the section entitled “Competition” in Item 1 of this report.

Severe sepsis and septic shock patients are among the most expensive patients to treat in a hospital.

For more information regarding our competitors, see the section entitled “Competition” in Item 1 of this report.

Severe sepsis and septic shock patients are among the most difficult and expensive patients to treat in a hospital.

Because of this, we believe that cost savings to hospitals and/or clinical efficacy, rather than the cost of treatment itself, will be the determining factor in the adoption of CytoSorb in the treatment of sepsis.

CytoSorb is approved in the EU and is being sold directly in Germany, Austria, Switzerland, Belgium, Luxembourg, Poland, Norway, Denmark, Sweden, and the Netherlands with our own direct sales force.

In December 2016, we announced the achievement of a permanent, dedicated reimbursement procedure code for CytoSorb therapy in Germany, providing for specific and enhanced reimbursement in the largest medical device market in Europe.

We have established strategic partnerships with Fresenius Medical Care, the world’s largest dialysis company, for exclusive distribution of CytoSorb for critical care applications in France, Finland, the Czech Republic, Mexico, and Korea, and Terumo Cardiovascular, the largest cardiac surgery disposables company, for exclusive distribution of the CytoSorb Cardiopulmonary Bypass Kit in France, Denmark, Sweden, Norway, Finland, and Iceland.

In December 2016, we announced the achievement of a dedicated reimbursement procedure code for CytoSorb therapy in Germany, providing for specific and enhanced reimbursement in the largest medical device market in Europe.

We are also partnered with Biocon Biologics Limited, India’s largest biopharmaceutical company, for exclusive distribution of CytoSorb in India, Sri Lanka, and other select emerging markets.

In March 2021, we announced a strategic partnership with B.

Braun Avitum AG, and the launch of a global co-marketing agreement to promote the use of CytoSorb with B Braun’s latest OMNI® continuous blood purification platform and OMNIset® Plus bloodline set (set version 3.0 or higher).

Braun Avitum AG, and the launch of a global co-marketing agreement to promote the use of CytoSorb with B.

Braun’s latest OMNI ® continuous blood purification platform and OMNIset ® Plus bloodline set (set version 3.0 or higher).

We have ongoing discussions with potential corporate partners and independent distributors to market CytoSorb in other select EU countries and in other countries outside the EU that accept CE Mark approval.

We have established direct sales or distribution of CytoSorb in 67 countries worldwide.

We estimate that the market potential in Europe for our products is larger than that in the U.S.

We have established direct sales or distribution of CytoSorb in more than 70 countries worldwide.

We estimate that the market potential in Europe for CytoSorb is larger than that in the U.S.

For example, in the U.S.

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After the surgery, CytoSorb can continue to be used similarly to dialysis on patients that develop a severe post-operative inflammatory response with hemodynamic instability.

Modified ultrafiltration is sometimes used after termination of cardiopulmonary bypass in cardiac surgery to remove excess fluid and inflammatory

substances, but has had mixed benefit.

Modified ultrafiltration is sometimes used after termination of cardiopulmonary bypass in cardiac surgery to remove excess fluid and inflammatory substances but has had mixed effect.

The peri-procedural total addressable market for CytoSorb in the U.S.

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In the acute management of these patients , especially when they need interventional procedures such as stent placement therapy is escalated using two antiplatelet drugs (dual antiplatelet therapy - DAPT).

Ticagrelor (Astra Zeneca - Brilinta(R), Brilique(R)) is considered best in class and is one of the most commonly used anti-platelet drugs to reduce the risk of cardiac death, heart attacks, and strokes in patients with either a history of a heart attack, or those actively undergoing percutaneous coronary intervention (PCI) with stent placement for acute coronary syndrome or heart attack.

Ticagrelor (Astra Zeneca - Brilinta ® , Brilique ® ) is considered best in class and is one of the most commonly used anti-platelet drugs to reduce the risk of cardiac death, heart attacks, and strokes in patients with either a history of a heart attack, or those actively undergoing percutaneous coronary intervention (PCI) with stent placement for acute coronary syndrome or heart attack.

On the other hand, patients with atrial fibrillation or venous thrombosis require chronic anticoagulation.

A new category of drugs called Direct Oral Anticoagulants (DOAC) is now the new standard of care with tens of millions of patients relying on them for lifelong protection.

The two leaders in the category,Apixaban (Bristol Myers Squibb - Eliquis(R)) and rivaroxaban (Janssen and Bayer - Xarelto(R)) aare estimated to reach 40 billion USD in sales by 2026.

There is a clear and large unmet medical when patients on these antithrombotic agents need to undergo surgery due to the very high risk of bleeding.

The two leaders in the category, apixaban (Bristol Myers Squibb - Eliquis ® ) and rivaroxaban (Janssen and Bayer - Xarelto ® ) are estimated to reach 40 billion USD in sales by 2026.

There is a clear and large unmet medical need when patients on these antithrombotic agents need to undergo surgery due to the very high risk of bleeding.

Specifically, in patients on these drugs requiring urgent or emergent cardiac surgery the risk of major fatal/life-threatening bleeding has been reported to be as high as 65%.

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In the US alone there are approximately 1.1 million ACS hospital admissions annually.

CytoSorb is able to very efficiently remove ticagrelor and DOACs from blood.

The use of CytoSorb during emergency coronary artery bypass surgery (CABG) in patients on ticagrelor or rivaroxaban significantly reduced post-operative bleeding complications in a landmark observational study and had projected cost savings of approximately $5,000 per patient, including the cost of the device.

Every year there are approximately 400,000 CABG procedures performed in the US and 250,000 CABG procedures in the EU with nearly 100,000 in Germany alone.

CytoSorb is able to very efficiently remove ticagrelor and DOACs from blood, and is approved in the E.U.

for the removal of both ticagrelor and rivaroxaban during cardiothoracic surgery requiring cardiopulmonary bypass.

The use of CytoSorb during emergency coronary artery bypass surgery (CABG) in patients on ticagrelor or rivaroxaban significantly reduced periooperative bleeding complications in a landmark observational study and had projected cost savings of approximately $5,000 per patient, including the cost of the device.

In the U.S., the Company is conducting two pivotal, randomized, controlled trials, the STAR-T and STAR-D trials, to evaluate the potential ability of the DrugSorb-ATR antithrombotic removal system, which uses an equivalent polymer technology to CytoSorb, to reduce perioperative bleeding risk in patients undergoing cardiothoracic surgery in the presence of ticagrelor, or the direct oral anticoagulants, apixaban and rivaroxaban, respectively.

Each study, if successful, is intended to independently support U.S.

FDA marketing approval for DrugSorb-ATR for this indication.

The initial annual addressable market in the U.S.

to remove these drugs during cardiothoracic surgery is estimated between $500-750 million.

Acute Respiratory Distress Syndrome

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each year, with even more cases in the EU.

During the COVID-19 pandemic in 2020-2021, ALI and ARDS were responsible for more than 500,000 deaths in the U.S.

Patients with ALI and ARDS typically require mechanical ventilation, and sometimes extracorporeal membrane oxygenation (ECMO) therapy, to help achieve adequate oxygenation of the blood.

Patients on mechanical ventilation are at high risk of ongoing ventilator-induced lung injury, oxygen toxicity, barotrauma, ventilator-acquired pneumonias, and other hospital acquired infections, and outcome is significantly dependent on the presence of other organ dysfunction as well as co-morbid conditions such as pre-existing lung disease (e.g., emphysema or chronic obstructive pulmonary disease) and age.

During the COVID-19 pandemic in 2020-2021, ALI and ARDS contributed or were responsible for more than 900,000 deaths in the U.S.

Patients with ALI and ARDS typically require mechanical ventilation, and sometimes extracorporeal membrane oxygenation (ECMO) therapy if the lungs become so diseased that mechanical ventilation fails, to help achieve adequate oxygenation of the blood.

Patients on mechanical ventilation are at high risk of ongoing

ventilator-induced lung injury, oxygen toxicity, barotrauma, ventilator-acquired pneumonias, and other hospital acquired infections, and outcome is significantly dependent on the presence of other organ dysfunction as well as co-morbid conditions such as pre-existing lung disease (e.g., emphysema or chronic obstructive pulmonary disease) and age.

Because of this, mortality has been high (16-33%) even with modern medicine and ventilation techniques.

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Cytokine injury plays a major role in the vascular compromise and cell-mediated damage to the lung through tight junction disruption of respiratory endothelium, leading to capillary leak syndrome, and other factors.

Reduction of cytokine levels may either prevent or mitigate lung injury, enabling patients to wean from mechanical ventilation faster, potentially reducing numerous sequelae such as infection, pneumothoraces, and respiratory muscle deconditioning, and allow faster ICU discharge, thereby potentially saving costs.

Reduction of cytokine levels may either prevent or mitigate lung injury, enabling patients to wean from mechanical ventilation and ECMO faster, potentially reducing numerous sequelae such as infection, pneumothoraces, and respiratory muscle deconditioning, and allow faster ICU discharge, thereby potentially saving costs.

CytoSorb treatment of patients with either ALI or ARDS in the setting of sepsis was the subject of our European Sepsis Trial where in a post-hoc analysis in patients with very high cytokine levels, we observed faster ventilator weaning in CytoSorb treated patients that showed a statistical trend towards benefit.

Published results from our CytoSorb Therapy in COVID-19 (CTC) registry in the medical journal, Frontiers in Medicine, in December 2021, demonstrated that in 52 consecutive patients from 5 U.S.

ECMO centers, 90-day survival was 73% in critically ill COVID-19 patients who failed mechanical ventilation and were treated with ECMO and CytoSorb under FDA Emergency Use Authorization, For context, 90-day survival was 50% (as of December 2021) among more than 6,400 adult patients in the North American cohort of the Extracorporeal Life Support Organization (ELSO) COVID-19 ECMO Registry.

Future, prospectively defined, larger studies are required to confirm these findings.

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However, even with these interventions, we believe mortality is still unacceptably high.

The total addressable market for CytoSorb to treat ARDS and ALI in the EU is estimated to be between $500 million to $1.25 billion, and approximately $2 billion for the U.S and EU combined.

The total addressable market for CytoSorb to treat ARDS and ALI in the EU is estimated to be between $500 million to $1.25 billion, and approximately $2 billion for the U.S.

and EU combined.

Severe Burn Injury

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According to the National Center for Health Statistics, in the U.S., there are more than 31 million visits to hospital emergency rooms, with 1.9 million hospitalizations, and 167,000 deaths every year due to injury.

The leading causes of injury are trauma from motor vehicle accidents, being struck by an object or other person, and falls.

The leading causes of injury are trauma from

motor vehicle accidents, being struck by an object or other person, and falls.

Trauma is a well-known trigger of the immune response and a surge in cytokine production or cytokine storm.

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were expanded to include the removal of bilirubin in liver disease.

The total addressable market for CytoSorb for the treatment of acute-on-chronic liver disease, acute hepatitis, and acute liver failure is estimated in excess of $15 billion worldwide.

The total addressable market for CytoSorb for the treatment of acute-on-chronic liver disease, acute hepatitis, and acute liver failure is estimated to bed more than $15 billion worldwide.

Severe Acute Pancreatitis

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Cancer cachexia is a systemic inflammatory condition, driven by excessive pro-inflammatory cytokines and other factors, that cripples the patient’s physical and immunologic reserve to fight cancer.

Despite afflicting millions of patients worldwide each year, there are no effective approved treatments for cancer cachexia, with only symptomatic treatments available.

afflicting millions of patients worldwide each year, there are no effective approved treatments for cancer cachexia, with only symptomatic treatments available.

CytoSorb blood purification may stop or reverse cancer cachexia through broad reduction of cytokines and other inflammatory mediators, when treated over time.

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According to Eurotransplant, there were approximately 6,400 transplants from deceased donors and roughly 14,000 patients on waiting list for organs in Europe last year.

In the United States, UNOS cites 39,035 organ transplants in 2020, with approximately 108,000 patients on the waiting list.

This represents a US and European total addressable market for the ECOS-300CY device of approximately $400-600 million.

In the United States, UNOS cites more than 41,000 organ transplants in 2020, with approximately 106,000 patients on the waiting list.

This represents a U.S.

and European total addressable market for the ECOS-300CY device of approximately $400-600 million.

Blood Transfusions

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Other early transfusion reactions such as transfusion-associated dyspnea, fever and allergic reactions occur in 3% to 5% of all transfusions and can vary in severity depending on the patient’s condition.

These are caused by cytokines, bioactive lipids, free hemoglobin, toxins, foreign antigens, and a number of other inflammatory mediators that accumulate in transfused blood products during storage.

These are caused by cytokines, bioactive lipids, free hemoglobin, toxins, foreign antigens, and a number of other inflammatory mediators that accumulate in transfused

blood products during storage.

Leukoreduction can remove the majority of white cells that can produce new cytokines but cannot eliminate those cytokines already in blood, and cannot otherwise remove other causative agents such as free hemoglobin and antibodies.

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In westernized countries alone, with a population of 1.5 billion, there are approximately 12 million units of plasma administered each year.

The total addressable market for HemoDefend-BGA in transfusion medicine in westernize countries alone is an estimated $400 million to $600 million, and represents a fraction of the global market.

The total addressable market for HemoDefend-BGA in transfusion medicine in westernized countries alone is an estimated $400 million to $600 million and represents a fraction of the global market.

Radiocontrast Removal

ContrastSorb is a development-stage blood purification technology that is being optimized for the removal of IV contrast from blood in order to prevent CIN.

Contrast-induced nephropathy is the acute loss of renal function within the first 48 hours following IV contrast administration.

ContrastSorb is a development-stage blood purification technology that is being optimized for the removal of IV contrast from blood in order to prevent contrast -induced nephropathy ("CIN").

CIN is the acute loss of renal function within the first 48 hours following IV contrast administration.

IV contrast is widely administered to patients undergoing CT scans, to enhance the images and make it easier to identify anatomic structures.

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Over time, β 2 -microglobulin can accumulate and cause amyloidosis in joints and elsewhere in the musculoskeletal system, leading to pain and disability.

Our BetaSorb device has been designed to remove these mid-molecular weight toxins when used in conjunction with standard dialysis.

Our BetaSorb device is intended to remove these mid-molecular weight toxins when used in conjunction with standard dialysis.

Standard dialysis care typically involves three sessions per week, averaging approximately 150 sessions per year.

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The trial successfully demonstrated the ability of CytoSorb to reduce levels of key cytokines from whole blood in treated patients, and that treatment was safe in these critically-ill patients with multiple organ failure.

We completed the CytoSorb technical file review with our notified body and CytoSorb subsequently received EU regulatory approval under the CE Mark as an extracorporeal cytokine filter indicated for use in any clinical situation where cytokines are elevated.

We completed the CytoSorb technical file review with our notified body and CytoSorb subsequently received EU regulatory approval under the CE Mark as an extracorporeal cytokine adsorber indicated for use in any clinical situation where cytokines are elevated.

