Broad Cytokine and Toxin Reduction
to Control Deadly Inflammation
CytoSorb® is the only specifically approved extracorporeal cytokine adsorber in the European Union, designed to reduce the “fuel to the fire” of deadly inflammation often seen in critically-ill patients in the intensive care unit (ICU) and those undergoing complex open heart surgery. Examples of this “fuel” include: excessive cytokines, bacterial toxins, activated complement, plasma free hemoglobin, bilirubin, and a host of other inflammatory mediators.
In doing so, CytoSorb® targets the prevention or treatment of one of the most dreaded consequences of an uncontrolled, systemic inflammatory response: the failure of vital organs such as the brain, heart, kidneys and lungs. Multiple organ failure has no effective therapy other than supportive care today, accounting for nearly half of all deaths in the ICU, and remains one of modern medicine’s greatest and most costly unmet medical needs.
When Inflammation Becomes Toxic
Localized inflammation is a normal response to injury or infection, and helps to bring blood cells, oxygen and nutrients to the affected area to assist in the healing process. However, the body’s immune system frequently overreacts in response to life-threatening conditions such as sepsis and infection, trauma, burn injury, severe lung injury, liver failure, pancreatitis, influenza, cytokine release syndrome, and many others. This overreaction can lead to the production of a massive excess of inflammatory mediators, particularly cytokines, which is often called a “cytokine storm”. Cytokines are a class of more than one hundred different small proteins that normally help to stimulate and regulate the immune response to help the body cope with injury and infection and include the family of interleukins, interferons, tumor necrosis factor, and many others.
Cytokine storm is toxic to the body, driving severe generalized inflammation (often called SIRS, or a systemic inflammatory response syndrome) and a cascade of pathophysiologic changes in the body that cause cell death, organ failure and often death of the patient. Reduction of cytokine storm has the potential to limit this cascade of events, thereby helping to mitigate organ injury, while reducing the severity of illness, and helping patients to recover and survive. Until recently, however, there were no effective ways to reduce cytokine storm broadly.
CytoSorb® – Removing the Fuel to the Fire of Inflammation
CytoSorb® is a best-in-class extracorporeal cytokine adsorber, approved in the European Union and broadly indicated for use in any clinical situation where cytokines are elevated. CytoSorb® not only targets the reduction of circulating cytokines, but can remove bacterial toxins, free hemoglobin, bilirubin, myoglobin, activated complement, and a host of other inflammatory mediators in whole blood that can drive an uncontrolled, deadly systemic inflammatory response syndrome (SIRS) that is often seen during critical illnesses treated in the ICU. Because of this, CytoSorb® represents a potentially major advance in the control of deadly inflammation in critically-ill patients and those undergoing complex cardiac surgery.
CytoSorb® is compatible with standard hemodialysis machines, continuous renal replacement therapy (CRRT) machines, heart-lung machines, most extracorporeal membrane oxygenation (ECMO) machines, and other blood pumps found in most hospitals. Using a standard hemodialysis machine, blood is pumped out of the body, through the CytoSorb® cartridge that contains the company’s proprietary blood compatible porous polymer beads, and the “purified” blood is recirculated back to the patient over and over again. In a twenty-four hour period, a patient’s entire blood volume can be treated more than 70 times.
CytoSorb® is clinically proven to reduce cytokines from the blood of critically-ill patients and has been generally safe and well-tolerated in more than 14,000 human treatments overall. Most of the treatments have been in critically-ill patients, but approximately 3,000 have been performed during open heart surgery.
Helping Physicians “Regain Control” of their Unstable Patients
Early studies suggest that CytoSorb® is associated with reduced organ injury and improved survival in septic shock patients with multiple organ failure at high risk of cytokine injury, particularly those patients with very high cytokine levels, and patients older than age 65. Newer data from case reports and case series repeatedly suggest the ability of CytoSorb® to help stabilize hemodynamics, even in many patients on maximal vasopressor support, enabling the weaning of vasopressors over time. Others have observed an improvement in respiratory, kidney, and cognitive function in patients with a variety of conditions. This ability to “regain control” of their patients with sepsis or SIRS is one of the main reasons CytoSorb® usage by physicians has continued to expand throughout the world.
