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Item 1. Business

2025-03-31 compared with 2024-03-15 · 330 added, 1461 removed, 269 unchanged (87% of the section changed)

We are a leader in the treatment of life-threatening conditions in 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 used 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 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.

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.

The first clinical trial, STAR-T, completed enrollment in July of 2023.

Final database lock in December 2023 triggered the initial data analysis on efficacy and the final Data Safety Monitoring Board (“DSMB”) safety review of the full unblinded data on all 140 patients in the STAR-T trial.

In late December 2023, we reported that the DSMB found no safety concerns with the device in the study, thereby meeting the primary safety endpoint of the trial.

Based on the initial analysis of the STAR-T data, the study did not meet the primary effectiveness endpoint in the overall patient population that underwent different types of cardiac surgeries.

However, the study did demonstrate evidence of reduced bleeding complications, including serious bleeding events, in patients in the pre-specified isolated coronary artery bypass graft (“CABG”) surgery population.

We believe that the safety and efficacy results of the STAR-T study will support regulatory submissions for marketing approval to U.S.

FDA and Health Canada.

The second clinical trial, STAR-D, has been terminated early for business reasons.

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 228,000 cumulative CytoSorb devices have been utilized globally as of December 31, 2023 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.

The technology is protected by 19 issued U.S.

patents and multiple international patents, with applications pending both in the U.S.

and internationally.

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.

The goal of CytoSorb is to prevent or treat organ failure by reducing cytokine storm and the potentially deadly systemic inflammatory response syndrome (“SIRS”) in diseases such as sepsis, trauma, burn injury, acute respiratory distress syndrome, pancreatitis, liver failure, and many others.

Organ failure is the leading cause of death in the ICU, and remains a major unmet medical need, with little more than supportive care therapy (e.g., mechanical ventilation, dialysis, vasopressors, fluid support, etc.) as treatment options.

By potentially preventing or treating organ failure, CytoSorb may improve clinical outcomes, including survival, while reducing the need for costly ICU treatment, thereby potentially saving significant healthcare costs.

Our CE Mark enables CytoSorb to be sold throughout the European Union and member states of the European Economic Area.

In addition, many countries outside the EU accept the CE Mark for medical devices but may also require registration with or without

additional clinical studies.

The broad indication for which CytoSorb is CE marked allows it to be used “on-label” in diseases where cytokines are elevated including, but not limited to, critical illnesses such as those mentioned above, autoimmune disease flares, cancer cachexia, and many other conditions where cytokine-induced inflammation plays a detrimental role.

Cytokines are small proteins that normally stimulate and regulate the immune response.

However, in certain diseases, particularly life-threatening conditions commonly seen in the ICU, such as sepsis and infection, trauma, acute respiratory distress syndrome (“ARDS”), severe burn injury, liver failure, and acute pancreatitis, cytokines are often produced in vast excess – a condition known as cytokine storm.

Left unchecked, this cytokine storm can lead to severe maladaptive SIRS that can then cause cell death, multiple organ dysfunction syndrome, and multiple organ failure.

Failure of vital organs such as the heart, lungs, and kidneys, accounts for nearly half of all deaths in the ICU, despite the wide availability of supportive care therapies, or “life support”, such as dialysis, mechanical ventilation, extracorporeal membrane oxygenation, and vasopressors.

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 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.

The trial established that CytoSorb was sufficiently safe in this critically-ill population, and that it was able to broadly reduce key cytokines in the blood of these patients.

In addition to CE Marking, 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.

In the past, we manufactured CytoSorb at our older manufacturing facilities in New Jersey for commercial sales abroad and for additional clinical studies.

Upon expanding our facility in June 2018, 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.

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

During this period, we expanded our direct sales efforts to include both Austria and Switzerland.

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

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.

This subsidiary began operations during the second quarter of 2016.

In 2017, we further expanded our direct sales efforts into Belgium and Luxembourg.

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

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.

z.o.o., a wholly-owned subsidiary of CytoSorbents Europe GmbH.

In the third quarter of 2019, we established CytoSorbents UK Limited, a wholly-owned subsidiary of CytoSorbents Medical, Inc., to manage our clinical trial activities in the United Kingdom.

In August 2019, we announced that CytoSorb had received renewal of its European Union CE Mark through May 2024 and ISO 13485:2016 Full Quality Assurance System certification of its manufacturing facility through September 2022.

In January 2020, we received CE-Mark label expansion approving the use of CytoSorb to remove the anti-platelet agent, ticagrelor, in cardiac patients during surgery requiring cardiopulmonary bypass.

In April 2020, the Company announced that the FDA granted EUA of CytoSorb for use in critically ill patients infected with COVID-19.

Under the EUA, the Company can make CytoSorb available, through commercial sales, to all hospitals in the United States for use in patients, 18 years of age or older, with confirmed COVID-19 infection who are admitted to the intensive care unit (ICU) with confirmed or imminent respiratory failure who have early acute lung injury or acute respiratory distress syndrome (ARDS), severe disease, or life-threatening illness resulting in respiratory failure, septic shock, and/or multiple organ dysfunction or failure.

The CytoSorb device has neither been cleared nor approved for the indication to treat patients with COVID-19 infection.

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 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 Device 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 2022, we also received FDA approval to expand the study to Canada and subsequently received Health Canada approval allowing inclusion of Canadian sites into the STAR-T trial in January 2023.

The study completed enrollment in July of 2023.

Final database lock in December 2023 triggered the initial data analysis on efficacy and the final DSMB safety review of the full unblinded data on all 140 patients in the STAR-T trial.

In late December 2023, we reported that the DSMB found no safety concerns with the device in the study, thereby meeting the primary safety endpoint of the trial.

Based on the initial analysis of the STAR-T data, the study did not meet the primary effectiveness endpoint in the overall patient population that underwent different types of cardiac surgeries.

Patients undergoing CABG surgery represented more than 90% of the overall study population.

Analysis of the efficacy results is ongoing with the intent of presenting them at an international cardiovascular conference in 2024.

We believe that the safety and efficacy results of the STAR-T study will support regulatory submissions for marketing approval to U.S.

FDA and Health Canada.

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 EU 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 EU as well.

We are a leader in the treatment of life-threatening conditions in the intensive care unit and cardiac surgery through blood purification.

CytoSorbents’ proprietary blood 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.

Cartridges filled with these beads can be used with standard blood pumps already in the hospital (e.g.

dialysis, continuous renal replacement therapy or CRRT, extracorporeal membrane oxygenation or ECMO, and heart-lung machines), where blood is repeatedly recirculated outside the body, through our cartridges where toxic substances are removed, and then back into the body.

CytoSorbents’ technologies are used in a number of broad applications.

Specifically, two important applications are 1) the removal of blood thinners during and after cardiothoracic surgery to reduce the risk of severe bleeding, and 2) the removal of inflammatory agents and toxins in common critical illnesses that can lead to massive inflammation, organ failure and patient death.

The breadth of these critical illnesses include, for example, sepsis, burn injury, trauma, lung injury, liver failure, cytokine release syndrome, and pancreatitis as well as the removal of liver toxins that accumulate in acute liver dysfunction or failure the removal of myoglobin in severe rhabdomyolysis that can otherwise lead to renal failure.

In these diseases, the risk of death can be extremely high, and there are few, if any, effective treatments.

CytoSorbents’ lead product, CytoSorb®, is approved in the European Union and distributed in dozens of countries worldwide, with more than 270,000 devices used cumulatively to date.

CytoSorb was originally launched in the European Union under CE mark as the first cytokine adsorber.

Additional CE mark extensions were granted for bilirubin and myoglobin removal in clinical conditions such as liver disease and trauma, respectively, and for ticagrelor and rivaroxaban removal in cardiothoracic surgery procedures.

CytoSorb has also received FDA EUA in the United States for use in adult critically ill COVID-19 patients with impending or confirmed respiratory failure, to reduce pro-inflammatory cytokine levels.

CytoSorb is not yet approved in the United States.

and Canada, CytoSorbents is developing the DrugSorb™-ATR antithrombotic removal system, an investigational device based on an equivalent polymer technology to CytoSorb, to reduce the severity of perioperative bleeding in high-risk surgery due to blood thinning drugs.

It has received two U.S.

Food and Drug Administration (“FDA”) Breakthrough Device Designations:

one for the removal of ticagrelor and another for the removal of the direct oral anticoagulants (DOAC) apixaban and rivaroxaban in a cardiopulmonary bypass circuit during urgent cardiothoracic procedures.

In September 2024, the Company submitted a De Novo medical device application to the FDA requesting marketing approval to reduce the severity of perioperative bleeding in CABG patients on the antithrombotic drug ticagrelor, which was accepted for substantive review in October 2024.

On November 1, 2024 we received Medical Device Single Audit Program (MDSAP) certification, a key regulatory milestone that certifies compliance of our quality management system with the standard regulatory requirements of Canada, the United States, Brazil, Japan and Australia;

and then promptly submitted our Medical Device License (MDL) marketing application to Health Canada on November 1, 2024, with MDSAP certification – a requirement for the submission.

Our applications with FDA and Health Canada continue to be in substantive and interactive review, and we continue to expect regulatory decisions from both agencies in 2025.

DrugSorb-ATR is not yet granted or approved in the United States and Canada, respectively.

Upon approval, the Company expects to rapidly commercialize DrugSorb-ATR in the U.S.

and Canada to address this large unmet medical need, with an initial estimated total addressable market of $300 million to $600 million that is anticipated to grow to $1-2 billion over time as we pursue additional indications for DrugSorb-ATR to remove additional classes of blood thinners and expansion of the antithrombotic removal application beyond cardiac surgery and across other surgical specialties.

We believe that DrugSorb-ATR has the potential to become an “all-in-one” countermeasure for these agents.

Our executive offices are located at 305 College Road East, Princeton, New Jersey 08540, and our telephone number is (732) 329-8885.

Our website address is http://www.cytosorbents.com .

We have included our website address as an inactive textual reference only.

We make available free of charge through our website our Annual Reports on Form 10-K, our Quarterly Reports on Form 10-Q, our Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after we electronically file such material, or furnish it to the SEC.

We also similarly make available, free of charge on our website, the reports filed with the SEC by our executive officers, directors and 10% stockholders pursuant to Section 16 under the Exchange Act as soon as reasonably practicable after copies of those filings are provided to us by those persons.

We are not including the information contained at http://www.cytosorbents.com , or at any other website address, as part of, or incorporating it by reference into, this Annual Report on Form 10-K.

Our Products and Applications

CytoSorbents’ technology platform centers on hemocompatible, highly porous polymer beads that act like tiny sponges to remove harmful substances from blood by pore capture and concentration-dependent adsorption, without the need for ligands, antibodies, cells or biologics.

CytoSorbents commercializes three different cartridges based on this bead technology.

CytoSorb for critical care and cardiac surgery and ECOS-300CY for ex vivo organ perfusion in transplant are approved in the E.U., while VetResQ for emergency and critical care in animals is commercialized primarily in the U.S.

CytoSorbents is currently seeking U.S.

FDA and Health Canada marketing approval for DrugSorb-ATR to reduce the severity of perioperative bleeding in patients on the blood thinning drug, Brilinta, undergoing coronary artery bypass graft (CABG) surgery.

The Company also commercializes the PuriFi hemoperfusion pump in select countries internationally.

CytoSorb is an extracorporeal blood purification cartridge that is approved in the European Union and distributed in more than 70 countries worldwide to reduce “cytokine storm” in common critical illnesses that can lead to massive inflammation, organ failure and patient death.

In these diseases, the risk of death can be extremely high, and there are few, if any, effective treatments.

CytoSorb removes the “fuel to the fire” of deadly inflammation that is often associated with organ failure and poor clinical outcomes.

Given that an estimated 40-60% of patients in the ICU suffer from severe inflammation (e.g.

sepsis, COVID, flu, trauma, burns, lung failure, complications of surgery, cytokine release syndrome, liver failure, pancreatitis, etc.) where the level of inflammation is directly correlated to severity of illness, CytoSorb is strategically positioned to help these patients.

CytoSorb is also approved to reduce bilirubin (e.g.

in liver failure) and myoglobin (e.g.

in trauma and critical illness).

CytoSorb is also used during and after cardiothoracic surgery to remove antithrombotic drugs and inflammatory mediators that can lead to postoperative complications, including severe bleeding, shock, failure to wean from mechanical ventilation, sepsis, and multiple organ failure.

CytoSorb is also used in cardiac surgery applications to reduce inflammatory mediators and blood thinners, targeting a reduction in complications of cardiac surgery like sepsis, bleeding, and shock.

In contrast to dialysis which works like the kidney to remove metabolic waste products, small molecules, and water-soluble drugs in about 10-15% of patients in the intensive care unit who develop kidney failure, CytoSorb functions like the liver to remove a broad range of small to mid-molecular weight toxins that dialysis does not remove well – including cytokines, inflammatory mediators, bacterial toxins, liver toxins such as bilirubin and bile acids, proteins such as myoglobin, hemoglobin, and activated complement, peptides, fat-soluble drugs, and hydrophobic protein-bound substances.

Because of this, CytoSorb is “Expanding the Dimension of Blood Purification™” in critical care and cardiac surgery, treating inflammation and also other conditions where toxic substances can cause harm, while restoring balance.

Based on numerous published studies, we believe treating the right patient, at the right time, with the right therapy of CytoSorb is leading to improved clinical outcomes.

In particular, when used early and aggressively on a hyperinflamed patient with worsening organ failure, CytoSorb treatment is associated with the reversal or prevention of many complications such as shock, acute respiratory distress syndrome (ARDS), and kidney failure.

CytoSorb was granted U.S.

FDA Emergency Use Authorization in April 2020 for use in adult critically ill COVID-19 patients with impending or confirmed respiratory failure.

CytoSorb is not yet cleared or approved in the U.S.

DrugSorb-ATR is an investigational device that uses an equivalent polymer technology to CytoSorb to address a large unmet need for blood thinner reversal in cardiothoracic surgery.

Millions of people worldwide are on anti-thrombotic drugs, also called blood thinners, to reduce the risk of heart attack and stroke.

However, when one of those patients requires emergent cardiac surgery, guidelines recommend they wait 3-5 days for the blood thinners to “wash out” of their systems to avoid bleeding complications.

Often the surgery cannot wait and patients are operated at a very high risk for major bleeding.

The goals of DrugSorb-ATR are to allow patients to get the critical surgery they need without delay while also reducing the severity of bleeding complications.

DrugSorb-ATR installs easily into a cardiopulmonary bypass (CPB) machine and as whole blood is pumped through the cartridge during an operation, it removes the free drug from blood to reverse its antithrombotic effect.

DrugSorb-ATR is initially focused on reducing the severity of perioperative bleeding in CABG patients on the anti-thrombotic drug Brilinta ® (ticagrelor, AstraZeneca) in the U.S.

and Canada, where approximately 60,000 patients on this medication will need urgent cardiovascular surgery annually in those two markets.

Given current U.S.

and Canadian prescribing trends that favor Brilinta over its competitors, Plavix (clopidogrel, BMS, Sanofi) and Effient (prasugrel, Daiichi Sankyo, Eli Lilly), and the recent availability of generic Brilinta, the number of eligible patients could increase substantially.

Coronary Artery Bypass Grafting (CABG) is the most common type of cardiac surgery worldwide, and per the European Multicenter Study on CABG (E-CABG) Registry, the rate of severe bleeding is more than 3 times higher when patients undergo CABG within two days of the last dose of Brilinta, compared to those who underwent a 4-5 day washout.

Data from our U.S.

and Canada pivotal STAR-T (Safe and Timely Antithrombotic Removal of Ticagrelor) trial and European STAR Registry suggest the use of CytoSorbents’ technology enables CABG patients to safely undergo surgery within 2 days of the last dose of Brilinta without the associated increased bleeding risk.

CytoSorbents’ technology was granted two FDA Breakthrough Device Designations, one for the removal of ticagrelor (2020) and another (2021) for the removal of the direct oral

anticoagulants (DOACs) Eliquis (apixaban, Pfizer, BMS) and Xarelto (rivaroxaban, Janssen, Bayer).

In September 2024, the Company submitted a De Novo medical device application to the U.S.

FDA requesting marketing approval to reduce the severity of perioperative bleeding in CABG patients on the antithrombotic drug ticagrelor, which was accepted for substantive review in October 2024.

In November 2024, the Company received its Medical Device Single Audit Program (MDSAP) certification and submitted its Medical Device License (MDL) application to Health Canada.

DrugSorb-ATR is not yet granted or approved in the United States and Canada, respectively.

If granted or approved, DrugSorb-ATR presents a potentially valuable value proposition to multiple stakeholders.

For patients, they would be able to undergo their critical CABG surgery without significant delay and have reduced bleeding risk.

For surgeons, it can potentially help get these patients into the operating room faster, while helping to avoid severe intra and postoperative bleeding complications that can be a nightmare scenario for surgeons while negatively impacting their surgical outcomes and the scheduling of new patient surgeries.

For hospitals, decreased washout times in the hospital, fewer bleeding complications that require expensive ICU recovery, and faster throughput of revenue-generating cardiac surgeries means potentially better resource utilization, lower costs, and improved revenues while decreased adverse events helps preserve a hospital’s quality rating.

Ahead of regulatory decisions for DrugSorb-ATR, we have been preparing our go-to-market strategy for the U.S.

This initially involves the building of a limited direct sales force and a controlled rollout of DrugSorb-ATR during the first three to six months following clearance or approval, starting with the original clinical sites from the STAR-T trial.

This phased approach allows us to assess the commercial introduction process, particularly the value analysis committee (VAC) review and approval procedures for new hospital products.

Additionally, it enables us to refine our messaging and establish a core group of sales representatives who will help train new hires as we scale nationally.

The Company has identified key positions essential to building the commercial team and has initiated hiring while awaiting approvals from Health Canada and FDA.

Given that DrugSorb-ATR is an FDA Breakthrough Device and that a large percentage of the target population fall under the U.S.

Centers for Medicare and Medicaid Services (CMS), the Company is also pursuing additional reimbursement and coverage options through the New Technology Add on Payment (NTAP) and Transitional Coverage for Emerging Technologies (TCET) programs.

Though we believe these additional programs are not necessary to sell DrugSorb, we believe they could enhance what we believe is an already strong value proposition based on expected clinical benefit and cost savings.

ECOS-300CY is approved in the E.U.

to reduce cytokines and other inflammatory mediators when used in an ex vivo organ perfusion system, with the goal of helping to preserve or improve the health and quality of harvested solid organs to be transplanted.

Due to the severe shortage of donor organs, the majority of transplanted solid organs come from brain dead donors (“BDD”) and donation after cardiac death (DCD).

However, cytokine storm and severe inflammation is common in these patients, which can degrade the functioning of solid organs like the heart, lungs, liver, and kidneys, resulting in substandard organs that often must be discarded.

Although data demonstrate improved clinical outcomes when these organs undergo ex vivo organ perfusion, an increasing amount of published data in animal transplant models and real-world human clinical data highlight that the use of our technology with ex vivo organ perfusion is associated with better outcomes in terms of organ function and post-transplant outcomes, compared to ex vivo organ perfusion alone.

Because of this, we believe the ECOS-300CY cartridge has the potential to significantly expand the solid organ donor pool and reduce the more than 150,000 patients on transplant waiting lists in the U.S.

CytoSorbents announced a development partnership with Aferetica srl in 2017 to provide its ECOS-300CY technology under the exclusive trade name, PerSorb™, as part of Aferetica’s program to develop the PerLife™ ex vivo organ perfusion system.

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.

The new production facility successfully passed its EU notified body audit in early 2022 and received ISO 13485 certification from its EU notified body in September 2022, clearing the way for full manufacturing of CytoSorb, DrugSorb-ATR, ECOS-300CY from this site.

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 2023, this study was terminated early for business reasons.