Given sufficient and timely financial resources, we intend to continue to commercialize in Europe and conduct additional clinical studies of our products.

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Background and Rationale:

We believe that the effective treatment of sepsis is the most valuable potential application for our technology.

We believe that the effective treatment of sepsis the largest market for our technology.

Severe sepsis (sepsis with organ dysfunction) and septic shock (severe sepsis with persistent hypotension despite fluid resuscitation) carries mortality rates of between 20% and 80%.

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With the exception of Xigris ® from Eli Lilly, no other products have been approved in either the U.S.

or Europe for the treatment of sepsis.

or Europe for

the treatment of sepsis.

In 2011, after completing a follow up study required by the FDA, it was subsequently determined that Xigris® did not have a statistically significant mortality benefit, and Eli Lilly withdrew Xigris® from all markets worldwide.

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The ability of CytoSorb to interact safely with blood (hemocompatibility) has been demonstrated through ISO 10993 testing, which includes testing for hemocompatibility, biocompatibility, cytotoxicity, genotoxicity, acute sensitivity and complement activation.

CytoSorb use has been considered safe and well-tolerated in more than 121,000 human treatments to date.

CytoSorb use has been considered safe and well-tolerated in more than 162,000 devices utilized as of December 31, 2021.

CytoSorb has been designed to achieve broad-spectrum removal of both pro- and anti-inflammatory cytokines, preventing or reducing the accumulation of high concentrations in the bloodstream.

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This approach is intended to modulate the immune response without causing damage to the immune system.

For this reason, researchers have referred to the approach reflected in our technology as “immunomodulatory” therapy.

Projected Timeline:

In 2011, the CytoSorb filter received EU regulatory approval under the CE Mark as an extracorporeal cytokine filter to be used in clinical situations where cytokines are elevated.

In 2011, the CytoSorb adsorber received EU regulatory approval under the CE Mark as an extracorporeal cytokine adsorber to be used in clinical situations where cytokines are elevated.

Our manufacturing facility has also achieved ISO 13485:2003 Full Quality Systems certification, an internationally recognized quality standard designed to ensure that medical device manufacturers have the necessary comprehensive management systems in place to safely design, develop, manufacture and distribute medical devices in the EU.

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Based on its CE Mark approval, CytoSorb can also be sold throughout all 27 countries of the EU, the United Kingdom and countries outside the EU that will accept European regulatory approval with registration.

Overall, we have established either direct sales or distribution (via distributors or strategic partners) of CytoSorb in 67 countries worldwide.

Overall, we have established either direct sales or distribution (via distributors or strategic partners) of CytoSorb in more than 70 countries worldwide.

Registration of CytoSorb is typically required in each of these countries prior to active commercialization.

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We actively support all of our distributors and strategic partners in the product registration process.

Outside of the EU, CytoSorb has distribution in Turkey, India, Sri Lanka, Australia, New Zealand, Russia, Serbia, Norway, Vietnam, Malaysia, Hong Kong, Chile, Panama, Costa Rica, Colombia, Brazil, Mexico, Argentina , Perú, Guatemala , Ecuador , Bolivia , the Dominican Republic , El Salvador , Iceland, Israel, UAE, Iran, Saudi Arabia and other Middle Eastern countries, and South Korea.

Outside of the EU, CytoSorb has distribution in Turkey, India, Sri Lanka, Australia, New Zealand, Russia, Serbia, Vietnam, Malaysia, Hong Kong, Chile, Panama, Costa Rica, Colombia, Brazil, Mexico, Argentina , Perú, Guatemala , Ecuador , Bolivia , the Dominican Republic , El Salvador , Iceland, Israel, UAE, Iran, Saudi Arabia and other Middle Eastern countries, and South Korea.

We cannot generally predict the timing of these registrations, and there can be no guarantee that we will ultimately achieve registration in countries where we have established distribution.

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We are currently actively evaluating other potential distributor and strategic partner networks in other major countries that accept CE Mark approval.

With sufficient resources and continued positive clinical data, assuming availability of adequate and timely funding, and continued positive results from our clinical studies, we intend to continue our commercialization plans for our product worldwide as well as to pursue U.S.

clinical trials to seek FDA regulatory approval for CytoSorb in the U.S.

Adjunctive Therapy in Other Critical Care Applications

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Background and Rationale:

A shared feature of many life-threatening conditions seen in the ICU is severe inflammation (either sepsis or systemic inflammatory response syndrome) due to an over-reactive immune system and high levels of cytokines that can cause or contribute to organ dysfunction, organ failure and patient death.

or contribute to organ dysfunction, organ failure and patient death.

Examples of such conditions include severe burn injury, trauma, acute respiratory distress syndrome and severe acute pancreatitis.

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Projected Timeline:

The EU CE Mark approval for CytoSorb as an extracorporeal cytokine filter and its broad approved indication to be used in any clinical situation where cytokines are elevated, allows it to be used “on label” in critical care applications such as acute respiratory distress syndrome, severe burn injury, trauma, liver failure, and pancreatitis, and in other conditions where cytokine storm, sepsis and/or SIRS plays a prominent role in disease pathology.

The EU CE Mark approval for CytoSorb as an extracorporeal cytokine adsorber and its broad approved indication to be used in any clinical situation where cytokines are elevated, allows it to be used “on label” in critical care applications such as acute respiratory distress syndrome, severe burn injury, trauma, liver failure, and pancreatitis, and in other conditions where cytokine storm, sepsis and/or SIRS plays a prominent role in disease pathology.

In addition, the expanded indications for use label now includes reduction of bilirubin and reduction of myoglobin, further strengthens the on-label use of the technology for the treatment of liver disease, and severe trauma, respectively.

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Currently, we have more than 45 investigator-initiated or company-sponsored studies being planned, enrolling, or completed.

We have been moving forward in parallel with a program to further understand the potential benefit of CytoSorb hemoperfusion in these conditions through additional investigational animal studies and potential human pilot studies in the U.S.

We have been moving forward in parallel with a program to further understand the potential benefit of CytoSorb hemoadsorption in these conditions through additional investigational animal studies and potential human pilot studies in the U.S.

funded either directly by us, through grants, or through third parties.

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human studies, FDA IDE approval of the respective human trial protocols.

Prevention and treatment of post-operative complications of cardiopulmonary bypass surgery

Prevention and treatment of perioperative complications of cardiopulmonary bypass surgery

Potential Benefits:

If CytoSorb is able to prevent or reduce high levels of cytokines, free hemoglobin, and other inflammatory mediators from accumulating in the bloodstream during and following cardiac surgery, we anticipate that post-operative complications of cardiopulmonary bypass surgery may be able to be prevented or mitigated.

In addition, CytoSorb can remove certain anti-thrombotics such as ticagrelor and rivaroxaban during cardiopulmonary bypass in patients requiring urgent or emergent surgery.

The primary goals for this application are to:

In addition, CytoSorb can remove certain antithrombotic drugs such as ticagrelor and rivaroxaban during cardiopulmonary bypass in patients requiring urgent or emergent surgery.

The primary goals for these applications are to:

reduce ventilator and oxygen therapy requirements;

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reduce the total cost of patient care;and

reduce the risk of post-operative bleeding complications such as need for blood and platelet transfusions, rethoracotomy, and death

reduce the risk of perioperative bleeding complications such as need for blood and platelet transfusions, rethoracotomy, and death.

Background and Rationale:

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If our products are able to prevent or reduce the accumulation of cytokines or free hemoglobin in a patient’s blood stream, we may be able to prevent or mitigate post-operative complications caused by an excessive or protracted inflammatory response to the surgery.

Intra-operative use of CytoSorb on high-risk cardiac surgery patients, where the risk of post-operative complications is the highest, is expected to be the main initial target market.

The use of CytoSorb in the post-operative period to treat post-operative SIRS is another application of the technology.

CytoSorb was recently approved to remove the anti-platelet agent, ticagrelor, during cardiac surgery involving cardiopulmonary bypass via label expansion of its CE Mark.

Intraoperative use of CytoSorb on high-risk cardiac surgery patients, where the risk of post-operative complications is the highest, is one of our main markets.

The use of CytoSorb in the post-operative period to treat postoperative SIRS is another application of the technology.

In 2020, CytoSorb was approved to remove the anti-platelet agent, ticagrelor, during cardiac surgery involving cardiopulmonary bypass via label expansion of its CE Mark.

Ticagrelor (Brilinta®, Astra Zeneca) is a widely used anti-platelet agent used to decrease cardiovascular risk and risk of stroke in patients with a known history of heart disease or heart attack.

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Georg in Hamburg, Germany on the investigational use of CytoSorb to reverse the effects of ticagrelor during emergency cardiac surgery demonstrated a greatly reduced risk of bleeding complications and the need for repeat surgery to explore the source of bleeding, with extrapolations showing projected cost savings of £3,982, or approximately $5,000 USD, per patient in a U.K.

CytoSorb was also approved for the removal of rivaroxaban, a widely used Factor Xa inhibitor and novel oral anticoagulant, during cardiothoracic surgery requiring cardiopulmonary bypass via label expansion of its CE Mark.

This new category of drugs called Direct Oral Anticoagulants (DOAC) is now the new standard of care with tens of millions of patients relying on them for chronic, often lifelong protection.

The two leaders in the category are apixaban (Bristol Myers Squibb - Eliquis ® ) and rivaroxaban (Janssen and Bayer - Xarelto ® ).

Projected Timeline:

Cardiac surgeons, cardiac perfusionists, and cardiothoracic ICU intensivists in Germany, Austria, and other countries have now used CytoSorb intra-operatively and post-operatively in more than 50,000 treatments in cardiac surgery patients.

This application is also the focus of number of planned and enrolling company-sponsored and investigator-initiated studies in the United States and Europe.

CytoSorb is the subject of a pivotal, 400-patient randomized controlled trial in the United States called the REFRESH 2-AKI trial.

Two CytoSorb cartridges are being used intraoperatively to reduce activated complement, free hemoglobin, and other inflammatory toxins that are generated during valve replacement surgery as well as aortic reconstruction with hypothermic cardiac

arrest, with the goal of reducing the risk of acute kidney injury.

Acute kidney injury following cardiac surgery is associated with an increased risk of death in the first 5 years after surgery.

The trial has enrolled more than 150 patients to date.

The Company has been undertaking multiple activities in preparation to resume the study, which is estimated to take place in the first half of 2021.

If the study is successful, we plan to submit a PMA application to the FDA in 2023 for U.S.

regulatory approval.

The 250-patient randomized controlled REMOVE infective endocarditis trial was completed in January 2020.

The COVID-19 pandemic has caused delays in data monitoring and data analysis.

Topline data are expected to be reported in the first half of 2021 with full data presentation at a major international conference also in 2021.

We are currently conducting the 30-patient, single arm trial in the United Kingdom called the TISORB trial, obtaining more country-specific data to support the use of CytoSorb to remove ticagrelor in emergent or urgent cardiac surgery to reduce perioperatively bleeding complications.

Due to the COVID-19 pandemic, the execution of the TISORB trial has been greatly impacted and ongoing national restrictions in the UK on the conduct of non-COVID clinical studies add further uncertainty to TISORB.

This application is also the focus of number of planned and enrolling company-sponsored and investigator-initiated studies of DrugSorb-ATR in the United States and CytoSorb in Europe.

In July 2021, we received full FDA approval of an Investigational Device Exemption (IDE) application to conduct a double-blind, randomized, controlled clinical study for up to 120 patients entitled, “ S afe and T imely A ntithrombotic R emoval - T icagrelor ( STAR-T ),” in the United States to support FDA marketing approval.

This was done under the previously announced FDA Breakthrough Designation granted for the removal of ticagrelor in a cardiopulmonary bypass circuit to reduce the likelihood of serious perioperative bleeding during urgent cardiac surgery.

In October 2021, the first patient was enrolled and the STAR-T study is now actively recruiting at multiple sites.

Pending any COVID-19 related delays we expect that the study will complete enrollment in the next 12 to 18 months.

In October 2021, we also received full FDA approval of an Investigational Device Exemption (IDE) application to conduct a double-blind, randomized, controlled clinical study for up to 120 patients entitled, “ S afe and T imely A ntithrombotic R emoval - D irect Oral Anticoagulants ( STAR-D ),” in the United States to support FDA marketing approval.

This was done under the previously announced 2 nd FDA Breakthrough Designation granted for our DrugSorb-ATR Antithrombotic Removal System.

This Breakthrough Device Designation covers the removal of the Direct Oral Anticoagulants (DOACs) apixaban and rivaroxaban in a cardiopulmonary bypass circuit to reduce the likelihood of serious perioperative bleeding during urgent cardiac surgery.

First sites have been activated and we expect the first patient to be enrolled in the first quarter of 2022 with target enrollment completion in 12-18 months after the first patient enrolled.

For further detailed information regarding our clinical trial strategy, see the section entitled "Clinical Studies"

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CytoSorb treatment in a porcine animal model of brain death demonstrated a reduction in cytokines as well as a preservation of cardiac function compared to untreated controls.

There is a shortage of donated organs worldwide, with approximately 100,000 people currently on the waiting list for organ transplants in the U.S.

There is a shortage of donated organs worldwide, with more than 100,000 people currently on the waiting list for organ transplants in the U.S.

Because there are an insufficient number of organs donated to satisfy demand, it is vital to maximize the number of viable organs donated, and optimize the probability of organ survival following transplant.

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CytoSorbents announced a partnership with Aferetica srl to provide the ECOS-300CY cartridge under the exclusive trade name, PerSorb™, that is compatible with Aferetica’s PerLife™ ex vivo organ perfusion system, recently approved in the E.U.

In 2021, commercialization of PerSorb™ and Aferetica's PerLife™ ex vivo organ perfusion system commenced in Italy.

CytoSorb for brain dead organ donors:

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The results were published in Critical Care Medicine, January 2008.

The next phase of this study, the treatment phase, would involve viable donors treated with the CytoSorb device.

In this phase of the project, viable donors will be treated and the survival and function of organs in transplant recipients will be tracked and measured.

The treatment phase would be contingent upon further discussion with the FDA and HRSA regarding study design, as well as obtaining additional funding.

The VetResQ Device (Animal Health Critical Care)

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Biological studies have demonstrated the accumulation of erythrocyte storage lesions that compromise the function and structural integrity of packed red blood cells and have also demonstrated the accumulation of substances during blood storage that can lead to transfusion reactions.

Three adult, prospective, randomized, controlled studies, RECESS (completed), ABLE (completed), and TRANSFUSE (completed) were designed to evaluate the morbidity and mortality in cardiovascular surgery patients (RECESS) and critically ill patients (ABLE and TRANSFUSE), treated with either “new or fresh” or “older” blood.

Three adult, prospective, randomized, controlled studies were designed to evaluate the morbidity and mortality in cardiovascular surgery patients (RECESS) and critically ill patients (ABLE and TRANSFUSE), treated with either “new or fresh” or “older” blood.

