CytoSorbents Corporation (NASDAQ: CTSO), a leader in the treatment
of life-threatening conditions in intensive care and cardiac
surgery using blood purification via its proprietary polymer
adsorption technology, highlights the growing momentum of ex vivo
organ perfusion in organ transplantation and the vital role
CytoSorb® and ECOS-300CY® are playing in this burgeoning field. In
particular, these technologies may help to improve the quality and
number of usable organs while improving transplant success rates.
Importantly, data from recent peer-reviewed publications highlight
how these innovative therapies may improve outcomes in the specific
field of lung transplantation.
Background – Organ
Transplantation, Ex Vivo Organ
Perfusion, and CytoSorb/ECOS-300CY
Organ transplantation is the gold standard
treatment for end-stage organ failure. However, suitable donor
organs are scarce and many patients often die waiting for an organ
to become available. According to the Global Observatory on
Donation and Transplantation, there were approximately 158,000
solid organ transplants in 2022 globally. According to the United
Network of Organ Sharing (UNOS) and the European Directorate for
the Quality of Medicine and Healthcare (EDQM), in 2022 in the U.S.
and E.U. alone, there were approximately an equal number of
patients, roughly 153,000, on the transplantation waitlist,
primarily due to the lack of suitable organs. Every 10 minutes,
someone is added to the waitlist, and roughly every half hour,
someone dies on the waiting list, waiting for an organ that never
comes.
The vast majority of donated organs are from
deceased donors, often due to irreversible cardiac or brain death.
However, due to a variety of factors, including ischemia and
reperfusion injury, cold storage, and the manner by which the donor
died, these organs are often damaged with significant inflammation,
jeopardizing organ health and importantly the success of the
transplantation. In the U.S., according to a 2020 Millman research
report, a single lung transplant costs approximately $930,000, a
two lung transplant: $1.3 million, a kidney transplant: $443,000, a
liver transplant: $878,000, and a heart transplant: $1.7 million.
Due to the expense of failure, many organs are discarded, despite
the significant need. In addition, many organs, despite being
deemed transplantable, develop problems of delayed graft function
or primary graft dysfunction after surgery. This is different from
organ rejection and can happen with any organ. For example, in lung
transplantation, the rates of potentially life-threatening lung
failure within the first several days after transplant, called
severe primary graft dysfunction (PGD), can be as high as 30%,
resulting in high 90-day (20-25%) and 1-year (30-35%) mortality,
which is 3-5 times higher than if PGD did not occur. Strategies
that can improve the health of organs or improve postoperative
outcomes are key to the future of solid organ transplant.
Ex vivo organ perfusion is an increasingly used
strategy to preserve and potentially improve the functioning of
lungs, hearts, livers and kidneys following organ harvest and
during transport by reducing ischemic, reperfusion, and cold
storage injuries caused by conventional static cold storage. It
also has the potential to increase the available donor pool of
organs by salvaging substandard ones that would otherwise be
discarded. Ex vivo perfusion circulates temperature controlled,
oxygenated, nutrient rich fluid or blood products through the organ
to improve its viability. However, ex vivo perfusion does not
adequately address the ongoing release of cytokines and other
inflammatory mediators generated by the damaged organ that cause
ongoing injury and compromised function. Based on recent data, we
believe the integration of our cytokine adsorptive technologies
(i.e. CytoSorb, ECOS-300CY) with ex vivo organ perfusion has the
potential to transform the field of organ transplantation by not
only elevating organ preservation and rehabilitation to a new
level, but by improving clinical outcomes after the surgery. The
combination has been used successfully in heart, liver, and kidney
transplants to date, but the largest body of data comes from lung
transplantation.
CytoSorb and ECOS-300CY in Lung
Transplantation
The final analysis of the U.S. CytoSorb Therapy
in COVID-19 (CTC) Registry was published recently in the journal
Critical Care and demonstrated that the combination of CytoSorb and
extracorporeal membrane oxygenation (ECMO) therapy resulted in 74%
90-day survival in 100 critically ill patients from 5 major U.S.
ECMO centers who had COVID-19 with severe acute respiratory
distress syndrome (ARDS) and who failed mechanical ventilation.
This compared favorably to the 52% 90-day survival rate reported by
the Extracorporeal Life Support Organization (ELSO) in over 15,000
comparably ill COVID-19 patients using ECMO alone. The paper
highlighted the concept of “enhanced lung rest,” where CytoSorb is
used to remove circulating inflammatory cytokines and toxins that
can cause or worsen lung injury via capillary leak syndrome,
pulmonary edema (i.e. fluid in the lungs), and severe inflammation.
The ultimate goal of CytoSorb therapy is to help stop severe
inflammation and promote lung healing and recovery.