If FDA marketing approval is obtained for either the removal of ticagrelor or direct oral anticoagulants indications, the device would be marketed as DrugSorb-ATR in the United States.

The DrugSorb-ATR Antithrombotic Removal System is based on the equivalent polymer technology as CytoSorb.

In March 2022, the Company formed CytoSorbents Medical UK Limited to provide marketing and direct sales services in the United Kingdom and the Republic of Ireland.

In May 2022, the Company announced that it entered into a 3-year preferred supplier agreement with the private German hospital network, Asklepios, making CytoSorb available without restrictions to all of the approximate 170 healthcare facilities across 14 states throughout Germany at which Asklepios operates.

This includes Asklepios Klinik St.

Georg in Hamburg, Germany, which pioneered the use of CytoSorb to remove antithrombotic drugs during cardiothoracic surgery and is well-known for their seminal publication on CytoSorb use for this application during emergency cardiac surgery in patients at high risk of bleeding.

In June 2022, the Company announced that, following a successful pilot program in three countries, the Company signed an expanded non-exclusive agreement with Nikkiso Europe GmbH (“Nikkiso”) to distribute Nikkiso’s PureADJUST stand-alone hemoperfusion pump and accessories in a total of 14 countries.

In addition to securing the rights to sell Nikkiso’s stand-alone pump and accessories in Germany, Austria, and Luxembourg, the Company entered into an expanded multi-country reseller agreement with Nikkiso covering the following countries:

Belgium, Bosnia and Herzegovina, Croatia, Finland, France, Iceland, Lichtenstein, Poland, Serbia, Slovenia and Switzerland.

The Company will provide field support services in these countries.

In August 2022, the Company entered into a Marketing Agreement (the “Marketing Agreement”) with Fresenius Medical Care Deutschland GmbH (“Fresenius”), which expands the Company’s strategic partnership with Fresenius by establishing a multi-stage global collaboration to combat life-threatening diseases in critical care.

The Marketing Agreement provides for the combined marketing and promotion of CytoSorb with Fresenius’ critical care products by Fresenius’ marketing organization worldwide, excluding the United States.

Compared to the prior co-marketing agreement between the parties, the Marketing Agreement intends to increase the commitments from both parties and to ensure an ongoing and consistent level of marketing and promotional activity specifically focused around CytoSorb, where Fresenius will actively market and promote CytoSorb as the featured blood purification therapy for removal of cytokines, bilirubin, and myoglobin on its critical care platforms.

Specifically, the Marketing Agreement provides that various Fresenius-led in-person, virtual, social media, and web-based marketing programs and events will feature the CytoSorb therapy and highlight the cooperation between the two companies in the field of critical care during the Term.

To help support the increased marketing and promotional efforts of the expanded collaboration, CytoSorbents has agreed to subsidize a portion of the marketing costs through a royalty payment to Fresenius Medical Care based on CytoSorb sales in the intensive care unit on Fresenius Medical Care platforms, excluding the United States.

In addition to strengthening and expanding the global marketing of CytoSorb, the Company and Fresenius also plan to work together to bring new innovative solutions to the market.

The Marketing Agreement also includes the certification of compatibility of CytoSorb for usage on Fresenius’ current critical care platforms.

Certain initial activities have been completed with the formal launch of this program expected to occur sometime in 2024.

In October 2022, the Company formed CytoSorbents France SAS to provide marketing and direct sales services in France.

In May 2023, the Company formed CytoSorbents India Private Limited to provide marketing and direct sales services in India.

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.

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.

Overall, we have established either direct sales or distribution (via distributors or strategic partners) of CytoSorb in more than 75 countries worldwide.

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

With CE Mark approval, this can be typically achieved within several months in EU countries.

Outside of the EU, the process is more variable and can take several months to more than a year due to different requirements for documentation and clinical data.

Variability in the timing of registration affects the initiation of active commercialization in these countries, which affects the timing of expected CytoSorb sales.

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

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.

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.

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

In February 2020, we announced an agreement with China Medical System Holdings Limited (“CMS”), a well-established, innovation-driven specialty pharma with a focus on sales and marketing in China and Asia, to bring CytoSorb to mainland China to treat critically-ill patients with COVID-19 (fka Wuhan or 2019-nCoV) coronavirus infection.

Under the terms of the agreement, CytoSorbents and CMS agreed to partner together to earn regulatory clearance to import CytoSorb into China under the “fast-track” review process established by the National Medical Products Administration of the People’s Republic of China (NMPA) to respond to the 2019 novel coronavirus (COVID-19) pandemic.

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 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/or distribute CytoSorb.

These partners include Fresenius Medical Care AG, B.

Braun Avitum AG, Aferetica s.r.l., and Terumo Cardiovascular Group.

For detailed information regarding these partnerships, see the section entitled “Commercial and Research Partners” in Item 1 of this Report.

The market focus for CytoSorb is the prevention or treatment of organ failure in life-threatening conditions, including commonly seen illnesses in the ICU such as infection and sepsis, trauma, burn injury, ARDS, and others.

Severe sepsis and septic shock, a potentially life-threatening systemic inflammatory response to a serious infection, accounts for approximately 10% to 20% of all ICU admissions, and is responsible for an estimated one in every five deaths worldwide.

Sepsis is one of the largest target markets for CytoSorb.

Sepsis is a major unmet medical need with no approved products in the U.S.

or Europe to treat it.

As with other critical care illnesses, multiple organ failure is the primary cause of death in sepsis.

When used with standard of care therapy, that includes antibiotics, the goal of CytoSorb in sepsis is to reduce excessive levels of cytokines and other inflammatory toxins, to help reduce the SIRS response and either prevent or treat organ failure.

In addition to the sepsis indication, we intend to conduct or support additional clinical studies in sepsis, cardiac surgery, and other critical care diseases where CytoSorb could be used, such as ARDS, trauma, severe burn injury, acute pancreatitis, and in other acute conditions that may benefit by the reduction of cytokines in the bloodstream.

Some examples include the prevention of post-operative complications of cardiac surgery (cardiopulmonary bypass surgery) and damage to organs donated for transplant prior to organ harvest.

We intend to generate additional clinical data to expand the scope of clinical experience for marketing purposes, to increase the number of treated patients, and to support potential future publications and regulatory submissions.

In 2014, we completed a single arm, dose ranging trial in Germany amongst several clinical trial sites to evaluate the safety and efficacy of CytoSorb when used 24 hours per day for seven days, each day with a new device.

These additional dosing data were used to support the label expansion to increase treatment time from 6 hours, the initial approval, to 24 hours of treatment.

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

There are approximately one million cardiac surgery procedures performed annually in the U.S.

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 mediators, such as cytokines, activated complement, and toxic plasma free hemoglobin released by hemolysis.

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

CytoSorb has a unique competitive advantage as the only cytokine and free hemoglobin removal technology that can be used during the operative procedure and can be easily installed in a bypass circuit in a heart-lung machine without the need for an additional pump.

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:

VetResQ is a broad-spectrum blood purification adsorber commercially available in the U.S.

animal health market to help treat drug intoxication, deadly inflammation (via hemoadsorption of cytokines, bacterial toxins and other inflammatory mediators) and toxic injury in animals with critical illnesses such as septic shock, toxic shock syndrome, toxin-mediated diseases, pancreatitis, trauma, liver failure, heat stroke and lung injury.

VetResQ is based upon an equivalent polymer technology to CytoSorb and is configured in three different sized cartridges (50, 150 and 300mL) to accommodate treatment of small, medium, and large animals such as cats, dogs, and high-value animals such as foals and horses.

VetResQ is compatible with standard hemodialysis, continuous renal replacement therapy (“CRRT”), and hemoperfusion blood pumps.

Based upon cumulative studies, VetResQ is capable of reducing a broad range of excessive inflammatory mediators and toxins that could otherwise cause direct tissue injury or serious systemic inflammation that can rapidly lead to instability, organ failure, and death.

VetResQ is available in the U.S.

only for veterinary animal usage and is not for human use.

PuriFi is an E.U.

Medical Device Regulation (MDR) approved advanced hemoperfusion pump that we co-developed with our original equipment manufacturer (OEM) partner, and launched in June 2024 in the E.U.

and other select countries that can replace standard hospital blood pumps to implement our various blood purification therapies.

The PuriFi peristaltic blood pump features a number of differentiating innovations that separate it from other standard hemoperfusion pumps including a pre-assembled adult and

pediatric blood line kit, auto-priming, an auto-leveling bubble catcher, an intuitive touchscreen graphical user interface with a step-by-step user-friendly set-up guide, optional blood warming, and a rapid 10-minute set-up time.

Together, these unique features enable an easy and rapid way to administer CytoSorbents’ blood purification technologies like CytoSorb and VetResQ for critically ill and cardiac surgery patients.

Clinical Studies

We are focusing our company sponsored clinical research efforts on critical care and cardiac surgery applications of our technology, including the following:

United States

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Real world outcomes in 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.

Even though we have obtained CE Mark approval for CytoSorb, no guarantee or assurance can be given that our CytoSorb product will work as intended or that we will be able to obtain FDA approval to sell CytoSorb in the U.S.

or approval in any other country or jurisdiction.

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, 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.

In 2024, our goal is to finalize our data analysis of the STAR-T trial, and file for U.S.

FDA and Health Canada regulatory approvals.

We are preparing for commercialization of DrugSorb-ATR in the U.S.

In addition, we are also seeing improvements in market conditions, and we are focused on a return to sales growth in our existing markets.

Corporate History

We were originally organized as a Delaware limited liability company in August 1997 as Advanced Renal Technologies, LLC.

We changed our name to RenalTech International, LLC in November 1998, and to MedaSorb Technologies, LLC in October 2003.

In December 2005, MedaSorb Technologies, LLC converted from a limited liability company to a corporation, called MedaSorb Technologies, Inc.

Separately, Gilder Enterprises, Inc., was incorporated in Nevada on April 25, 2002, and was originally engaged in the business of installing and operating computer networks that provided high-speed access to the Internet.

On June 30, 2006, Gilder Enterprises, Inc disposed of its original business, and pursuant to an Agreement and Plan of Merger, acquired all of the stock of MedaSorb Technologies, Inc., in a merger, and the business of MedaSorb Technologies, Inc.

became its business.

Following the merger, in July 2006, we changed our name to MedaSorb Technologies Corporation.

In November 2008, we changed the name of our operating subsidiary from MedaSorb Technologies, Inc.

to CytoSorbents, Inc.

In May 2010, we finalized the name change of MedaSorb Technologies Corporation to CytoSorbents Corporation.

On October 28, 2014, we changed the name of our operating subsidiary from CytoSorbents, Inc.

to CytoSorbents Medical, Inc.

On December 3, 2014, we effected a twenty-five-for-one (25:1) reverse split of our common stock.

As a result of this reverse stock split, shares of our common stock outstanding were reduced by approximately 96%.

Immediately after the reverse stock split, pursuant to an Agreement and Plan of Merger dated December 3, 2014, we changed our state of incorporation from the State of Nevada to the State of Delaware, whereby we merged with and into our wholly-owned Delaware subsidiary.

At the effective time of the merger, (i) we merged with and into our Delaware subsidiary, (ii) our separate corporate existence in Nevada ceased to exist, (iii) the Delaware subsidiary became the surviving corporation, (iv) the certificate of incorporation, as amended and restated, and the bylaws of the Delaware subsidiary became our certificate of incorporation and bylaws, and (v) each share of our common stock outstanding immediately prior to the effective time was converted into one fully-paid and non-assessable share of our common stock as a Delaware corporation.

The reverse stock split, the merger and the Agreement and Plan of Merger were approved by our Board of Directors and stockholders representing a majority of our then-outstanding common stock.

All references to “us”, “we”, or the Company, on or after December 3, 2014, refer to CytoSorbents Corporation, a Delaware corporation.

CytoSorbents Corporation uplisted to, and began trading on, the NASDAQ Capital Markets on December 23, 2014.

Our executive offices are located at 305 College Road East, Princeton, New Jersey 08540, and our telephone number is (732) 329-8885.

Our website address is http://www.cytosorbents.com .

We have included our website address as an inactive textual reference only.

We are not including the information contained at http://www.cytosorbents.com , or at any other website address, as part of, or incorporating it by reference into, this Annual Report on Form 10-K.

We have been engaged in research and development and product commercialization and have raised approximately $229 million from investors as of December 31, 2023.

These proceeds have been used to fund the development of multiple product applications, to conduct clinical studies, to establish in-house manufacturing capacity to meet commercial and clinical testing needs, expand our intellectual property through additional patents, to develop extensive proprietary know-how with regard to our products and to commercialize our products internationally.

We have raised funds through various means including convertible note offerings, equity transactions, and term loans.

Our most recent financing transactions are discussed below.

December 13, 2023 Offering

On December 13, 2023, the Company closed on a registered direct offering for the sale, directly to investors, of 7,733,090 registered shares of common stock and warrants to purchase up to 2,706,561 shares of common stock (the “Offering”).

Each share of common stock and accompanying warrant to purchase up to 0.35 shares of common stock, were sold together for a combined purchase price of $1.33, for an aggregate purchase price of approximately $10,285,000.

After deducting transaction fees and expenses payable by the Company in connection with the Offering, the Company received net proceeds of approximately $9,785,000, excluding any proceeds that may be received upon the exercise of the warrants.

Each warrant is immediately cash exercisable at an exercise price of $2.00 per share and will expire on the fifth anniversary of the issue date.

The Company’s executive officers, directors, and certain non-executive officer employees of the Company also participated in the Offering with a combined investment of $435,000.

Shelf Registration

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

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 Amended Sale Agreement during the year ended December 31, 2022.

During the year ended December 31, 2023, the Company sold 2,656,464 shares pursuant to the Sale Agreement, at an average selling price of $1.76 per share, generating net proceeds of approximately $4,532,000.

Critical Care

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 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.

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.

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 90-day survival rates (73%).

This is in contrast to the approximately 50% 90-day survival rates when CytoSorb was not used, as reported from the North American cohort of the Extracorporeal Life Support Organization (ELSO) Registry.

The initial CTC results on the first 52 critically ill patients from five U.S.

ECMO centers 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 registry completed enrollment with 100 patients from five centers, and the final results mirror the high survival (74%) seen in the previous analysis and have been published in the peer reviewed journal Critical Care.

The data further demonstrate that earlier intervention with CytoSorb and ECMO was associated with shorter need for mechanical ventilation, ECMO support, and ICU length of stay.

These results lend support to our concept of “enhanced lung rest,” where ECMO helps the lungs rest by oxygenating blood extracorporeally and reducing the need for mechanical ventilation that can cause ventilator-induced lung injury, while CytoSorb reduces the circulating inflammatory mediators that cause continued capillary leak syndrome in the lungs.

Together, the goal of this dual-therapy strategy is to give the lungs a chance to recover and heal, a pre-requisite for weaning off mechanical ventilation and ECMO.

The German PROCYSS multicenter, randomized controlled trial evaluating the ability of CytoSorb to restore hemodynamic stability in patients with refractory septic shock is enrolling, however, at significantly slower rate than expected.

The Company in collaboration with Principal Investigator and scientific committee of the trial are critically reviewing options to modify the current study design with the intent of enabling better study progress and anticipate this process to be completed in 2025.

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, rhabdomyolysis, acute liver failure, and acute pancreatitis.

The Registry is actively enrolling in Spain, Germany, Portugal, and Italy with plans to expand in more countries in 2025.

The Registry is expected to contribute original analyses for presentations at international critical care conferences and publications in peer-reviewed journals on an ongoing basis starting in 2025.

Cardiac Surgery

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.

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 recruiting in the U.K., Germany, Austria, Belgium and Sweden and is planned to expand to additional countries in 2025.

Initial data outputs from the STAR Registry have already been presented at the EuroPCR and at the European Association of Cardiothoracic Surgery conferences in previous years with new analyses expected to be presented on an ongoing basis at international conferences and published in peer-reviewed journals in 2025 and beyond.

In July 2021, we received full FDA approval of an Investigational Device Exemption (IDE) application to conduct a double-blind, randomized, controlled clinical study in 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 with multiple U.S.

STAR-T study sites open.

In November 2022, the first milestone was completed with the first one-third of patients enrolled, triggering the first Data Safety Monitoring Board (DSMB) meeting.

The DSMB recommended to continue the study as planned without any modifications.

In 2022, we also received FDA approval to expand the study to Canada and subsequently received Health Canada approval allowing inclusion of Canadian sites into the STAR-T trial in January 2023.

In early 2023, the study exceeded 50% enrollment and reached the 2 nd milestone of 67% enrollment in the Spring of 2023, triggering another DSMB safety review, which found no safety concerns and recommended completion of the trial.

The study completed enrollment in July of 2023 triggering the final DSMB safety review following database lock in December 2023, which reported no safety concerns thereby meeting the primary safety endpoint of the study.

Based on the initial analysis of the STAR-T data, the study did not meet the primary effectiveness endpoint in the overall patient population that underwent different types of cardiac surgeries.

Patients undergoing CABG surgery represented more than 90% of the overall study population.

The topline results of the U.S.

and Canadian 140-patient, pivotal STAR-T randomized controlled trial were presented at the 104th Annual Meeting of the American Association for Thoracic Surgery (“AATS”) held in Toronto, Canada on April 28, 2024.

The Company submitted the DrugSorb-ATR medical device De Novo marketing application to the FDA on September 27, 2024.

and promptly submitted our Medical Device License (MDL) marketing application to Health Canada on November 1, 2024.

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.

The STAR-D study was initiated, but the Company ultimately decided to place it on hold for business reasons, specifically related to prioritization and focused resource allocation to the completion of the STAR-T study and the subsequent regulatory submissions to FDA and Health Canada.

Further discussions with the FDA to determine an appropriate label expansion strategy to include the removal of DOACs will ensue following the completion of the ongoing review of the current FDA application for DrugSorb-ATR for the removal of ticagrelor.

Research and Development

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and $4.3M JWMRP), Lipopolysaccharide Adsorption In Sepsis (National Institution of General Medical Sciences $282K), the U.S.

Air Force program ($75K), New Jersey Technology Business Tax Certificate Program for research related expenses ($7.7M), and others to further develop our technologies for sepsis, trauma and burn injury, and blood transfusions, respectively.

Air Force program ($75K), New Jersey Technology Business Tax Certificate Program for research related

expenses ($8.6M), and others to further develop our technologies for sepsis, trauma and burn injury, and blood transfusions, respectively.

Some payments are based on achieving certain technology milestones.

Technology, Products and Applications

For approximately the past half-century, the field of blood purification has been focused on hemodialysis, a mature, well-accepted medical technique primarily used to sustain the lives of patients with permanent or temporary loss of kidney function.

It is widely understood by the medical community that dialysis has inherent limitations in that its ability to remove toxic substances from blood drops precipitously as the size of toxins increases.

Our hemocompatible adsorbent technology helps to address this shortcoming by removing toxins and toxic compounds poorly removed by dialysis technology.

Our polymer adsorbent technology can remove many different substances from whole blood and physiologic fluids, including for example, drugs, bioactive lipids, inflammatory mediators such as cytokines, free hemoglobin, and bacterial toxins, immunoglobulin, bilirubin, and myoglobin, depending on the polymer construct.

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

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.

The extracorporeal circuit consists of plastic blood tubing, our blood filtration cartridges containing 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 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.

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.

Examples of such conditions include severe sepsis and septic shock, severe burn injury, trauma, acute respiratory distress syndrome, acute liver disease, and severe acute pancreatitis.

In the U.S., an estimated $110 billion or 0.7% of the U.S.

gross domestic product is spent annually on critical care medicine.

In larger hospitals, critical care treatment accounts for up to 20% of a hospital’s overall budget and often results in financial losses for the hospital.

In many critical care illnesses, the mortality is often higher than 30%.