The RECESS Trial was a randomized, controlled trial in a total of 1,098 evaluable patients undergoing complex cardiac surgery given fresh blood (≤10 days old) as compared to older blood (≥21 days old).

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long-term storage:

22.4 days mean, N=2,462, m) on 90-day mortality in critically-ill patients.

22.4 days mean, N=2,462) on 90-day mortality in critically-ill patients.

There was no significant difference in 90-day mortality (24.8% mortality short-term storage vs 24.1% long-term storage) though there were statistically more febrile non-hemolytic transfusion reactions (n=123;

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Also, patients who had short-term storage blood with APACHE III > 21.5% (median risk), demonstrated higher mortality (37.7% vs 34% long-term storage, p=0.05).

The outcomes of these trials do not alter the current pressing need for better solutions to purify transfused blood products in order to reduce transfusion-related adverse events and improve clinical outcome, but suggest that age of blood is not the critical factor.

The outcomes of these trials do not alter the current pressing need for better solutions to purify transfused blood products , particularly in patients who receive massive transfusions defined as more than 10 pRBC units in 24 hours, those patients who receive blood chronically, and pediatric patients, in order to reduce transfusion-related adverse events and improve clinical outcome, but suggest that age of blood is not the critical factor.

Projected Timeline:

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The technology has been supported by the NHLBI, a division of the National Institute of Health, under a Phase I SBIR, an awarded $1.5M Phase II SBIR contract (funded by NHLBI and U.S.

Special Operations Command (USSOCOM)), and more recently under a $3M multi-year Phase IIB bridge contract funded by NHLBI.

As a result of delays caused by the COVID-19 pandemic, we expect to complete bench testing required for U.S.

approval in 2021, and advance the in-line filter to human testing in the first half of 2022.

Special Operations Command (USSOCOM)), and more recently

under a $3M multi-year Phase IIB bridge contract funded by NHLBI.

Barring additional delays due to the COVID-19 pandemic, including nationwide blood shortages, we expect to advance the in-line filter to human testing in 2022.

Removal of anti-A and anti-B blood group antibodies from fresh whole blood and plasma

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The transfusion of plasma, or plasma-derived products, is used widely to help save the lives of trauma and bleeding victims, septic and other critically-ill patients, and patients with life-threatening blood coagulation and autoimmune disorders.

In 2008, more than 4.5 million units of plasma were transfused in the United States alone.

Approximately 4.0 million units of plasma are transfused annually in the United States alone.

With the exception of the relatively uncommon Type AB, or “universal” plasma, most plasma contains blood-type specific antibodies and must be cross-matched with the intended recipient ahead of time or risk serious transfusion reactions.

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Prototype filtration devices have been evaluated by a government agency, resulting in excellent depletion of both anti-A and anti-B antibodies.

Work is continuing to advance these prototypes to commercial-ready devices.

Work is continuing to advance these prototypes to clinical study-ready devices.

This work has received cumulatively approximately $9.6 million in Phase I and II Small Business Technology Transfer (STTR) funding by the U.S.

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Orally administered potassium sorbents such as Kayexalate® (Sanofi-Aventis) and Veltassa® (Relypsa) are only recommended for the non-emergent lowering of mild to moderate hyperkalemia, while the use of insulin and glucose to drive potassium into cells in severe hyperkalemia is only a temporary strategy.

Dialysis has been the definitive treatment of severe hyperkalemia, but requires a large dialysis machine, electricity, bags of dialysate, a skilled technician, and prolonged treatment times that are not practical in certain situations such as in remote locations, during prolonged field care in combat, in areas that lack modern medical facilities, or in situations where the numbers of victims outstrip available dialysis equipment and supplies.

numbers of victims outstrip available dialysis equipment and supplies.

Because of this, there is a major need for simple, but effective ways to rapidly treat severe hyperkalemia.

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K + ontrol has demonstrated the ability to reduce potassium in several animal models of hyperkalemia and is currently being optimized with funding support from the U.S.

Army and Defense Health Agency under under a Phase I and Phase II SBIR contract for a total of $1.15 million and a $3 million Rapid Innovation Fund (RIF) award from the U.S.

Army and Defense Health Agency under a Phase I and Phase II SBIR contract for a total of $1.15 million and a $3 million Rapid Innovation Fund (RIF) award from the U.S.

Air Force Materiel Command.

We plan to move forward with clinical development of this product, pending the successful outcome of these animal studies.

We are currently discussing the potential clinical development plan of K + ontrol with the FDA.

ContrastSorb (Radiology and Interventional Radiology)

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Industry research has identified links between many of these toxins and poor patient outcomes.

If our BetaSorb device is able to routinely remove these toxins during dialysis and prevent or reduce their accumulation, we expect our BetaSorb device to maintain or improve patient health in the long-term.

We believe that by reducing the incidence of health complications, the annual cost of patient care will be reduced and life expectancy increased.

If our BetaSorb device is able to routinely remove these toxins during dialysis and prevent or reduce their accumulation, we expect our BetaSorb device could maintain or improve patient health in the long-term.

We believe that by reducing the incidence of health complications, the annual cost of patient care would be reduced and life expectancy increased.

The poor health experienced by beta 2 -microglobulin patients is illustrated by the fact that in the U.S.

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In December 2018, the Fresenius agreement signed in December 2014 was amended, to grant Fresenius exclusive distribution rights for the Czech Republic and Finland and all critical care medicine and ICU applications on dialysis or ECMO machines for France.

In addition, in 2019, Poland, Sweden, Denmark, and Norway were transitioned into the co-marketing program.

Finally, the guaranteed minimum quarterly purchases and payments requirements were removed for 2019.

In addition, in 2019, Poland, Sweden, Denmark, and Norway were transitioned into the co-marketing program, while guaranteed minimum quarterly purchases and payments requirements were removed.

In January 2022, we converted the agreement with Fresenius in France, Finland, and the Czech Republic to be non-exclusive.

In addition, also in December 2018, we entered into agreements to expand the partnership with Fresenius into South Korea and Mexico.

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These agreements, which commenced on January 1, 2019, have an initial term of three years and will automatically renew for an additional two years unless terminated by either party.

In 2020, we entered into agreements to expand the partnership with Fresenius into Columbia and Equador.

Aferetica s.r.l.

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At the same time, CytoSorbents announced CE Mark approval of the ECOS-300CY cartridge for the removal of inflammatory mediators during ex vivo perfusion, which has been designated, PerSorb™, a trade name exclusive to the PerLife system.

In August 2021, we announced that commercialization of PerSorb(TM) and Aferetica's PerLife(TM) ex vivo organ perfusion system commenced in Italy.

Terumo Cardiovascular Group

In September 2016, we entered into a multi-country strategic partnership with Terumo Cardiovascular Group (“Terumo”) to commercialize CytoSorb for cardiac surgery applications.

Under the terms of the agreement, Terumo has exclusive rights to distribute the CytoSorb CPB procedure pack for intra-operative use during cardiac surgery in France, Sweden, Denmark, N

Under the terms of the agreement, Terumo has exclusive rights to distribute the CytoSorb CPB procedure pack for intra-operative use during cardiac surgery in France, Sweden, Denmark, Norway, Finland and Iceland.

Terumo launched CytoSorb in its six exclusive countries in December 2016.

In 2021, the agreement was revised to a non-exclusive collaboration agreement in Sweden, Denmark, Norway and Iceland.

This agreement allows the Company to sell directly to customers in these countries for the cardiac surgery application.

supported by marketing and promotional activities with Terumo.

Financial terms of this agreement have not been disclosed.

This agreement expires on March 31, 2022.

In August 2020, we announced an initial collaboration with Terumo to exclusively sell CytoSorb to hospitals in ten U.S.

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Food and Drug Administration (FDA) for use in adult, critically ill COVID-19 patients with imminent or confirmed respiratory failure.

Under the initial terms of the agreement, Terumo will ensure hospitals in the defined hot-spot states have access to the CytoSorb therapy for use in critically-ill COVID-19 patients that meet strict criteria under CytoSorbents' EUA.

CytoSorbents will provide all primary clinical and technical training, customer support, and product fulfillment.

Braun Avitum AG

In March 2021, we announced announce the launch of a global co-marketing agreement with B.

Braun Avitum AG to promote the use of CytoSorb® with B.

Braun Avitum AG, one of the world's leading manufacturers of medical devices and pharmaceutical products and services, to promote the use of CytoSorb ® with B.

Braun’s latest OMNI ® continuous blood purification platform and OMNIset ® Plus bloodline set (set version 3.0 or higher).

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Financial terms of this agreement have not been disclosed.

Braun is one of the world's leading manufacturers of medical devices and pharmaceutical products and services.

With 64,000 employees in 64 countries, B.

Braun develops high quality product systems and services for users around the world.

In 2019, the Group generated sales of €7.5 billion.

University of Pittsburgh Medical Center

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The observational and dosing phases of the study, involving 30 viable donors and eight non-viable donors, respectively, have been completed.

The next phase of this

study, the treatment phase, was planned to involve viable donors.

The next phase of this study, the treatment phase, was planned to involve viable donors.

However, we are not currently focusing our efforts on the commercialization of CytoSorb for application in organ donors.

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Advisory Boards

From time to time our management meets with scientific advisors who sit on our Scientific Advisory Boards (“SAB”).

We have 3 SABs that include a Basic Science and Technology SAB, a Critical Care Medicine SAB, and a Cardiac Surgery SAB.

Each SAB comprises of approximately five scientists with deep expertise in their respective fields.

We compensate all our SAB members according to fair market value and reimburse them for their travel expenses when attending meetings in person.

From time to time our management meets with scientific advisors to obtain expert opinions on basic science, critical care medicine and cardiac surgery.We compensate all our SAB members according to fair market value and reimburse them for their travel expenses when attending meetings in person.

Royalty Agreement

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Under this system, hospitals would purchase CytoSorb and subtract the cost from a pre-determined lump-sum payment made by the payor to the hospital based on the patient’s diagnosis.

In 2019, CytoSorb was assigned two specific procedure codes from the Swiss Federal Statistical Office, a division of the Federal Department of Home Affairs in Switzerland.

With cost data related to use of the CytoSorb device, a prerequisite for receiving reimbursement from the Swiss DRG system, we expect to receive a response soon regarding reimbursement levels.

In 2019, CytoSorb was assigned a procedure code from the Swiss Federal Statistical Office, a division of the Federal Department of Home Affairs in Switzerland under the category “Adsorption of Cytokines and Interleukin”.

During 2020, this code category was replaced by a new category entitled “Extracorporeal Adsorption of Specific Substances”.

Use of this code gives Swiss hospitals the ability to collect cost data related to CytoSorb treatments.

In 2021, SwissDRG performed the first cost analysis of CytoSorb.

This analysis showed that there were no additional treatment costs associated with use of CytoSorb against the relevant DRGs, suggesting CytoSorb may be cost neutral or even cost-saving across all indications.

The Company is working with these Swiss hospitals to publish the analysis.

Europe (excluding Germany and Switzerland)

Payment for our CytoSorb device for the removal of cytokines in patients with life-threatening illnesses is country dependent in Europe.

We are pursuing reimbursement of CytoSorb in other major territories, with our partners, such as France, England, Italy and Spain, representing the other four economic leaders in Europe.

There can be no assurances that reimbursement will be granted.

Additional clinical data may be required to establish reimbursement.

Payment for our CytoSorb device in patients with life-threatening illnesses is country dependent in Europe.

Most European markets issue reimbursement for standard therapies only, i.e.

those recommended in relevant treatment guidelines.

The Company is currently conducting randomized controlled trials (RCTs) to achieve this in all major indications.

In the meantime, we are leveraging health economics, local data generation and KOL management in all major territories, with our partners and local sales teams, such as France, England, Italy, Spain, Russia, Belgium, Netherlands, Luxembourg, Poland, Sweden, Norway, Denmark and Finland.

In the United Kingdom, market access and reimbursement of drugs, medical devices and diagnostics is heavily dependent on the guidance published by the National Institute for Health and Care Excellence (NICE).

In 2021, NICE published its report on CytoSorb for the removal of ticagrelor in urgent and emergent cardiac surgery patients in a MedTech Innovation Briefing (MIB) called “CytoSorb for reducing risk of bleeding during cardiac surgery".

The MIB highlights the safety and efficacy of CytoSorb in this indication, as well its innovative nature and the substantial cost savings CytoSorb generates and has aided adoption in the UK.

Other Markets

CytoSorb is currently marketed and distributed in more than 70 countries around the world.

It is generally paid for through the standard DRG (diagnosis related group) payment, dedicated reimbursement codes, tender orders, private insurance, and/or self-pay.

We are actively pursuing generation of new procedure codes in many countries we are currently serving.

Across all countries, we are mitigating financial barriers though use of health economics, local data generation and targeted KOL management.

United States

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Payment for our CytoSorb device in the U.S.

for this application falls under the DRG prospective repayment system, which is currently the predominant inpatient hospital reimbursement methodology in the U.S.

for this application falls under the DRG prospective repayment system, which is currently the predominant inpatient hospital reimbursement methodology in the U.S., that was increased for COVID-19 applications as part of the CARES Act.

Under this system, hospital reimbursement is generally based upon pre-determined amounts payable for specific diagnoses (e.g.

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If CytoSorb can improve outcomes and reduce the costs of ICU treatment and hospital length of stay, it could potentially save hospitals a significant amount of money.

In January 2021, the Centers for the Centers for Medicare & Medicaid Services (CMS) announced the Medicare Coverage of Innovative Technology pathway that will provide national Medicare coverage as early as the same day as FDA market authorization for Breakthrough medical devices, where coverage would last 4 years.

This program may be applicable to CytoSorb, if it can achieve U.S.

approval for the removal of ticagrelor during emergent or urgent cardiothoracic surgery, which was granted FDA Breakthrough Designation in April 2020.

We believe that our products represent a unique approach to disease states and health complications associated with the presence of larger toxins (often referred to as middle molecular weight toxins) in the bloodstream, including sepsis, acute respiratory distress syndrome, trauma, severe burn injury, pancreatitis, post-operative complications of cardiac surgery, damage to organs donated for transplant prior to organ harvest, renal disease and drug intoxication.

Researchers have explored the potential of using existing membrane-based dialysis technology to treat patients suffering from sepsis.

In January 2021, the Centers for the Centers for Medicare & Medicaid Services (CMS) announced the Medicare Coverage of Innovative Technology pathway that will provide national Medicare coverage as early as the same day as FDA market authorization for Breakthrough Designated medical devices, where coverage would last 4 years.

Although this program was rescinded by CMS in November 2021, a legislative version of the program is currently contained within the CARES 2.0 bill, though not yet approved.

If passed, this program may be applicable to DrugSorb-ATR, if it can achieve U.S.

approval for the removal of ticagrelor and Direct Oral Anticoagulants (DOACs) apixaban and rivaroxaban during emergent or urgent cardiothoracic surgery.