This same “enhanced lung rest” concept has
carried over to lung transplant, where inflammation in donated
lungs causes the same capillary leak syndrome, pulmonary edema, and
compromised lung function, and is a major contributor to primary
graft dysfunction (PGD), as mentioned earlier.
In 2017, Iskender and Inci, et al., from
University Hospital Zurich in Switzerland, published the first
study in the Journal of Heart and Lung Transplantation using
CytoSorb with ex vivo lung perfusion (EVLP) in a controlled pig
lung model, demonstrating decreased circulating cytokines,
decreased microscopic lung injury, improved electrolyte balance,
and improved lung mechanics with easier ventilation of the lung. In
2021, the team published a follow-up study in the Journal of Heart
and Lung Transplantation where they took the model to the next step
by transplanting the EVLP-treated lungs (with or without CytoSorb)
into pig recipients. They found that EVLP with CytoSorb
significantly improved the functioning of the transplanted lung
from both a mechanics and gas exchange standpoint.
In the 2022 landmark paper published in the
prestigious journal Nature Communications, Ghaidan and Lindstedt,
et. al., studied the impact of CytoSorb and EVLP in a pig lung
transplantation model. Lung injury and ARDS were induced in pig
donors by endotoxin injection. Once harvested, these compromised
lungs all underwent EVLP and single lung transplantation into a new
pig recipient. The study was divided into three groups. The
“untreated” group did not have CytoSorb at any
time. The “treated” group was subdivided into a) the
“One-step” group that did not receive CytoSorb
during EVLP but received CytoSorb postoperatively following lung
transplant, and b) the “Two-step” group had
CytoSorb both during EVLP, and then again postoperatively following
lung transplant. In a detailed and well-controlled study, the
researchers followed many parameters, including cytokines and
inflammatory cells in the blood and lung, level of lung
inflammation, changes in histopathology and gross pathology in the
lungs, and many clinical parameters including recovery of lung
function, oxygenation, hemodynamic stability, and development of
severe (Grade 3) primary graft dysfunction (PGD). Importantly, the
rates of PGD in the first 72 hours after transplantation, which
directly correlates with risk of death, were much lower when
CytoSorb was used. Researchers noted that 83% (5/6) in the Two-Step
group, and 50% (2/4) in the One-Step group had no PGD at all,
compared to the 83% (5/6) in the non-treated group that developed
Grade 3 severe PGD. Overall, researchers concluded that the use of
CytoSorb both during EVLP and in the recipient after
transplantation was superior in virtually all respects compared to
not using it at all, or using it only after transplantation. They
concluded that the use of CytoSorb in this model has been shown
to:
“(i) reduce
inflammation and restore pulmonary function during EVLP, (ii)
restore function and decrease inflammation following
transplantation, and (iii) reduce the incidence of PGD (primary
graft dysfunction) in transplanted recipients. The work outlined
here represents the utilization of the cytokine adsorber in the
context of lung transplantation using severely damaged donor lungs.
It is thus envisioned that adsorption may be an intervention that
could lead to the acceptance of more lungs for transplantation. It
may also further increase the tolerability of such lungs in a
recipient, a needed outcome given the role that PGD continues to
play as the leading cause of early mortality and as a contributor
to the development of chronic graft dysfunction.”
Based upon this work, Prof. Sandra Lindstedt and
her team at Lund University Hospital, Sweden are now conducting a
ten patient randomized controlled pilot study in human lung
transplantation using CytoSorb. They recently published a brief
communication based on the first 4 human lung transplant subjects,
where 2 received CytoSorb intraoperatively, and 2 did not. Those
treated with CytoSorb had lower circulating nucleosome levels
(inversely correlated with PGD) and did not develop PGD, while the
two patients not treated with CytoSorb had higher nucleosome levels
and developed Grade 1 and Grade 3 (severe) PGD postoperatively,
respectively.
Recently, Prof. Massimo Boffini and his group
from the University of Turin, Italy published the largest
retrospective human clinical study to date investigating the
feasibility and safety of CytoSorb® adsorption during EVLP in the
peer-reviewed journal, Transplant International. From July 2011 to
March 2020, physicians performed a total of 54 EVLP procedures on
lungs that had originally failed to qualify for transplantation. Of
these, 33 were performed without CytoSorb and 21 were performed
with CytoSorb integrated with EVLP. Among the 38 patients who
ultimately underwent lung transplant, the CytoSorb treated group
had significantly decreased cytokines in the perfusate compared to
the control group, with 76% (16/21) of lungs from the CytoSorb
group qualifying for transplantation after the EVLP procedure
versus 67% (22/33) from the non-treated control. Importantly,
patients receiving lung transplants treated with CytoSorb during
EVLP had significantly lower in-hospital mortality (0% vs. 13%;
p=0.03) and a lower 1-year mortality rate (0% vs. 36%; p=0.01)
compared to those who received lungs treated with EVLP alone. In
addition, the use of CytoSorb was associated with a trend of fewer
cases of Grade 3 severe PGD, and less need for ECMO support, which
likely was associated with significant cost savings. These results
were observed despite none of these patients receiving additional
intraoperative or postoperative CytoSorb treatment.