A major cause of death is multiple organ failure, where vital organs such as the lungs, kidneys, heart and liver are damaged and no longer function properly.

These patients are kept alive with supportive care therapy, or “life support”, such as mechanical ventilation, dialysis, extracorporeal liver support, and vasopressor treatment, that is designed to keep the patient from dying while using careful patient management to tip the balance towards gradual recovery over time.

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 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.

In 2020, the Company received CE-Mark label expansions for CytoSorb to remove the anti-platelet agent ticagrelor and the direct oral anticoagulant rivaroxaban in patients undergoing cardiac surgery on cardiopulmonary bypass.

In addition to critical care, CytoSorb is used in many applications related to cardiac surgery.

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.

Together, the total addressable market for these numerous critical care and cardiac surgery applications with CytoSorb is estimated to be in excess of $30 billion worldwide.

Sepsis is characterized by a systemic inflammatory response triggered by a severe infection.

It is commonly seen in the ICU, accounting for approximately 10% to 20% of all ICU admissions.

However, there are currently no approved products that are available to treat sepsis in the U.S.

A 2020 study published in The Lancet estimated that there were 49 million new cases of sepsis globally, killing 11 million people every year.

The researchers estimate that 1 in every 5 deaths worldwide is due to sepsis.

Data released by the Healthcare Cost and Utilization Project (H-CUP) identified approximately 1.6 million cases of sepsis each year in the U.S.

to the CDC, the incidence of serious infection and sepsis has doubled in the U.S.

in the past 10 years.

The main driver of sepsis incidence is the aging demographic, specifically patients who are older than age 65 who are more prone to infection and now account for two-thirds of patients hospitalized for sepsis and the majority of sepsis deaths.

Other factors contributing to the increase in sepsis incidence include the spread of antibiotic resistant bacteria like methicillin-resistant Staphylococcus aureus (“MRSA”), an increase in co-morbid conditions like HIV, cancer, obesity, and diabetes that increases the risk of infection, an increasing use of implantable devices like artificial hips, knees and heart valves that are prone to colonization by bacteria, and the appearance of new highly virulent or contagious strains of common pathogens such as H3N2 or H1N1 influenza, COVID-19 coronavirus, and others.

There are generally three categories of sepsis, including mild to moderate sepsis, severe sepsis and septic shock.

Mild to moderate sepsis typically occurs with an infection that is responsive to antibiotics or antiviral medication.

An example is a patient with self-limiting influenza or a treatable community acquired pneumonia.

Mortality is generally very low.

Severe sepsis is sepsis with evidence of organ dysfunction.

An example is a patient who develops respiratory failure due to a severe pneumonia and requires mechanical ventilation in the ICU.

Severe sepsis has a mortality rate of approximately 20% to 25% despite the use of antibiotics and the highest level of available care.

Septic shock, or severe sepsis with low blood pressure that is not responsive to fluid resuscitation, is the most serious form of sepsis with an expected mortality in excess of 40% to 50%, and up to 80-100% if it is refractory to vasopressors and other therapies.

In sepsis, there are two major problems:

the infection and the body’s immune response to the infection.

Antibiotics are the main therapy used to treat the triggering infection, and although antibiotic resistance is growing, the infection is often eventually controlled.

However, it is the body’s immune response to this infection that frequently leads to the most devastating damage.

In recognition of this, in 2016 the 3 rd International Consensus Definition Task Force re-defined sepsis as “life-threatening organ dysfunction due to a dysregulated host response to infection.” The body’s immune system normally produces large amounts of inflammatory mediators called cytokines to help stimulate and regulate the immune response during an infection.

In severe infection, however, many people suffer from a massive, unregulated overproduction of cytokines, often termed “cytokine storm” that can kill cells and damage organs, leading to multiple organ dysfunction syndrome and multiple organ failure, and in many cases death.

Until recently, there have been no available therapies in the U.S.

or EU that can control the aberrant immune response and cytokine storm.

Our CytoSorb device is a first-in-class, clinically-proven broad-spectrum extracorporeal cytokine adsorber currently approved for sale in the E.U.

The goal of CytoSorb is to prevent or treat organ failure by reducing cytokine storm and controlling a “run-away” immune response, while antibiotics work to control the actual infection.

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.

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

In a post-hoc analysis, this was associated with improvements in clinical outcome in two high-risk patient populations – those with very high cytokine levels and patients 65 years of age and older.

We have completed a follow-up dosing study at several clinical trial sites in Germany, supporting the safety of continuous treatment, exchanging a new device daily for up to seven days.

The only treatment that had been approved to treat sepsis in the U.S.

or EU was Xigris from Eli Lilly.

Because of concerns of cost, limited efficacy, and potentially dangerous side effects including the increased risk of fatal bleeding events such as intracranial bleeding for those at risk, and also because of problems with reimbursement, worldwide sales of Xigris decreased from $160 million in 2009 to $104 million in 2010.

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, selective cytapheresis from CytoPheryx, and others.

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, the United Kingdom and the Netherlands with our own direct sales force.

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

We were 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 November 2023, Eris Lifesciences (“Eris”), a publicly-listed Indian

pharmaceutical company and a leading player in the domestic branded formulation market, entered into a definitive agreement to acquire Biocon Biologics’ dermatology and nephrology branded formulations business units in India, and with it, Biocon’s key leadership and field force of these businesses, including the personnel commercializing CytoSorb in India.

In connection with this proposed transfer, the Company and Eris entered into a temporary agreement for the distribution of CytoSorb products in India.

This temporary agreement has the same terms as the Company’s existing distribution agreement with Biocon except for the expiration date of the agreement, which has been updated from September 13, 2026, under the existing Biocon distribution agreement to December 31, 2025, under the temporary agreement.

Both the Company and Eris have agreed that they will use their best efforts to negotiate and finalize a new distribution agreement that will be commercially attractive to both parties.

As a result, Eris would act the Company’s exclusive distributor of CytoSorb ® products in India.

If a new distribution agreement with Eris is not executed by December 31, 2025, this temporary agreement will become null and void.

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).

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 approximately 75 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.

there are an estimated 1.6 million cases of sepsis each year, while the European Sepsis Alliance estimates 3.4 million individuals in Europe become septic each year.

In Germany alone, according to the Center of Sepsis Control and Care, there are approximately 175,000 cases of severe sepsis each year.

Germany is the largest medical device market in Europe and the third largest in the world.

Sepsis patients are treated in the ICU for 12 to 18 days on average and for a total of 20 to 25 days in the hospital.

A typical severe sepsis or septic shock patient in the U.S.

costs approximately $45,000 to $60,000 to treat without using CytoSorb.

CytoSorb therapy for sepsis typically costs in the range of $1,000 to $5,000, depending on the number of treatments.

The goal of therapy is to not only improve clinical outcomes, but to also reduce the severity of illness and reduce the need for costly ICU care (estimated at approximately $4,300 per day in the ICU in the U.S.).

The cost of CytoSorb therapy represents a fraction of what is currently spent on the treatment of patients with sepsis and would be cost-effective if it decreased ICU stay by one to two days.

Based upon this price point, the total addressable market for CytoSorb for the treatment of sepsis in the U.S.

and EU is approximately $6 billion to $8 billion.

Cardiac Surgery

There are approximately 500,000 cardiac surgery procedures performed on cardiopulmonary bypass annually in the U.S., another 500,000 in the EU, and approximately a total of 1.5 million procedures worldwide.

These include relatively common procedures, including coronary artery bypass graft surgery, valve replacement surgery, heart and lung transplantation, aortic reconstruction, congenital heart defect repair, and LVAD placements for the treatment of heart failure.

Cardiac surgery can result in inflammation and the production of high levels of inflammatory cytokines, activation of complement, as well as hemolysis, causing the release of free hemoglobin.

These can lead to post-operative complications including infection, pulmonary, renal, and neurological dysfunction.

Complications lead to longer ICU recovery times and hospital stays, increased morbidity and mortality, and higher costs.

An average coronary artery bypass graft procedure already costs approximately $36,000 in the U.S.

without complications.

According to the National Foundation for Transplants, a heart and lung transplant plus first year expenses total $1.2 million in the U.S.

Valve replacement surgery for infective endocarditis is poorly reimbursed and may cost up to $150,000-$250,000 in the U.S.

The use of CytoSorb to reduce cytokines and other inflammatory mediators during and after the surgical procedure may prevent or mitigate these post-operative complications.

During the procedure, the CytoSorb adsorber can be easily incorporated in the heart-lung machine circuit without the need for a separate pump, a unique competitive advantage over other technologies.

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 effect.

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

and EU in cardiothoracic surgery procedures is estimated to be $500 million to $1 billion.

Removal of Antithrombotic Drugs in Cardiac Patients During Surgery Requiring Cardiopulmonary Bypass

The role of antithrombotics, a category that includes both antiplatelet and anticoagulant drugs in cardiovascular medicine is constantly growing.

Antiplatelet drugs are routinely used in patients with atherosclerotic cardiovascular disease such coronary disease, vascular disease or stroke.

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 ® , 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 ® ) and rivaroxaban (Janssen and Bayer - Xarelto ® ) are estimated to reach $40 billion 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%.

This scenario is most common in patients presenting with an acute coronary syndrome (ACS).

alone there are approximately 1.1 million ACS hospital admissions annually.

CytoSorb is able to efficiently remove ticagrelor and DOACs from blood and is approved in the EU 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.

and Canada, the Company has completed the pivotal, randomized, controlled STAR-T trial 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.

As described above, the STAR-T trial met the primary safety endpoint but missed the primary efficacy endpoint in the overall population that included different types of surgeries.

However, in the pre-specified isolated coronary artery bypass graft (“CABG”) surgery population, the study demonstrated evidence of reduced bleeding complications, including serious bleeding events, in patients.

Analysis of the efficacy results is ongoing with the intent of presenting them at an international cardiovascular conference in 2024.

We believe that the safety and efficacy results of the STAR-T trial will support regulatory submissions for marketing approval by the FDA and Health Canada.

If FDA marketing approval is obtained, the device will be marketed as DrugSorb-ATR in the United States and Canada.

The initial annual addressable market in the U.S.

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

Acute Respiratory Distress Syndrome

Acute lung injury (“ALI”) and acute respiratory distress syndrome (ARDS) are two of the most serious conditions on the continuum of respiratory failure when both lungs are compromised by inflammation and fluid infiltration, severely compromising their ability to both oxygenate the blood and rid the blood of carbon dioxide produced by the body.

There are an estimated 165,000 cases of ARDS in the U.S.

each year, with even more cases in the EU.

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.

ALI and ARDS can be precipitated by a number of conditions including pneumonia and other infections, burn and smoke inhalation injury, aspiration, reperfusion injury and shock.

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 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 U.S.

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.

The CTC Registry completed enrollment at 100 patients.

As published in the peer reviewed journal, Critical Care, in June 2023, the data on these 100 patients confirmed 90-day survival of 74% and demonstrated that earlier intervention with CytoSorb and ECMO was associated with shorter need for mechanical ventilation, ECMO, and ICU stay.

Together, the goal of this dual-therapy strategy is to give the lungs a chance to recover and heal, a pre-requisite for weaning off of mechanical ventilation and ECMO.

For context, when ECMO was used alone, 90-day survival was 53% (as of December 2022) among more than 7,300 adult patients with refractory ARDS on ECMO in the North American cohort of the Extracorporeal Life Support Organization (ELSO) COVID-19 ECMO Registry.

We believe early intervention of enhanced lung rest with CytoSorb and ECMO represents one of the newest and most promising strategies to treat severe ARDS.

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.

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.

In general, patients studied in the RECOVERY study were not as severely ill as those treated for refractory respiratory failure with CytoSorb and ECMO in the CTC Registry.

Techniques to improve ventilation and reduce ongoing lung injury are also being used.

For example, low tidal volume ventilation has been demonstrated to improve mortality (31.0% as compared to 39.8% control) in this patient population in the ARDSNet Trial.

Prone positioning, or placing a patient chest-side down, in severe ARDS patients in order to redistribute gravity-dependent pulmonary edema and allow ventilation of collapsed or atelectatic alveoli, is also used, following studies that suggest benefit including the PROSEVA trial (16% vs 32.8% in the control).

A combination of some or all of these approaches may yield even greater improvements in the survival of ARDS patients.

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

In the U.S., there are approximately 2.4 million burn injuries per year, with 650,000 treated by medical professionals and approximately 75,000 requiring hospitalization.

Aggressive modern management of burn injury, including debridement, skin grafts, anti-microbial dressings and mechanical ventilation for smoke and chemical inhalation injury has led to significant improvements in survival of burn injury to approximately 95% on average at leading burns centers.

However, there remains a need for better therapies to reduce the mortality in those patients with large burns and inhalation injury as well as to reduce complications of burn injury and hospital length of stay for all patients.

According to National Burn Repository Data, the average hospital stay for burn patients is directly correlated with the percent total body surface area (“TBSA”) burned.

Every 1% increase of TBSA burned equates to approximately 1 additional day in the hospital.

A single patient with more than 30% TBSA burned who survives, is hospitalized for an average of 30 days and costs approximately $200,000 to treat.

Major causes of death following severe burn and smoke inhalation injury are multiple organ failure (hemodynamic shock, respiratory failure, acute renal failure) and sepsis, particularly in patients with greater than 30% TBSA burns.

Burns and inhalation injury lead to severe systemic and localized lung inflammation, loss of fluid, and cytokine overproduction.

This “cytokine storm” causes numerous problems, including:

hypovolemic shock and inadequate oxygen and blood flow to critical organs, ARDS preventing adequate oxygenation of blood, capillary leakage resulting in tissue edema and intravascular depletion, hypermetabolism leading to massive protein degradation and catabolism and is also associated with increased risk of infection, impaired healing, severe weakness and delayed recovery, immune dysfunction causing a higher risk of secondary infections (wound infections, pneumonia) and sepsis, and direct apoptosis and cell-mediated killing of cells, leading to organ damage.

Up to a third of severe hospitalized burn patients develop multiple organ failure and sepsis that can often lead to complicated, extended hospital courses, or death.

Broad reduction of cytokine storm has not been previously feasible and represents a novel approach to limiting or reversing organ failure, potentially enabling more rapid mechanical ventilation weaning, prevention of shock, reversal of the hypermetabolic state encouraging faster healing and patient recovery, reducing hospital costs, and potentially improving survival.

The total addressable market in the EU for CytoSorb to address burn and smoke inhalation injury is estimated at $150 million to $350 million and up to $600 million for the U.S.

and EU combined.

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.

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

In trauma, cytokine storm contributes to the systemic inflammatory response syndrome triggering a cascade of events that cause cell death, organ damage, organ failure and often death.

Cytokine storm exacerbates physical trauma in many ways.

For instance, trauma can cause hypovolemic shock due to blood loss, while cytokine storm causes capillary leak and intravascular volume loss, and triggers nitric oxide production that causes cardiac depression and peripheral dilation.

Shock can lead to a lack of oxygenated blood flow to vital organs, causing organ injury.

Severe systemic inflammation and cytokine storm can lead to ALI and ARDS as is often seen in ischemia and reperfusion injury following severe bleeding injuries.

Penetrating wound injury from bullets, shrapnel and knives, can lead to infection and sepsis, another significant cause of organ failure in trauma.

Complicating matters is the breakdown of damaged skeletal muscle, or rhabdomyolysis, from blunt trauma that can lead to a massive release of myoglobin into the blood that can crystallize in the kidneys, leading to acute kidney injury and renal failure.

Renal failure in trauma is associated with a significant increase in expected mortality.

Myoglobin is poorly removed by standard dialysis or continuous renal replacement therapy.

Cytokine and myoglobin reduction by CytoSorb and related technologies may have benefit in trauma, potentially improving clinical outcome.

In May 2018, the approved indications for use of CytoSorb in the EU were expanded to include

the removal of myoglobin in trauma.

The total addressable market for CytoSorb for the treatment of trauma is estimated to be $1.5 billion to $2.0 billion in the U.S.

Trauma patients on antithrombotic drugs represent an especially challenging cohort since any necessary surgery would be associated with very high bleeding risk.

The ability of CytoSorb to efficiently remove some of the most popular antithrombotic drugs may represent an additional mode of benefit to improve clinical outcomes in trauma patients.

Acute Liver Disease

Chronic liver disease afflicts an estimated 850 million people worldwide, or 11% of the world population, due to the prevalence of viral hepatitis infection, alcohol abuse, and non-alcoholic steatohepatitis (NASH or “fatty liver”).

Chronic liver disease is blamed for nearly one million deaths a year, with another one million dying of hepatic cancer and acute hepatitis.

In the U.S., liver disease is the second leading cause of death from digestive disease, and the 10 th leading cause of death amongst men.

Many patients with advanced chronic liver disease will develop an acute exacerbation or decompensation (“acute-on-chronic”) of their disease, with associated inflammation and cytokine elevation, often requiring hospitalization.

Also, many patients will present with acute hepatitis triggered by viral infection or alcohol.

A range of symptoms, depending on the severity of illness, include jaundice (high bilirubin), variceal hemorrhage, cognitive dysfunction and hepatic encephalopathy, ascites, coagulopathy, renal failure, liver failure, and others.

The extracorporeal blood purification of liver toxins such as bilirubin has been used to help treat patients and is often called “liver dialysis”.

Current liver dialysis therapies include MARS (Molecular Adsorbent Recirculation System;

Baxter), Prometheus (Fresenius), SPAD (single pass albumin dialysis), and others.

However, none of these therapies can remove cytokines, key elements in acute-on-chronic exacerbations and cases of acute hepatitis.

CytoSorb represents a potentially superior liver dialysis therapy, as it can remove both liver toxins such as bilirubin and bile salts, as well as cytokines.

In May 2018, the approved indications for use of CytoSorb in the EU 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 to be more than $15 billion worldwide.

Severe Acute Pancreatitis

Acute pancreatitis is the inflammation of the pancreas that results in the local release of digestive enzymes and chemicals that cause severe inflammation, necrosis and hemorrhage of the pancreas and local tissues.

Approximately 210,000 people in the U.S.

are hospitalized each year with acute pancreatitis with roughly 20% requiring ICU care.

It is caused most frequently by a blockage of the pancreatic duct or biliary duct with gallstones, cancer, hyperlipidemia, or from excessive alcohol use.

Severe acute pancreatitis is characterized by severe pain, inflammation, and edema in the abdominal cavity, as well as progressive systemic inflammation, generalized edema, and multiple organ failure that is correlated with high levels of cytokines and digestive enzymes in the blood.

Little can be done to treat severe acute pancreatitis today, except for pancreatic duct decompression with endoscopic techniques, supportive care therapy, pain control, enteral tube feeding, and fluid support.

ICU stay is frequently measured in weeks and although overall ICU mortality is approximately 10%, patients with multiple organ failure have a much higher risk of death.

CytoSorb may potentially benefit overall outcomes in episodes of acute pancreatitis by removing a diverse set of toxins and cytokines from blood.

The total addressable market for CytoSorb for the treatment of severe acute pancreatitis in the U.S.

and EU is estimated to be between $400 million to $600 million.

Cancer Cachexia and Cancer Immunotherapy

Cancer cachexia is a progressive wasting syndrome characterized by rapid weight loss, anorexia, and physical debilitation that significantly contributes to death in many cancer patients.

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.

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

For example, CytoSorb efficiently removes TNF-alpha (originally called “cachectin” or “cachexin” when first isolated in cancer cachexia patients) and other major pro-inflammatory cytokines including IL-1, IL-6, and gamma interferon that can cause cachexia.

This broad immunotherapy approach may lead to improved clinical outcomes while reducing patient suffering.

CytoSorb may also represent a rescue or salvage therapy in activated CAR T-cell cancer immunotherapy, where cytokine release syndrome (i.e.

CRS or cytokine storm) is common, and can lead to organ failure and death in certain patients.