These applications were granted FDA Breakthrough Designation in April 2020 and August 2021, respectively.

Our core adsorbent porous polymer bead technology is used in our marketed products, such as the CytoSorb, ECOS-300CY, and VetResQ cartridges, and other products under advanced development, such as CytoSorb XL and DrugSorb-ATR.

We believe these products represent a unique approach to disease states and health complications associated with the presence of larger toxins (often referred to as middle molecular weight toxins) and poorly dialyzable drugs in the bloodstream, including sepsis, acute respiratory distress syndrome, trauma, severe burn injury, pancreatitis, post-operative complications of cardiac surgery, damage to organs donated for transplant prior to organ harvest, renal disease and drug intoxication.

For example, researchers have explored the potential of using standard membrane-based dialysis technology to treat patients suffering from sepsis.

These techniques are unable to effectively remove the middle molecular weight toxins.

We have demonstrated the ability of CytoSorb to reduce key cytokines in the blood of human patients with

predominantly septic shock and acute respiratory distress syndrome.

We have demonstrated the ability of CytoSorb to reduce key cytokines in the blood of human patients with predominantly septic shock and acute respiratory distress syndrome.

In a post-hoc subgroup analysis of our European Sepsis Trial, we have also demonstrated statistically significant improvements in mortality in patients at high risk of death, including patients with either very high cytokine levels or patients older than age 65, both of which have a high predicted mortality.

Larger studies are needed to confirm these preliminary data.

The CytoSorb, VetResQ, CytoSorb XL, DrugSorb, ContrastSorb, and BetaSorb devices consist of a cartridge containing adsorbent polymer beads.

The cartridge incorporates industry standard connectors at either end of the device which connect directly to an extra-corporeal circuit (bloodlines) on a standalone basis.

The extra-corporeal circuit consists of plastic tubing through which the blood flows, our cartridge containing our adsorbent polymer beads, pressure monitoring gauges, and a blood pump to maintain blood flow.

The patient’s blood is accessed through a catheter inserted into his or her veins.

The catheter is connected to the extra-corporeal circuit and the blood pump draws blood from the patient, pumps it through the cartridge and returns it back to the patient in a closed loop system.

As blood passes over the polymer beads in the cartridge, toxins are adsorbed from the blood, without removing any fluids from the blood or the need for replacement fluid or dialysate.

There are three common forms of blood purification, including hemodialysis, hemofiltration, and hemoperfusion.

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Clinical studies demonstrated that use of Xigris® resulted in an average absolute 6% reduction in 28-day mortality, and an absolute 13% reduction in 28-day mortality in the most severe sepsis patients.

The drug remains controversial and is considered expensive when compared to the percentage of patients who benefit.

The drug was controversial and considered expensive when compared to the percentage of patients who benefit.

In 2011, after completing a follow up study required by the FDA, it was subsequently determined that Xigris® did not have a statistically significant mortality benefit, and in October 2011, Eli Lilly withdrew Xigris® from all markets worldwide.

There have been many large scale clinical trials in sepsis.

The primary outcomes of these studies have generally included:

● number of days alive without CV, renal, or pulmonary organ support

● number of days free of treatment with vasopressors

● 28-day survival and all-cause mortality

● 60-day hospital mortality

● reduction rate of IL-6 serum concentration

● change in biomarkers indicative of endothelial activation and damage

● change in microvascular perfusion

● hemodynamic effects

● immune reconstitution of lymphocytopenic sepsis patients

● immunomodulatory effect (IL6/IL10 ratio)

● lymphocyte counts and percentage

● post-operative sepsis

● reduction in Sequential Organ Failure Assessment score (SOFA)

COVID-19 disrupted many clinical studies in 2020.

COVID-19 disrupted many clinical studies in 2020 and 2021.

Notable active Phase III trials in sepsis include the following:

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The status of the trial is unknown.

Another study is being conducted by Atox Bio, a development stage company in clinical studies with peptide therapeutics that are designed to prevent superactivation of the immune response by certain toxins such as toxic shock syndrome toxin.

Atox Bio, a development stage company in clinical studies with peptide therapeutics that are designed to prevent superactivation of the immune response by certain toxins such as toxic shock syndrome toxin.

It is currently focused on necrotizing soft tissue infections.

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A prespecified, per protocol (PP) analysis excluded 17 patients with major protocol violations before unblinding.

There was no difference in 28-day mortality of 15% in each group, and the study did not reach significant improvement in the primary endpoint in the pre-defined mITT population.

There was no difference in 28-day mortality of 15% in each group, and the study did not reach significant improvement in the primary endpoint in the

pre-defined mITT population.

However, in the PP analysis that excluded 17 patients, the company claims clinical composite endpoint success of 54.3% treatment vs 40.3% control.

In December 2020, Atox Bio announced that they had filed an NDA under the FDA Accelerated Approval Program with a PDUFA date of September 30, 2021.In January 2021, the company announced the termination of its Phase 3 REAKT (Reltecimod Efficacy for Acute Kidney Injury Trial) trial in patients with abdominal sepsis induced AKI due to slow enrollment.

In December 2020, Atox Bio announced that they had filed an NDA under the FDA Accelerated Approval Program with a PDUFA date of September 30, 2021.

To date, no publicly available update has been provided.

Spectral Medical, Inc.

collaborated with Toray on the EUPHRATES trial, combining an endotoxin assay with extracorporeal endotoxin removal by Toraymyxin, a polymyxin-B immobilized polystyrene fiber cartridge.

The study began in June 2010 and completed enrollment in June 2016.

The study began in June 2010 and completed enrollment of 450 patients in June 2016.

Endotoxemia is a result of Gram negative sepsis, which only accounts for 45% of cases of sepsis.

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However, all anti-endotoxin strategies have failed pivotal studies to date, believed to be the result of intervening too late in the sepsis cascade.

The original trial was designed as a randomized control trial in 360 patients with septic shock and high endotoxin levels (≥ 0.60 EAA units) as confirmed by Spectral’s Endotoxin Activity Assay (“EAA”).

In a second interim analysis finalized in April 2014, following the enrollment of 184 patients with 28-day follow-up, the DSMB recommended that the trial continue.

However, the expected trial size was increased to 650 patients and the exclusion criteria was modified to only accept sicker patients with a multiple organ dysfunction syndrome score greater than 9.

In September 2015, Spectral reported that the composite mortality in the new subgroup had risen to ~50%, from ~30% previously.

New statistical analysis on patients in the new subgroup, and comparable patients in a European treatment registry, led to a sample size recalculation of 446 evaluable patients.

Spectral announced in June 2016 that they had completed enrollment for the EUPHRATES trial.

In October 2016, Spectral announced top-line results that the trial did not meet the main goal of absolute reduction in 28-day all-cause mortality, but reiterated safety of treatment and potential benefit in the sickest group of patients (multiple organ dysfunction score > 9).

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The TIGRIS study will be in US sites only, randomized (2:1), open label trial, with an additional 150 new patients (100 treated, 50 control) to be added.

Projected completion of trial enrollment at 10 sites is 18 months (projected June 2022).

As of February 11, 2022, 30 patients of the targeted 150 patients have been enrolled.

Enlivex has developed an investigational cell-based therapy called Allocetra that is an infusion of donor mononuclear cells that have been chemically induced to be apoptotic.

Once infused, the patient’s macrophages and dendritic cells phagocytose these apoptotic cells which purportedly then causes them to reduce inflammatory signals that results in immune modulation.

Enlivex recently reported on the use of its therapy, as a single or double dose in a single arm Phase IB study in 10 patients who presented with sepsis to the emergency room with a SOFA score > 2 above baseline.

The severity of illness in this patient population was low, with a mean APACHE II score of 12.9 (range 8-21) and a predicted mortality of approximately 15%, and a mean SOFA score of 3.4 (range 2-6), with a predicted mortality of less than 10%.

There were no deaths reported in the study.

Results were compared with a poorly matched and significantly sicker control population who were admitted to the intensive care unit or intermediate care unit.

In September 2021, Enlivex announced the start of a Phase IIb study using Allocetra in severe and critical COVID-19 patients with acute respiratory distress syndrome (ARDS).

In November 2021, Enlivex reported that Allocetra is being evaluated in a randomized, controlled, multi-center trial in patients with pneumonia-associated sepsis.

It is expected to enroll 120-160 patients across 4 cohorts of varying doses of Allocetra or placebo.

The primary endpoints of the trial are safety, and change in SOFA score from baseline at 28 days.

In 2017, a single center, retrospective, non-randomized, unblinded before-after clinical study evaluating the effect of hydrocortisone, intravenous Vitamin C, and thiamine in a total of 94 patients with severe sepsis and septic shock was published suggesting a significant decrease in hospital mortality of 8.5% (4 of 47 treated) versus mortality of 40.4% (19 of 47 control), p<0.001.

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Vitamin C or steroids alone have not demonstrated a significant benefit in patients with severe sepsis and septic shock in large scale clinical trials.

Observational studies in septic patients have demonstrated a deficiency in Vitamin C and thiamine.

Critics of this study cite weaknesses in the study design, and confounders such as the significantly higher incidence of renal replacement therapy in the control arm (33% vs 10% treatment, p=0.02), that is an independent and significant risk factor for mortality in sepsis.

Many compare it to another well-known single center trial in 2001 in 263 patients that suggested a significant reduction in hospital mortality (30.5%, N=130 treatment versus 46.5%, N=133 control) due to early goal directed therapy (EGDT), which protocolized resuscitation, oxygenation, and hemodynamic targets in the emergency room for patients with severe sepsis or septic shock prior to being admitted to the ICU.

Three subsequent large scale randomized controlled trials failed to demonstrate any benefit.

Regardless, the results of the Vitamin C, thiamine and steroid single center trial have spawned a number of randomized controlled clinical trials evaluating this therapeutic strategy, including VICTAS, VITAMINS, ACTS, and others.

The largest of these studies is VICTAS, a 2,000 patient U.S.

multi-center randomized controlled trial that started in August 2018 comparing intravenous Vitamin C, thiamine, and hydrocortisone for 4 days or until ICU discharge versus placebo and standard of care in patients with suspected or confirmed infection and either respiratory dysfunction requiring mechanical support or shock of less than 24 hours from enrollment.

The primary outcome is vasopressor and ventilator-free days at 30 days.

The trial was terminated early at 501 patients due to a withdrawal of funding from the study, with results published in JAMA in February 2021.

Ventilator- and vasopressor-free days showed no significant improvement with a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of −1 day (95% CI, −4 to 2 days;

Thirty-day mortality was 22% in the intervention group and 24% in the placebo group and was not statistically significant.

The ACTS trial is a 200 patient U.S.

multicenter study that started in February 2018 comparing 4 days of treatment with intravenous Vitamin C (1500 mg/d), thiamine (100 mg/d), and hydrocortisone (50 mg every 6 hours) versus saline placebo in patients having suspected or confirmed infection, requiring vasopressors.

The primary endpoint is change in SOFA score in 72 hours.

Results from this study were published in JAMA in August 2020.

Change in the SOFA score was 4.7 in the intervention group vs 4.1 in the placebo group over 72 hours, a difference that was not statistically significant.

The VITAMINS RCT began in Australia and New Zealand in November 2017, comparing the effect of Vitamin C (6g/d), thiamine (400 mg/d) and hydrocortisone (50mg every 6 hours) versus hydrocortisone (50mg every 6 hours) alone, in 216 patients with septic shock and a blood lactate > 2 mmol/L, with a primary endpoint of time alive and free of vasopressors at day 7 after randomization.

The results of the VITAMINS trial were published in JAMA in January 2020, concluding that treatment with vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days, and does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.

Ninety-day mortality was 28.6% in the treatment group, and 24.5% in the control group.

Also, multiple large scale randomized controlled trials have since failed to demonstrate clinical or mortality benefit including VICTAS, VITAMINS, ACTS, and others.

The authors of these studies do not recommend the routine use of the combination of Vitamin C, corticosteroids, and thiamine in septic shock patients.

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Toray Industries currently markets an endotoxin removal cartridge called Toraymyxin™ for the treatment of sepsis in Europe, Japan, and 16 other countries, but is not yet approved in the United States.

To date, it has been used in more than 100,000 treatments since 1994.

Toraymyxin does not directly reduce cytokines.

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for Toraymyxin, with plans to combine the use of its endotoxin activity assay to create a theranostic product.

Spectral collaborated with Toray on the EUPHRATES trial, combining an endotoxin assay with extracorporeal endotoxin removal by Toraymyxin, a polymyxin-B immobilized polystyrene fiber cartridge.

Spectral collaborated with Toray on the EUPHRATES trial.

As noted above, the EUPHRATES trial failed to demonstrate its primary endpoint.

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However, Baxter has expanded the label to now include reduction of cytokines based on a set of in vitro experiments evaluating cytokine reduction from recirculating plasma over two hours.

In December 2018, Baxter began a 40 patient randomized, controlled trial, called ECRO, evaluating the effect of endotoxin and cytokine (IL-6) removal during continuous hemofiltration with oXiris in patients with septic shock due to peritonitis, as compared to a standard polysulfone filter.

The estimated study completion date is March 2022.

As of February 2022, clinicaltrials.gov currently lists 12 small studies recruiting, evaluating oXiris in the fields of sepsis and cardiac surgery.

In 2020, oXiris received FDA Emergency Use Authorization for use in adult critically ill COVID-19 patients in imminent or confirmed respiratory failure.

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Mortality was 66.6% in patients receiving oXiris treatment after 14 days from admission, and a mortality of 47.4% mortality when used earlier.

In addition, Baxter also launched the Theranova mid-molecular weight cutoff or high retention onset (HRO) hemodialysis membrane to improve the efficiency of hemodialysis, claiming improved mid-molecular weight substance removal.

In addition, Baxter also launched the Theranova mid-

molecular weight cutoff or high retention onset (HRO) hemodialysis membrane to improve the efficiency of hemodialysis, claiming improved mid-molecular weight substance removal.

Neither oXiris nor Theranova are approved in the U.S.

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Gambro also launched the oXiris dialyzer, based upon the AN69 CRRT membrane, to bind endotoxin.

To our knowledge, neither are specifically approved for the treatment of sepsis.

As noted above, Baxter acquired Gambro in 2013.

Fresenius had launched a high molecular weight cut off filter in response to SepteX called the Ultraflux EMiC2.

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In April 2018, Medtronic issued a field safety notice informing all users of CPFA that the COMPACT-2 study using CPFA in septic shock patients was terminated early due to observed higher mortality rates in septic shock patients receiving CPFA therapy compared to patients receiving standard care.

The CPFA system is similar to the I.M.P.A.C.T.

System that was commercialized outside of the U.S.

by Hemolife Medical Inc.

that requires a three-cartridge system and a proprietary blood pump.

In 2018, Hemolife Medical filed for Chapter 11 bankruptcy.