Use CytoSorb® Aggressively and Early
Human clinical usage strongly suggests that earlier and aggressive intervention during the onset of organ dysfunction and failure leads to more reproducible and successful outcomes. Today, most patients are being treated continuously with CytoSorb® for up to 24 hours per day with each cartridge, with most receiving multiple days (and multiple cartridges) of treatment.
The goal of early treatment is to take the harmful edge off of the runaway immune response, and prevent patients from spiraling into multiple organ failure, where they need to be kept alive with machines and where the risk of hospital acquired infections, complications, and death are very high. In doing so, CytoSorb® has the potential to reduce the severity of illness, reduce the risk of death, get patients out of the ICU faster, and decrease the massive costs of ICU care.In those patients that are treated late with protracted organ failure, such as patients transferred from outside hospitals, more aggressive treatment appears to be helpful.
For example, recent data from a German, prospective single arm trial in 22 critically-ill refractory shock patients with late stage multiple organ failure demonstrated that continuous CytoSorb® treatment with a new cartridge every 12 hours led to a resolution of shock in 68% of patients. By definition, refractory shock is severe hypotension and inadequate organ perfusion despite the use of fluids, vasopressors and other standard of care therapies.
CytoSorb® is typically stopped when there is significant clinical improvement in the patient, such as improvement in hemodynamic stability and the weaning of vasopressors, a return of kidney function, or improved lung function.
CytoSorb® Sits At the Treatment Nexus of Critical Care
CytoSorb® has now been used successfully in many conditions where deadly inflammation can lead to organ injury and failure. Some of major clinical applications include:
There are now hundreds of key opinion leaders supporting CytoSorb® in 40 countries where CytoSorb is distributed. More than 55 investigator-initiated studies are in various stages of planning and execution in a diverse set of applications, with approximately a third of these already enrolling patients, with many already completed. In the United States, the U.S. Air Force is funding a 30-patient, FDA-approved randomized controlled human pilot study in trauma and rhabdomyolysis.
As these other independent studies progress, CytoSorbents collaborates with many leading researchers in critical care, including Dr. John Kellum, Professor of Critical Care Medicine and Vice Chair of Critical Care Research at the University of Pittsburgh Medical Center, and is sponsoring clinical studies in the area of severe sepsis and septic shock, and other critical illnesses. Sepsis is the result of an overzealous immune response to a severe infection such as pneumonia, a kidney infection, or a ruptured appendix. Severe sepsis and septic shock are collectively a top ten cause of death worldwide, afflicting approximately 30 million people annually, and killing approximately 1 in 3 patients despite the best antibiotics and medical care. CytoSorbents is conducting clinical trials in Europe and currently has an FDA-approved IDE application to run a small sepsis trial in the U.S.
Open Heart Surgery, CytoSorb®, and REFRESH Trial: The Next Frontier
Because of the versatility of CytoSorb®, there are many other potential applications of the technology outside of critical care medicine as well. In particular, CytoSorb® has been used without incident approximately 3,000 times intra-operatively during open heart surgery, where the heart must be stopped in order to operate on it, and blood is instead pumped outside of the body by a heart-lung machine that oxygenates the blood and pumps it back to the rest of the body. The procedure causes the production of inflammatory mediators such as cytokines and activated complement, as well as hemolysis of red blood cells and the release of plasma free hemoglobin into the blood. This can result in inflammation and post-operative complications such as respiratory failure, kidney failure, circulatory collapse, and intestinal ischemia. Plasma free hemoglobin, in particular, not only creates inflammation and tissue injury through oxygen radical formation, but as a very potent scavenger of nitric oxide – the body’s main vasodilator – also creates high systemic and organ vascular resistance, resulting in high blood pressure and decreased blood flow to vital organs like the lungs, kidneys, intestines, and brain. This can lead to organ injury, organ failure, and excessive work on the heart, which is vulnerable after cardiac surgery. There are more than 1.5 million open heart surgeries worldwide each year, with a total addressable market of more than $1.5 billion for CytoSorb®.