In the CRS literature, researchers have drawn parallels to both macrophage activating syndrome and secondary hemophagocytic lymphohistiocytosis (HLH) which produce a similar clinical picture and cytokine storm profile.

CytoSorb has been used successfully in many cases of secondary HLH.

In March 2017, the pioneer of CAR T-cell immunotherapy, Dr.

Carl June at University of Pennsylvania,

joined our scientific advisory board.

In 2017, both Kymriah from University of Pennsylvania and Novartis, and Yescarta from Kite Pharma and Gilead Sciences, received FDA approval for the treatment of certain hematologic cancers.

In early 2020, the first two case reports of CRS successfully treated with the adjunctive use of CytoSorb were published.

The total addressable market for CytoSorb for the treatment of cancer cachexia and cancer in the U.S.

and EU is estimated to be in excess of $4 billion.

Organ Transplant and Brain-Dead Organ Donors

There are in excess of 6,000 brain dead organ donors each year in the United States;

worldwide, the number of these organ donors is estimated to be at least double the U.S.

brain dead organ donor population.

There is a severe shortage of donor organs.

Currently, there are more than 100,000 individuals on transplant waiting lists in the United States.

Cytokine storm is common in these organ donors, resulting in reduced viability of potential donor organs.

The potential use of CytoSorb hemoperfusion to control cytokine storm in brain dead organ donors could increase the number of viable organs harvested from the donor pool and improve the survival of transplanted organs.

A proof-of-concept pilot study using our technology in human brain dead donors has been published.

In addition, 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.

In October 2020, CytoSorbents announced the EU approval of the ECOS-300CY cartridge for the removal of inflammatory mediators during ex vivo organ perfusion (EVOP), with the goal of either preserving organ function in healthy organs or rehabilitating dysfunctional organs that would otherwise have been discarded.

We believe the ECOS-300CY cartridge has the potential to expand the organ donor pool and improve clinical outcomes For example, recent published research in porcine and human lung transplant suggests that when used during EVOP as well as intraoperatively during transplant, our technology can improve lung function prior to transplant, and can reduce the incidence of primary graft dysfunction – a major problem in lung transplant, and may have a benefit in reducing acute rejection..

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 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 million to $600 million.

Blood Transfusions

The HemoDefend platform is a development-stage technology designed to be a practical, low cost, and effective way to safeguard the quality and safety of the blood supply.

alone, 15 million packed red blood cell (“pRBC”) transfusions and another 15 million transfusions of other blood products (e.g., platelet, plasma, and cryoprecipitate) are administered each year with an average of 10% of all U.S.

hospital admissions requiring a blood transfusion.

The sheer volume of transfusions, not just in the U.S., but worldwide, complicates an already difficult task of maintaining a safe and reliable blood supply.

Trauma, invasive operative procedures, critical care illnesses, supportive care in cancer, military usage, and inherited blood disorders are just some of the drivers of the use of transfused blood.

In war, hemorrhage from trauma is a leading cause of preventable death, accounting for an estimated 30% to 40% of all fatalities.

For example, in Operation Iraqi Freedom, due to a high rate of penetrating wound injuries, up to 8% of admissions required massive transfusions, defined as 10 units of blood or more in the first 24 hours.

There is a clear need for a stable and safe source of blood products.

However, blood shortages are common and exacerbated by the finite lifespan of blood.

According to the Red Cross, pRBC units have a refrigerated life span of 42 days.

However, many medical experts believe there is an increased risk of infection and transfusion reactions once stored blood ages beyond two weeks.

Transfusion-related acute lung injury is the leading cause of non-hemolytic transfusion-related morbidity and mortality, with an incidence of 1 in 2,000-5,000 transfusions and a mortality rate of up to 10%.

Fatal cases of transfusion-related acute lung injury have been most closely related to anti-HLA or anti-granulocyte antibodies found in a donor’s transfused blood.

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.

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.

Automated washing of pRBC is effective but is impractical due to the time, cost, and logistics of washing each unit of blood.

The HemoDefend platform is a potentially superior alternative to purify blood transfusion products to these methods.

The total addressable market for HemoDefend is more than $500 million for pRBCs alone.

CytoSorbents has also received grant and contract funding to develop the HemoDefend platform to enable both universal plasma and fresh whole blood transfusions through the reduction of anti-A and anti-B blood group antibodies.

Today, plasma and whole blood products must be carefully blood-type matched to prevent potentially fatal hemolytic transfusion reactions in the recipient, caused by the accidental administration of mismatched blood products.

The reduction of anti-A and anti-B antibodies could potentially reduce or eliminate this risk, allowing for a broader range of available donors

and simplifying the transfusion process.

According to the American Red Cross, nearly 10,000 units of plasma are needed daily in the United States, or more than 3.5 million units a year.

The World Health Organization (WHO) reports that plasma is transfused at a rate of 2.2 – 18.9 units per 1,000 population (median 7.7 units) globally.

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 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 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.

IV contrast is also administered during invasive and interventional cardiovascular procedures in the brain, heart, limbs, and other parts of the body to diagnose and treat atherosclerosis (narrowing of blood vessels due to cholesterol deposits), vascular injury, aneurysms, etc.

For example, an estimated 10 million coronary angiograms are performed worldwide each year to diagnose and treat coronary artery disease by placing coronary stents, performing balloon angioplasty, or atherectomy (removal of plaque in arteries).

Overall, there are an estimated 80 million doses of IV contrast administered worldwide each year, split between approximately 65 million contrast-enhanced CT scans, 10 million coronary angiograms, and 5 million conventional angiograms.

There are an estimated 30 million doses administered each year in the U.S.

The reported risk of CIN in patients undergoing contrast enhanced CT scans has been reported to be 2% to 13%.

For coronary intervention, the risk has been estimated to be as high as 20% to 30% in high risk patients with pre-existing renal insufficiency, long-term diabetes, hypertension, congestive heart failure, and older age.

The use of low osmolar IV contrast, hydration of patients pre-procedure, orally administration of N-acetylcysteine, and other agents to prevent CIN have demonstrated modest benefit in some clinical studies, but in many cases, the results across studies have been equivocal and inconsistent.

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

The worldwide market opportunity for ContrastSorb in this high risk group is approximately $1 billion to $2 billion.

DrugSorb is a development-stage blood purification technology that is capable of removing a wide variety of drugs and chemicals from blood, as a potential treatment for drug overdose, drug toxicity, toxic chemical exposure, use in high-dose regional chemotherapy, and other applications.

It has demonstrated extremely high single pass removal efficiency of a number of different drugs that exceeds the extraction capability of hemodialysis or other filtration technologies.

It is similar in action to activated charcoal hemoperfusion cartridges that have been available for many years, but has the advantage of having inherent biocompatibility and hemocompatibility without coatings, and can be easily customized for specific agents.

Chronic Kidney Failure

The National Kidney Foundation estimates that more than 20 million Americans have chronic kidney disease.

Left untreated, chronic kidney disease can ultimately lead to chronic kidney failure, which requires a kidney transplant or chronic dialysis (generally three times per week) to sustain life.

There are approximately 500,000 patients in the U.S.

currently receiving chronic dialysis and more than 3.0 million worldwide.

Approximately 66% of patients with chronic kidney disease are treated with hemodialysis.

One of the problems with standard high-flux dialysis is the limited ability to remove certain mid-molecular weight toxins such as β 2 -microglobulin.

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 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.

The polymer adsorbent technology used in our products can remove middle molecular weight toxins, such as cytokines, from blood and physiologic fluids.

All of the potential applications described below (i.e., the adjunctive treatment and/or prevention of sepsis;

the adjunctive treatment and/or prevention of other critical care conditions such as acute respiratory distress syndrome, burn injury, trauma and pancreatitis;

the prevention of damage to organs donated by brain-dead donors prior to organ harvest;

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

the prevention of kidney injury from IV contrast;

and the treatment of chronic kidney failure) share in common high concentrations of toxins in the circulating blood.

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

In 2011, we completed our European Sepsis Trial of our CytoSorb device.

The study was a randomized, open label,

controlled clinical study in 14 sites in Germany of 100 critically ill patients with predominantly septic shock and respiratory failure.

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 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.

However, there can be no assurance that we will ever obtain regulatory approval for any other device, or that the CytoSorb device will be able to generate significant sales.

We manufacture the CytoSorb device at our facility located in Princeton, New Jersey.

We purchase our raw materials from multiple vendors located primarily in the United States.

We believe that our risk of an interruption in the supply of our raw materials is minimal due to the use of multiple vendors and the availability of alternate vendors.

We do not have contractual minimum finished goods inventory requirements, however our practice is to maintain a minimum inventory level sufficient to provide a supply of products for the next three months.

The CytoSorb Device (Critical Care)

Adjunctive Therapy in the Treatment of Sepsis

Sepsis is a potentially life-threatening disease defined as “life-threatening organ dysfunction caused by a dysregulated host response to an infection”.

Sepsis is mediated by high levels of inflammatory mediators such as cytokines, which are released into the bloodstream as part of the body’s immune response to severe infection or injury.

Excessive concentrations of these mediators cause severe inflammation and damage healthy tissues, which can lead to organ dysfunction and failure.

Organ failure is the leading cause of death in the ICU.

Sepsis is very expensive to treat and has a high mortality rate.

Potential Benefits:

To the extent our adsorbent blood purification technology is able to prevent or reduce the accumulation of cytokines, toxins, or other inflammatory mediators in the circulating blood, we believe our products may be able to prevent or mitigate severe inflammation, organ dysfunction and failure in sepsis patients.

Therapeutic goals as an adjunctive therapy include improved clinical outcome, reduced ICU and total hospitalization time, and reduced hospital costs.

Background and Rationale:

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%.

Death can occur within hours or days, depending on many variables, including cause, severity, patient age and co-morbidities.

There are approximately 1.6 million new cases of sepsis in the U.S.

and based on a recent 2020 The Lancet study, the worldwide incidence is estimated to be 49 million cases annually, accounting for 1 in every 5 deaths globally.

The incidence of sepsis is also rising due to:

● an aging population;

● increased incidence of antibiotic resistance;

● increase in co-morbid conditions like cancer and diabetes;

● increased use of indwelling medical devices that are susceptible to infection.

alone, treatment of sepsis costs nearly $20 billion annually.

According to the CDC, sepsis is a top ten cause of death in the U.S.

The incidence of sepsis is believed to be under-reported as the primary infection (i.e., pneumonia, pyelonephritis, etc.) is often cited as the cause of death.

An effective treatment for sepsis has been elusive.

Pharmaceutical companies have been trying to develop drug therapies to treat the condition.

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.

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.

Many medical professionals believe that blood purification for the treatment of sepsis holds tremendous promise.

Studies using dialysis and hemofiltration technology have been encouraging, but have only had limited benefit to sepsis patients.

The reason for this appears to be rooted in a primary limitation of dialysis technology itself:

the inability of standard dialysis to effectively and efficiently remove significant quantities of larger toxins such as cytokines from circulating blood.

CytoSorb has demonstrated the ability to safely reduce key cytokines in the blood of septic patients with multiple organ failure in our European Sepsis Trial.

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 228,000 devices utilized as of December 31, 2023.

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.

It also removes a wide range of inflammatory mediators such as activated complement, bacterial toxins, myoglobin, free hemoglobin, bilirubin, and many others.

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

Projected Timeline:

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.

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.

We are currently manufacturing our CytoSorb device for commercial sale in the EU.

We are currently selling CytoSorb in Germany, Austria, Switzerland, Belgium, Luxembourg, Poland, Norway, Finland, Sweden, Denmark, the United Kingdom and the Netherlands with a direct sales force.

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 more than 75 countries worldwide.

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

With CE Mark approval, this can be typically achieved within several months in EU countries.

Outside of the EU, the process is more variable and can take months to more than a year due to different requirements for documentation and clinical data.

Variability in the timing of registration affects the initiation of active commercialization in these countries, which affects the timing of expected CytoSorb sales.

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, 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.

We also 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.

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.

Adjunctive Therapy in Other Critical Care Applications

Potential Benefits:

Cytokine-mediated organ damage and immune suppression can increase the risk of death and infection in patients with commonly seen critical care illnesses such as acute respiratory distress syndrome, severe burn injury, trauma and pancreatitis.

By reducing both pro- and anti-inflammatory cytokines, CytoSorb has the potential to reduce the systemic inflammatory response and:

● prevent or mitigate multiple organ dysfunction syndrome (“MODS”) and/or multiple organ failure (“MOF”);

● prevent or reduce secondary infections;

● reduce the need for expensive life-sparing supportive care therapies such as mechanical ventilation;

● reduce the need for ICU care, freeing expensive critical care resources, and reducing hospital costs and costs to the healthcare system.

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.

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

MODS and MOF are common causes of death in these illnesses and mortality is directly correlated with the number of organs involved.

There are currently few active therapies to prevent or treat MODS or MOF.

If CytoSorb can reduce direct or indirect cytokine injury of organs, it may mitigate MODS or MOF, improve overall patient outcome and reduce costs of treatment.

In addition, secondary infection, such as ventilator-acquired pneumonia, urinary tract infections, or catheter-related line infections, are another major cause of morbidity and mortality in all patients treated in the ICU that increase with longer ICU stay.

Prolonged illness, malnutrition, age, multiple interventional procedures, and exposure to antibiotic resistant pathogens are just some of the many risk factors for functional immune suppression and infection.

In sepsis and SIRS, the overexpression of pro-

inflammatory cytokines can also cause a depletion of immune effector cells through apoptosis and other means, and anti-inflammatory cytokines can cause profound immune suppression, both major risk factors for infection.

Projected Timeline:

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.

Our goal is to stimulate investigator-initiated clinical studies with our device for these applications.

Currently, we have many 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 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.

Commencement of these and other formal studies is contingent upon adequate funding and, in the case of U.S.

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

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 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;

● reduce post-operative complications such as ARDS, acute kidney injury, post-perfusion syndrome, and the SIRS;

● reduce length of stay in hospital ICUs;

● reduce the total cost of patient care;and

● reduce the risk of perioperative bleeding complications such as need for blood and platelet transfusions, re-thoracotomy, and death.

Background and Rationale:

Due to the highly invasive nature of cardiopulmonary bypass surgery, high levels of cytokines are produced by the body, triggering severe inflammation.

In addition, hemolysis of red blood cells frequently occurs, resulting in the release of free hemoglobin into the bloodstream.

These inflammatory mediators can lead to post-operative complications.

CytoSorb is the only cytokine reduction technology approved in the EU that can be used intraoperatively in a bypass circuit in a heart-lung machine during cardiopulmonary bypass without the need for another machine.

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.

Intraoperative use of CytoSorb on high-risk cardiac surgery patients, such as those with infective endocarditis, aortic dissection, or heart or lung transplantation, 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 EU 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.

It is also widely used during dual-anti platelet therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention and stent placement.

However, when patients on ticagrelor require emergent or urgent cardiac surgery, up to 65% of patients will have severe or massive peri-operative bleeding complications that contributes to a high risk of death and major costs to the healthcare system.

CytoSorb has already demonstrated the ability to remove ticagrelor rapidly and efficiently from human blood in vitro .

Meanwhile, a retrospective case series reported by clinicians at Asklepios Klinik St.

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 EU 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 70,000 treatments in cardiac surgery patients.

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

In October 2021, the first patient was enrolled and the STAR-T study was actively recruiting at multiple U.S.

In November 2022, the first milestone was completed with the first one-third of patients enrolled, triggering the first Data Safety Monitoring Board (DSMB) meeting.

The DSMB recommended to continue the study as planned without any modifications.

In 2022, we also received FDA approval to expand the study to Canada and subsequently received Health Canada approval allowing inclusion of Canadian sites into the STAR-T trial in January 2023.

The study completed enrollment in July of 2023.

As described above, the STAR-T trial met the primary safety endpoint but missed the primary efficacy endpoint in the overall population that included different types of surgeries.

Analysis of the efficacy results is ongoing with the intent of presenting them at an international cardiovascular conference in 2024.

We believe that the safety and efficacy results of the STAR-T study will support regulatory submissions for marketing approval by the FDA and Health Canada.

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

The study was terminated in 2023 for business reasons.

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

Maintaining or improving the quality of solid organs harvested from donors for organ transplant

Potential Benefits:

Solid organ transplant is very costly, and the success of the transplant is heavily dependent upon the health and quality of the harvested organs.

ECOS-300CY was designed to maintain or improve the quality of these organs prior to transplant in an ex vivo perfusion system, and may have the benefit of improving outcomes in organ transplant and also increasing the availability of organs by rehabilitating organs that would have otherwise been discarded.

By preventing or reducing high-levels of cytokines from accumulating in the bloodstream of brain-dead organ donors, we believe CytoSorb may be able to mitigate organ dysfunction and failure, which results from severe inflammation following brain-death.

The primary goals for this application are:

● improving the viability of organs which can be harvested from brain-dead organ donors, and

● increasing the likelihood of organ survival following transplant.

Background and Rationale:

When brain death occurs, the body responds by generating large quantities of inflammatory cytokines.

This process is similar to the systemic inflammatory response syndrome and sepsis.

A high percentage of donated organs are never transplanted due to this response, which damages healthy organs and prevents transplant.

In addition, inflammation in the donor may damage organs that are harvested and reduce the probability of graft survival following transplant.

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 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.

Projected Timeline:

The ECOS-300CY was approved in the E.U.

for the removal of inflammatory mediators during ex vivo organ perfusion under CE Mark designation in 2020.

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:

Studies have been conducted under a $1 million grant from the Health Resources and Services Administration (“HRSA”), an agency of the U.S.

Department of Health and Human Services.

Researchers at the University of Pittsburgh Medical Center and the University of Texas, Houston Medical Center have completed the observational and dosing phases of the project.

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

The VetResQ Device (Animal Health Critical Care)

Adjunctive Therapy in the Treatment of Sepsis, Pancreatitis and Other Critical Illnesses in Animals

Potential Benefits and Rationale:

In January 2017, the VetResQ device became commercially available for the United States veterinary market.

VetResQ is a broad-spectrum blood purification adsorber based upon similar underlying technology to CytoSorb and has been configured in 3 sizes (50, 150 and 300mL sized cartridges) to accommodate treatment of small, medium, and large animals such as cats, dogs, and high-value animals such as foals and horses.

VetResQ is compatible with standard hemodialysis, continuous renal replacement therapy (“CRRT”), and hemoperfusion blood pumps.

Like CytoSorb, VetResQ is designed to help treat (via hemoadsorption of cytokines, bacterial toxins and other inflammatory mediators) deadly inflammation and toxic injury in animals with critical illnesses such as septic shock, toxic shock syndrome, toxin-mediated diseases, pancreatitis, trauma, liver failure, drug intoxication, heat stroke and lung injury.

Critical illness in animals is similar to that in humans.

Based upon cumulative studies, VetResQ is capable of reducing a broad range of excessive hydrophobic drugs, inflammatory mediators and toxins that could otherwise cause direct tissue injury or serious systemic inflammation that can rapidly lead to instability, organ failure, and death.

VetResQ is available in the U.S.

only for veterinary animal usage and is not for human use.

Projected Timeline :

VetResQ is available for commercial purchase for animal health applications in the United States.

The FDA was notified of the launch in 2016 and we have provided the FDA with the related instructions for use and a marketing brochure.

The CytoSorb-XL Device (Critical Care)

Adjunctive Therapy in the Treatment of Sepsis and other critical illnesses

Potential Benefits and Rationale:

The CytoSorb-XL device is a next-generation porous polymer under advanced development and targets the same markets as CytoSorb.

Through novel patent-pending chemistry, CytoSorb-XL adds the ability to reduce Gram negative bacterial endotoxin (lipopolysaccharide) to broad spectrum cytokine, exotoxin, and other inflammatory mediator removal.