We believe that CytoSorb, which can treat whole blood directly, and which works with standard hemodialysis pumps already found in hospitals worldwide, has significant competitive advantages compared to these multi-cartridge sorbent systems.

Kaneka Corporation currently markets Lixelle™, a modified porous cellulosic bead, for the removal of beta 2 –microglobulin during hemodialysis in Japan.

Lixelle has been used in several small human pilot studies including a 5 patient pilot study in 2002 and a 4 patient pilot study in 2009.

Though these studies correlate Lixelle use with cytokine reduction, they are not randomized, controlled studies and so do not control for natural cytokine clearance.

To our knowledge, no large, randomized, controlled trials have been conducted with Lixelle as a treatment for sepsis.

Kaneka Corporation currently markets Lixelle™, a modified porous cellulosic bead, for the removal of beta 2 –microglobulin during hemodialysis in Japan To our knowledge, no large, randomized, controlled trials have been conducted with Lixelle as a treatment for sepsis.

Kaneka obtained U.S.

humanitarian device exemption for Lixelle in March 2015, but is restricted to treating amyloidosis in chronic dialysis patients.

Kaneka has since developed a modified cellulosic resin called CTR that can also remove cytokines from experimental pre-clinical systems.

In 2009, CTR was used in an 18-patient randomized, controlled trial in patients with septic shock with undisclosed improvements in APACHE II scores and IL-6 and IL-8.

To our knowledge, Kaneka has not conducted or published any other study using CTR to treat human sepsis patients since then.

To our knowledge, none of the following technologies are approved in the U.S.

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Jafron Biomedical is an integrated dialysis public company in China selling dialysis machines and hemodialysis and hemoperfusion cartridges containing a neutral microporous adsorption resin to purify blood of toxins in liver failure, critical illness, poisoning, and autoimmune diseases.

According to clinicaltrials.gov, there are 5 investigator-initiated studies evaluating Jafron's technology in sepsis, and cardiac and respiratory failure.

Jafron is currently recruiting a 144 patient efficacy and safety study in China using its CA330 cartridge to reduce IL-6 in septic patients.

The estimated study completion date is October 2020.

The estimated study completion date was October 2020.

Foshan Biosun Medical Technology Co, Ltd, and Baihe Medical Technology Co, market hemoperfusion cartridges under the BioSky brand name, including the MG series claiming cytokine reduction, and the DX series for bilirubin reduction.

Ube Industries, Ltd was currently developing an adsorbent resin called CF-X for the removal of cytokines.

To our knowledge, Ube has not published any study using CF-X to treat human sepsis patients.

CytoPherx Inc., had developed an extracorporeal system based on selective cytapheresis, or the inactivation or removal of activated leukocytes.

It was enrolling a 344 patient pivotal trial that began in August 2011 and was expected to be completed by December 2014 in patients with acute kidney injury with or without severe sepsis, on continuous renal replacement therapy with the goal of reducing mortality.

This system does not remove cytokines directly, but attempts to reduce the numbers of activated white blood cells that can produce cytokines or cause cell-mediated injury.

The company appears to no longer be in business.

ExThera Medical Corporation is a privately held company that has developed its Seraph™ (Selective Removal by Apheresis) platform that consists of heparin coated, solid polyurethane beads.

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It received EU CE-Mark approval in July 2019, and established distribution in Germany, Italy and Benelux.

In addition, in 2013, it partnered with BioBridge Global to apply its technology to pathogen reduction in transfused

blood products.

In 2020, Seraph received FDA Emergency Use Authorization for use in adult critically ill COVID-19 patients to reduce pathogens and inflammatory mediators from the bloodstream.

Seraph was recently designated by FDA for inclusion into the Expedited Access Pathway (EAP) Program for the specific application of removing drug resistant pathogens from whole blood.

In 2021 and 2022, Exthera expanded distribution to market Seraph in select European countries and Mexico with Fresenius to remove certain bacterial and viral pathogens during dialysis.

We believe our CytoSorb cartridge has significant competitive, technological, and/or economic advantages over systems by these other companies.

Acute Respiratory Distress Syndrome

Treatment of ARDS is predominantly supportive care using supplemental oxygen, careful fluid management, multiple modes of ventilation incorporating the concepts of low tidal volume, prone ventilation, and extracorporeal membrane oxygenation (“ECMO”).

Although a number of therapies have been tried such as nitric oxide, surfactant therapy, and others, only corticosteroids, such a dexamethasone or methylprednisolone, have demonstrated mortality benefit in patients with ARDS.

Treatment of ARDS is predominantly supportive care using supplemental oxygen, careful fluid management, multiple modes of ventilation incorporating the concepts of low tidal volume, ventilation and prone positioning, and extracorporeal membrane oxygenation (“ECMO”).

Although a number of pharmacologic therapies have been tried such as nitric oxide, surfactant therapy, and others, only corticosteroids, such a dexamethasone or methylprednisolone, have demonstrated mortality benefit in patients with ARDS.

For example, in critically ill COVID-19 patients on mechanical ventilation, the RECOVERY study demonstrated use of once daily dexamethasone led to a reduction in mortality from 41.4% control to 29.3% treatment.

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To our knowledge, CytoSorb is the leading cytokine reduction therapy capable of being placed directly into a bypass circuit in the heart-lung machine and used during cardiopulmonary bypass without the need for another pump.

Modified ultrafiltration is sometimes used after termination of

cardiopulmonary bypass in cardiac surgery to remove excess fluid and inflammatory substances, but has had mixed benefit.

Modified ultrafiltration is sometimes used after termination of cardiopulmonary bypass in cardiac surgery to remove excess fluid and inflammatory substances, but has had mixed benefit.

Cell saver machines that collect and wash pericardial shed blood is one potential alternative, but is typically done in batches and not a real-time filter during surgery.

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RenalGuard encourages excretion of IV contrast and a reduction of CIN, by administering IV hydration that matches urine output in patients receiving a loop diuretic.

Hemodialysis can remove IV contrast, but is relatively slow (46% at 1 hour, 65% at 2 hours, and 75% at 3 hours) in chronic renal failure patients who lack normal renal clearance.

Hemodialysis can remove IV contrast, but is relatively slow (46% at 1

hour, 65% at 2 hours, and 75% at 3 hours) in chronic renal failure patients who lack normal renal clearance.

In high risk patients, the rapid and direct removal of IV contrast from the blood with ContrastSorb to prevent CIN represents a potentially more effective alternative.

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Although standard dialysis treatment effectively removes urea and creatinine from the blood stream (which are normally filtered by functioning kidneys), standard dialysis has not been effective in removing beta 2 -microglobulin toxins from the blood of patients suffering from chronic kidney failure.

High flux dialyzers by Gambro, Fresenius, Nephros and others are capable of removing some beta 2- microglobulin.

High flux dialyzers, and mid to high molecular weight cutoff filters by Baxter, Fresenius, Nephros and others are capable of removing some beta 2 -microglobulin.

However, we believe our technology would significantly improve clearance of this and other toxins.

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HDE approval applies to the treatment of diseases with an incidence of less than 8,000 cases a year in the U.S.

Other than blood compatible sorbents, we know of no other device, medication or therapy considered directly competitive with our technology.

Other than those mentioned above and blood compatible sorbents, we know of no other device, medication or therapy considered directly competitive with our technology.

Use for Organ Transplant in Ex Vivo Organ Perfusion Systems or in the Treatment of Organ Dysfunction in Brain-Dead Organ Donors

We are not aware of any directly competitive products to address the application of our technology for the mitigation of organ dysfunction and failure resulting from severe inflammation following brain-death, or in the removal of inflammatory mediators during ex vivo organ perfusion

Removal of Anti-thrombotics such as Ticagrelor in Cardiac Patients During Surgery Requiring Cardiopulmonary Bypass

Removal of Anti-thrombotics such as Ticagrelor and Direct Oral Anticoagulants in Cardiac Patients During Surgery Requiring Cardiopulmonary Bypass

There are more than $20 billion in annual worldwide sales of anti-thrombotic drugs such as the P2Y 12 platelet inhibitors (e.g.

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apixaban, rivaroxaban, edoxaban).

These are generally used to reduce thromboembolic events in a wide range of applications, including dual anti-platelet therapy in percutaneous coronary intervention and stent placement, myocardial

infarction, stroke, peripheral artery disease, atrial fibrillation, deep vein thrombosis, pulmonary embolus, and others.

These are generally used to reduce thromboembolic events in a wide range of applications, including dual anti-platelet therapy in percutaneous coronary intervention and stent placement, myocardial infarction, stroke, peripheral artery disease, atrial fibrillation, deep vein thrombosis, pulmonary embolus, and others.

For example, ticagrelor (Brilinta®, Astra Zeneca) is a widely-used anti-platelet agent used to decrease cardiovascular risk in patients with acute coronary syndromes or a past history of heart attack.

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based economics study.

CytoSorb recently received E.U.

In 2020, CytoSorb received E.U.

CE Mark label expansion to remove ticagrelor and rivaroxaban during cardiac surgery involving cardiopulmonary bypass via label expansion of its CE Mark.

We are currently executing the Safe and Timely Antithrombotic Removal (STAR) international registry collecting real world evidence in this application and two multicenter prospective single arm studies (TISORB in the UK and CYTATION in Germany) to obtain more country-specific data to support the use of CytoSorb for reduction of peri-operative bleeding complications in urgent or emergent cardiac surgery.

The use of platelet transfusions, Kcentra® (CSL Behring;

In 2021, we also began enrolling the STAR (Safe and Timely Antithrombotic Removal) international registry collecting real world evidence in this application.

In the U.S., we are currently executing the U.S.

STAR-T and STAR-D (Safe and Timely Antithrombotic Removal of Ticagrelor, or DOACs, respectively) pivotal randomized, controlled clinical trials designed to support U.S.

FDA Marketing approval of the DrugSorb-ATR antithrombotic removal system, which uses an equivalent polymer technology to CytoSorb.The use of platelet transfusions, Kcentra ® (CSL Behring;

four factor prothrombin complex concentrate;

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PhaseBio is seeking US FDA approval of PB2452 in the United States through an accelerated approval process.

PhaseBio is currently conducting a U.S.

Phase 2b clinical study evaluating the safety and efficacy of PB2452 in approximately 200 healthy volunteers aged 50-80.

Patients receive loading with dual anti-platelet therapy consisting of aspirin and ticagrelor in the U.S.

and will be evaluated on the ability of PB2452 to reverse platelet dysfunction.

PhaseBio has also launched its REVERSE-IT (Rapid and SustainEd ReVERSal of TicagrElor – Intervention Trial) study, a Phase 3, multi-center, open-label, prospective single-arm trial designed to study reversal of the antiplatelet effects of ticagrelor with bentracimab in patients who present with uncontrolled major or life-threatening bleeding or who require urgent surgery or invasive procedure.

Approximately 200 adult patients, within 72 hours of ticagrelor intake who require urgent reversal of the antiplatelet effects of ticagrelor, are being targeted to be enrolled from centers in the U.S.

and worldwide.

Patients with reported use of ticagrelor within the prior 3 days who require urgent ticagrelor reversal are eligible for enrollment.

Patients receive an intravenous (IV) infusion comprised of an initial IV bolus of 6 grams (g) infused over 10 minutes for rapid reversal, followed immediately by a 6g IV loading infusion over 4 hours and then a 6 g IV maintenance infusion over 12 hours.

In January 2021, PhaseBio expanded the study to include patients in the European Union.

The primary endpoints of the study are:

1) reversal of platelet inhibition 2) Major life-threatening bleeding and 3) achievement of hemostasis in urgent surgery or invasive procedures.

PhaseBio is currently conducting its U.S.

REVERSE-IT (Rapid and SustainEd ReVERSal of TicagrElor – Intervention Trial) study, a Phase 3, prospective, multi-center, open-label, single-arm trial designed to study reversal of the antiplatelet effects of ticagrelor with bentracimab to treat patients who present with uncontrolled major or life-threatening bleeding or when used prophylactically in patients who require urgent surgery or an invasive procedure to prevent bleeding.

In November 2021, PhaseBio presented top-line data from an interim analysis of the study, having enrolled 142 patients who required urgent surgery or an invasive procedure and 8 patients with an uncontrolled major or life-threatening bleed.

For the end-point analysis, 129 patients had analyzable platelet data, 122 had data on adjudicated hemostasis.

Investigators reported a rapid reversal of anti-platelet activity in both subgroups.

Among surgical patients, 66.4% had mild GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries bleeding scale) bleeding, and 33.6% had moderate GUSTO bleeding perioperatively.

Treatment-emergent adverse events (i.e.

adverse events that were not present prior to treatment initiation or an event already present that worsens in either intensity or frequency following exposure to the treatment) were reported by 92.7% of enrolled patients.

Four patients died (2.8%):

two with septic shock, and two with cardiogenic shock.

Of 150 patients, 8 patients (5.3%) had thrombotic events, including 2 ischemic strokes, 1 transient ischemic attack, 3 myocardial infarctions, and two with arterial thromboembolisms in the right lower extremity.

The FDA had recommended an interim analysis of approximately 100 patients, comprising approximately 50 patients in each arm, in order to support the submission of a Biologics License Application (BLA) for accelerated approval of bentracimab.

In November 2021, PhaseBio announced that it continues to enroll more patients into the uncontrolled major or life-threatening bleeding arm of the study and intends to submit a BLA for both subgroups by Summer 2022.

Bentracimab is not yet approved in any market.

Based on feedback from the FDA, PhaseBio intends to submit a Biologics License Application, or BLA, for potential accelerated approval based on an interim analysis of the first approximately 100 patients treated in their Phase 3 trial, with approximately 50 subjects from each of the major bleeding and surgical populations.

To support full approval for patients with major bleeding or requiring urgent surgery, the FDA recommended enrollment of 200 total patients in the Phase 3 trial.

For post-approval commitments, the FDA recommended the completion of the remaining portions of the Phase 3 trial and the establishment of post-approval registry.

Meanwhile, Andexxa is a Factor Xa analog that competes for binding to Factor Xa inhibitors.

Due to the short duration of action, pro-thrombotic effect, and very high cost, it is not indicated to reduce the risk of perioperative bleeding in cardiac surgery.

Due to the short duration of action, pro-thrombotic effect, interference with heparin anticoagulation, and very high cost, it is not indicated to reduce the risk of perioperative bleeding in cardiac surgery.

CytoSorb has demonstrated very efficient removal of all the major drugs of the DOAC category in clinical use today including rivaroxaban (Xarelto®;

Bayer, Janssen), apixaban (Eliquis®, Bristol-Myers Squibb), edoxaban (Savaysa®, Daiichi-Sankyo) and dabigatran (Pradaxa®, Boehringer Ingelheim).

We believe that CytoSorb represents a more cost-effective, readily available, and easy to implement solution for ticagrelor or DOAC reversal in cardiac surgery than these biologic alternatives.