CytoSorbents is has completed enrollment in the U.S. based REFRESH (Reduction in FREe Hemoglobin) I trial – a 40-patient, 8 center randomized controlled safety and feasibility study evaluating CytoSorb® use intra-operatively during elective, complex cardiac surgery that is expected to last longer than 3 hours. The study met the primary safety endpoint, with no serious device related adverse events. Free hemoglobin data are planned to be announced at an upcoming U.S. cardiothoracic surgery conference. A protocol for a pivotal, registration REFRESH II Trial will be submitted to the FDA, to start in early 2017.
CytoSorb® in Cardiopulmonary Bypass (CPB) during Cardiac Surgery
- Effective removal of excess cytokines and free hemoglobin
- Installs into CPB circuit easily and within minutes
- Drop-in replacement for leukoreduction filters
- Utilizes blood flow generated by the CPB circuit; No need for perfusionist to worry about another machine to run
- Blood in, blood out; No dialysate, ultra-filtrate to be concerned about
- High flow, low resistance and can accommodate high blood flow rates at least to 700 mL/min without hemolysis
- 7+ football fields of surface area vs. 1-3 m2 in membrane-based filters
- Compatible with systemic heparin anti-coagulation used during CPB
CytoSorb® + ECMO = Therapeutic ECMO: A Novel Lung Preservation Strategy
Extracorporeal membrane oxygenation (ECMO) therapy has been used in ICUs around the world for several decades as a rescue therapy for patients with such severe lung injury that even standard mechanical ventilation fails. Like a heart-lung machine, ECMO takes blood out of the body, oxygenates it, and recirculates it back into the body. Given the many complications of standard mechanical ventilation, such as ventilator acquired pneumonia, oxygen toxicity, barotrauma, aspiration, and pneumothorax, there is rapidly growing interest in ECMO as a potential first-line alternative to provide gas exchange for critically-ill patients. To be clear, ECMO is not intended to be used in emergency situations where the main goal is stabilization and securing the airway (where intubation and mechanical ventilation are much faster to implement), but to be used shortly thereafter. There are more than 1.5 million open heart surgeries worldwide each year, with a total addressable market of more than $1.5 billion for CytoSorb®.
Theoretically, ECMO offers a lung preservation strategy, or a way to “rest the lungs” and to prevent exacerbation of lung injury caused by infection, barotrauma, aspiration, and oxygen toxicity during standard mechanical ventilation. However, ECMO is predominantly a supportive care treatment, which keeps a patient alive, but does not help reverse the underlying cause of the respiratory failure. This is where a combination of CytoSorb® + ECMO makes sense, particularly in cases where a reduction in cytokine storm, circulating toxins and other inflammatory mediators by CytoSorb® may lead to a reversal of the underlying cause of respiratory failure and mitigate ongoing lung injury. To date, there have been many successful uses of CytoSorb® and ECMO when standard mechanical ventilation fails.
CytoSorb® in Extracorporeal Membrane Oxygenation (ECMO)
- Similarly to CPB, CytoSorb® can be integrated into ECMO in a bypass circuit
- The use of CytoSorb® would be intended to reduce circulating levels of cytokines, free hemoglobin, and other inflammatory mediators generated by the underlying inflammatory condition (e.g. sepsis, ARDS) or by the ECMO circuit
- CytoSorb® + ECMO could potentially become a useful as a therapeutic intervention for lung injury in the ICU, though not intended to be used in emergency situations where the main goal is stabilization. “Therapeutic ECMO” represents a novel lung preservation strategy intended to prevent exacerbation of lung injury caused by complications of standard mechanical ventilation including barotrauma, oxygen toxicity, infection and aspiration
- CytoSorb® has already shown success in applications to improve lung function and reduce pulmonary edema
Cancer Immunotherapy and Other Future Applications
Immunotherapy, or modulating the immune response to treat disease, is one of the most prolific and fruitful areas in all of medicine. Many of the largest blockbuster drugs and biologics areas such as Enbrel®, Remicade®, Humira®, Yervoy®, corticosteroids, vaccines, and many others fall into this category that collectively garners more than $100 billion in sales each year. CytoSorb® is a leader in critical care immunotherapy – helping to control dangerous levels of inflammation in life-threatening illnesses.
