Having a life-threatening illness is so common that most people have been touched by it, whether from a serious infection, a car accident, complications from surgery, a heart attack, or even a drug overdose.
A hospital’s intensive care unit is where the sickest patients are treated, but for many of them, the tools to treat their conditions are fairly limited, focusing mainly on supportive care therapies designed to keep the patient alive, but not necessarily helping them get better. As a result, mortality can be very high.
“In severe sepsis, the end result of an overwhelming infection, one in every three people die in the U.S.,” says Phillip Chan, right, CEO of CytoSorbents, a small, publicly-traded company on Deer Park Drive. Those are worse than heart attacks, strokes, and any single form of cancer.
And it gets worse. “In its more severe form, septic shock, the mortality is greater than 50 percent, Chan says. “In severe burn injuries, up to 50 percent die; and in severe lung injury, 35 to 50 percent don’t make it out of the hospital alive.”
To try to reduce mortality in critical-care diseases, CytoSorbents is taking an entirely new approach. Rather than focusing on the effects of toxic substances in the body that are causing disease, the company’s technology is designed to remove them directly from the blood and body with its novel blood-purification technologies.
“It’s akin to cleaning a garage,” says Chan. “You can buy all the storage you want, but sometimes the best way is to just throw things out.” The company’s lead product is called CytoSorb, a cartridge roughly the size of a drinking glass, filled with blood-compatible polymer beads containing millions of tiny pores. The design is meant to treat something called “cytokine storm.” This is when cytokines — small proteins that normally help stimulate and regulate the immune system and enable it to fight infection — expand rapidly to an uncontrolled “storm” level that can cause severe inflammation and often death.
A cytokine storm might be likened to what happens with a police force, whose purpose is to protect the public. Under normal conditions, a well-trained force is designed to keep crime under control. But sometimes in extreme situations, police power expands to the point that the police themselves become a dangerous, antisocial force. A cytokine storm is similarly dangerous, as we see in the flu, where a miniature cytokine storm is responsible for most of the symptoms — fever, chills, bodily aches, severe fatigue, and the feeling of being really sick. They are not a result of the virus itself, but of the rapid expansion of cytokines.
What happens in this small way with the flu can reach gigantic proportions in sepsis and septic shock, which are the end result of massive cytokine storm produced in response to overwhelming infection. Burns, smoke inhalation, severe lung injury, and trauma from injuries sustained in everyday automobile accidents — or in devastating, infrequent events like earthquakes — are also triggers of cytokine storm. Chan says, “It is remarkable how common it is — killing cells and damaging organs, leading to organ failure and death in many people.”
According to Chan, trying to treat cytokine storm has been the target of drug companies for many years. Some biotech companies have developed very targeted anti-cytokine therapies like Remicade, Enbrel, and Humira, with collective annual worldwide sales of $14 billion, to treat autoimmune diseases like rheumatoid arthritis, psoriasis, and bowel diseases like Crohn’s.
But in life-threatening illnesses such as sepsis, these therapies have not been able to effectively control cytokine storm because there are too many different cytokines that have overlapping functions. If one is removed, others will take its place. A broader approach is needed, says Chan.
CytoSorbents is now testing CytoSorb, its broad-spectrum cytokine-removal device filled with biocompatible, porous plastic beads, that specifically targets what Chan calls the “cytokine sweet spot.” Each bead is roughly the size of a grain of salt, looks like a tiny sponge, and can sop up excessive cytokines.
CytoSorb does not just randomly remove molecules from a liquid. Rather, the size of the pores dictate what gets through and what doesn’t. “Big substances like blood cells that don’t fit the pores are not removed by the resin, and very small things go straight through it,” says Chan. “But molecules of an appropriate size get caught up in pores and are removed.” Then the sticking power of the polymer keeps the molecules trapped within the bead.
“This is a very powerful fluid-purification platform,” says Chan. “During the manufacturing process, we can adjust the pore size to be very small or very large; in doing so, we can dictate the types of molecules we can remove.” As a result, the same technology can be used to remove substances as small as drugs or as large as antibodies from the blood and other bodily fluids.