We believe that CytoSorb and DrugSorb-ATR, if it receives FDA marketing approval in the United States, would represent a more cost-effective, readily available, and easy to implement solution for ticagrelor or DOAC reversal in cardiac surgery than these biologic alternatives.

HemoDefend Purification Technology Platform for Transfused Blood Products

There are only a few directly competitive approved products to address the removal of substances from blood and blood products that can cause transfusion reactions.

Leukoreduction (Haemonetics, Terumo-BCT, Hemerus Corporation, others) is widely used in transfusion medicine and can remove the majority of white cells that can produce new cytokines but cannot eliminate those cytokines already in blood, and cannot otherwise remove other causative agents.

Leukoreduction (Haemonetics, Terumo-BCT, Hemerus Corporation, others) is widely

used in transfusion medicine and can remove the majority of white cells that can produce new cytokines but cannot eliminate those cytokines already in blood, and cannot otherwise remove other causative agents.

Automated washing of pRBC is very effective at cleansing contaminants from blood, but is impractical due to the time, cost, materials, and logistics of washing each unit of blood and is not widely used.

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Clinical Studies

Our first clinical studies were conducted in patients with chronic renal failure.

The health of these patients is challenged by high levels of toxins circulating in their blood but, unlike sepsis patients, they are not at imminent risk of death.

The toxins involved in chronic renal failure are generally different from those involved in sepsis, eroding health gradually over time.

The treatment of patients with chronic renal failure is a significant target market for us, although not the current focus of our efforts and resources.

Our clinical studies and product development work in this application functioned to obtain safety and instrument data without the need to put the patient at additional risk (e.g.

placing a new temporary dialysis catheter), with direct benefit to the development of the critical care applications on which we are now focusing our efforts.

We are focusing our research efforts on critical care and cardiac surgery applications of our technology.

We are focusing our company sponsored clinical research efforts on critical care and cardiac surgery applications of our technology.

Critical Care

In 2011, the CytoSorb adsorber received EU regulatory approval under the CE Mark as an extracorporeal cytokine filter to be used in clinical situations where cytokines are elevated.

In 2011, CytoSorb received EU regulatory approval under the CE Mark as an extracorporeal cytokine adsorber to be used in clinical situations where cytokines are elevated.

As part of the CE Mark process, in 2011 we completed our randomized, controlled, European Sepsis Trial amongst 14 trial sites in Germany, with enrollment of 100 patients with sepsis and respiratory failure.

The trial established that CytoSorb was sufficiently safe in this critically-ill population to support the CE mark and published in PLOS ONE.

In the European Sepsis Trial, the treatment was well-tolerated with no serious device related adverse events reported.

The trial established that CytoSorb was well-tolerated and safe with no serious device related adverse events reported.

The trial also demonstrated the ability of CytoSorb to reduce cytokines such as IL-6 from the blood of septic patients.

The trial was not powered to demonstrate significant reduction in other clinical endpoints such as mortality.

In September 2019, a new publication entitled, "Hemoadsorption with CytoSorb showed a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock:

a propensity-score-weighted retrospective study,"

in the journal Critical Care.

In this study, clinical researchers at Maasstad Hospital and at Erasmus University Medical Center in Rotterdam, Netherlands conducted a retrospective evaluation of 116 patients with septic shock, who required vasopressors to increase their blood pressure, and renal replacement therapy (RRT) due to kidney failure.

Of these, 49 patients received standard of care therapy, and 67 were treated with standard of care plus CytoSorb.

Both groups were compared by stabilized Inverse Probability of Treatment Weights (sIPTW) to overcome baseline differences in the type of sepsis, age, comorbidities, surgery vs no surgery, Sequential Organ Failure Assessment (SOFA) score, use of the vasopressor noradrenaline, and lactate levels.

Patients treated with standard of care and CytoSorb had a statistically significant reduction in 28-day all-cause mortality compared to standard of care alone (53% vs 72% control, p<0.04), based on the sIPTW analysis.

In addition, observed 28-day all-cause mortality in the CytoSorb treatment group was significantly lower than the predicted mortality (48% observed vs 75% predicted, p<0.001), based on SOFA score.

In April 2020 the FDA granted Emergency Use Authorization for CytoSorb use in critically ill COVID-19 patients treated in the ICU.

The company is conducting the CytoSorb Therapy in COVID-19 (CTC) Registry to systematically capture high fidelity data from U.S.institutions using CytoSorb under the EUA.

In April 2020, we received U.S.

FDA Emergency Use Authorization for the treatment of adult critically ill COVID-19 patients with confirmed or imminent respiratory failure.

The C ytoSorb T herapy in C OVID-19 ( CTC ) Registry was launched to capture outcomes and device utilization patterns from multiple U.S.

participating centers.

Initial results on critically ill COVID-19 patients on extracorporeal membrane oxygenation (ECMO) treated with CytoSorb at participating U.S.

centers showed high survival rates compared with the international benchmark Extracorporeal Life Support Organization (ELSO) Registry.

The initial CTC results were presented at the International Symposium of Intensive Care Medicine conference in August 2021 in Brussels, Belgium, and published in the peer reviewed journal Frontiers in Medicine.

The CTC has completed enrollment and the final results will also be submitted for publication.

The German PROCYSS multicenter, randomized controlled trial evaluating the ability of CytoSorb to restore hemodynamic stability in patients with refractory septic shock is now actively enrolling.

The speed of enrollment remains uncertain due to COVID-19, however we currently estimate that the next important milestone of the interim analysis after 50% enrollment will occur in 2023.

The German multicenter Hep-On-Fire single-arm trial evaluating CytoSorb in patients suffering from acute liver failure due to alcoholic hepatitis received Ethics Committee approval in October 2021 and study start-up activities are ongoing.

We expect that the study will begin enrollment in the first half of 2022 and that the next important milestone of the interim analysis after 50% enrollment will occur in 2023.

The international COSMOS Registry was designed to capture real world outcomes and device utilization patterns across multiple critical care indications including but not limited to sepsis, acute respiratory failure, postoperative vasoplegia, acute liver failure, and acute pancreatitis.

The Registry is undergoing start-up activities and scheduled to begin enrollment in the first half of 2022 with the goal of being active in multiple countries in 2023.

The intent of the Registry is to report outcomes at international conferences and submit the results for publication on a rolling basis as enrollment progresses.

Cardiac Surgery

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Food and Drug Administration (the “FDA”) approved our Investigational Device Exemption (“IDE”) application to commence a planned U.S.

cardiac surgery feasibility study called REFRESH I (REduction of FREe Hemoglobin) amongst 20 patients and three U.S.

clinical sites.

The FDA subsequently approved an amendment to the protocol, expanding the study to a 40-patient randomized controlled study (20 treatment, 20 control) in eight clinical centers.

REFRESH I represented the first part of a larger clinical trial strategy intended to support the approval of CytoSorb in the U.S.

for intra-operative use during cardiac surgery.

The REFRESH I study was designed to evaluate the safety and feasibility of two CytoSorb devices used intra-operatively with a heart-lung machine to reduce plasma free hemoglobin (pfHb) and cytokines in patients undergoing complex cardiac surgery.

The study was not powered to measure effect on clinical outcomes.

The length, complexity and invasiveness of these procedures cause hemolysis and inflammation, leading to high levels of plasma free hemoglobin, cytokines, activated complement, and other substances.

These inflammatory mediators are correlated with the incidence of serious post-operative complications such as kidney injury, renal failure and other organ dysfunction.

The goal of CytoSorb is to actively remove these inflammatory and toxic substances as they are being generated during the surgery and reduce complications.

Enrollment was completed with 46 patients.

A total of 38 patients were evaluable for pfHb and completed all aspects of the study.

The primary safety and efficacy endpoints of the study were the assessment of serious device related adverse events and the change in plasma free hemoglobin levels, respectively.

On October 5, 2016, we announced positive top-line safety data.

In addition, following a detailed review of all reported adverse events in a total of 46 enrolled patients, the independent Data Safety Monitoring Board (“DSMB”) found no serious device related adverse events with the CytoSorb device, achieving the primary safety endpoint of the study.

In addition, the therapy was well-tolerated and technically feasible, implementing easily into the cardiopulmonary bypass circuit without the need for an additional external blood pump.

The REFRESH I study represented the first randomized controlled study demonstrating the safety of intra-operative CytoSorb use in patients undergoing high risk cardiac operations.

Investigators of the REFRESH I study submitted an abstract with data, including free hemoglobin data, from the REFRESH I study which was selected for a podium presentation at the American Association of Thoracic Surgery conference on May 1, 2017.

On May 5, 2017, we announced additional REFRESH I data, including data from the study on the reduction of pfHb and activated complement, and in May 2019, the manuscript of the REFRESH I study was electronically published in the journal, Seminars in Thoracic and Cardiovascular Surgery.

In December 2017, the FDA approved our IDE application for our REFRESH 2-AKI study, permitting us to conduct this pivotal study designed to provide the key safety and efficacy data needed to support United States regulatory approval for CytoSorb in cardiac surgery, which we plan to pursue via the premarket approval (PMA) pathway.

The REFRESH 2-AKI study is a randomized, controlled, multi-center, clinical study designed to evaluate intraoperative use of two CytoSorb devices as a therapy to reduce the incidence and severity of AKI, as measured by Kidney Disease Improving Global Outcomes (KDIGO) criteria, following complex cardiac surgery.

cardiac surgery feasibility randomized controlled study called REFRESH I.

The study was designed to evaluate the safety and feasibility of two CytoSorb devices used intra-operatively with a heart-lung machine to reduce plasma free hemoglobin (pfHb) and cytokines in patients undergoing complex cardiac surgery.

On October 5, 2016, we announced that the independent Data Safety Monitoring Board (“DSMB”) found no serious device related adverse events with CytoSorb, achieving the primary safety endpoint of the study and demonstrating the safety of intra-operative use in patients undergoing high risk cardiac surgery.

The study was published in the peer reviewed journal Seminars in Thoracic and Cardiovascular Surgery.

In December 2017, the FDA approved our IDE application for the randomized, controlled, multi-center REFRESH 2-AKI study designed to evaluate intraoperative use of two CytoSorb devices as a therapy to reduce the incidence and severity of acute kidney

Postoperative AKI following cardiac surgery is common and is associated with higher mortality, and is a risk factor for developing chronic kidney disease requiring hemodialysis in the future.

The study will enroll up to 400 patients at increased risk of cardiovascular surgery-associated AKI, undergoing elective, non-emergent open-heart surgery for either valve replacement, or aortic reconstruction with hypothermic cardiac arrest.

In April 2018, we announced the first patient enrollment into the pivotal U.S.

REFRESH 2-AKI study.

Based on the recommendations of key clinical advisors, a protocol amendment was submitted to the FDA on July 19, 2018 to improve operational aspects of the patient screening process and expand the inclusion criteria.

It was the preference of clinical trial sites to defer enrollment until the amendment was approved by the FDA, announced in September 2018.

On November 25, 2019 the Company announced a pause in enrollment for the REFRESH 2-AKI study.

The study’s Data Monitoring Committee (the “DMC”) recommended this pause following a blinded, interim, milestone review of clinical study data.

The DMC requested that additional clinical data and data analysis, not pre-specified in the current version of the protocol, be provided by Company.

In addition, the Company appointed NAMSA as the new contract research organization (“CRO”) for the study to improve the monitoring of patient safety endpoints.

As of November 25, 2019, the study had enrolled 153 patients at 25 initiated sites.

Since then, the Company and its new CRO have completed a comprehensive program to re-monitor existing data, collect new data, and analyze the safety data from the 153 patients included in the trial to date.

These data were reviewed by the DMC resulting in a favorable opinion on safety, dated July 24, 2020, and the recommendation to resume the trial with only minor modifications.

The Company has been undertaking multiple activities in preparation to resume the study, which is planned in the first half of 2021, notwithstanding potential COVID-19 related delays.

If the study is successful, we plan to submit a PMA application to the FDA in 2023 for U.S.

regulatory approval.

In October 2019, CytoSorbents initiated TISORB (Ticagrelor CytoSorb Hemoadsorption), a Company-sponsored, multi-center single arm study in the United Kingdom to prospectively evaluate the removal of ticagrelor during cardiopulmonary bypass in patients on ticagrelor undergoing emergent cardiothoracic surgery.

A protocol amendment was submitted to expand the population of eligible patients to now include patients requiring urgent cardiac surgery.

These changes were approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) at the end of February 2020.

In December 2020, CytoSorbents initiated CYTATION (CytoSorb Ticagrelor Hemoadsorption), a Company-sponsored multicenter study in Germany to prospectively evaluate the removal of ticagrelor during cardiopulmonary bypass in patients on ticagrelor undergoing emergent cardiothoracic surgery.

Ticagrelor (Brilinta®, Astra Zeneca) is a potent platelet inhibitor and antithrombotic therapy and recognized as a standard of care to reduce the risk of heart attacks and strokes in patients with acute coronary syndromes.

Unfortunately, given the absence of an approved treatment to reverse the antithrombotic effects of ticagrelor, treated patients who require urgent or emergent cardiothoracic surgery may either proceed at high risk for severe perioperative bleeding (as high as 65% higher risk due to ticagrelor) or stay waiting for days in the hospital until the ticagrelor antithrombotic effect washes out.

Neither option is optimal since patients proceeding to surgery are at great risk for serious or even fatal bleeding and patients waiting for washout are at risk of a thrombotic complications such as a stroke or heart attack, while delaying surgery and increasing hospitalization costs.

The benefits of CytoSorb in this setting are both clinical and economic.

In the publication in 2019 by Hassan et al, outcomes of 55 patients requiring emergent cardiac surgery while on ticagrelor or rivaroxaban therapy were evaluated according to the use of CytoSorb.

Antithrombotic (either ticagrelor or rivaroxaban) removal with CytoSorb was associated with significant reductions in operative time, need for red blood cell and platelet transfusions and re-operations to control bleeding and those clinical benefits resulted in shorter length of ICU stay.

These significant clinical benefits are expected to also result in substantial economic benefits.

This was demonstrated in the publication by Javanbakht et al.

in 2019, that projected an average cost savings of £3,982 per patient (approximately $5,000 USD per patient), including the cost of the CytoSorb adsorber.

The primary objective in both TISORB and CYTATION studies is the change in platelet reactivity and ticagrelor blood concentration before and after cardiopulmonary bypass for patients undergoing CytoSorb hemoadsorption removal of ticagrelor from their blood.

In Germany, however, clinical research is continuing and we therefore expect that the CYTATION study will not be equally impacted.

The study was scheduled to enroll up to 400 patients and completed the first scheduled Data Monitoring Committee (DMC) safety review after the first 153 patients enrolled on July 24, 2020 with no safety concerns.

The decision was made to stop the REFRESH 2-AKI study in January 2022 for business reasons to shift resource allocation to the prioritized U.S.

STAR-T and STAR-D trials discussed below.