One of the potential future applications of CytoSorb® is to help control the deadly cytokine release syndrome (CRS) that occurs in many patients undergoing certain types of cancer immunotherapy. One such example is CAR T-Cell immunotherapy, one of the most promising new immunotherapy strategies to treat leukemias and lymphomas. Following chemotherapy pre-treatment and the administration of T-cells that have been modified to hunt and kill tumor cells, patients often develop a hyper-activation of the immune response, leading rapidly to a cytokine release syndrome (a form of cytokine storm) in up to 20% of patients, which can degenerate into organ failure and death in a number of cases. CytoSorb® was specifically designed to treat cytokine storm and could help to limit this hyper-inflammation, thereby protecting the patient and salvaging the therapy.
Another potential application is cancer cachexia, a wasting condition that occurs in most cancers that leads to rapid uncontrolled weight loss, anorexia, and physical debilitation. Patients lose the physical reserve needed to tolerate treatment and fight the cancer. Because CytoSorb® can remove a broad range of cytokines and other inflammatory mediators that drive cancer cachexia, it may be helpful in this condition. CytoSorbents is exploring this application, as well as the use of CytoSorb® as a primary cancer immunotherapy to kickstart the immune system to attack cancer, with researchers at the University Of Pennsylvania School Of Veterinary Medicine.
Acute exacerbations of autoimmune diseases that are treated in the hospital such as inflammatory bowel disease, lupus, multiple sclerosis, and other diseases are also potential targets for CytoSorb®, as high systemic levels of cytokines and other inflammatory mediators exacerbate the uncontrolled inflammation that is the hallmark of these acute flares.
Additional applications of CytoSorb® are being funded by groups such as:
- DARPA (Defense Advanced Research Projects Agency): ~$4 million over 5 years in its “Dialysis-Like Therapeutics” program to treat sepsis and remove inflammatory toxins from blood using blood purification. CytoSorbents is currently in Year 5 of the contract
- U.S. Army: ~$1.2 million in Phase I and II SBIR contracts to treat trauma and burn injury
- U.S. Air Force: Funding a 30-patient randomized controlled pilot study in the treatment of trauma and rhabdomyolysis
- JPEO-CBD (Joint Program Executive Office for Chemical and Biological Defense): $150,000 in a Phase I SBIR for mycotoxin removal
CytoSorb® Availability is Expanding Worldwide
CytoSorb® Availability is Expanding Worldwide CytoSorb® is available in most countries of the European Union and is distributed in countries outside of the European Union that accept European CE Mark approval such as India, Russia, Turkey, the Middle East, Israel, Australia, Vietnam and others. The total addressable market for CytoSorb® in critical care applications (such as sepsis, burn injury, trauma, ARDS, pancreatitis and other diseases) and cardiac surgery is estimated at more than $20 billion worldwide.
The Science Behind CytoSorb®
A CytoSorb® cartridge is filled with CytoSorbents’ proprietary hemocompatible, porous polymer beads that are roughly the size of grains of salt. The dimensions of the pores in each bead are specifically designed so that large objects such as blood cells go around the bead while small objects like electrolytes pass through it. However, appropriately sized substances are captured and trapped inside the bead’s pores and channels via pore capture and surface adsorption and are permanently eliminated from blood. In particular, hydrophobic substances are preferentially adsorbed to the hydrophobic polymer beads. CytoSorb® has been optimized to broadly remove many cytokines, toxins and other inflammatory mediators in the “cytokine sweet spot”, a 5-60 kDa molecular weight range where most cytokines reside.
This is in contrast to traditional hemodialysis filters that only remove substances in a low molecular weight range (® beads also have massive contaminant removal capacity, with over 40,000 square meters (the equivalent of seven U.S. football or five international soccer fields) of surface area and binding capacity in a single CytoSorb® cartridge. The combination of these characteristics enables a powerful therapy to reduce inflammatory toxins.