CytoSorb-XL removed comparable amounts of endotoxin when compared in vitro against the leading standalone endotoxin filter, Toraymyxin (Toray, Japan).

This could potentially increase the effectiveness of CytoSorb in sepsis and septic shock caused by Gram negative bacteria.

Projected Timeline :

CytoSorb-XL is in advanced pre-clinical development as a potential next generation polymer to CytoSorb.

It is expected to follow a similar path to E.U.

approval as CytoSorb, expected within four to five years.

The HemoDefend Blood Purification Technology Platform (Acute and Critical Care)

Reduction of contaminants in the blood supply that can cause transfusion reactions or disease when administering blood and blood products to patients.

Potential Benefits:

The HemoDefend RBC blood purification technology platform is designed to reduce contaminants in the blood supply that can cause transfusion reactions or disease.

It is a development stage technology that is not yet approved in any markets,

but is comprised of our highly advanced, biocompatible, polymer bead technology.

If this technology is successfully developed and then incorporated into a regulatory approved product, it could have a number of important benefits, including:

● reduce the risk of transfusion reactions and improve patient outcome;

● improve the quality, or extend the shelf life of stored blood products;

● improve the availability of blood and reduce blood shortages by reducing the limitations of donors to donate blood;

● allow easier processing of blood.

Background and Rationale:

The HemoDefend technology platform was built upon our successes in designing and manufacturing porous polymer beads that can remove cytokines.

We have expanded the technology to be able to remove substances as small as drugs and bioactive lipids, to proteins as large as antibodies from blood that can cause transfusion reactions and disease.

Although the frequency of these reactions are relatively low (approximately 3% to 5%), the sheer number of blood transfusions is so large, that the number of transfusion reactions, ranging from mild to life-threatening, is substantial, ranging from several hundreds of thousands to millions of reactions each year.

In critically-ill patients, the risk of transfusion reactions is significantly higher than in the general population and can increase the risk of death because their underlying illnesses have depleted protective mechanisms and have primed their bodies to respond more vigorously to transfusion-associated insults.

A number of retrospective studies have also suggested that administration of older blood leads to increased adverse events and even increased mortality, compared with blood recently harvested.

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 such as free hemoglobin, bioactive lipids, potassium, and others during blood storage that can lead to transfusion reactions.

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).

The overall conclusion was that the age of blood had no statistically significant impact on the progression to organ dysfunction (as measured by the multiple organ dysfunction syndrome score) or death.

However, a statistically significant increase in hepatobiliary-related serious adverse events (5% fresh vs 9% older, p=0.02) was related to hyperbilirubinemia, possibly caused by hemolysis and release of free hemoglobin in old blood.

The serious adverse event rate in both new and old blood groups was approximately 50%, which is considered high for this group of patients.

There are many details and subgroup analyses that were not discussed, particularly an analysis of those patients receiving more units of blood than average, as the risk of adverse events is cumulative.

The ABLE Trial was a randomized, controlled trial in 2,430 critically-ill patients receiving either fresh (≤ 7 days) or standard issue blood.

There was no difference in 90-day mortality between the two groups.

The TRANSFUSE Trial was a large scale RCT in Australia evaluating the impact of age of leukodepleted pRBCs (short-term storage:

11.8 days mean, N=2,457, mean 4.1 units transfused;

long-term storage:

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;

5% short-term storage vs n=88;

3.6% long-term storage).

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, 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:

The HemoDefend platform is a development stage product based on our advanced polymer technology.

The base polymer is ISO 10993 biocompatible, meeting standards for biocompatibility, hemocompatibility, cytotoxicity, genotoxicity, acute sensitivity and complement activation.

HemoDefend has demonstrated the in vitro removal of many different substances from blood such as antibodies, free hemoglobin, potassium, cytokines and bioactive lipids.

We have also prototyped a number of different implementations of the HemoDefend technology, including the “Beads in a Bag” blood treatment blood storage bag, and standard in-line blood filters.

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

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

We seek to out-license this technology platform to a potential strategic partner.

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

Potential Benefits:

The HemoDefend-BGA blood purification technology platform is designed to reduce anti-A and anti-B antibodies in plasma and whole blood.

The goal is to either enable the production of universal plasma or enable fresh warm whole blood

transfusions.

If this technology is successfully developed and then incorporated into a regulatory approved product, it could have a number of important benefits, including:

● reduce the risk of transfusion reactions and improve patient outcome;

● eliminate the need to blood-type plasma, improving its availability

● enable the use of low titer whole blood, ideal for trauma resuscitation;

● easier processing of blood products.

Background and Rationale:

Plasma is the straw-colored, cell-free portion of whole blood.

It contains a wide range of important substances such as electrolytes, hormones, proteins such as albumin, clotting factors, and antibodies.

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.

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.

By reducing these blood-type specific antibodies, the goal is to create a cost-effective, reliable, and expanded source of “universal” plasma that can be administered immediately, without blood-typing, in a wide range of emergent and non-emergent situations.

Projected Timeline:

The HemoDefend-BGA platform is a development stage product based on our advanced blood purification technology.

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 clinical study-ready devices and have had preliminary discussions with the U.S.

FDA on the regulatory path forward.

This work has received cumulative funding of approximately $15.9 million in Phase I and II Small Business Technology Transfer (STTR) funding by the U.S.

Army Medical Research Acquisition Activity (USAMRAA), U.S.

Army Medical Research and Materiel Command (USAMRMC), Defense Health Agency, CDMRP, DMRDP, and JWMRP.

K + ontrol (Acute and Critical Care)

Treatment of severe hyperkalemia that can occur in patients with life-threatening conditions such as trauma, burn injury, kidney failure, tumor lysis syndrome, and those with no access to dialysis

Potential Benefits:

K + ontrol was developed to rapidly treat severe hyperkalemia by reducing potassium in the blood.

Although hemodialysis remains the definitive treatment for severe hyperkalemia, K + ontrol represents a simpler, and more flexible alternative.

The primary goals for this application are to:

● Enable the rapid treatment of deadly hyperkalemia without the need for hemodialysis

● Prevent potentially fatal cardiac arrhythmias following severe injury

● Improve survival in victims in remote areas and during prolonged field care in combat

Background and Rationale:

Potassium is an important electrolyte in the body that is present inside cells at high concentrations, with the amount in blood tightly regulated.

Following injury to cells by, for example, trauma, burn injury, ischemia, or cytotoxic drugs, such cells will continuously leak high levels of potassium into the blood, resulting in hyperkalemia.

The kidneys normally excrete excess potassium from the blood, but when compromised, as in critically-ill patients suffering from kidney failure or in chronic dialysis patients with end-stage kidney disease, the levels of blood potassium can rapidly rise unabated.

When the potassium level in the blood exceeds a concentration of 6.0 mmol/L (normal 3.6 - 5.2 mmol/L), the risk of heart arrhythmias and sudden cardiac death increases significantly.

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.

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

Hyperkalemia is a common problem and has been reported to occur in 1.7-5.2% of hospitalized patients in a number of studies.

It has also been recognized as a serious complication of combat injury since World War II, when hyperkalemia and acute kidney injury was associated with a mortality rate of 90%, and was a leading cause of post-traumatic death in the Korean War, until the advent of dialysis therapy.

In the wars in Iraq and Afghanistan, an estimated 5.8% of all combat casualties developed hyperkalemia within 48

hours of injury.

Even in non-crush traumatic injury, severe hyperkalemia (>6 mmol/L) occurred in approximately 20% of patients.

Hyperkalemia was also observed in approximately 16% of victims of natural disasters such as earthquakes, where crush injury is common.

Projected Timeline:

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 a Phase I and Phase II SBIR contract for a total of $1.5 million and a $3 million Rapid Innovation Fund (RIF) award from the U.S.

Air Force Materiel Command.

We seek to outlicense this technology platform to a potential strategic partner.

ContrastSorb (Radiology and Interventional Radiology)

Removal of IV contrast in blood administered during CT imaging, an angiogram, or during a vascular interventional radiology procedure, in order to reduce the risk of contrast-induced nephropathy.

Potential Benefits:

IV contrast can lead to CIN, in susceptible patients.

Risk factors include chronic kidney disease and renal insufficiency caused by age, diabetes, congestive heart failure, long-standing hypertension, and others co-morbid illnesses.

CIN can lead to increased risk of patient morbidity and mortality.

Removal of IV contrast by ContrastSorb may:

● reduce the risk of acute kidney injury

● improve the safety of these procedures and reduce the risk of morbidity and mortality

Background and Rationale:

Contrast-induced nephropathy 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.

IV contrast is also administered during vascular interventional radiology procedures and angiography of blood vessels in the brain, heart, limbs, and other parts of the body to diagnose and treat atherosclerosis (narrowing of blood vessels due to cholesterol deposits), vascular injury, aneurysms, etc.

The reported risk of CIN undergoing contrast enhanced CT scans has been reported to be 2% to 13%.

For coronary intervention, the risk has been estimated to be as high as 20% to 30% in high risk patients with pre-existing renal insufficiency, and other risk factors.

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

Projected Timeline:

ContrastSorb has demonstrated the high efficiency single pass removal of IV contrast and is in the process of optimization.

The underlying polymer is made of the same ISO 10993 biocompatible polymer as CytoSorb, but with different structural characteristics.

The ContrastSorb device is a hemoperfusion device similar in construction to CytoSorb and BetaSorb.

Assuming successful optimization of the ContrastSorb polymer, safety and efficacy of IV contrast removal will need to be established in human clinical studies.

We seek to out-license this technology platform to a potential strategic partner.

The BetaSorb Device (Chronic Care)

Prevention and treatment of health complications caused by the accumulation of metabolic toxins in patients with chronic renal failure

Potential Benefits:

If BetaSorb is able to prevent or reduce high levels of metabolic waste products from accumulating in the blood and tissues of long-term dialysis patients, we anticipate that certain health complications characteristic to these patients can be prevented or mitigated.

The primary goals for this application are to:

● improve and maintain the general health of dialysis patients;

● reduce disability and improve the quality of life of these patients

● reduce the total cost of patient care;

● increase life expectancy.

Background and Rationale:

Our BetaSorb device is intended for use on patients suffering from chronic kidney failure who rely on long-term dialysis therapy to sustain life.

Due to the widely recognized inability of dialysis to remove larger proteins from blood, metabolic waste products, such as beta 2 -microglobulin, accumulate to toxic levels and are deposited in the joints and tissues of patients.

Specific toxins known to accumulate in these patients have been linked to their severe health complications, increased healthcare costs, and reduced quality of life.

Researchers also believe that the accumulation of toxins may play an important role in the significantly reduced life expectancy experienced by dialysis patients.

In the U.S., the average life expectancy of a dialysis patient is five years.

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 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.

alone, more than $33 billion is spent annually caring for this patient population according to the United States Renal Data System, at a cost of approximately $88,000 per patient annually.

Projected Timeline:

We have collected a significant amount of empirical data for the development of this application.

As the developer of this technology, we had to undertake extensive research, as no comparable technology was available for reference purposes.

We have completed four human pilot studies, including a clinical pilot of six patients in California for up to 24 weeks in which our BetaSorb device removed the targeted toxin, beta 2 -microglobulin, as expected.

In total, we have sponsored clinical studies utilizing our BetaSorb device on 20 patients involving approximately 345 total treatments.

Each study was conducted by clinic or hospital personnel with us providing technical assistance as requested.

As discussed above, due to practical and economic considerations, we are focusing our efforts and resources on commercializing our CytoSorb device for critical care and cardiac surgery applications.

Following commercial introduction of the CytoSorb device, and with sufficient additional resources, we may continue development of the BetaSorb resin and may conduct additional clinical studies using the BetaSorb device in the treatment of end stage renal disease patients.

Commercial and Research Partners

Biocon Biologics Limited

On November 8, 2023, Biocon Biologics (“Biocon”) announced that it entered into a definitive agreement with Eris Lifesciences (“Eris”) for the divestiture of its Dermatology and Nephrology branded formulations business units in India.

This transaction closed in November 2023.

In connection with this proposed transfer, the Company and Eris have entered into a temporary agreement for the distribution of CytoSorb ® products in India.

Both the Company and Eris have agreed that they will use their best efforts to negotiate and finalize a new distribution agreement that will be commercially attractive to both parties.

As a result, Eris would act the Company’s exclusive distributor of CytoSorb ® products in India.

If a new distribution agreement with Eris is not executed by December 31, 2025, this temporary agreement will become null and void.

Fresenius Medical Care AG

In December 2014, we entered into a multi-country strategic partnership with Fresenius Medical Care AG & Co KGaA (together with its affiliates, as appropriate, “Fresenius”) to commercialize the CytoSorb therapy.

Under the agreement reflecting the terms of the partnership, Fresenius was granted exclusive rights to distribute CytoSorb for critical care applications in France, Poland, Sweden, Denmark, Norway, and Finland.

The partnership allows Fresenius to offer an innovative and easy way to use blood purification therapy for removing cytokines in patients that are treated in the ICU.

To promote the success of CytoSorb, Fresenius agreed to also engage in the ongoing clinical development of the product.

This includes the support and publication of a number of small case series and patient case reports as well as the potential for future larger, clinical collaborations.

In May 2016, Fresenius launched the product in the six countries for which it was granted exclusive distribution rights.

In January 2017, the Fresenius partnership was expanded pursuant to a revised three-year agreement.

The terms of the revised agreement extended Fresenius’ exclusive distributorship of CytoSorb for all critical care applications in their existing territories through 2019 and include guaranteed minimum quarterly orders and payments, evaluable every one and a half years.

At the same time, we entered into a comprehensive co-marketing agreement with Fresenius.

Under the terms of the co-marketing agreement, CytoSorbents and Fresenius agreed to jointly market CytoSorb to Fresenius’ critical care customer base in all countries where CytoSorb is being actively commercialized.

CytoSorb continues to be sold by our direct sales force or through our international network of distributors and partners, while Fresenius sells all ancillary products to their customers.

Fresenius further provides written endorsements of CytoSorb for use with their multiFiltrate and multiFiltratePRO acute care dialysis machines that can be used by us and our distribution partners to promote CytoSorb worldwide.

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, 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.

Under the terms of these agreements, Fresenius has exclusive rights to distribute CytoSorb for acute care and other hospital applications in South Korea and Mexico.

Registration clearance was obtained from the South Korean and Mexican health authorities in 2021 and 2020, respectively.

These multi-year agreements include an initial stocking order and are subject to annual minimum purchases of CytoSorb to maintain exclusivity.

These agreements, which commenced on January 1, 2019, have an initial term of three years and 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 Colombia and Ecuador.

In August 2022, the Company entered into a Marketing Agreement (the “Marketing Agreement”) with Fresenius, which expanded the Company’s current strategic partnership with Fresenius by establishing a multi-stage global collaboration to combat life-threatening diseases in critical care.

In addition to strengthening and expanding the global marketing of CytoSorb, the Company and Fresenius also plan to work together to bring new innovative solutions to the market.

The Marketing Agreement also includes the certification of compatibility of CytoSorb for usage on Fresenius’ current critical care platforms.

Certain initial activities have been completed with the formal launch of this program expected to occur in 2024.

In December 2014, we established a multi-country partnership with Fresenius Medical Care to commercialize CytoSorb in France, Poland, Sweden, Denmark, Norway, and Finland.

Fresenius received exclusive distribution rights and supported clinical development.

A revised three-year agreement (effective January 2017) extended Fresenius’ exclusive distribution for critical care applications through 2019 and included guaranteed minimum quarterly orders.

Additionally, we entered into a comprehensive co-marketing agreement with Fresenius.

CytoSorb continued to be sold by our direct sales force or through our international network of distributors and partners, while Fresenius sold all ancillary products to their customers.

Fresenius further provided written endorsements of CytoSorb for use with their multiFiltrate and multiFiltratePRO acute care dialysis machines that could be used by us and our distribution partners to promote CytoSorb worldwide.

In December 2018, the Company amended its 2014 Fresenius distribution agreement, granting exclusivity for certain applications in France, Czech Republic, and Finland.

In 2019, several countries transitioned to co-marketing, and minimum purchase requirements were removed.

The aforementioned exclusive agreements became non-exclusive in January 2022.

In addition, also in December 2018 and in 2020, we entered into agreements to expand the partnership with Fresenius into South Korea, Mexico, Colombia and Ecuador.

In August 2022, CytoSorbents and Fresenius expanded their partnership with a new Marketing Agreement to promote CytoSorb globally (excluding the US) for critical care.

Fresenius would promote CytoSorb as the featured solution for cytokine, bilirubin, and myoglobin on its critical care platforms worldwide with the exception of the U.S., in a comprehensive marketing campaign.

The Marketing Agreement also included the certification of compatibility of CytoSorb for usage on Fresenius’ current critical care platforms and provided for potential new collaborations on novel future innovations.

The initial three-year agreement automatically renews for two years.

Under the terms of this agreement, CytoSorbents would pay royalties on sales to offset program-specific marketing costs.

Due to delays in the full implementation of this Marketing Agreement, no royalties were paid under this agreement in 2024 or 2023.

Aferetica s.r.l.

In 2015, we entered into a distribution agreement with Aferetica s.r.l., a distributor based in Bologna, Italy that specializes in the sale of certain medical products and devices, specifically extracorporeal therapies, in the critical care, cardiac surgery and liver disease markets (“Aferetica”).

Under the terms of the agreement, we granted Aferetica the exclusive right to distribute CytoSorb in Italy, San Marino and the Vatican for application in CRRT (Continuous Renal Replacement Therapies), dialysis and hemoperfusion machine run treatments, as described in the agreement.

In connection with the grant of distribution rights, Aferetica agreed to certain minimum purchase and inventory requirements.

Aferetica further agreed not to market or sell products competitive with CytoSorb in Italy, San Marino and the Vatican.

The agreement was renewed through 2023.

In addition, in September 2017, we announced a partnership with Aferetica to provide dedicated, branded sorbent cartridges for use with Aferetica’s proprietary PerLife™ ex-vivo organ perfusion system, with the goal of rehabilitating or preserving the function solid organs destined for eventual transplant.

In July 2018, Aferetica and CytoSorbents debuted the PerLife™ system for organ preservation at the 27 th International Congress of the Transplantation Society.

In the fourth quarter of 2020, Aferetica announced CE Mark registration of the PerLife system.

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 various European countries.

In 2015, we entered into a distribution agreement for CytoSorb with Aferetica s.r.l., a distributor based in Bologna, Italy that specializes in the sale of certain medical products and devices, specifically extracorporeal therapies, in the critical care, cardiac surgery and liver disease markets (“Aferetica”).

The agreement was renewed and is ongoing.

In 2021, CytoSorbents and Aferetica announced the commercial launch in Italy of the PerSorb™ adsorber and the PerLife™ ex vivo organ perfusion system, respectively, to help restore and preserve harvested organs for transplant.

The PerSorb adsorber is a private-label version of CytoSorbents’ ECOS-300CY cartridge that is approved in the E.U.

for this application.

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, 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 expired on March 31, 2022.

On January 1, 2023, we amended and restated the original distribution agreement from October 2016.

Under the terms of the amended and restated agreement, Terumo will have non-exclusive distribution rights in France to promote and sell the CytoSorb CPB procedure pack for intra-operative use during cardiac surgery at specifically named hospitals in France.

The amended and restated agreement allows the Company to sell directly to other hospital customers in France for the cardiac surgery application.

On January 1, 2024, we entered into a second amended and restated agreement to the original distribution agreement from October 2016.

Under the terms of this amended and restated agreement, Terumo received non-exclusive distribution rights in France to promote and sell the CytoSorb CPB procedure pack for intra-operative use during cardiac surgery at specifically named hospitals in France.

This amended and restated agreement allowed the Company to sell directly to other hospital customers in France for the cardiac surgery application.

Financial terms of this agreement have not been disclosed.