Importantly, there were no safety issues in the REFRESH 2-AKI trial.

In January 2020, CytoSorb received European Union CE Mark label expansion to include the removal of ticagrelor during cardiopulmonary bypass in patients undergoing cardiothoracic surgery.

In May 2020, CytoSorb also received European Union CE Mark label expansion to include rivaroxaban removal for the same indication.

We have recently announced the Safe and Timely Antithrombotic Removal (STAR) development program that will comprise of a number of clinical projects relating to the antithrombotic removal application.

The first study is the STAR Registry scheduled to commence enrollment in 2021 that will capture real world use of CytoSorb for this indication.

The registry will initially launch in Europe with the intent of expanding to the United States and the rest of the territories where CytoSorb is available in the future.

We anticipate that additional clinical studies, including randomized clinical trials on antithrombotic removal will be conducted as part of the STAR program.

The international S afe and T imely A ntithrombotic R emoval ( STAR ) Registry is designed to capture real world clinical and health economic outcomes with intraoperative antithrombotic drug removal.

The Registry is actively enrolling in the U.K.

and Germany and is planned to expand to additional EU countries before the end of 2022.

The intent of the Registry is to report outcomes at international conferences and submit the results for publication on a rolling basis as enrollment progresses.

In July 2021, we received full FDA approval of an Investigational Device Exemption (IDE) application to conduct a double-blind, randomized, controlled clinical study for up to 120 patients entitled, “ S afe and T imely A ntithrombotic R emoval – T icagrelor ( STAR-T ),” in the United States to support FDA marketing approval.

This was done under the previously announced FDA Breakthrough Device Designation granted for the removal of ticagrelor in a cardiopulmonary bypass circuit to reduce the likelihood of serious perioperative bleeding during urgent cardiac surgery.

In October 2021, the first patient was enrolled and the STAR-T study is now actively recruiting at multiple sites.

We expect the study to reach its first scheduled milestone of the first Data Safety Monitoring Board (DSMB) meeting after 33% of patients are enrolled this summer.

Enrollment is expected to be complete within 12 months from today.

In October 2021, we also received full FDA approval of an Investigational Device Exemption (IDE) application to conduct a double-blind, randomized, controlled clinical study for up to 120 patients entitled, “ S afe and T imely A ntithrombotic R emoval – D irect Oral Anticoagulants ( STAR-D ),” in the United States to support FDA marketing approval.

This was done under the previously announced 2 nd FDA Breakthrough Device Designation granted for our DrugSorb-ATR Antithrombotic Removal System.

First sites have been activated and we expect the first patient to be enrolled in the first quarter of 2022 with target study enrollment completion in 12-18 months following the first patient enrolled.

The single arm TISORB study executed in the U.K.

and the single arm CYTATION study in Germany evaluating ticagrelor removal during cardiac surgery were both stopped in 2021.

The decision was made since the larger, far more rigorous double blind RCT STAR-T will generate much higher quality data on ticagrelor removal and is powered to also report clinical outcomes rendering these two single arm studies redundant.

Once again, it is important to emphasize that this was a business decision to enhance the focus and resource allocation to the STAR programs and that there were no safety concerns in either of the two stopped studies as confirmed by the independent DSMBs of each study.

Update on the REMOVE Investigator Initiated Study

The German government, via the German Federal Ministry of Education and Research, is funding a 250 patient, multi-center randomized, controlled study (“REMOVE”) using CytoSorb during valve replacement open heart surgery in patients with infective endocarditis.

The study enrolled its first patient in January 2018.

An interim analysis of the first 50 patients has been completed.

On February 4, 2019, Prof.

Frank Brunkhorst, Director of the Center for Clinical Studies at Jena University Hospital, who is providing management and oversight to the REMOVE study, and Prof.

Torsten Doenst, Director of the Clinic for Cardiac and Thoracic Surgery at the University of Jena, provided the following joint statement, “The Scientific Advisory Board (SAB) of the Center of Sepsis Control and Care (CSCC) and the Data Safety Monitoring Board (DSMB) of the REMOVE study recommended continuation of the study, based upon results of a pre-specified interim analysis that analyzed cytokine and vasoactive mediator levels as an indicator of the mechanistic mode of action of the device in 28 CytoSorb-treated patients and 22 control patients.

There were no device-associated adverse events in the CytoSorb group.” The study completed enrollment in 2020 but the COVID-19 pandemic has caused delays in data monitoring and data analysis.

Topline data are expected to be reported in the first half of 2021 with full data presentation at a major international conference also in 2021.

The German government funded, investigator initiated, REMOVE clinical study reported topline results at the European Association of Cardiothoracic Surgery in October 2021.

The primary efficacy endpoint was not met;

however, the intraoperative use of CytoSorb was well tolerated and safe without any excess in adverse events compared to controls and the mechanism of action for the reduction of cytokines was validated.

We are awaiting publication of the results and plan to review the results carefully in close collaboration with the investigators to determine the potential for a company-sponsored study in infective endocarditis.

COVID-19 Business Update

COVID-19 patients develop life-threatening complications such as ARDS, shock (i.e.

a potentially fatal drop in blood pressure), kidney failure, acute cardiac injury and secondary bacterial infections.

The underlying cause for these complications is often a cytokine storm that results in a massive, systemic inflammatory response, leading to the damage of vital organs such as the lungs, heart, and kidneys, and ultimately multiple organ failure and death in many cases.

CytoSorb has been used in more than 121,000 treatments as an approved treatment of cytokine storm in the European Union and is distributed in 67 countries around the world, where it has helped physicians control severe inflammation while helping to reverse shock and improve lung and other organ function.

COVID-19 patients develop life-threatening complications such as acute respiratory distress syndrome (ARDS), shock (i.e.

a potentially fatal drop in blood pressure), kidney failure, acute cardiac injury, thromboses and emboli, and secondary bacterial infections.

The underlying cause for these complications is often a massive, systemic inflammatory response, leading to the damage of vital organs such as the lungs, heart, and kidneys, and ultimately multiple organ failure and death in many cases.

Hypercoagulability, thought triggered by inflammation, and resulting thromboembolic events such as pulmonary emboli and thrombotic microangiopathy, play another critical role in the pathophysiology of COVID-19 infection and severity of illness.

The use of CytoSorb in patients infected with COVID-19 in Italy, China, Germany and France began in March 2020.

CytoSorb has now been used in approximately 5,000 COVID-19 patients to help treat cytokine storm and the related life-threatening complications in more than 30 countries.

CytoSorb has now been used to treat dangerous inflammation and related life-threatening complications in more than 7,600 COVID-19 patients in more than 30 countries as of December 31, 2021.

Based upon initial data and reports from physicians treating these complications, CytoSorb use has generally been associated with a marked reduction in cytokine storm and inflammation, improved lung function, weaning from mechanical ventilation, decannulation from extracorporeal membrane oxygenation (ECMO), and a reversal of shock.

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CytoSorb has also been recommended in the National Treatment Guidelines from Panama for Adult COVID-19 Patients if patients have either refractory shock or have severe or refractory respiratory failure requiring either high ventilator support or extracorporeal membrane oxygenation.

CytoSorb has now received approval from the Drugs Controller General of India to treat COVID-19 patients in certain instances.

CytoSorb has received approval from the Drugs Controller General of India to treat COVID-19 patients in certain instances.

CytoSorb has also received approval to treat patients with COVID-19 from the Israel Ministry of Health (AMAR).

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under the FDA’s Expanded Access Program (“EAP”).

On April 13, 2020, we announced that the FDA, in a different program than the EAP, granted Emergency Use Authorization (EUA) of CytoSorb for use in U.S.

COVID-19 patients.

On April 13, 2020, we announced that the FDA, in a different program than the EAP, granted U.S.

Emergency Use Authorization (EUA) of CytoSorb for use in adult critically ill COVID-19 patients.

Under the EUA, CytoSorbents can make CytoSorb available, through commercial sales, to all hospitals in the U.S.

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The EUA will be effective until a declaration is made that the circumstances justifying the EUA have terminated or until revoked by the FDA.

The CTC (CytoSorb Therapy in COVID-19) Registry has been launched and is actively enrolling patients with the intent of systematically capturing usage patterns and outcomes associated with the use of CytoSorb under the EUA at U.S.

institutions.

The CTC Registry may be expanded to outside-U.S.

territories based on the evolution of the pandemic in an effort to better characterize best practice patterns and clinical outcomes.

To meet the growing demand for CytoSorb worldwide, our manufacturing team continues to make any adjustments required to the production schedule to meet the increased sales demand.

The CTC (CytoSorb Therapy in COVID-19) Registry was launched to capture outcomes and device utilization patterns from multiple U.S.

participating centers.

Primary results on observed ICU mortality of COVID-19 patients with acute respiratory distress syndrome (ARDS) requiring extracorporeal membrane oxygenation (ECMO) and treated with CytoSorb according to FDA EUA criteria were presented at the International Symposium of Intensive Care Medicine conference in September 2021 in Brussels, Belgium.

In December 2021, we announced the publication of these results in the peer-reviewed journal Frontiers in Medicine .

Government Research Grants

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Army Medical Research Acquisition Activity (“USAMRAA”), the NHLBI, and the USAF/AFMC.

In August 2012, we were awarded a $3.8 million, five-year contract by DARPA for our “Dialysis-Like Therapeutics” (“DLT”) program to treat sepsis.

DARPA has been instrumental in funding many of the major technological and medical advances since its inception in 1958, including development of the Internet, development of GPS, and robotic surgery.

The DLT program in sepsis sought to develop a therapeutic blood purification device that was capable of identifying the cause of sepsis (e.g., cytokines, toxins, pathogens, activated cells) and remove these substances in an intelligent, automated, and efficient manner.

Our contract was for advanced technology development of our hemocompatible porous polymer technologies to remove cytokines and a number of pathogen and biowarfare toxins from blood.

We have completed our work under the contract with DARPA and SSC Pacific under Contract No.

N66001-12-C-4199, that provided for maximum funding of approximately $3,825,000.

We received approximately $3,825,000 in funding under this contract and no funding remains.

Our performance under this contract has been completed.

In September 2012, we were awarded a Phase II SBIR contract by the U.S.

Army Medical Research and Material Command to evaluate our technology for the treatment of trauma and burn injury in large animal models.

In 2013, we finalized the Phase II SBIR contract which provided for a maximum funding of approximately $803,000 with the granting agency.

This work is supported by the U.S.

Army Medical Research and Material Command under an amendment to Contract W81XWH-12-C-0038.

In June 2016, this contract was further amended to increase the maximum funding by $443,000 to approximately $1,246,000.

We received approximately $1,246,000 in funding under this contract and no funding remains.

Our performance under this contract has been completed.

In September 2013, the National Heart Lung and Blood Institute (“NHLBI”) awarded us a Phase I Small Business Innovation Research (“SBIR”) contract, (number HHSN-268201-300044C), valued at $203,351, to further advance our HemoDefend blood purification technology for pRBC transfusions.

The University of Dartmouth collaborated with us as a subcontractor on the project, entitled “Elimination of blood contaminants from pRBCs using HemoDefend hemocompatible porous polymer beads.” The overall goal of this program was to reduce the risk of potential side effects of blood transfusions, and help to extend the useful life of pRBCs.

Our performance under this contract has been completed.

In October 2015, we were awarded a Phase II SBIR contract by the NHLBI and USSOCOM to help advance our HemoDefend blood purification technology towards commercialization for the purification of pRBC transfusions.

The contract, entitled “pRBCs Contaminant Removal with Porous Polymer Beads”, (contract number HHSN-268201-600006C), provided for maximum funding of approximately $1,524,000 over a two-year period.

We received approximately $1,524,000 under this contract and no funding remains.

Our performance under this contract has been completed.

In March 2016, we were awarded a Phase I SBIR contract for a development program entitled “Mycotoxin Adsorption with Hemocompatible Porous Polymer Beads.” The purpose of this contract was to develop effective blood purification countermeasures for weaponized mycotoxins that can be easily disseminated in water, food and air.

This work was funded by the U.S.

Joint Program Executive Office for Chemical and Biological Defense, or JPEO-CBD, under contract number W911QY-16-P-0048 and provided for maximum funding of $150,000.

We received approximately $150,000 and no funding remains under this contract.

Our performance under this contract has been completed.

In June 2016, we were awarded a Phase I Small Business Technology Transfer (“STTR”) contract for its development program entitled “Use of Highly Porous Polymer Beads to Remove Anti-A and Anti-B antibodies from Plasma for Transfusion”.

The purpose of this contract was to develop our HemoDefend blood purification technology to potentially enable universal plasma.

This work was funded by the USAMRAA under contract W81XWH-16-C-0025 and provided for maximum funding of $150,000.

We received approximately $150,000 and no funding remains under this contract.

Our performance under this contract has been completed.

In July 2016, we were awarded a Phase I SBIR contract for its development program entitled “Investigation of a sorbent-based potassium adsorber for the treatment of hyperkalemia induced by traumatic injury and acute kidney injury in austere conditions”.

The objective of this Phase I project was to develop two novel and distinct treatment options for life-threatening hyperkalemia.

This work was funded by the U.S.

Army Medical Research Acquisition Activity (“USAMRAA”) under contract W81XWH-16-C-0080 and provided for maximum funding of approximately $150,000.

We received approximately $150,000 and no funding remains under this contract.

Our performance under this contract has been completed.

In January 2017, we were awarded a Phase II SBIR contract to continue development of CytoSorb for fungal mycotoxin blood purification.

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Our performance under this contract has been completed.

In May 2017, we were awarded a Phase II STTR contract entitled “Use of Highly Porous Polymer Beads to Remove Anti-A and Anti-B Antibiotics from Plasma Transfusion”.

The purpose of this contract is to continue development of our HemoDefend blood purification technology to potentially enable universal plasma.

We collaborate with researchers at Penn State University on this project.

This contract provides for maximum funding of $999,070 over two years.

This work is being funded by the USAMRAA under contract number W81XWH-17-C-0053.

We received approximately $999,070 and no further funding remaining under this contract.

Our performance under this contract has been completed.

In May 2017, the Company was awarded a Congressionally Directed Medical Research Program (“CDMRP”) Phase I contract to improve delayed evacuation and prolonged field care for severe burn injury via novel hemoadsorptive and hydration therapies.

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As of December 31, 2021, we received approximately $890,000 funding under this contract and have approximately $2,007,000 remaining under this contract.

In July 2020, the Company was awarded by the Assistant Secretary of Defense for Health Affairs, endorsed by the Department of Defense office of the Congressionally Directed Medical Research Programs (CDMRP), a three-year contract as part of a Peer Reviewed Medical Research Program Technology/ Therapeutic Development Award to complete preclinical development of the HemoDefend™-BGA plasma and whole blood adsorber, (award number W81XWH2010712), provides for maximum funding of approximately $4,422,000 over a three-year period.