CytoSorb® broadly reduces cytokines, toxins, DAMPs, PAMPs and many other inflammatory mediators CytoSorb® efficiently removes a broad range of cytokines from whole blood. During the company’s European Sepsis Trial – a randomized, controlled, multi-center study in Germany of 78 patients with mainly septic shock and respiratory failure (predominantly ARDS), patients treated with CytoSorb demonstrated an average initial clearance of IL-6 of 25% and a sustained cytokine-statisticsaverage 6% clearance of IL-6 per unit time or blood volume across the entire 6 hour treatment period (p=0.02).
An average patient had up to 20 total blood volumes treated, which in an in vitro hemoperfusion setting, resulted in a more than 90% reduction in IL-6. These findings are consistent with ex vivo serum perfusion experiments where CytoSorb® effectively reduced a broad spectrum of cytokines (Fig 2).
Cytokines play an extremely important, but not exclusive, role in the inflammatory response. There are hundreds of other mediators of inflammation ranging from pathogen associated molecular patterns (PAMPs) such as bacterial exotoxins and endotoxins, damage associated molecular patterns (DAMPs) such as cellular debris, myoglobin, and plasma free hemoglobin, and many others such as activated complement, platelet activating factor, and bioactive lipids, that contribute to inflammation (Fig. 4). The advantage of CytoSorb® is that it is designed to broadly remove many of the inflammatory toxins in this range (Fig 1), thereby providing an elegant and unprecedented mechanism to control the inflammatory process.
In vitro extraction studies using whole blood confirms the ability of CytoSorb remove, for example, over 90% of deadly fungal toxins such as aflatoxin (0.3 kDa) and T-2 toxin (0.5 kDa), and inflammatory proteins including MIP1-α (8 kDa), complement C5a (8.2 kDa), procalcitonin (13 kDa), and S100A8 (20 kDa). CytoSorb also removed approximately 80% or more of other inflammatory mediators, such as IL-6 (26 kDa), IFN-γ (25 kDa), HMGB-1 (25 kDa), Staph aureus toxic shock syndrome toxin (TSST-1; 24 kDa), Staph aureus α-toxin (33 kDa) and Streptococcal SPE B toxin (40 kDa).
CytoSorb® is “Plug and Play” and Easy to Use and Implement
CytoSorb works with standard hospital dialysis equipment and blood lines (Figure 5). No additional expensive equipment is required or needed to be purchased. CytoSorb® is also compatible when used with a standard hemoperfusion pump or in a bypass circuit with either a heart-lung machine used for cardiopulmonary bypass (CPB) in cardiac surgery or an extracorporeal membrane oxygenation (ECMO) pump used for life support.
CytoSorb is also easy to implement. In brief, as with dialysis therapy, a temporary dialysis catheter is placed into a patient’s femoral or jugular vein. The patient’s blood is then anti-coagulated with either systemic heparin or regional citrate anti-coagulation using standard dialysis protocols. The device is primed using a 2L saline flush. It is attached to blood lines in the dialysis circuit using standard dialysis connectors with blood flowing first through the bottom of the cartridge, and then through the top, with the device in a vertical configuration. CytoSorb® can either be used alone in a hemoperfusion circuit, or in series with a standard CRRT hemofilter or dialysis membrane. If a hemofilter or hemodialysis filter is required, it is connected in series after the CytoSorb cartridge, with blood flowing through the CytoSorb® cartridge first. Blood is pumped out of the body and through the cartridge at a rate of 100-400 mL/min, where the polymer beads directly contact blood and remove unwanted or toxic substances. The newly “purified” blood is then recirculated back into the patient. In a 24-hour treatment, a patient’s entire blood volume can be treated more than 70 times. Each new treatment requires a new CytoSorb® cartridge. When used with a heart-lung machine, CytoSorb® has been evaluated at flow rates of up to 700 mL/min without causing hemolysis.
CytoSorb® is Safe to Use
CytoSorb® has been used safely in more than 14,000 human treatments. The majority of these treatments were in critically-ill patients in the intensive care unit (ICU) but approximately 3,000 have been used intra-operatively during cardiac surgery. These treatments were generally well-tolerated with no serious device related adverse events reported.