The agreement terminates on December 31, 2023.

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

COVID-19 hotspot states including Alabama, Arizona, California, Georgia, Louisiana, Mississippi, New Mexico, Oregon, Texas, and Washington.

CytoSorb previously received Emergency Use Authorization (EUA) by the U.S.

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

The agreement terminated on December 31, 2023 and is currently under re-negotiation.

Braun Avitum AG

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

The CytoSorb ® adsorber is used in critical care for the extracorporeal removal of cytokines and inflammatory mediators from the bloodstream and can be operated with the B.

CytoSorb ® adsorber is used in critical care for the extracorporeal removal of cytokines and inflammatory mediators from the bloodstream and can be operated with the B.

Braun OMNI ® acute dialysis machine.

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Financial terms of this agreement have not been disclosed.

Nikkiso Europe GmbH

The Nikkiso agreement to distribute its PureAdjust ® hemoperfusion pump in selected countries expired in September 2023.

The Company is actively working with a new supplier to provide a stand-alone hemoperfusion pump.

University of Pittsburgh Medical Center

Two government research grants by the National Institutes of Health (“NIH”) and the U.S.

Department of Health and Human Services were awarded to investigators at the University of Pittsburgh to explore the use of adsorbent polymers in the treatment of sepsis and organ transplant preservation.

Under “Sub Award Agreements” with the University of Pittsburgh, we developed polymers for use in these studies.

A grant of $1 million was awarded to the University of Pittsburgh Medical Center in 2003.

The project sought to improve the quantity and viability of organs donated for transplant by using CytoSorb to detoxify the donor’s blood.

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.

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

In September 2005, the University of Pittsburgh Medical Center was awarded a grant of approximately $7 million from NIH entitled “Systems Engineering of a Pheresis Intervention for Sepsis (SEPsIS)” to study the use of our adsorbent polymer technology in the treatment of severe sepsis.

The study, which lasted for a total of five years, commenced in September 2005.

Under a SubAward Agreement, we worked with researchers at the University of Pittsburgh - Critical Care Medicine Department.

We believe that the only polymers used in this study were polymers we have developed specifically for use in the study, which are similar to the polymers used in our devices.

Under the SubAward Agreement, for our efforts in support of the grant during 2006 through 2010, we received approximately $402,000.

John Kellum, a member of the UPMC faculty since 1994, was the Chairman of our Sepsis Advisory Board.

On March 1, 2021, Dr.

Kellum became the Chief Medical Officer for Toronto, Canada-based Spectral Medical, Inc.

Concurrent with his appointment at Spectral, Dr.

Kellum formally resigned from our Advisory Board.

Advisory Boards

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.

The Advisory Boards

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

In August 2003, in order to induce Guillermina Vega Montiel, a principal member of RenalTech International, LLC at the time, to make a $4 million investment in RenalTech International, LLC, Ms.

Montiel was granted a perpetual royalty (the “Royalty”) equal to three percent of all gross revenues received by us from sales of CytoSorb in the applications of sepsis, cardiopulmonary bypass surgery, organ donor, chemotherapy and inflammation control.

Montiel was granted a perpetual royalty (the “Royalty”) equal to three percent of all gross revenues, license fees, or sales of CytoSorb intellectual property received by us from sales or license of CytoSorb in the applications of sepsis, cardiopulmonary bypass surgery, organ donor, chemotherapy and inflammation control.

In addition, for her investment, Ms.

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Such membership units ultimately were converted into and became 7,420 shares of our common stock following our June 30, 2006 merger.

In February 2017, all rights, title and interest to the Royalty was assigned to The Robert Shipley Living Trust.

In February 2017, all rights, title and interest to the Royalty were assigned to The Robert Shipley Living Trust.

In November 2022, all rights, title and interest to the Royalty was assigned to ROKK, LLC.

In August 2024, the Company and ROKK entered into the Amended and Restated Agreement to, among other items, clarify the scope of the term “gross revenue” from which the three percent royalty payment is calculated.

Under the Amended and Restated Agreement, the term “Covered Product” means the Company’s flagship product, CytoSorb, together with the currently commercialized versions of VetResQ and ECOS-300CY, as well as the versions of DrugSorb and DrugSorb-ATR that have been evaluated in human clinical trials, in each case as of the date of the Amended and Restated Agreement.

For the year ended December 31, 2024 we have recorded royalty costs of approximately $1,060,000.

On August 1, 2022, the Company entered into the Marketing Agreement with Fresenius, which expands the Company’s strategic partnership with Fresenius by establishing a multi-stage global collaboration to combat life-threatening diseases in critical care.

The Marketing Agreement has an initial term of three years, with an automatic renewal for an additional two years at the end of such initial term, subject to earlier termination by either of the parties (the “Term”) To help support the increased marketing and promotional efforts of the expanded collaboration, the Company has agreed to subsidize a portion of the marketing costs through royalty payments to Fresenius.

Initially, the Marketing Agreement provides for royalty payments equal to 0.9% of the Company’s net sales of CytoSorb products made during the Term (excluding net sales in the United States).

This initial royalty rate was determined based on certain assumptions regarding the percentage of the Company’s sale of CytoSorb products that are used with the Fresenius critical care platforms in the intensive care unit outside of the United States but is subject to adjustment if the Company determines that the underlying assumptions have changed significantly.

For the years ended December 31, 2023 and 2022, the Company did not record any expense related to this agreement as the launch of this program is expected to occur in 2024.

License Agreement

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Under the terms of the Settlement Agreement, we have agreed to pay Purolite royalties of 2.5% to 5% on the sale of those of our products, if and when those products are sold commercially, that are used in direct contact with blood or, in certain cases, in direct contact with a physiological fluid other than blood.

The royalty payments provided for under the Settlement Agreement would apply to

our currently envisioned CytoSorb, VetResQ, and BetaSorb products.

The royalty payments provided for under the Settlement Agreement would apply to our currently envisioned CytoSorb, VetResQ, and BetaSorb products.

For the year ended December 31, 2024 per the terms of the license agreement we have recorded royalty costs of approximately $809,000.

The 18-year term of this license agreement expired in August of 2024, and no further payments were made.

Product Payment & Reimbursement

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“ZE2023-09” as this code is being updated annually).

A dedicated coding as well as reimbursement for hemoadsorption was effective since January 1, 2017 (procedure code “8-821.2 adsorption of hydrophobic, small and middle-sized molecular substances”).

A dedicated coding as well as reimbursement for hemoadsorption was effective

since January 1, 2017 (procedure code “8-821.2 adsorption of hydrophobic, small and middle-sized molecular substances”).

According to the hospital’s budget negotiations, the reimbursement rate not only covers the cost of the device, but the procedural costs as well.

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Other Markets

CytoSorb is currently marketed and distributed in more than 75 countries around the world.

CytoSorb is currently marketed and distributed in more than 76 countries around the world including Russia, Turkey and Israel.

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

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

Effective in 2018, in all hospitals in Moscow and St Petersburg the CytoSorb therapy is being fully reimbursed (polymer-based system for cytokine adsorption/extracorporeal haemocorrection, pos.

In hospitals in Ekaterinburg the therapy costs are being covered by 50%.

Since commercialization of CytoSorb in Turkey it could be coded under the apheresis code “sepsis column” with a reimbursement rate of approximately 5,400 TL (≈ 800 €).

However, this code was only applicable to septic patients in the ICU, and three signatures were needed to obtain reimbursement (hematologist, anesthesiologist and infection control doctor).

In 2022, the Turkish Ministry of Health has approved national reimbursement for CytoSorb® in the public sector, which is now a reimbursed catalog product in the State Supply Office of Turkey (DMO) portal and can be purchased directly by hospitals and physicians without restrictions.

In August 2022, we disclosed that the Israeli Ministry of Health (MoH) had approved national reimbursement for CytoSorb in certain cardiac surgery indications, including the intraoperative treatment for urgent or emergency cardiac surgery in patients treated with ticagrelor or rivaroxaban, the intraoperative treatment during cardiac surgery in patients with acute infective endocarditis, and the intraoperative treatment during surgery for correction of aortic dissection.

United States

Critical care applications such as those targeted by our CytoSorb device involve a high mortality rate and extended hospitalization, coupled with extremely expensive ICU time.

In view of these high costs and high mortality rates, we believe acceptance of our proprietary technology by critical care practitioners and hospital administrators will primarily depend on safety and efficacy factors rather than solely based on cost.

CytoSorb is not yet approved in the U.S.

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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.

In addition, in June 2023, CMS has announced a new initiative called “Transitional Coverage for Emerging Technologies” (TCET) as a potential replacement for MCIT, that would provide coverage to FDA Breakthrough Devices for 3 to 5 years.

There has been significant industry feedback to CMS on the new program, which has not been finalized.

If passed, either of these programs 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 indications were granted FDA Breakthrough Designation in April 2020 and August 2021, respectively.

In June 2023, CMS announced a new initiative called “Transitional Coverage for Emerging Technologies” (TCET) as a potential replacement for MCIT, that would provide guaranteed coverage to FDA Breakthrough Devices for a certain period of time.

In August 2024, CMS published a final notice detailing the TCET pathway.

Eligibility requires a) FDA Breakthrough Device Designation, b) Determination that the device falls within a Medicare benefit category c) It is not also covered by a CMS National Coverage

Determination (NCD), and d) that no other law or regulation excludes participation.

Manufacturers can voluntarily submit a formal self-nomination to be evaluated for the TCET program within 12 months of anticipated FDA marketing authorization.

The FDA reviews applications on a quarterly basis with a strong focus on clinical evidence and will approve up to 5 devices a year for the program using existing NCD criteria.

CMS anticipates that approved devices will have coverage under a TCET NCD for approximately 5 or more years as evidence is generated to address identified evidence gaps that can lead to a predictable, long-term Medicare coverage determination.

CytoSorbents plans to pursue CMS TCET coverage given that it believes that DrugSorb-ATR, which was granted FDA Breakthrough Device Designation for the removal of ticagrelor (April 2020) and Direct Oral Anticoagulants (DOACs) apixaban and rivaroxaban (August 2021) during emergent or urgent cardiothoracic surgery, meets these criteria.

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.

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.

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

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 (ARDS), trauma, severe burn injury, pancreatitis, post-operative complications of cardiac surgery, damage to organs donated for transplant prior to organ harvest, renal disease, drug intoxication, and perioperative bleeding due to antithrombotic drugs.

In many of these illnesses, with the exception of antibiotics and in some cases steroids, current standard of care therapy in the ICU is predominantly supportive care.

Technologies such as mechanical ventilation, vasopressors and inotropes, and dialysis are often called “life support” and can keep critically ill patients alive, but do not actively reverse the underlying pathology, and in many cases can exacerbate illness.

This is a major reason why critical illness remains a major unmet medical need and is associated with high morbidity and mortality, often exceeding 30%.

There are four common forms of blood purification, including hemodialysis, hemofiltration, hemoperfusion, and therapeutic plasma exchange (TPE).

All modes are generally supported by standard hemodialysis machines.

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Dialysis and hemofiltration remove substances from blood by diffusion and ultrafiltration, respectively, through a semi-permeable membrane, allowing the passage of certain sized molecules across the membrane, but preventing the passage of other, larger molecules.

Therapeutic plasma exchange can use either apheresis machines to centrifugally remove plasma or fluid from whole blood, or specialized plasma separator hemofilters that do the same, but requires replacement of plasma and/or fluid.

Hemoperfusion utilizes solid or porous sorbents to remove substances based on pore capture and surface adsorption, not filtration.

CytoSorb is a hemoperfusion cartridge, using an adsorbent of specified pore size, which controls the size of the molecules which can pass into the adsorbent and vastly increases the area available for surface adsorption.

As blood flows over our polymer adsorbent, middle molecules such as cytokines flow into the polymer adsorbent and are adsorbed.

Of the four blood purification modalities, hemoperfusion is the easiest to implement.

CytoSorb is a hemoperfusion cartridge, using an adsorbent of specified pore size, which controls the size of the molecules which can diffuse into the adsorbent and vastly increases the area available for surface adsorption.

As whole blood flows over our polymer adsorbent, middle molecules such as cytokines diffuse into the polymer adsorbent and are adsorbed and removed from blood.

For example, we have demonstrated the ability of CytoSorb to reduce key cytokines in the blood of human patients in a wide variety of settings, including for example, septic shock, ARDS, and endotoxemia.

Our devices do not use semipermeable membranes or dialysate.

In addition, our devices do not remove fluids from the blood like hemodialysis or hemofiltration.

Accordingly, we believe that our technology has significant advantages as compared to traditional dialysis techniques, including ease of use.

Our HemoDefend platform is a development-stage technology utilizing a mixture of proprietary porous polymer beads that target the removal of contaminants that can cause transfusion reactions or cause disease in patients receiving transfused blood products.

The HemoDefend beads can be used in multiple configurations, including the common in-line filter between the blood bag and the patient as well as a unique, patent-pending “Beads in a Bag” treatment configuration, where the beads are placed directly into a blood storage bag.

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

These techniques are unable to effectively remove middle molecular weight toxins, which leading researchers have shown to cause and complicate sepsis.

The same experts believe that a blood purification technique that efficiently removes, or significantly reduces, the circulating concentrations of such toxins might represent a successful therapeutic option.

CytoSorb has demonstrated the ability to remove middle molecular weight toxins, such as cytokines, from circulating blood in a statistically significant manner.

Medical research during the past two decades has focused on drug interventions aimed at chemically blocking or suppressing the function of one or two inflammatory agents.

In hindsight, some researchers now believe this approach has little chance of significantly improving patient outcomes because of the complex pathways and multiple chemical factors at play.

Clinical studies of these drug therapies have been largely unsuccessful.

An Eli Lilly drug, Xigris®, cleared by the FDA in November 2001, is the first and only drug to be approved for the treatment of severe sepsis.

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 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.

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

Notable active Phase III trials in sepsis include the following:

Initiated in November 2012, the 800 patient Phase III randomized controlled SCARLET study began for Recomodulin (ART 123, Artisan/Asahi Kasei), a recombinant human thrombomodulin, for the treatment of septic patients with coagulopathy.

In 2019, the results of the study were published in JAMA, demonstrating no benefit in 28-day all-cause mortality.

The 800 patient Phase III SCARLET-2 randomized, controlled trial, evaluating Recomodulin in patients with sepsis and coagulopathy, was scheduled to begin in July 2019, but was withdrawn to be amended following the results of the SCARLET trial and now has been terminated.

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.

The investigational peptide, AB103 or Reltecimod, binds to the CD28 co-stimulatory receptor to attempt to restore the host’s appropriate immune response to severe infections and was evaluated in the ACCUTE Trial, a Phase III randomized controlled trial in 60 investigative sites in the U.S in 290 patients with necrotizing soft tissue infections.

The primary endpoint of the study was based on a modified Intent-to-treat (mITT) analysis of a primary composite endpoint that was defined as:

alive at day 28, ≤ 3 debridements, no amputation beyond first operation, and day 14 mSOFA ≤ 1 with ≥ 3 point reduction (organ dysfunction resolution).

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.

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.

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 of 450 patients in June 2016.

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

It is a potent stimulator of cytokine storm.

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

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).

A secondary analysis of the sub-population of patients with septic shock and high circulating endotoxin activity also failed to demonstrate a beneficial effect of Toraymyxin on 28-day mortality in sepsis, however, an exploratory post-hoc analysis of the suggested trends toward improvements in changes in mean arterial pressure and ventilator-free days.

In February 2019, Spectral announced an amendment of the original EUPHRATES trial to enroll an additional 150 septic shock patients under the TIGRIS expansion, in patients with a MODS score > 9 and an EAA level between 0.60 and 0.90, and will analyze the combined data from these two trials using a Bayesian statistical approach.

Based on the 179 patients from the EUPHRATES trial, treated patients had a mortality of 38% (N=90) compared to 48% mortality in the control (N=89), but not statistically significant.

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.

As of February 28, 2024, 93 patients of the targeted 150 patients have been enrolled, with an expansion of trial sites to a total of 25, with 21 currently active.

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.

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 blinded, randomized, controlled, Phase II multi-center trial in patients with moderate to severe sepsis related to pneumonia, biliary, urinary tract, or peritoneal infections.

As of February 21, 2024, it enrolled all 120 patients 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.

Topline data is expected by the end of March 2024.

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.

Mechanistically, Vitamin C is an antioxidant that scavenges free oxygen radicals, and plays a role in preserving endothelial function and microcirculatory flow.

Thiamine is a co-factor of pyruvate dehydrogenase that is a key step in the conversion of lactate to pyruvate to acetyl-CoA, then to the Krebs cycle, leading to a consumption of lactate.

Steroids are anti-inflammatory.

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

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.

Using a medical device to treat sepsis remains a relatively novel treatment approach.

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.

Toraymyxin does not directly reduce cytokines.

Spectral Medical Inc.

has obtained exclusive development and commercial rights in the U.S.

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.

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

Spectral is now pursuing an amendment to the EUPHRATES trial, called TIGRIS.

There have been now several large

scale studies failing to demonstrate a benefit of Toraymyxin on 28-day mortality in sepsis.

Toraymyxin represents a competitive, although potentially complementary, therapeutic approach to CytoSorb.

In September 2017, Baxter re-launched oXiris in the E.U., a hollow-fiber acrylonitrile and methalylsulfonate (AN69) membrane hemofilter coated with polyethyleneimine (PEI) that was originally launched by Gambro in 2008 for use in hemodialysis as a strategy to treat acute kidney injury and gram negative septic shock while reducing endotoxin.

The filter itself has not changed.

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.

As of February 2022, clinicaltrials.gov currently lists 6 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.

In October 2020, results from 4 hospitals on 37 patients from its OxirisNet Registry in the journal, Critical Care.

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

In addition, Baxter also launched the Theranova mid-molecular weight cutoff or high retention onset (HRO) hemodialysis membrane internationally, including in the U.S.

to improve the efficiency of hemodialysis, claiming improved mid-molecular weight substance removal.

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

for treatment of sepsis or respiratory failure.

Each of the following technologies claims to remove inflammatory mediators such as cytokines, or to treat sepsis, and represents a potential competitive alternative to CytoSorb.

However, to our knowledge, none of these technologies are approved in the U.S.

and none are approved in the European Union to reduce cytokines.

Toray markets its Hemofeel CH1.0 polymethylmethacrylate membrane (“PMMA”) in Japan and it has been used in several non-controlled, or historically controlled, clinical or case studies treating patients with sepsis, acute respiratory distress syndrome and pancreatitis.

We are not aware of any prospective, randomized controlled studies using this PMMA hemofilter in patients with sepsis.

Without such studies, it is difficult to assess the true impact of this technology in these conditions.

Gambro AB launched its Prismaflex eXeed system in August 2009 and introduced the SepteX high molecular weight cutoff hemodialyzer in Europe, intended to treat patients with acute renal failure and the removal of inflammatory mediators from blood.

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

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.

To our knowledge, there has been a lack of published data on the treatment of sepsis with these devices.

Bellco S.R.L, acquired by Medtronic in February 2016, also sells the CPFA (coupled plasma filtration and adsorption) system in Europe.

This uses a sorbent cartridge to remove cytokines from plasma.

However, because the sorbent cannot treat blood directly, it requires the cost and complexity of an additional plasma separator to treat blood.

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.

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.

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.

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

and no large scale pivotal randomized controlled trials are being conducted in sepsis.

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 6 investigator-initiated studies evaluating Jafron’s technology in sepsis, cardiac and respiratory failure and liver disease.

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 status of the trial has not been updated since February 2019 on clinicaltrials.gov.

Another investigator-initiated RCT evaluating the HA-330 device in 200 patients with norepinephrine-resistant septic shock (CLEANSE) began in Thailand in November 2021, with no update on clinicaltrials.gov since November 2021.

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.

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.