But removing specific components from blood is not simple. Blood, after all, is an extremely complex fluid comprised blood cells, platelets, proteins, sugars, and fatty acids. Other blood-purification technologies, like dialysis, cannot effectively remove cytokines, due to a lack of binding capacity.
CytoSorb’s polymer beads, on the other hand, have such a massive capacity that, even if they capture unnecessary elements, their capacity to grab cytokines remains very strong. For example, the combined surface area of the beads in a single CytoSorb cartridge is seven football fields long.
“Our device is ‘plug and play’ compatible with standard hemodialysis machines found in most major hospitals,” Chan says. After inserting a temporary dialysis catheter into a major vein, blood is pumped out of the body using the dialysis machine and then directly through the CytoSorb cartridge. Blood comes in direct contact with the polymer beads in the cartridge. As blood moves through the cartridge, cytokines and other inflammatory mediators are removed.
“The purified’ blood then exits the device and is pumped back into the body,” Chan says. “It is a simple, yet very elegant system.”
CytoSorbents’ pre-clinical work on sepsis has revolved around a collaboration with John Kellum, professor of critical care medicine and anesthesiology at the University of Pittsburgh Medical Center, that began about eight years ago. Kellum has worked on animal models of sepsis and used the company’s CytoSorb resin to purify blood and reduce cytokine storm. In rat models of sepsis akin to a patient with a ruptured appendix, a single three-hour treatment of CytoSorb, in the absence of antibiotics, increased the animals’ survival rate from about 12 percent in the control group to about 65 percent in the treated group.
“What he was able to demonstrate was that CytoSorb treatment prevented the onset of septic shock in these animals, which is a life-threatening drop in blood pressure that deprives critical organs of blood and oxygen, while also demonstrating a significant reduction in cytokine storm as well,” says Chan.
So far no other therapies in the United States have been developed to treat cytokine storm, although in Europe one product is being marketed.
Right now CytoSorbents is running a major clinical trial in Germany to evaluate the ability of CytoSorb therapy to reduce cytokine storm in patients with sepsis and lung injury. In this randomized, controlled trial, patients in the treatment group are treated for seven days, six hours each day, each day with a new CytoSorb cartridge. The company has already enrolled about 75 percent of the 100 patients who will take part in the trial, with half getting CytoSorb treatment and standard of care therapy and the other half getting standard of care therapy alone. The endpoint of this trial is cytokine reduction, and Chan hopes it will be finished by year’s end.
“Our goal is to obtain European regulatory approval shortly thereafter and be on the market in Europe in early 2011,” says Chan. If the safety and efficacy data from the German trial are good and the device is approved as a cytokine filter, CytoSorb can be used in Germany for sepsis and a number of other intensive care unit illnesses or conditions, such as cardiopulmonary bypass surgery, burn and smoke inhalation injury, trauma, pancreatitis, organ donation, and drug overdose, all of which share a common theme of blood-borne toxins.
Although no results of this trial are available yet for public disclosure, Chan shares the results of a sepsis pilot study that the company reported in November, 2009. At a major academic medical center in Germany, six patients were treated with CytoSorb and six served as controls. The treated patients showed substantial improvements in several different clinical end points, including 28-day mortality, getting off mechanical ventilation more quickly, improving organ function, better weathering shock, and reducing the time spent in the intensive care unit.
In 2007 the Food and Drug Administration approved CytoSorbents’ investigational device exempt (IDE) application to begin a small clinical trial in patients with sepsis in the United States. “Our goal is to take the data from the European sepsis trial, bring it back to the FDA, and negotiate with them to allow us to do a pivotal study beginning sometime in 2011,” says Chan. This would be a major study in the United States, with 300 to 500 patients, with a primary endpoint of 28-day mortality, and the goal of getting regulatory approval.
CytoSorbents got its start as Advanced Renal Technologies and later RenalTech. The latter acquired the basis of its purification technology from Russian scientists, with the goal of improving hemodialysis therapy in patients with kidney failure. Dialysis replaces failed kidneys by removing toxins from the blood.
