Cytosorbents Inc. is a company developing blood purification technology to attempt to treat life-threatening illnesses such as sepsis and infection . Recently, one of Medgadget’s editors, Ronney Shantouf, had the opportunity to ask Cytosorbents’ CEO Phillip Chan, MD, PhD a few questions to learn a little more about the company and its products.
Ronney Shantouf, Medgadget: Can you tell me a little about CytoSorbents and where the idea of CytoSorb stemmed from?
Dr Phillip Chan: CytoSorbents is a critical care-focused, publicly-traded company (OTCBB: CTSO) located just north of Princeton, New Jersey, specializing in blood purification to treat life-threatening illnesses. CytoSorbents’ flagship product, CytoSorb®, is the first blood filter specifically approved in the European Union for the safe and effective reduction of inflammatory substances called cytokines from the blood. The goal of cytokine reduction is to control deadly inflammation and prevent or treat organ failure in critically ill patients. Organ failure, or the failure of vital organs such as the lungs, heart and kidneys, is extremely common among this patient population and accounts for nearly half of all deaths in the intensive care unit (ICU) today, despite the best medical treatment.
Cytokines are small proteins produced by the immune system that normally help to regulate the inflammatory response in injury or infection. However, in deadly conditions commonly seen in the intensive care unit such as infection and sepsis, burn injury, trauma, severe lung injury, pancreatitis and others, the immune system often goes haywire, producing massive quantities of these cytokines. Left unchecked, this “cytokine storm” can cause direct cell death and deadly body-wide inflammation, culminating in fulminant organ failure and in many cases, death.
Until recently, there have been no effective ways to control cytokine storm and massive inflammation, and few, if any, ways to prevent or treat organ failure. Most of the therapies available to intensivists in the ICU, such as mechanical ventilation and dialysis, are supportive care therapies, often called “life support”, that can help keep a patient alive once their organs have failed, but do not help the patient get better. As many as one out of every three patients will die because of the lack of effective therapies to treat organ failure, despite receiving the best available medical treatment. The goal of CytoSorb® is to prevent or treat organ failure in critical illnesses by controlling cytokine storm and reducing the inflammatory response. In a randomized controlled trial, CytoSorb was effective in safely reducing cytokine storm and key cytokines by 30-50 percent with improved clinical outcome.
The idea of removing “evil humors” from the body to treat disease dates back to ancient Greece and the father of medicine, Hippocrates. Of course, it has only been with the advent of modern medicine that we have finally begun to unravel the true complexity of what these evil humors are and how they lead to organ failure. In many cases, these substances are true toxins produced by bacteria and other pathogens that can destroy tissues and organs and poison the delicately balanced mechanics that make the body function. But in other cases, the evil humors are actually normally occuring substances that are causing toxicity due to excessive production, or production in the wrong place. Cytokine storm is a clear example. However, the technology to broadly cleanse the blood of these kinds of “evil humors” has not been possible until recently.
CytoSorb® is a first-in-class blood purification therapy poised to potentially revolutionize the treatment of critically ill patients. It is a leading technology capable of reducing many of the toxic substances that accumulate during critical illness that contribute to the development of organ failure. For patients with existing acute organ failure, the goal is to reduce ongoing toxic inflammation to help the body heal. The long-term goal of CytoSorb therapy, however, is to use it rapidly following a patient’s admission to the ICU when they are unstable, but have not yet developed full-blown organ failure. If CytoSorb® can prevent organ failure from occurring, it could lessen the severity of illness, and help patients get better, faster. At a cost of $2,000-3,000 per day in the ICU, this could dramatically reduce the costs of treatment, while potentially reducing the billions of dollars lost by hospitals each year due to critical care, and reduce the nearly $80-90 billion dollars, or approximately 1% of the gross domestic product, spent on critical care in the US each year.
Medgadget: How does the CytoSorb work? How is it unique?
Dr Phillip Chan: CytoSorb® is a deceptively simple, yet very powerful and elegant technology. Packed within each CytoSorb® filter cartridge are the Company’s proprietary biocompatible, porous polymer beads – each roughly the size of a grain of salt – which act like tiny sponges to extract and bind toxic levels of cytokines and other toxins from the blood. Cells and other large molecules go around the beads, while very small substances like electrolytes go straight through the beads. But appropriately sized molecules such as cytokines get trapped and bound in the vast network of pores and channels within each individual bead. In fact, in a single CytoSorb cartridge, roughly the size of a drinking glass, there is more than 7 football fields of surface area on which to bind cytokines and toxins. Blood is continuously circulated out of the body using standard hemodialysis machines found in hospital ICUs, purified through the CytoSorb® cartridge, and recirculated back into the body. In a 6 hour period, CytoSorb can treat the entire blood volume of a patient 20-30 times.