Heparin has the ability to bind some, but not all viruses, bacteria, toxins and cytokines.

In in vitro studies using 1 mL of human septic blood, there was no statistically different change in IL-6 or Interferon-gamma compared to control, but effected a ~50% reduction in TNF-alpha.

This inability to remove a broad range of cytokines will likely limit its efficacy as a treatment in sepsis.

It has repositioned Seraph™ as a pathogen removal technology, and has completed a 15 patient CE Mark registration trial in Germany evaluating the safety and efficacy of bacterial removal from blood.

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

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.

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, 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.

See “Markets:

Acute Respiratory Distress Syndrome” above for a more detailed discussion.

Severe Burn Injury

Modern management of severe burn injury patients involves a combination of therapies.

From a burn standpoint, patients undergo active escharotomy and debridement of burns, the use of skin grafts and substitutes, anti-microbial dressings and negative pressure dressings.

Tight fluid control, nutrition, prevention of hypothermia and infection are also priorities.

Smoke and chemical inhalation injury in burn victims is also common and increasing as a cause of death in severe burn injury.

Carbon monoxide and cyanide poisoning is also an issue.

Supplemental oxygen, mechanical ventilation, and ECMO are often required and are the mainstay of supportive care treatment.

Recently continuous renal replacement therapy has been used to treat patients with acute kidney injury with an improvement in survival compared to a historical control cohort.

We believe CytoSorb therapy may yield improved results.

We are not aware of any specific products approved to directly address inhalational lung injury or multiple organ failure in severe burn injury.

Trauma management initially involves respiratory, hemodynamic and physical stabilization of the patient.

However, in the days to weeks that ensue, the focus shifts to preventing or treating organ failure and preventing or treating infection.

We are not aware of any specific therapies to prevent or treat multiple organ dysfunction or multiple organ failure in trauma.

Rhabdomyolysis, or the breakdown of muscle fibers due to crush injury or other means, occurs in trauma and can lead to acute kidney injury or renal failure.

Aggressive hydration, urine alkalinization, and forced diuresis are the main therapies to prevent renal injury.

Continuous hemodiafiltration with super-high-flux membranes has demonstrated modest myoglobin clearance but was associated with albumin loss.

In general, however, most extracorporeal therapies are not well-suited to remove myoglobin.

CytoSorb reduces myoglobin, and other polymers under development, reduces myoglobin, some without significant losses of albumin.

Severe Acute Pancreatitis

Treatment of severe acute pancreatitis is predominantly supportive care focused on aggressive hydration, enteral nutrition and pain control.

Mechanical ventilation, hemodialysis and vasopressor use is common in cases of multiple organ failure.

In cases where cholelithiasis or other obstruction is the underlying cause of the pancreatitis, endoscopic retrograde cholangiopancreatography and/or stent placement can be used to relieve the obstruction.

Antibiotics are often instituted to prevent or treat infection.

Surgery is sometimes indicated to remove or drain necrotic or infected portions of the pancreas.

To our knowledge, there are no other specific treatments approved to treat severe acute pancreatitis or multiple organ failure that is caused by systemic inflammation in this disease.

Cardiopulmonary Bypass Surgery

Previously, leukocyte reduction filters sold by Pall Corporation, Terumo Medical Corporation and others were used in the cardiopulmonary bypass circuit to reduce cytokine-producing white blood cells from blood.

They did not remove cytokines, free hemoglobin, or activated complement directly and were not considered by many to be an effective solution for the reduction of these substances.

Other than blood compatible sorbent technologies, we are not aware of any practical competitive approaches for removing cytokines, free hemoglobin, activated complement, and a broad range of other inflammatory mediators in patients undergoing cardiopulmonary bypass during cardiac surgery.

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.

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.

Alternative therapies such as “off-pump” surgeries are available but “post-bypass” syndrome and cytokine production still remain a problem in this less invasive, but more technically challenging procedure.

CytoSorb has been used in both on-pump and off-pump procedures.

CytoSorb is also being used with a dialysis machine to treat the development of a post-cardiac surgery systemic inflammatory response syndrome, a deadly complication of open-heart surgery that if left untreated, can lead to multiple organ dysfunction syndrome, multiple organ failure, and potentially death.

Radiocontrast Removal

ContrastSorb has demonstrated the rapid, high efficiency single pass removal of IV contrast.

The use of low osmolar IV contrast, oral administration of N-acetylcysteine, and other agents to prevent CIN have demonstrated modest benefit in some clinical studies, but in many cases, the results across studies have been equivocal and inconsistent.

Hydration of high risk patients pre-procedure is standard of care but has limited efficacy.

PLC Medical Systems, Inc., now Renalguard Solutions, received CE Mark approval for its RenalGuard system in 2007.

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.

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.

Drug Intoxication

Treatment of patients suffering from drug overdose often involves a number of pharmacological treatments and mechanical interventions to detoxify and stabilize the patient.

Mechanical interventions include procedures such as gastric lavage, activated charcoal, whole bowel irrigation and extracorporeal blood purification.

Each method has its own limitations, many of which are associated with the timing of administration following overdose.

Blood purification with therapeutic plasma exchange, high flux dialyzers or with activated charcoal cartridges by Gambro, Fresenius, Nephros and others are typically efficient at removing hydrophilic drugs that are not protein bound.

However, they are inefficient at removing drugs that have a large volume of distribution, or drugs that are hydrophobic or lipophilic.

Many drugs of overdose fall into this category.

The administration of lipid emulsions, such as Intralipid, have been used with some success to create a depot for lipophilic drugs.

Resin based hemoperfusion devices have been used to remove lipophilic drugs that are protein bound, but have historically had issues of biocompatibility.

DrugSorb is a highly biocompatible resin-based hemoperfusion device that can remove a wide range of drugs of overdose in vitro very rapidly, with high single pass removal.

Chronic Dialysis

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, 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.

Kaneka markets Lixelle™, a cellulosic resin, outside the US to remove beta 2 -microglobulin in dialysis patients.

In March 2015, Lixelle received Humanitarian Device Exemption (“HDE”) approval in the U.S.

for the treatment of beta-amyloidosis and removal of beta 2 –microglobulin, a complication of chronic dialysis.

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 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 Antithrombotics 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.

clopidogrel, ticagrelor, prasugrel), and the Direct Oral AntiCoagulants (DOAC) comprising of direct thrombin inhibitors (dabigatran), and Factor Xa inhibitors (e.g.

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.

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.

It is also widely used during as part of the dual-anti platelet therapy regimen in patients undergoing percutaneous coronary intervention and stent placement.

In addition, our devices do not remove fluids from the blood like hemodialysis, hemofiltration, or TPE.

Finally, our technology can be easily connected to a wide range of extracorporeal blood pumps and support high blood flow rates over the course of 24 hours, whereas other blood purification technologies require much more complexity and can only support relatively low flow rates.

Accordingly, we believe that our technology has significant advantages as compared to other blood purification products, including ease of use.

We believe we are the leader in acute care blood purification for most of our various clinical applications, which is highlighted by the significantly greater number of peer-reviewed publications than any of our competitors.

Examples of E.U.

approved blood purification competitors that claim to reduce cytokines include Oxiris and SepteX (Baxter/Vantiv), PMMA (Toray), HA330 and HA380 (Jafron), TPE (multiple manufacturers), Efferon-CT and Efferon-LPS (Efferon), and EMIC-2 (Fresenius Medical Care).

DrugSorb-ATR:

To our knowledge, CytoSorb is the only therapy approved for the removal of ticagrelor and rivaroxaban (Xarelto®, Janssen, Bayer) in the E.U.

during cardiopulmonary bypass in urgent or emergent cardiopulmonary bypass.

during cardiac surgery in urgent or emergent cardiopulmonary bypass.

The only recommended alternative is to wait for 3 to 5 days to allow natural drug elimination and washout prior to surgery.

CytoSorb has already demonstrated the ability to remove ticagrelor rapidly and efficiently from human blood in vitro .

Meanwhile, a retrospective case series reported by clinicians at Asklepios Klinik St.

Georg in Hamburg, Germany on the investigational use of CytoSorb to reverse the effects of ticagrelor and the Factor Xa inhibitor, rivaroxaban, during emergency cardiac surgery demonstrated a greatly reduced risk of bleeding complications and the need for repeat surgery to explore the source of bleeding.

Extrapolations of the clinical benefits showed projected cost savings of £3,982, or approximately $5,000 USD, per patient in a U.K.

based economics study.

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.

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 (Safe and Timely Antithrombotic Removal of Ticagrelor, ) 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;

reversal for warfarin anticoagulation), Andexxa ® (recombinant Factor Xa;

reversal for rivaroxaban and apixaban), Praxbind ® (idarucizumab, Boeringer Ingelheim;

reversal agent for dabigatran) and other interventions have either not demonstrated consistent benefit, or are not used because of potential safety concerns, in the reversal of antithrombotics in the setting of cardiopulmonary bypass.

Due to business reasons, we have terminated the STAR-D (Safe and Timely Antithrombotic Removal of DOACs) trial but may revisit this study in the future.

PhaseBio, a now defunct clinical-stage biopharmaceutical company, had licensed an intravenously administered monoclonal antibody fragment with high affinity reversal agent for ticagrelor called bentracimab (PB2452) from Medimmune, a division of AstraZeneca.

PhaseBio paid AstraZeneca $100,000 upfront, with $68 million in potential future milestones.

AstraZeneca owned approximately 5% of PhaseBio’s stock.

The FDA granted Breakthrough Therapy designation for PB2452 in April 2019.

PhaseBio was 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.

In the U.S., there are no approved or cleared therapies to reverse the effects of ticagrelor or DOAC anticoagulants during cardiac surgery.

Besides DrugSorb-ATR, PhaseBio, a now defunct clinical-stage biopharmaceutical company, had licensed an intravenously administered monoclonal antibody fragment with high affinity for ticagrelor called bentracimab and conducted the U.S.

(n=8) or when used prophylactically in patients who require urgent surgery or an invasive procedure to prevent bleeding (n=142).

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

5 unchanged sentences

Of 150 patients, eight patients (5.3%) had thrombotic events, including two ischemic strokes, one transient ischemic attack, three 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.

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

However, in October 2022, PhaseBio filed for Chapter 11 bankruptcy.

The bentracimab asset was transferred to PhaseBio’s creditor, SFJ Pharmaceuticals in December 2022.

Serb Pharma acquired exclusive US rights for bentracimab from SFJ Pharmaceuticals in May 2023, and expected to file the BLA by end of 2023.

There have been no public updates on the status of this submission.

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, 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 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.

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.

Blood filters that utilize affinity technologies are in development to remove certain substances such as antibodies from blood, but have other issues, such as cost and concern about the stability or leachability of the affinity technology.

The HemoDefend platform represents a potentially superior alternative to these methods, as it can provide comprehensive removal of a wide variety of contaminants that can trigger transfusion reactions without washing blood, requires no additional equipment, energy source, or manipulation, and can be incorporated directly into the blood storage bag or used as an in-line blood filter.

In terms of HemoDefend - BGA, to our knowledge there are no commercially ready or available solutions to produce universal plasma in the U.S.

Clinical Studies

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

Critical Care

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.

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.

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.

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 (73%) compared with the international benchmark Extracorporeal Life Support Organization (ELSO) Registry.

The initial CTC results on the first 52 critically ill patients from five U.S.

ECMO centers 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 registry completed enrollment with 100 patients from five centers, and the final results mirror the high survival (74%) seen in the previous analysis, and have been published in the peer reviewed journal Critical Care.

The data further demonstrate that earlier intervention with CytoSorb and ECMO was associated with shorter need for mechanical ventilation, ECMO, and ICU stay.

Together, the goal of this dual-therapy strategy is to give the lungs a chance to recover and heal, a pre-requisite for weaning off of mechanical ventilation and ECMO.

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 related institutional research staff shortages, however we anticipate conditions to gradually improve that together with a recently completed protocol amendment should help recruitment going forward.

The Registry is actively enrolling in Spain, Germany and Italy with plans to expand in more countries in 2024.

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

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.

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 recruiting in the U.K., Germany, Austria, Belgium and Sweden and is planned to expand to additional countries in 2024.

Data outputs from the STAR Registry have already been reported at the EuroPCR 2023 conference in Paris in May 2023 and at the European Association of Cardiothoracic Surgery conference in Vienna in October 2023.

The Registry will continue to report analyses at international conferences in 2024 and submit the results for publication on a rolling basis as enrollment progresses.

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 with estimated first data readouts in 2023.

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

In November 2022, the first milestone was completed with the first one-third of patients enrolled, triggering the first Data Safety Monitoring Board (DSMB) meeting.

The DSMB recommended to continue the study as planned without any modifications.

In 2022, we also received FDA approval to expand the study to Canada and subsequently received Health Canada approval allowing inclusion of Canadian sites into the STAR-T trial in January 2023.

In early 2023, the study exceeded 50% enrollment

and reached the 2 nd milestone of 67% enrollment in the spring of 2023, triggering another DSMB safety review, which found no safety concerns and recommended completion of the trial.

Based on the initial analysis of the STAR-T data, the study did not meet the primary effectiveness endpoint in the overall patient population that underwent different types of cardiac surgeries.

Patients undergoing CABG surgery represented more than 90% of the overall study population.

Analysis of the efficacy results is ongoing with the intent of presenting them at an international cardiovascular conference in 2024.

We believe that the safety and efficacy results of the STAR-T study will support regulatory submissions for marketing approval by the FDA and Health Canada.

March 13, 2024, we were notified that the 140-patient, double-blinded, multicenter, pivotal STAR-T randomized, controlled trial was selected for a Breakout Presentation at the American Association of Thoracic Surgery (AATS) Annual Meeting being held April 27-30, 2024 in Toronto, Canada.

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

The study has been terminated early for business reasons.

COVID-19 Business Update

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 to treat dangerous inflammation and related life-threatening complications in more than 7,650 COVID-19 patients in more than 30 countries as of December 31, 2022.

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.

CytoSorb has been specifically recommended in the Italy Brescia Renal COVID Task Force Guidelines to treat patients with severe COVID-19 infection and Stage 3 renal failure on continuous renal replacement therapy.

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 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).

In January 2021, Health Canada granted Medical Device Authorization for the importation, sale, and emergency use of CytoSorb in hospitalized COVID-19 patients.

The use of CytoSorb has not been approved in the U.S.

However, under certain circumstances, investigational medical devices that have not yet been FDA-approved may be made available for emergency use in the U.S.

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 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.

for use in patients, 18 years of age or older, with confirmed COVID-19 infection who are admitted to the intensive care unit with confirmed or imminent respiratory failure.

It has neither been cleared nor approved for the indication to treat patients with COVID-19 infection.

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

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 .

The CTC Registry has completed enrollment at 100 patients and the final results confirming high survival (74%) were presented at the European Society of Intensive Care Medicine conference in October 2022.

As published in the peer reviewed journal, Critical Care, in June 2023, the data on these 100 patients further demonstrated that earlier intervention with CytoSorb and ECMO was associated with shorter need for mechanical ventilation, ECMO, and ICU stay.

Together, the goal of this dual-therapy strategy is to give the lungs a chance to recover and heal, a pre-requisite for weaning off of mechanical ventilation and ECMO.

The bentracimab asset was transferred to PhaseBio’s creditor, SFJ Pharmaceuticals in December 2022, who filed an FDA Biologics License Application (BLA) for bentracimab in mid-2024 based on a second interim analysis of the REVERSE-IT trial, presumably including more patients with major and life-threatening bleeding related to ticagrelor, and announced that it expected a target action date in Q1 2025.

The requested indications for use are not publicly available.

SERB Pharmaceuticals has acquired exclusive U.S.

commercial rights for the biologic.

We believe DrugSorb-ATR has significant advantages, particularly safety, cost, and ease of use, over bentracimab in cardiac surgery.

To our knowledge, there are no specifically approved therapies for cytokine removal other than ECOS-300CY for ex vivo organ perfusion.

Because VetResQ uses the equivalent polymer technology to CytoSorb, it benefits from the extensive human clinical experience in critical care, including diseases that also affect animals such as sepsis and infection, drug intoxication, pancreatitis, ARDS, and many other illnesses.

Aimalojic competes with VetResQ in the U.S.

animal health market primarily in the indication of drug overdose.

Government Research Grants

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Air Force, Air Force Material Command (“USAF/AFMC”) and others.

Currently, we have ongoing projects funded, in part, by the U.S.

Currently, we are continuing to develop HemoDefend-BGA for universal plasma based on funding, in part, by the U.S.

Army Medical Research Acquisition Activity (“USAMRAA”), the NHLBI, and the USAF/AFMC.

In January 2017, we were awarded a Phase II SBIR contract to continue development of CytoSorb for fungal mycotoxin blood purification.

This program focused on demonstrating the ability of CytoSorb to adsorb mycotoxins in vivo and improve survival in animals.

This contract, W911QY-17-C-0007, provided for maximum funding of $999,996 over two years.

This program was funded by the Joint Program Executive Office - Chemical and Biological Defense (“CBD”) SBIR program.

We received $999,996 in funding under this contract and no further funding remains 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.

This work is being funded by the USAMRAA under contract number W81WH-17-2-0013.

This contract provides for maximum funding of $719,000 over four years.

As of December 31, 2022, we received $719,000 and have no further funding remaining under this contract.

In September 2017, the Company was awarded a Phase II 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”.

The purpose of this contract is to continue development of two novel and distinct treatment options for life-threatening hyperkalemia.

This work is being funded by the USAMRAA under contract W81XWH-17-C-0142 and provides for maximum funding of $999,871.

As of December 31, 2022, we received $999,871 and no further funding remains under this contract.

In August 2018, the Company was awarded a Phase IIB Bridge SBIR contract by the NHLBI to facilitate and accelerate the commercialization of our HemoDefend blood purification technology for the purification of pRBC transfusions.

The contract, entitled “pRBCs Contaminant Removal with Hemocompatible Porous Polymer Beads” (award number 2R44HL141928-03), provides for maximum funding of approximately $2,971,000 over a three-year period.

As of December 31, 2023, we received approximately $2,570,000 in funding under this contract and no further funding will be received under this contract.

In September 2019, the Company was awarded a Rapid Innovation Fund contract by the USAF/AFMC to develop a simple, easy-to-use renal support system to treat severe hyperkalemia.

The contract, entitled “K+ontrol Renal Support System for Reduction of Hyperkalemia” (award number FA8650-19-C-6065), provides for maximum funding of approximately $2,960,000 over a two-year period.

As of December 31, 2023, we received approximately $2,851,000 in funding under this contract and no further funding will be received under this contract.

In June 2020, the Company was awarded a two-year Defense Health Agency Small Business Technology transfer (STTR) Phase III contract to advance its HemoDefend-BGA plasma and whole blood adsorber to human clinical trials.

(award number W81XWH20C0050 ), provides for maximum funding of approximately $2,897,000 over a two-year period.

As of December 31, 2023, we received approximately $2,897,000 funding under this contract and no further funding remaining under this contract.

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).

The HemoDefend-BGA blood purification technology platform is designed to reduce anti-A and anti-B antibodies in plasma and whole blood.

The goal is to either enable the production of freeze dried or frozen “universal plasma” that can administered to anyone, regardless of blood type, or enable fresh warm whole blood transfusions.

If this technology is successfully developed and approved, it could have a number of important benefits, including:

a) eliminating the need for blood-typed plasma, enabling its rapid use in trauma resuscitation and mass casualty events b) freeze-dried universal plasma would not require refrigeration, making it ideal for first responders, paramedics, medics, and stockpiling c) reducing the risk of transfusion reactions and improving patient outcome d) Enabling the use of low titer whole blood, ideal for trauma resuscitation;

and e) reducing the risk of hemolytic transfusion reactions from blood-derived products.