- Protection from over-treatment: CytoSorb® removes cytokines in a concentration dependent fashion. Higher cytokine levels lead to greater cytokine extraction efficiency. When cytokines are reduced to high normal levels, the extraction efficiency drops significantly, preventing excessive cytokine removal without the need to closely monitor cytokine levels. In clinical practice, treatment has been titrated based on clinical picture rather than real-time cytokine testing
- No change in blood chemistries: In our European Sepsis Trial, a randomized controlled trial involving 100 septic shock patients with multiple organ failure, receiving either standard of care treatment or standard of care treatment plus 6 hours of CytoSorb therapy per day for 7 days, blood chemistries were unchanged, with acceptable reductions in albumin (<10% over the 7 day treatment period) and platelets (<10% per treatment, comparable to other extracorporeal therapies). CytoSorb® is compatible with both systemic heparin anticoagulation and regional citrate anti-coagulation. The latter is recommended for patients at risk for bleeding, such as trauma or post-surgical patients
- Management of drug removal: Hemodialysis and hemofiltration, the two leading blood purification technologies, are well-known to remove a broad range of drugs and antibiotics efficiently, based predominantly on size. CytoSorb® also can remove certain drugs and antibiotics, but does so more selectively than dialysis, and is based upon surface adsorption. Water soluble drugs are typically not significantly removed by CytoSorb® and can usually be administered without the need for dose adjustment. Fat-soluble or hydrophobic drugs, however, are often easily adsorbed by CytoSorb®. When these drugs are toxic, as in digoxin toxicity or in calcium channel blocker overdose, CytoSorb® has the potential to treat these life-threatening conditions by removing these drugs quickly. When the drugs are desirable, as with antibiotics, there are a number of different ways to mitigate this issue. First, as is done in dialysis, medications can be administered after CytoSorb® treatment. Second, medication dosages can be increased based on expected removal or drug level testing. Third, following medication administration, time is given to allow for the drug to achieve full tissue penetration prior to CytoSorb treatment, since CytoSorb only removes drug from the blood compartment. All of these strategies have been successfully used in the past.
CytoSorb® is one of the highest grade medical sorbents
CytoSorb® beads are composed of a highly pure and chemically inert polystyrenic polymer that can be used in direct contact with whole blood or plasma. The beads are ISO 10993 biocompatible, certified for biocompatibility and hemocompatibility, while not being genotoxic or cytotoxic, and not causing acute sensitivity or complement activation. CytoSorb® utilizes solid state chemistry with no cells, biologics, drugs, or other perishable materials that can degrade over time. As a result, CytoSorb® is easily gamma-sterilized and has a 3-year shelf life at room temperature. In addition, the effluent of a CytoSorb® cartridge contains no residual organics or leachables and meets USP particulate standards for large volume intravenous fluids. CytoSorb® is manufactured at CytoSorbents’ ISO 13485 certified manufacturing facility in the United States and is protected by 32 issued U.S. patents with multiple applications pending worldwide.
CytoSorb®: State of the Art Technology
- Highly Adsorbent: Massive capacity with more than 7 US football or 5 international soccer fields (>40,000 m2) of surface area per CytoSorb cartridge to bind toxic materials
- Biocompatible: Porous polymer beads are ISO 10993 certified. Biocompatible, hemocompatible, non-genotoxic, non-cytotoxic, with no acute sensitivity or complement activation.
- Safe: 14,000+ human treatments, well-tolerated. No significant change in blood chemistries
- Pure: No residual organics, no leachables, meets USP particulate standards for large parenteral injections.
- Robust: High flow, low resistance cartridge capable of treating whole blood or plasma with flow rates of 100-400 mL/min using a dialysis or CRRT machine and up to 700 mL/min using a heart-lung machine without hemolysis helpful in countering ongoing cytokine production.
- Stable with Long Shelf Life: Solid state chemistry with no cells, biologics or other perishable materials, gamma sterilized with 3-year shelf life at room temperature
- Easy to use: Blood in, blood out. No dialysate or replacement fluid needed.
- “Plug and Play”: Compatible with a wide range of extracorporeal blood pumps