In July 2020, the Company was a three-year contract awarded by the Assistant Secretary of Defense for Health Affairs, endorsed by the Department of Defense office of the Congressionally Directed Medical Research Programs (CDMRP), as part of a Peer Reviewed Medical Research Program Technology/ Therapeutic Development Award to complete preclinical development of the HemoDefend™-BGA plasma and whole blood adsorber (award number W81XWH2010712).

This award provides for maximum funding of approximately $4,422,000 over a three-year period.

As of December 31, 2021, we received approximately $394,000 funding under this contract and have approximately $4,028,000 remaining under this contract.

In October 2020, the Company was awarded a two-year SBIR Sequential Phase II contract by the U.S.

Army Medical Research Acquisition Activity (USAMRAA), to optimize development of the HemoDefend-BGA™ adsorber.

(award number W81XWH20C0087), provides for maximum funding of approximately $1,100,000 over a two-year period.

Army Medical Research Acquisition Activity (USAMRAA), to optimize development of the HemoDefend-BGA™ adsorber (award number W81XWH20C0087).

This award provides for maximum funding of approximately $1,100,000 over a two-year period.

As of December 31, 2021, we received approximately $310,000 funding under this contract and have approximately $790,000 remaining under this contract.

On April 19, 2021, the Company received notification that it received a U.S.

Army Medical Research Acquisition Activity Award (the “USAMRAAA”) entitled "Investigation of a potassium adsorber for the treatment of hyperkalemia induced by traumatic injury and acute kidney injury in austere medicine."

The USAMRAAA Phase II Sequential Award, for up to $1,499,987, was granted to the Company to continue development of two novel and distinct treatment options for life-threatening hyperkalemia.

This award is being funded by the USAMRAAA under Contract No.

W81XWH21C0045.

As of December 31, 2021, we have received $217,000 funding under the contract and have approximately $1,283,000 remaining under the contract.

Our business could be adversely impacted by automatic cuts in Federal spending.

The American Taxpayer Relief Act (“ATRA”) of 2012, referred to generally as the fiscal cliff deal, that went into effect on March 1, 2013, enacted automatic spending cuts

of nearly $1 trillion over the next 10 years (commonly known as sequestration) that were included under the Budget Control Act of 2011.

The American Taxpayer Relief Act (“ATRA”) of 2012, referred to generally as the fiscal cliff deal, that went into effect on March 1, 2013, enacted automatic spending cuts of nearly $1 trillion over the next 10 years (commonly known as sequestration) that were included under the Budget Control Act of 2011.

Sequestration may delay payments under the SBIR grant agreements, although no material delays have occurred to date.

The short term and long-term economic impact of the sequestration will not be known until the actual spending cuts are implemented and the economic impact of the changes in the budget and taxes are known.

It will take an extended number of years to understand the impact of any changes brought about from the sequester.

The COVID-19 pandemic also has slowed progress on executing and invoicing for our funded grant and contract programs.

This was due to social distancing and remote working requirements in our laboratories and at the facilities of our collaborators.

Given the uncertain nature of COVID-19, we cannot predict the future impact of the pandemic on our research and development efforts and on our revenue recognition for total revenue.

Given the uncertain nature of COVID-19, we cannot predict the future impact of the pandemic on our research and development efforts and on our revenue recognition of grant revenue.

These grants represent a substantial research cost savings to us and we believe demonstrate the strong interest of the medical and scientific communities in our technology.

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These agencies require manufacturers of medical devices to comply with applicable laws and regulations governing the development, testing, manufacturing, labeling, marketing and distribution of medical devices.

Devices are generally subject to varying levels of regulatory control, the most comprehensive of which requires that a clinical evaluation be conducted before a device receives approval for commercial distribution.

are generally subject to varying levels of regulatory control, the most comprehensive of which requires that a clinical evaluation be conducted before a device receives approval for commercial distribution.

In the EU, medical devices that we manufacture are required to comply with the Medical Devices Directive 93/42/EC (“MDD”) and obtain CE Mark certification in order to market medical devices.

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CE Mark through May 2024.

In March 2011, we successfully completed our technical file review with our notified body, and received approval to apply the CE Mark to the CytoSorb device as an extracorporeal cytokine filter.

In March 2011, we successfully completed our technical file review with our notified body, and received approval to apply the CE Mark to the CytoSorb device as an extracorporeal cytokine adsorber.

We also achieved ISO 13485:2003 Full Quality Systems certification, an internationally recognized quality standard designed to ensure that medical device manufacturers have the necessary comprehensive management systems in place to safely design, develop, manufacture and distribute medical devices in the EU.

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In the EU, as in other geographies, there are limits to the claims we are allowed to make, associated with the use of our devices.

Specifically, any claims that we make should be included in our Clinical Evaluation Report, which is part of the conformity assessment process conducted by the Notified Body.

Specifically, claims that are made are required to be included in our Clinical Evaluation Report, which is part of the conformity assessment process conducted by the Notified Body.

If our claims exceed the assessed claims, either regarding performance or intended uses, we may be subject to regulatory actions, which could include customer notifications or even product or literature (i.e.

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The first process requires that a pre-market notification (510(k) Submission) be made to the FDA to demonstrate that the device is as safe and effective as, or “substantially equivalent” to, a legally marketed device that is not subject to pre-market approval (“PMA”).

A legally marketed device is a device that (i) was legally marketed prior to May 28,

1976, (ii) has been reclassified from Class III to Class II or I, or (iii) has been found to be substantially equivalent to another legally marketed device following a 510(k) Submission.

A legally marketed device is a device that (i) was legally marketed prior to May 28, 1976, (ii) has been reclassified from Class III to Class II or I, or (iii) has been found to be substantially equivalent to another legally marketed device following a 510(k) Submission.

The legally marketed device to which equivalence is drawn is known as the “predicate” device.

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The FDA may require additional information, including clinical data, to make a determination regarding substantial equivalence.

After an applicant has obtained clearance, the changes to existing devices covered by a 510(k) Changes to the device which do not significantly affect safety or effectiveness can generally be made without additional 510(k) Submissions, but evaluation of whether a new 510(k) is needed is a complex regulatory issue, and changes must be evaluated on an ongoing basis to determine whether a proposed change triggers the need for a new 510(k), or even PMA .The 510(k) clearance pathway is not available for all devices:

After an applicant has obtained clearance, changes to the device (which do not significantly affect safety or effectiveness) which do not significantly affect safety or effectiveness can generally be made without additional 510(k) Submissions, but evaluation of whether a new 510(k) is needed is a complex regulatory issue, and changes must be evaluated on an ongoing basis to determine whether a proposed change triggers the need for a new 510(k), or even PMA .The 510(k) clearance pathway is not available for all devices:

whether it is a suitable path to market depends on several factors, including regulatory classifications, the intended use of the device, and technical and risk-related issues for the device.

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Also, FDA may impose a variety of conditions on the approval of a PMA.

In the U.S., we believe that our potential devices, if we were to pursue marketing authorization, would likely fall under the classification for “Sorbent Hemoperfusion Systems” (21 C.F.R.

This category of device is Class II (subject to a 510(k) and special controls) when the device is intended for the treatment of poisoning and drug overdose, and Class III (subject to PMA) when the device is intended for the treatment of sepsis, hepatic coma and metabolic disturbances or other life-threatening illnesses.

Both before and after a device for the U.S.

Regardless of the path to FDA clearance or approval, both before and after a device for the U.S.

market is commercially released, we would have ongoing responsibilities under FDA regulations.

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Although physicians are permitted to use their medical judgment to employ medical devices for indications other than those cleared or approved by the FDA, we are prohibited from promoting products for such “off-label” uses and can only market our products for cleared or approved uses.

If the FDA were to conclude that we are not in compliance with applicable laws or regulations, or that any of our medical devices are ineffective or pose an

unreasonable health risk, the FDA could require us to notify health professionals and others that the devices present unreasonable risks of substantial harm to the public health;

If the FDA were to conclude that we are not in compliance with applicable laws or regulations, or that any of our medical devices are ineffective or pose an unreasonable health risk, the FDA could require us to notify health professionals and others that the devices present unreasonable risks of substantial harm to the public health;

order a recall, repair, replacement, or refund of such devices, detain or seize adulterated or misbranded medical devices;

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Conduct giving rise to civil or criminal penalties may also form the basis for private civil litigation by third-party payers or other persons allegedly harmed by our conduct.

On April 10, 2020 the FDA granted CytoSorbents Emergency Use Authorization of CytoSorb for the treatment of COVID-19.

Per the FDA, "The Emergency Use Authorization (EUA) authority allows FDA to help strengthen the nation's public health protections against chemical, biological, radiological, and nuclear (CBRN) threats by facilitating the availability and use of medical countermeasures needed during public health emergencies.

On April 10, 2020 the FDA granted CytoSorbents Emergency Use Authorization of CytoSorb to treat patients 18 years of age or older, with confirmed COVID-19 admitted to the ICU with confirmed or imminent respiratory failure.

Per the FDA, "The Emergency Use Authorization (EUA) authority allows the FDA to help strengthen the nation's public health protections against chemical, biological, radiological, and nuclear (CBRN) threats by facilitating the availability and use of medical countermeasures needed during public health emergencies.

Under Section 564 of the Federal Food, Drug, and Cosmetic Act (the "Act"), the FDA commissioner may allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening disease or conditions caused by CBRN threat agents when there are no adequate, approved, and available alternatives."

EUA is an approval limited in scope and, subject to FDA discretion regarding duration of the approval.

Devices with EUA are neither formally cleared nor approved for the indication to treat patients with COVID-19 infection.

Such devices are authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of the device under Section 564(b)(l) of the Act, 21 U.S.C § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.

The FDA can at its discretion cancel the EUA approval when there is no longer a threat to public health.

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Department of Health and Human Services and comparable state agencies responsible for reimbursement and regulation of health care items and services.

laws and regulations are imposed primarily in connection with the Medicare and Medicaid programs, as well as the government’s interest in regulating the quality and cost of health care.

regulations are imposed primarily in connection with the Medicare and Medicaid programs, as well as the government’s interest in regulating the quality and cost of health care.

Federal health care laws apply when we or customers submit claims for items or services that are reimbursed under Medicare, Medicaid, or other federally-funded health care programs.

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Countries around the world have recently adopted more stringent regulatory requirements, which are expected to add to the delays and uncertainties associated with new product releases, as well as the clinical and regulatory costs of supporting those releases.

No assurance can be given that any of our other medical devices will be approved on a timely basis, if at all, or that our CytoSorb® device will be approved for CE Mark labeling under the MDR in other potential medical applications or that it will be approved for cytokine filtration in markets not covered by the CE Mark on a timely basis, or at all.

No assurance can be given that any of our other medical devices will be approved on a timely basis, if at all, or that our CytoSorb® device will be approved for CE Mark labeling under the MDR in other potential medical applications or that it will be approved for cytokine adsorption in markets not covered by the CE Mark on a timely basis, or at all.

In addition, regulations regarding the development, manufacture and sale of medical devices are subject to future change.

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Pertaining to our VetResQ™ device (offered for veterinary use only), in the U.S., the FDA does not require submission of a 510(k), PMA, or any other pre-market review application for devices used in veterinary medicine.

Device manufacturers who exclusively manufacture or distribute veterinary devices are not required to register their establishments and list veterinary devices and are exempt

from post-marketing reporting.

Device manufacturers who exclusively manufacture or distribute veterinary devices are not required to register their establishments and list veterinary devices and are exempt from post-marketing reporting.

FDA does have regulatory oversight over veterinary devices and can take appropriate regulatory action if a veterinary device is misbranded or adulterated.

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On March 5, 2019, the Company announced the expansion of direct sales of CytoSorb for all applications to Poland and the Netherlands, and critical care applications to Sweden, Denmark and Norway.

As part of this effort, the Company established CytoSorbents Poland Sp.

In 2021, we expanded direct sales to include all applications in Sweden, Denmark and Norway.

As part of this effort, the Company established

CytoSorbents Poland Sp.

z.o.o., a wholly-owned subsidiary of CytoSorbents Europe GmbH.

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During this time period, the CytoSorb device represented substantially all of our product sales.

At the end of 2020, we had hundreds of KOLs worldwide who are either using CytoSorb or supporting its use in clinical practice and/or in clinical studies.

We are approved to sell CytoSorb in all 27 countries in the EU, including Germany, Italy, France and Spain as well as the United Kingdom, and currently have either direct sales or distributors or strategic partnerships in 67 countries worldwide.

We plan to expand to other countries in the EU, and with registration, other countries outside the EU that will accept CE Mark approval with a mixed direct and independent distributor strategy, that can be augmented through strategic partnerships.

Overall, we have established either direct sales or distribution (via distributors or strategic partners) of CytoSorb in 67 countries worldwide.

Registration of CytoSorb is typically required in each of these countries prior to active commercialization, in a process that can take several months to more than a year to achieve.

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We cannot generally predict the timing of these registrations, and there can be no guarantee that we will ultimately achieve registration in countries where we have established distribution.

For example, in August 2014 we announced exclusive distribution of CytoSorb in Taiwan with Hemoscien Corporation.

However, in March 2015, due to the complexity we encountered with Taiwanese product registration, we elected to terminate our agreement with Hemoscien.

Outside of the EU, CytoSorb has distribution in Turkey, India, Sri Lanka, Australia, New Zealand, Russia, Serbia, Vietnam, Malaysia, Hong Kong, Chile, Panama, Costa Rica, Colombia, Brazil, Mexico, Argentina, Perú, Peru, Guatemala, Ecuador, Bolivia, the Dominican Republic, El Salvador, Iceland, Israel, UAE, Iran, Saudi Arabia and other Middle Eastern countries, and South Korea.

We cannot guarantee that we will generate meaningful sales in the countries where we have established registration, due to other factors such as market adoption and reimbursement.

For example, in December 2019, we discontinued our distributor relationship with Dr.

Reddy’s in South Africa due to lack of market adoption.

We continuously evaluate other potential distributor and strategic partner networks in other countries that accept CE Mark approval.

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A significant portion of our revenues are from product sales in Germany.

Substantially all of our grant and other income are from grant agencies in the United States.

Substantially all of our grant and other income are from government agencies in the United States.

During the years ended 2021, 2020 and 2019, no agency, distributor or direct customer represented more than 10 percent of the Company’s total revenue.

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Description/Indications

Devices, systems, and methods for reducing levels of pro-inflammatory or anti-inflammatory stimulators or mediators in the blood

Method of Producing Devices

Hemocompatible Coated Polymer and Related One-Step Methods

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Use of Polymeric Sorbent Polymers

Method of Treating Inflammation

Hemocompatible Modifiers

Hemocompatible Porous Beads

Method of Treating Inflammation

Removal of Endotoxemia

Method of Removing Toxins From Blood

There can be no assurance that pending patent applications will result in issued patents, that patents issued to us will not be challenged or circumvented by competitors, or that such patents will be found to be valid or sufficiently broad to protect our technology or to provide us with a competitive advantage.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business