Defibrotide in COVID-19 Pneumonia

As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048
people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality
rate of less than 1% from influenza. There is an urgent need for effective treatment. The
2019 novel Coronavirus (2019-nCoV; severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2)) has spread rapidly since its recent identification in patients with severe
pneumonia in Wuhan, China. The clinical spectrum of COVID-19 varies from asymptomatic or
pauci-symptomatic forms to clinical conditions characterized by respiratory failure that
necessitates mechanical ventilation and support in an intensive care unit (ICU), to
multiorgan and systemic manifestations in terms of sepsis, septic shock, and multiple organ
dysfunction syndromes (MODS). Current management of COVID-19 is supportive, and respiratory
failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality.

The cytokine profile of COVID-19 patients supports that the fatality is driven by a
virally-triggered, self-propagating, hyper-inflammatory state (Mehta et al, 2020). Elevated
ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p<0·001) and IL-6
(p<0·0001) have been found to be independent predictors of fatality in COVID-19 patients in
China (Ruan et al, 2020).

VOD, known as Veno-Occlusive-Disease or Synusoidal Obstruction Syndrome, is the most
characterized of a spectrum of post bone marrow transplantation (BMT) syndromes (including
ELS, IPS or aGVHD) characterized by reactive endothelial activation and damage,
endothelial-driven paracrine signaling and a pro-inflammatory and pro-coagulant state. Severe
VOD frequently progresses to Multi Organ Failure and is characterized by high mortality
(>80%), characterized mostly by lung and kidney failure.

High levels (elevated early in the course of the disease) of IL-6, IL-8 and TNF-alpha
characterize VOD and the other post-BMT endothelial diseases (Schots et al, 2003, Gugliotta
et al 1994, Remberger et al 1997, Symington et al, 1992). In detail, IL-8 may be involved in
the respiratory failure following ARDS, a frequent and fatal outcome of sVOD patients.
Intriguingly, high ferritin levels are a well recognized risk factor for the development of
VOD in both adult and pediatric settings.

Furthermore, the histopathological examination of lung lesions in VOD syndromes show early
alveolar epithelial and lung endothelial injury, resulting in accumulation of protein- and
fibrin-rich inflammatory edematous fluid in the alveolar space and progression to
interstitial fibrosis, at later stages.

These patterns are reminiscent of what observed in the only three cases of autoptic
examination of lung tissue so far obtained from COVID-19 infected individuals: two from
putatively early phase and one from a late phase of the disease: such as, early diffuse
alveolar damage with proteinaceous exudates, and chronical inflammation with intra alveolar
deposition of fibrin and interstitial fibrosis, respectively.

Thus, we suggest here that the pattern of circulating cytokines, similar histopathological
findings in infected patients and hyper-ferritinemia represent some hallmarks common to both
COVID-19 induced pathology and VOD/SOS (and other endothelial damage syndromes), possibly
underlying common mechanisms of progression.

Defibrotide, a polydisperse mixture of predominantly single-stranded
polydeoxyribonucleotides, is currently the only therapy approved to treat hepatic VOD/SOS
with pulmonary/renal dysfunction (ie, multiorgan dysfunction/multiorgan failure [MOD/MOF])
following HSCT in the United States and to treat severe hepatic VOD/SOS post-HSCT in the
European Union. In preclinical and human studies, defibrotide has demonstrated
profibrinolytic, antithrombotic, anti-inflammatory, and angio-protective actions, thus
promoting an anticoagulant phenotype of the endothelium that protects and stabilizes the
function of endothelial cells. In a phase 3, historically controlled, multicenter trial in
adults and children with VOD/SOS and MOD/MOF (defibrotide: n = 102; controls treated before
defibrotide availability: n = 32), defibrotide resulted in significantly greater day +100
survival following HSCT (38.2%) vs controls (25.0%; propensity analysis-estimated
between-group difference: 23%; P = .0109). Importantly, a posthoc analysis of a conspicuous
number of defibrotide-treated patients (n=651) has recently shown that defibrotide treatment
also to critically ill patients, such as those with ventilator dependence at study entry,
could highly benefit from defibrotide treatment.

Defibrotide has, overall, demonstrated endothelial-protective properties, with
pro-fibrinolytic, anti-thrombotic, anti-ischemic, anti-inflammatory, and antiadhesive
activities, but no significant systemic anticoagulant effects. Defibrotide appears to exert
several anti-inflammatory and antioxidant effects through interaction with the EC membrane,
as shown in an endothelial cell line of hepatic origin.

At least part of defibrotide's lifesaving activity is due to downregulation of circulating
cytokines, chiefly IL-6 and TNF-alpha and by reducing PAI-1 levels, NFKB activation and
expression of MHCI and MHCII molecules. As compared to other agents, targeting a specific
cytokines or a specific factor, defibrotide's pleiotropic mechanism of action may underlie
its effectiveness in both early and late progressed states of MOF and in prophylactic
settings as well.

Patients with clinical and radiological evidence consistent with idiopathic pneumonia
syndrome, all showed underlying disease processes which can be interpreted as associated with
endothelial cell activation injury. Idiopathic pneumonia syndrome is a rare complication
following hematopoietic stem cell transplantation (HSCT), defined by diffuse lung injury with
no identified etiology, with an incidence of 2-12%.; it shows histological evidence of type
II endothelial cell activation, with display of ICAM-1 and/or VCAM-1, and endothelial injury,
with endothelial upregulation of eNOS. This, together with histological findings of
intra-alveolar fibrin and pulmonary hypertension suggests that endothelial cell activation
injury may be a causative factor underlying idiopathic pneumonia syndrome Defibrotide may
prove to be useful in the treatment of patients with idiopathic pneumonia syndrome, although
stratifying which patients will benefit from this treatment requires further study.

A potential beneficial effect from defibrotide in treating pulmonary veno-occlusive disease
(PVOD) has been suggested. Its action is probably due to the drug's ability to selectively
increase prostaglandin I2 and E2 levels and to increase tissue plasminogen activator and
decrease plasminogen activator inhibitor function.

The use of defibrotide does not change the pathway of care, therefore the only changes to the
budget are drug acquisition costs and cost avoidance as a result of reduced ICU/HDU use.
Defibrotide reduces the length of stay avoiding extended use of ICU or HDU beds (NHS England
Clinical Commissioning Policy.