In July 2020, the Company was awarded a three-year contract by the Assistant Secretary of Defense for Health Affairs, endorsed by the 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, 2023, we received approximately $3,875,000 funding under this contract and have approximately $547,000 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).

This award provides for maximum funding of approximately $1,100,000 over a two-year period.

As of December 31, 2023, we received approximately $840,000 funding under this contract and have approximately $260,000 remaining under this contract.

As of December 31, 2024, we received approximately $4,422,000 funding under this contract and no further funding remaining under this contract.

On April 19, 2021, the Company received notification that it received a U.S.

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W81XWH21C0045.

As of December 31, 2023, we have received $1,291,000 funding under the contract and have approximately $209,000 remaining under the contract.

On May 9, 2022, the Company received a U.S.

Army Medical Research Acquisition Activity Award (the “USAMRAAA”) entitled “Demonstration of the Safety and Efficacy of Field-Ready Blood Group Antibody (BGA) Adsorber in the Porcine Universal Transfusion Model.” The Department of Defense (DoD) Defense Medical Research and Development Program (DMRDP) Joint Program Committee 6 (JPC-6) Combat Casualty Care Research Program (CCCRP) Battlefield Resuscitation for the Immediate Stabilization of Combat Casualties Award, for up to $1,977,024, was granted to the Company to validate the safety and efficacy of the BGA device in a preclinical study in pigs.

As of December 31, 2024, we received $1,499,987 funding under the contract and no further funding remaining under the contract.

On May 9, 2022, the Company received a USAMRAA Award (“USAMRAAA”) entitled “Demonstration of the Safety and Efficacy of Field-Ready Blood Group Antibody (BGA) Adsorber in the Porcine Universal Transfusion Model.” The Department of Defense (DoD) Defense Medical Research and Development Program (DMRDP) Joint Program Committee 6 (JPC-6) Combat Casualty

Care Research Program (CCCRP) Battlefield Resuscitation for the Immediate Stabilization of Combat Casualties Award, for up to $1,977,024, was granted to the Company to validate the safety and efficacy of the BGA device in a preclinical study in pigs.

This award is being funded by the USAMRAAA under Contract No.

W81XWH-22-1-0235.

As of December 31, 2023, we have received $499,000 funding under the contract and have approximately $1,478,000 remaining under the contract.

On August 22, 2022, the Company received a U.S.

Army Medical Research Acquisition Activity Award (the “USAMRAAA”) entitled “Integrating Isoagglutinin Reduction for a Universal Dried Plasma Product for Battlefield and First Responder Use.” This three-year Phase III contract, which is valued at $4,292,641, is to be used to customize the design of the HemoDefend-BGA™ filter for sterile integration into collections systems for freeze-dried plasma processing to generate freeze-dried universal plasma.

As of December 31, 2024, we received $1,174,000 funding under the contract and have approximately $803,000 remaining under the contract, which is expected to be completed in 2025.

On August 22, 2022, the Company received a USAMRAAA entitled “Integrating Isoagglutinin Reduction for a Universal Dried Plasma Product for Battlefield and First Responder Use.” This three-year Phase III contract, which is valued at $4,292,641, is to be used to customize the design of the HemoDefend-BGA™ filter for sterile integration into collections systems for freeze-dried plasma processing to generate freeze-dried universal plasma.

Without the need for blood typing, widespread availability of universal plasma could help save lives via faster emergency treatment in both civilian and military settings.

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W81XWH-22-C0046.

As of December 31, 2023, we have received $ 740,000 funding under the contract and have approximately $3,552,000 remaining under the contract.

On August 29.

2022, the Company was granted a Phase I Small Business Innovation Research (SBIR) award entitled “Novel Extracorporeal Therapy for the Reversal of Septic Shock and Restoring Hemodynamic Stability” by the National Institute of General Medical Sciences (NIGMS), a division of the U.S.

National Institutes of Health.

This eight-month award, which is valued at $288,335, will allow CytoSorbents to test the ability of its novel and existing polymers to remove cytokines and lipopolysaccharide (LPS) endotoxin, a well-known potent and deadly trigger of sepsis and septic shock, from septic porcine plasma.

As of December 31, 2023, we have received $288,335 in funding under the contract and no further funding remaining under the contract.

On December 1, 2022, the Company was granted a Phase I Small Business Innovation Research (SBIR) award by AFWERX, a United States Air Force program with the goal of fostering a culture of innovation within the service.

This three-month award, which is valued at $74,955, will allow CytoSorbents to perform customer discovery within the Department of the Air Force (DAF) and to better understand DAF end-user needs and help define product requirements for our solution to prevent and treat certain infectious diseases that threaten warfighters.

As of December 31, 2023, we have received $74,955 of funding under the contract and no further funding remains under the contract.

On June 1, 2023, the Company was granted a Phase I Small Business Innovation Research (SBIR) award by AFWERX Joint Injury, a United States Air Force program with the goal of fostering a culture of innovation within the service.

This three-month award, which is valued at $74,918, will allow CytoSorbents to perform customer discovery within the Department of the Air Force (DAF) and to better understand DAF end-user needs and help define product requirements for our solution to prevent and treat certain infectious diseases that threaten warfighters related to Joint Injuries.

As of December 31, 2023, we have received $74,918 of funding under the contract and no further funding remains 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.

Sequestration may delay payments under the SBIR grant agreements, although no material delays have occurred to date.

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 of grant revenue.

As of December 31, 2024, we have received $2,922,000 funding under the contract and have approximately $1,371,000 remaining under the contract, which is expected to be completed in 2025.

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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Devices are generally subject to varying levels of regulatory control, the most comprehensive of which require that a clinical evaluation be conducted before a device receives approval for commercial distribution.

European Union Regulatory Process

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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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.

In February 2015, we extended the coverage of our ISO 13485 Certificate with the inclusion of Canadian Quality Systems requirements, however, Canada has replaced this earlier program with the Medical Device Single Audit Program (“MDSAP”) and the Company is now evaluating the requirements for this certification.

In June of 2024 we completed our MDSAP audit and received approval in November of 2024 extending the coverage of our ISO 13485 Certificate with the inclusion of Canadian Quality Systems requirements under MDSAP.

Since 2011, CytoSorbents has maintained a valid ISO13485 certificate.

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In April 2022, we successfully completed an annual ISO 13485:2016 surveillance audit that encompassed both the Deer Park manufacturing site and the new manufacturing facility at 305 College Road East, Princeton, NJ.

In September 2022, we received ISO 13485 Certification of this new facility, clearing the way for full manufacturing of CytoSorb, DrugSorb-ATR, and ECOS-300C from this site.

In September 2022, we received ISO 13485 Certification of this new facility, clearing the way for full manufacturing of CytoSorb, DrugSorb-ATR, and ECOS-300CY from this site.

This certification is currently maintained.

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, claims that are made are required to be in applicable CE Certificate and based on 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 in applicable CE Certificate and based on 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 recalls.

We are currently tracking a proposal for healthcare reform of Germany’s hospital system.

In July 2023, Germany’s federal and state governments issued a consensus white paper that could result in new laws that change how hospitals are funded.

Government payments to hospitals would de-emphasize the DRG (diagnosis-related group) “lump sum” payment system that incentivizes revenue generation through more patients treated and procedures performed, and instead emphasize base payments focused on quality measures and appropriate patient care.

This is expected to favor a shift of routine operations and procedures to outpatient centers, consolidation of smaller hospitals into larger ones, and importantly, an increased focus of remaining hospitals on sicker patients, more complex operations such as cardiothoracic surgery and organ transplant, and on therapies that help reduce the severity of illness and help patients recover faster.

Given that the goal of our therapies is to improve clinical outcomes while reducing the costs of critical care and cardiac surgery by controlling deadly inflammation and other life-threatening conditions, while reducing the need for expensive life support measures that keep patients in the hospital, we believe such reform may favor our business in the longer-term.

Hospital administrators expect such change will take careful planning and time, potentially years, to implement.

However, given there is no formal law enacted to our knowledge, the overall impact to our business cannot yet be determined.

In the U.S., specific permission from FDA to distribute a new device is usually required (that is, other than in the case of very low risk devices), and we expect that some form of marketing authorization will be necessary for our devices.

Marketing authorization is generally sought and obtained in one of three ways.

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.

The legally marketed device to which equivalence is drawn is known as the “predicate” device.

Applicants must submit descriptive data and, when necessary, performance data to establish that the device is substantially equivalent to a predicate device.

In some instances, data from human clinical studies must also be submitted in support of a 510(k) Submission.

If so, these data must be collected in a manner that conforms with specific requirements in accordance with federal regulations including the Investigational Device Exemption (IDE) and human subject protections or “Good Clinical Practice” regulations.

After the 510(k) application is submitted, the applicant cannot market the device unless FDA issues “510(k) clearance” deeming the device substantially equivalent.

The FDA’s 510(k) review process usually takes from three to six months but may take longer.

The FDA may require additional information, including clinical data, to make a determination regarding substantial equivalence.

After an applicant has obtained clearance, 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:

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.

Should a suitable predicate device not be available, the second pathway is the 510(k) De Novo request.

The de novo pathway is available for medium risk novel device technologies, including novel device changes, that have not been previously classified by FDA and for which there is no suitable predicate device.

To obtain marketing authorization via the de novo pathway, the applicant must show that the subject device can be reclassified as Class I or Class II.

The de novo request pathway typically requires additional testing data, which includes clinical data.

The third, more rigorous, process requires that an application for PMA be made to the FDA to demonstrate that the device is safe and effective for its intended use as manufactured.

This approval process applies to most Class III devices.

A PMA submission is the most rigorous FDA premarket submission type for devices and includes data regarding design, materials, bench and animal testing, and human clinical data for the medical device.

Again, clinical trials are subject to extensive FDA regulation.

Following completion of clinical trials, an applicant will submit a PMA with the required data.

Within 45 days after a PMA is received by the FDA, the agency will notify the applicant whether the application has been “filed” (a threshold determination that the application is sufficiently complete to begin an in-depth review), then a substantive review period begins on the date of filing.

Although the stated regulatory timeframe for the FDA’s review of PMAs is 180 days, FDA does not meet this goal for all applications;

review often takes at least one year and may take significantly longer.

During this review period, the FDA may request additional information or clarification of information already provided.

Also, during the review period, an advisory panel of experts from outside the FDA may be convened to review and evaluate the application and provide recommendations to the FDA.

In addition, the FDA will conduct a pre-approval inspection of the manufacturing facilities to evaluate compliance with the FDA’s Quality System Regulation (“QSR”), which requires manufacturers to implement and follow design, testing, control, documentation and other quality assurance and good manufacturing practice procedures.

Following approval of a PMA, the FDA will authorize commercial distribution if it determines there is reasonable assurance that the medical device is safe and effective for its intended purpose.

This determination is based on the benefit outweighing the risk for the population intended to be treated with the device.

Alternatively, the agency may issue an “approvable letter” or “not approvable letter” identifying deficiencies of varying degrees or issue an order denying approval.

The PMA process is much more detailed, time-consuming, and expensive than the 510(k) process.

Also, FDA may impose a variety of conditions on the approval of a PMA.

Regardless of the path to FDA clearance or approval, both before and after a device for the U.S.

FDA Medical Device Regulatory Process:

The FDA approval process for medical devices ensures that products entering the market meet safety and efficacy standards.

Medical devices are classified into three categories—Class I, II, and III—based on risk.

Class I devices pose the lowest risk and are often exempt from premarket review, while Class II and III devices require more rigorous regulatory oversight.

There are three primary pathways for FDA approval:

the 510(k) clearance, De Novo classification, and Premarket Approval (PMA).

The 510(k) clearance pathway is the most common and applies primarily to Class II devices.

It requires manufacturers to demonstrate that their device is “substantially equivalent” to a legally marketed predicate device.

This means that the new device must have the same intended use and similar technological characteristics as the predicate.

If the FDA determines substantial equivalence, the device can be marketed without undergoing extensive clinical testing.

However, if no suitable predicate exists, the manufacturer must pursue an alternative pathway.

The De Novo classification pathway is intended for novel, low-to-moderate-risk devices that do not have a predicate but are not high-risk enough to require PMA.

This process allows the FDA to classify new devices into Class I or II based on a risk assessment.

Unlike the 510(k) pathway, De Novo requires more robust evidence of safety and effectiveness, but it does not demand the extensive clinical trial data needed for PMA.

The Premarket Approval (PMA) process is the most stringent pathway and typically reserved for high-risk Class III devices.

It requires comprehensive scientific and clinical data to demonstrate reasonable assurance of safety and effectiveness.

This pathway is typically reserved for life-sustaining or life-supporting devices, as well as those that pose significant risks.

The PMA process includes rigorous clinical trials, manufacturing inspections, and post-market surveillance requirements.

Because of the extensive data and regulatory scrutiny, the PMA process is the most time-consuming and expensive of the three pathways.

Each of these regulatory pathways is designed to balance patient safety with innovation, ensuring that medical devices entering the market are both effective and appropriately regulated based on their level of risk.

We seek FDA clearance of DrugSorb-ATR to reduce the severity of perioperative bleeding in patients on the blood thinning drug ticagrelor that require CABG surgery under the De Novo classification, which we believe is supported by the favorable benefit to risk profile established by the pivotal STAR-T trial data and STAR Registry data for this application.

On September 27, 2024, the Company submitted a De Novo medical device application to the FDA requesting marketing approval of DrugSorb-ATR to reduce the severity of perioperative bleeding in patients on ticagrelor undergoing CABG surgery, which was accepted for substantive review in October 2024.

Because DrugSorb-ATR has already received FDA Breakthrough Device Designation for this application, it is eligible for priority review.

We are currently in the interactive review process with FDA and expect a regulatory decision in 2025.

With 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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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 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 authorization limited in scope and subject to FDA discretion regarding EUA duration.

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.

The placement of our devices in the U.S.

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Failure to comply with regulatory requirements could have a material adverse effect on our business, financial condition, and results of operations.

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.

Health Canada Regulatory Process:

In Canada, DrugSorb-ATR is classified as a Class III medical device (range Class I to IV).

These devices require regulatory approval from Health Canada through the Medical Devices Bureau (MDB) within the Therapeutic Products Directorate.

Manufacturers must submit a Medical Device License Application (MDLA) which includes detailed information on a device’s safety, effectiveness, quality and risk mitigation measures.

The application must comply with MDR and include a summary of clinical evidence, risk assessments, biocompatibility testing, and performance data.

Health Canada conducts a scientific and regulatory review to ensure the device meets the Canadian Medical Device Conformity Assessment System (CMDCAS) requirements.

In addition, Medical Device Single Audit Program (MDSAP) certification, that certifies medical device manufacturer compliance of its quality management system with the standard and regulatory requirements of Canada, the U.S., Brazil, Japan, and Australia, is a pre-requisite for filing an MDLA.

If approved, the manufacturer receives a Medical Device License (MDL), allowing commercial distribution in Canada.

Post-market surveillance, including mandatory incident reporting and compliance with MDSAP ensures continued safety and effectiveness.

CytoSorbents received MDSAP certification and then submitted its MDLA for DrugSorb-ATR to Health Canada on November 1, 2024.

We are currently in the review process with Health Canada and expect a regulatory decision in 2025.

Other Regulatory Matters:

FDA Emergency Use Authorization:

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 authorization limited in scope and subject to FDA discretion regarding EUA duration.

Devices with EUA are neither formally cleared nor approved for the indication to treat patients with COVID-19 infection.

The FDA can at its discretion cancel the EUA approval when there is no longer a threat to public health.

Hospital Reform in Germany:

In July 2023, Germany’s federal and state governments issued a consensus white paper that proposed hospital reform and a change in how hospitals are funded.

In October 2024, the German Parliament fully passed the Hospital Care Improvement Act mandating hospital reform beginning in January 2025 through 2029.

As part of the reform, government payments to hospitals would de-emphasize the DRG (diagnosis-related group) “lump sum” payment system that incentivizes revenue generation through more patients treated and procedures performed, and instead emphasize base payments focused on quality measures and appropriate patient care.

Hospitals must meet strict quality standards to receive money for operations.

In addition, a 50 billion euro Hospital Transformation Fund is being established to make investments in modern infrastructure over 10 years to improve efficiency and reduce costs.

Hospital administrators expect such change will take careful planning and time, potentially years, to implement.

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 some post-marketing reporting.

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It is the responsibility of the manufacturer and/or distributor of these articles to assure that these animal devices are safe, effective, and properly labeled.

Other Country Requirements:

Exported devices are subject to the regulatory requirements of each country to which the device is exported.

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In 2012, we established our European subsidiary, CytoSorbents Europe GmbH, a wholly-owned subsidiary of CytoSorbents Corporation.

Following the completion of a controlled market release in late June 2012, CytoSorb was formally launched in Germany with reimbursement established at more than $500 per cartridge.

We recruited Dr.

Christian Steiner, MD as our Vice President of Sales and Marketing and hired three additional sales representatives.

The fourth quarter of 2012 was the first full quarter of direct CytoSorb sales with our sales force in place.

We began expansion into Austria, where reimbursement for CytoSorb is now available, and Switzerland.

Following the completion of a controlled market release in late June 2012, CytoSorb was formally launched in Germany with the fourth quarter of 2012 being the first full quarter of direct CytoSorb sales with our sales force in place.

We began expansion into 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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In May 2023, the Company formed CytoSorbents India Private Limited to provide marketing and direct sales services in India.

In January 2025, we announced the opening of our new Regional Sales Subsidiary in Dubai, United Arab Emirates (UAE), providing a gateway into the Middle East and Africa.

From the beginning of the controlled market release in the fourth quarter of 2011 through December 31, 2024, we achieved cumulative sales of CytoSorb of approximately $248.2 million.

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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.

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, reimbursement and/or geopolitical developments.

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

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These partners include Fresenius Medical Care AG, B.

Braun Avitum AG, Eris LifeSciences, Aferetica s.r.l.

and Terumo Cardiovascular Group.

Braun Avitum AG, Aferetica s.r.l., and Terumo Cardiovascular Group.

In August 2022, we expanded our partnership with Fresenius Medical Care to a global marketing collaboration.

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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 government agencies in the United States.

During the years ended 2023, 2022 and 2021, no agency, distributor or direct customer represented more than 10 percent of the Company’s total revenue.

Substantially all of our grant receipts are from government agencies in the United States.

During the years ended December 31, 2024 and 2023, one distributor accounted for 11% and 10%, respectively, of the Company’s total revenue.

Orders received for product from both direct customers and distributors are fulfilled upon receipt.

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We rely on a combination of patents, trademarks, trade secrets and non-disclosure agreements to protect our intellectual property.

As of March 9, 2024, our patent portfolio includes19 issued United States patents as well as multiple issued foreign patents and pending patent applications both in the U.S.

As of the issuance date of this Annual Report on Form 10-K, our patent portfolio includes 22 issued United States patents as well as multiple issued foreign patents and pending patent applications both in the U.S.

and internationally, directed to various compositions and methods of use related to our blood purification technologies, which are expected to expire between 2026 and 2044 absent any patent term extensions.

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Method of Removing Toxins From Blood

Connector Assembly and Methods of Use

Method of Treating Traumatic Brain Injury

Absorbents for Removal of Antibodies from Human Plasma and Whole 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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We believe that there are no compliance issues associated with applicable environmental laws and regulations that would have a material adverse effect on us or our business.

We incur waste removal costs in connection with both our solid and liquid wastes which are byproducts of our manufacturing process.

We incur waste removal costs in connection with both our solid and liquid wastes which

are byproducts of our manufacturing process.

We utilize the services of various qualified contractors to dispose of these waste products.

These waste removal costs amounted to approximately $322,000 for the year ended December 31, 2024.

As of March 7, 2024, we had 186 full-time and part-time employees.

As of the issuance date of this Annual Report on Form 10-K, we had 149 employees.

We also utilize consultants and temporary service providers who are not our employees, as necessary.

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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