The problem with dialysis, however, is that it is only good at removing very small toxins, whereas healthy kidneys are able to remove medium-sized toxins as well. As a result, medium-sized toxins that are not removed end up accumulating in the blood and can cause long-term problems. One protein, beta-2 microglobulin, that builds up in the musculoskeletal system, particularly in the joints, can cause disability and pain after three to four years of dialysis, with profound disability in 10 years.
Advanced Renal Technologies worked hard to develop the technology and also a robust manufacturing process. Although the company completed four human pilot studies to remove blood toxins of medium molecular weight, the business prospects for this medical device diminished. “It became clear that dialysis was becoming a high-volume, low-margin, commoditized business where reimbursement was declining and could no longer support newer technologies,” observes Chan.
The issue was that renal disease was becoming an epidemic, being driven by diabetes and an aging population. Treated patients were living a fairly long time. As the number of patients has increased, it has put a strain on the healthcare system and its relatively fixed resources for reimbursement. In response, the company decided in the mid-2000s to change direction and focus on acute care medicine, particularly critical care medicine dealing with life-and-death situations. Because the medical need was great, there was an excellent fit with its technology, and reimbursement was much stronger. The company changed its name to MedaSorb Technologies and later to CytoSorbents Corporation.
At CytoSorbents’ facility in Monmouth Junction, the company manufactures its polymer beads, purifies them, and packs them into standard blood-purification cartridges. The company currently has seven full-time employees and fills out with consultants where necessary. To date, it has manufactured several thousand of its devices. “We have a very robust, scalable manufacturing process,” says Chan, “and we are preparing for a transition from being a development-stage company into a commercialization-stage company.”
Chan graduated from Cornell University in 1992 with a bachelor’s in cell and molecular biology. After completing the M.D./Ph.D. program at Yale, he did his internal medicine residency at Beth Israel-Deaconess Medical Center at Harvard University. He is a board-certified internal medicine physician.
On the side, Chan was busy in other areas. “Not only did I have a passion for research as well as clinical medicine,” he says, “but since college I have also had a passion for discovering new companies through the stock market. I had been a student of fundamental analysis as a hobby.”
Finding himself fairly adept at finding promising, up-and-coming companies, he wanted to combine his passions for investing, research, and medicine into one position, and he decided to go into venture capital. He joined NJTC Venture Fund, where he later became a partner, heading up its healthcare and life science investments for five years. In this capacity he co-founded Andrew Technologies, a medical device company developing advanced surgical instruments for minimally invasive surgery.
In 2008, along with his colleague Jim Gunton, he led the Series B financing for the company, raising $5,250,000. In January, 2009, when chief executive officer Al Kraus retired at age 65, the board elected Chan to succeed him.
CytoSorbents has raised a total approximately $65 million in investment capital since its inception, predominantly from high-net worth individuals and institutional investors. The company went public in 2006 and has raised approximately $12 million since doing so. It also recently closed on a company-favorable $6 million equity line of credit and would like to raise a small amount of additional money to bolster its balance sheet.
CytoSorbents currently has an active business development program to look for strategic partners for CytoSorb and other technologies in its portfolio. “We could potentially license our technology and provide resources to conduct clinical trials for a number of different applications,” says Chan. CytoSorbents’ distribution partner for its first filtration product, which is focused on patients with kidney failure, is Fresenius, which Chan notes is the largest dialysis company in the world.
If the company gets European regulatory approval of CytoSorb after the successful completion of the current trial, Chan says the company will have reached a major inflection point.
“We were founded in 1997 and have come a tremendous way to this point. We feel that the next year to two years will be pivotal for the company,” he says. “We have worked very hard at creating a number of opportunities at that company that, if they become successful, could make CytoSorbents one of the next major successes in New Jersey.”
CytoSorbents, 7 Deer Park Drive, Suite K, Monmouth Junction 08852; 732-329-8885; fax, 732-329-8650. Phillip Chan, CEO. www.cytosorbents.com.