Dr. Phillip Chan, MD, PhD, Chief Executive
Officer of CytoSorbents, stated, “Collectively, these data are very
exciting for a number of reasons. First, the data support the
potentially pivotal role that our cytokine adsorption technologies,
including CytoSorb and ECOS-300CY - which is specifically approved
in the E.U. for ex vivo organ perfusion, has in lung
transplantation. We see multiple opportunities in improving the
functioning of the lung graft, expanding the donor pool of
transplant-eligible lungs by reconditioning substandard ones, and
most importantly reducing the rates of severe primary graft
dysfunction and mortality. Secondly, although lung transplantation
is not as common as kidney or liver transplantation, we believe the
fundamental principles of cytokine reduction and treating
inflammation in both the organ and the host will translate into
similar benefits in other solid organ transplants. For example,
Hosgood, et al., published that ex vivo kidney perfusion with
CytoSorb reduced inflammation, inflammatory mediators, and improved
renal blood flow in pig kidneys. One of our key partners,
Aferetica, is currently working with transplant surgeons to
investigate the benefit of our technology, private-labeled as
PerSorb® in their ex vivo organ perfusion system PerLife®, in human
kidney and liver transplants, and PerLungs® platform for lung
transplant. We plan to increase awareness of these publications and
concepts in the organ transplant community to foster increasing
innovation and opportunities in this space.”
Dr. Chan continued, “Finally, these important
data corroborate the ability of CytoSorb to help improve lung
function in multiple different settings and importantly provide
mechanistic data on how CytoSorb can help to treat acute
respiratory distress syndrome (ARDS) by promoting lung rest and
healing. Even prior to the COVID pandemic, ARDS was highly
prevalent, diagnosed in approximately 10% of all ICU admissions.
ARDS and associated complications such a respiratory failure and
hospital acquired infections, were the primary cause of morbidity
and mortality in both the 2009 H1N1 influenza and 2020-2022
COVID-19 pandemics. We believe CytoSorb represents a new innovation
to treat ARDS, which has the potential to drive significant revenue
growth.”
Commenting on the Boffini study specifically,
Mr. Mauro Atti, Chief Executive Officer of Aferetica SRL, stated,
“This published study comes from a project started in 2015 with the
City of Health and Science University Hospital of Turin in the
field of organ transplantation, where researchers were among the
first pioneers to use CytoSorb for this purpose. In fact, their
early findings with CytoSorb were a major driving force leading us
to develop our PerLife® and PerLungs® platforms to enable perfusion
and purification of liver and kidneys, and lungs, respectively.
Both integrate perfectly with the PerSorb® sorbent that
CytoSorbents provides us thanks to an international strategic
agreement. These data demonstrate how the perfusion and
purification of organs can recover marginal organs, reduce
post-transplant side effects, and even improve the survival of
transplanted patients – further confirming our correct decision to
invest in this field and partner with CytoSorbents.”
About CytoSorbents Corporation (NASDAQ:
CTSO)
CytoSorbents Corporation is a leader in the
treatment of life-threatening conditions in the intensive care unit
and in cardiac surgery through blood purification. Its flagship
product, CytoSorb®, is approved in the European Union, distributed
in 75 countries worldwide, and has accumulated more than 212,000
human treatments to date, to reduce "cytokine storm" and other
toxins that can cause organ failure. The DrugSorb™-ATR
antithrombotic removal system, based on the same polymer technology
as CytoSorb, has received two U.S. FDA Breakthrough Device
Designations to remove two separate blood thinners during
cardiothoracic surgery, including ticagrelor and the direct oral
anticoagulants (DOAC) apixaban and rivaroxaban, and is undergoing
pivotal clinical studies. For more information, please visit the
Company’s websites
at www.cytosorbents.com and www.cytosorb.com or
follow us on Facebook and Twitter.
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forward-looking statements in this press release represent
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risks discussed in our Annual Report on Form 10-K, filed with the
SEC on March 9, 2023, as updated by the risks reported in our
Quarterly Reports on Form 10-Q, and in the press releases and other
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attempt to advise interested parties of the risks and factors which
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CytoSorbents Contact: Kathleen Bloch(732)
398-5429 kbloch@cytosorbents.com
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