CytoSorb’s broad spectrum of activity is key to its unique capabilities. Unlike other therapies that have tried to focus too narrowly on one aspect of the massively deranged human physiology in critical illness, CytoSorb® has been now shown to have many activities. For example, CytoSorb® is clinically proven to safely reduce cytokine storm and key cytokines by 30-50 percent in critically-ill patients. This is associated with improvement in organ function and survival in high risk patients in a post-hoc analysis. CytoSorb also has demonstrated the removal of many bacterial toxins in vitro as well, which cannot be managed effectively today. In addition, through work with one of our main academic collaborators, Dr. John Kellum, Professor and Vice Chair for Research at the University of Pittsburgh Medical Center, we have learned that CytoSorb® also reduces “immune confusion” caused by cytokine storm, which causes activated white blood cells, or the body’s “soldiers against infection”, to infiltrate healthy uninfected organs and release a barrage of toxic chemicals and enzymes that are normally intended to kill bacteria and viruses, but end up damaging vital organs instead.
The CytoSorb® polymer is manufactured at the Company’s ISO 13485 certified facility in New Jersey and is one of the highest grade medical sorbents commercially available today. The technology is protected by 32 issued U.S. patents and multiple applications pending and is supported by $5 million in contract awards from the US Army and the Defense Advanced Research Projects Agency (DARPA).
Medgadget: You conducted a small 43 person randomized controlled trial demonstrating the ability of Cytosorb to reduce cytokine levels by 30-50% in septic patients. Do you plan on conducting larger trials looking at hard end-points such as all-cause mortality as a primary endpoint?
Dr Phillip Chan: Severe sepsis and septic shock is the result of an overzealous immune response to a serious infection. Despite the best medical treatment, patients with severe sepsis have a risk of death of 25-30 percent, while patients with septic shock have a risk of death of 30% or more. In our randomized controlled European Sepsis Trial, we evaluated standard of care therapy with standard of care therapy plus seven days of CytoSorb treatment in septic shock patients with multiple organ failure. In this extremely sick patient population, CytoSorb safely and effectively reduced cytokine storm and key cytokines by 30-50 percent and in a post-hoc analysis, improved organ dysfunction and survival in patients at high risk of death: those with high levels of cytokines and in patients 65 years and older who make up two-thirds of patients hospitalized for sepsis.
We are in the midst of a dose-ranging study to optimize CytoSorb treatment. Following this study, we plan to leverage our European data and convert our existing FDA-approved investigational device exemption (IDE) approval to run a small sepsis study, into a pivotal trial IDE. We look to begin a 200-300 patient US pivotal pre-market approval (PMA) sepsis trial in early 2014, where 28-day all-cause mortality, required by the FDA for US approval, will be the primary endpoint. Given that sepsis is a major unmet medical need with no approved therapies and only a handful of ongoing pivotal sepsis studies, we expect an expedited FDA review following submission of our data. If we are successful with our US pivotal trial, we hope to enter the US market potentially by 2016-2017.
Medgadget: Where is the product currently available? What are the plans in regards to entering the US market?
Dr Phillip Chan: CytoSorb® is currently approved in all 27 countries of the European Union and can be sold, with registration, in countries outside the E.U., such as India, Brazil, and the Middle East, that accept European regulatory approval. The Company is selling CytoSorb® directly in Germany, Austria and Switzerland through its direct sales force, with now more than 60 key opinion leaders using or committed to using CytoSorb®. Physicians have been using CytoSorb® in many clinical applications, including sepsis, burn injury, trauma, acute respiratory distress syndrome, liver failure, pancreatitis, influenza, and cardiac surgery with success. We are initially expanding the market to major countries within the E.U. through distributors and/or potential strategic partners.
Medgadget: Are there any other future products down the pipeline that we may expect?
Dr Phillip Chan: Our biocompatible, porous polymer bead technology forms the basis of a robust and flexible blood and bodily fluid purification technology platform. We have the expertise to change the dimensions and characteristics of the beads to be able to remove substances as small as drugs and chemicals, to materials as large as antibodies, and things of various sizes in between. Another advantage of the technology is the ability to mix and match beads that can remove different things.
One of our most advanced development candidates is our HemoDefend blood purification technology. HemoDefend is designed to remove non-infectious contaminants in blood transfusion products that can cause transfusion reactions, effectively “washing blood” without the cost, time and trouble of actually doing so. These contaminants, from the blood donor or generated during blood storage, can cause common transfusion reactions such as fever and mild allergic reactions, to much more serious and potentially deadly illnesses such as transfusion related acute lung injury (TRALI) and anaphylaxis. With more than 100 million blood transfusions administered each year, there are and estimated 3-5 million such transfusion reactions worldwide. In addition, there is a belief amongst many physicians and surgeons that the administration of “old blood”, typically blood older than 2 weeks old, can lead to adverse outcome including a higher risk of death, particularly in high risk patients. Part of the problem is the accumulation of contaminants in these blood products. There are two large-scale randomized controlled studies ongoing in the US and Canada that are looking specifically at the risks of old blood. Should these studies be positive, it would be a major catalyst for technologies, such as HemoDefend, that may reduce the risks of older blood.
Another product under development is our ContrastSorb technology. ContrastSorb is designed to try to prevent kidney failure caused by the injection of intravenous contrast, or IV contrast, used to enhance images during radiologic imaging and interventional radiology procedures such as cardiac stent placement for heart disease. If you have ever had a CT scan with contrast, you have received IV contrast. Patients with existing kidney injury from diseases such as diabetes and hypertension are at higher risk of kidney injury when undergoing these standard procedures. There are more than 10 million procedures done each year in high risk patients, making it yet another large potential opportunity for CytoSorbents.