Since April 10, 2020, the FDA has issued emergency use authorizations (EUAs) to several companies that make blood purification devices that can clear excess cytokines in the blood of patients with COVID-19. In some patients, the immune response goes haywire and hyperinflammation via a "cytokine storm" leads to septic shock, which can advance to organ injury and death. Monmouth Junction, N.J.-based Cytosorbents Corp.; Lakewood, Colo.-based Terumo BCT Inc.; and Marker Therapeutics AG, a subsidiary of Marker AG, of Zug, Switzerland, have all recently received EUAs for use of their products in adults with confirmed COVID-19 infections who are admitted to intensive care.
The patients must have confirmed or imminent respiratory failure, severe disease, or life-threatening illness resulting in respiratory failure, septic shock, and/or multiple organ dysfunction or failure, according to the FDA authorization.
Another company, Spectral Medical Inc. of Toronto, received an FDA supplemental investigational device exemption for the use of the company’s PMX cartridge in the treatment of patients with COVID-19 who have sepsis or septic shock.
While each company approaches the problem differently, they all address the same issue – excessive cytokines in the blood.
Many patients with COVID-19 who develop serious illness appear to be under attack not just by the SARS-CoV-2 virus, but by their own immune systems. When the immune system overreacts, it produces excess cytokines which attract immune cells. In turn, those immune cells release more cytokines in an accelerating and dangerous spiral as the immune cells move from targeting the virus to attacking healthy cells.
A cytokine storm can trigger acute respiratory distress syndrome (ARDS), a frequently fatal complication in which so much fluid leaks into the lungs that breathing without external support becomes impossible. Excessive cytokine production also underlies sepsis, which often damages the lungs, heart, and kidneys, and can ultimately cause multiple organ failure and death.
Cytosorbents’ Cytosorb is an extracorporeal blood purification cartridge that has been used in more than 80,000 human treatments in Europe and in 58 countries worldwide to treat cytokine storm and deadly inflammation in critically ill and cardiac surgery patients.
The company has a 30-patient COVID-19 trial underway in Freiberg, Germany and hopes to start a larger study in the U.S. shortly. The cartridges are in use with COVID-19 patients in China and Italy already. Cytosorb has been added to the coronavirus treatment guidelines in Italy and Panama.
In an analyst call with Cowen and Company on April 4, Cytosorbents’ CEO Phillip Chan said that the company had received more than 40 emergency use requests for the device from U.S. hospitals. That number exceeded 70 hospitals a week later.
The cartridge works with most blood purification machines or pumps found in hospitals today, including dialysis, continuous renal replacement therapy, and extracorporeal membrane oxygenation machines (ECMO). It required no adaptation to be used for COVID-19.
“Each Cytosorb cartridge is filled with biocompatible, highly porous polymer beads roughly the size of a grain of salt,” Cyotsorbents’ CEO Phillip Chan told BioWorld. “Each bead has millions of pores and channels in them that allow them to act like tiny sponges and to extract inflammatory toxins from blood based on size, surface adsorption and concentration.”
As blood is pumped out of the body and through the cartridge, it removes inflammatory toxins. “The purified blood is recirculated back into the body over and over such that a patient’s entire blood volume is treated more than 70 times in a 24-hour period,” Chan said. The cartridge is replaced daily.
Unlike absorbent materials, which depend on volume to store extracted material, adsorbents require greater surface area on which extracted material creates a film. The Cytosorb cartridge contains seven football fields of surface area, according to Chan.
“Also, Cytosorb is highly biocompatible and hemocompatible, allowing the beads to contact whole blood without causing hemolysis,” he noted.
Other materials do not work as well, Chan said. “Charcoal is typically made from burning organic materials with very small pores that are not suitable to removing big substances such as cytokines. Other sorbent materials are typically not hemocompatible and cannot touch whole blood without causing red blood cells to be destroyed, and therefore are relegated to only treating plasma (the non-cellular portion of blood), making treatment much more complex.”
The announcement of the EUA boosted the company’s shares up 30% on April 13, but trading since then has been somewhat lower. The company reported a banner year in 2019, with revenues of $7.4 million, up from $6.1 million in 2018. Beyond the COVID-19 application, the company expects to announce results from a cardiac study, REFRESH 2-AKI, in the next few months.
Terumo BCT and Marker Therapeutics
The FDA issued an EUA for the use of Terumo BCT’s Spectra Optia Apheresis System combined with Marker’s D2000 adsorption cartridge. Blood circulated through the Optia system is purified by the D2000 cartridge.
The D2000 in vitro plasma adsorption cartridge is currently in use to reduce cytokines and other toxins from plasma for patients with ARDS, sepsis, liver failure, drug overdose and poisoning. The device runs on plasma separation platforms, like the Spectra Optia. It recently received CE mark approval.
The two companies quickly formed a collaboration to bring their technologies to bear on the growing pandemic. “The pace of this collaboration between the companies is incredible. We are leaving no stone unturned in exploring existing and new ways for our products to mitigate the impact of COVID-19," said Antoinette Gawin, CEO and president of Terumo BCT.
"By combining our plasma adsorption cartridge with Terumo BCT's technology, this partnership offers the potential to develop a unique global solution for treatment of acute respiratory failure in COVID-19," says David Cohen, chairman of Marker.
Spectral Medical’s PMS cartridge is a little different from the others in that it removes endotoxins, a primary driver of the cytokine storm. The cartridge has been used for COVID-19 patients in the U.S. on a compassionate use basis as well as in Japan and Italy.
The EUA will allow the company to expand it phase III Tigris trial in the U.S. to additional hospitals and to patients in septic shock who have COVID-19.
“We are encouraged by the results of PMX in treating COVID-19 patients in Japan, Italy, and the U.S., and are collecting data regarding the increase in endotoxin activity in patients with COVID-19 in collaboration with our EAA distribution partners mainly in Italy and Japan. Spectral now hopes to contribute more to the treatment of septic shock patients during this pandemic,” said Paul Walker, president and CEO of the company.
On March 12, Spectral withdrew its preliminary short form prospectus for a public offering that was filed on March 5, “in light of current market conditions,” the company said.