To explore the efficacy of treatment of pulmonary cytokine storm induced by SARS-CoV2with a monoclonal antibody to IL-2 (Basiliximab) in addition to current standard of carevs current standard of care with the primary efficacy endpoint being the proportion ofsubjects alive and free of ventilator support, defined as intubation and requiringmechanical ventilation, at Day 28 from time of randomization.
The current pandemic driven by SARS-CoV2 creating the COVID-19 disease state is creating
enormous healthcare challenges globally with limited treatment paradigms outside of
supportive medical, and intensive care measures.
As the human population was entirely naïve to this viral pathogen, a particularly
vigorous response of the immune cascade through cell-mediated mechanisms is a driving
force behind the lethality of this disease in susceptible individuals. It is not
presently understood why specific populations are at higher risk for disease state
progression outside of traditional parameters such as age and pre-existing co-morbid
health states. Furthermore, we lack a priori ways of identifying which SARS-COv2 infected
patient may ultimately develop a "hyperactive" immune response that leads to the
"cytokine storm" or "cytokine release syndrome", and the resultant cell, tissue, and
organ system dysfunction.(1) Hypotheses in this area may include viral load phenomenon,
aberration in immune/inflammatory regulatory check-points (JAK-STAT, JNK etc.), or
underlying case dependent genetic factors (HLA etc.) influencing the immune system (2).
Once the cytokine storm drives the clinical endpoint above, an affected patient who
survives will become high risk for secondary pathogenic infection.
Intravenous remdesivir (3) along with dexamethasone (4, 5) have become standard of care
therapeutics. The FDA recently provided emergency use authorization (EUA) for a novel
SARS-COV2 neutralizing monoclonal antibody cocktail targeting the spike protein that
docks with the ACE2 receptor on susceptible cells (Regeneron) (5). Rapid development of
robust viral treatment strategies and vaccine development are the key strategies to
managing SARS-COV2 in the long term. To this end, the FDA will be reviewing an EUA
application for Pfizer's mRNA vaccine in early December, with similar review expected for
Moderna's mRNA vaccine.
However, promising these developments are, thousands of patients are dying from cytokine
storm mediated endpoints on a daily basis in the United States and across the world
during the ongoing third wave/surge of COVID-19. There is broad recognition of this
cytokine phenomenon, and in this era of targeted interleukin therapy for autoimmune
disease states, a multitude of FDA approved monoclonal antibodies targeted to specific
interleukins exist. Many institutions adopted IL-6 as a target for mitigation of the
cytokine storm, and are utilizing tocilizumab (Actemra ®, Roche/Genentech) as a treatment
(6) Sarilumab (Kevzara ®, Sanofi/Regeneron), another monoclonal Ab to IL-6, underwent
rapid assessment for use in COVID-19(7). Both therapeutics did not meet primary specified
endpoints in broader, Phase 2-3 studies.
These studies targeted the Th2/Tfh cytokine IL-6, as it plays a role in cytokine mediated
inflammation in the lungs (9, 10) There is evidence that Il-6 can be induced within
several hours by certain viral species (11) perhaps providing another reason why this was
chosen as a target. Finally, this cytokine may serve as a target based on existing
protocols to treat macrophage activation syndrome (MAS), and based on early evidence of
cytokine expression patterns in patients infected with SARS-COV2 in Wuhan, PRC (2,
12-14). Classically, however, Th2/Tfh related cytokines are associated with antibody
mediated immune memory and response, and though Th2/Tfh cytokines play a crucial role in
acute inflammation, we have not seen protocols that target differentiating cytokines that
drive Th0 to Th1 maturation, or Th1 specific cytokines. The Th1 cytokine profile is more
consistently demonstrated in almost all early viral infection, and therefore, we view
these cytokines as potential targets for therapy to prevent or mitigate the cytokine
storm (Figure 1) (2, 12). Cytokine storm is a downstream manifestation of the viral
induced host response that represents either failure of the initial host response to
mitigate viral load, an uncontrolled late cytotoxic T-cell activity, or both. There is no
evidence that targeted therapy against Th1 cytokines impairs the host response with
strong clinical evidence supporting use in other EBV mediated secondary HLH syndromes
(15).
The cytokine environment in which antigen primed T cells differentiate determines the
subset that develops. In particular, IL-4 is essential for the development of Th2
response and IFN-gamma, IL-12 and IL-18 all are important in the development of Th1
cells. Th1 cells produce IL-2 and IFN-g, which in turn, promote the differentiation of
fully cytotoxic T cells from CD8+ precursors.
A recent report published in Nature Medicine by Long et al. demonstrated a multi-fold
higher expression of Th-1 cytokines, in particular, TNF alpha and IL-2, and significant
expression of the IL-2 receptor subunit alpha in symptomatic COVID 19 patients in
Wuhan.(16) A subsequent report published in Science Immunology by Lee et al. (17)
demonstrated similar results through transcriptional and immuno-profiling techniques, and
most recently a report in Nature (18) did the same. Therefore, among all immunomodulatory
therapies, we view that targeting the Th1 response to be a key strategy. We propose
targeting the IL-2R with Basiliximab.
Basiliximab (Simulect ®) is a monoclonal antibody against a subunit of IL-2 and is FDA
approved for the treatment of acute renal transplant rejection, and is used off label in
many other cases of transplant rejection mitigation.(2, 12) This agent has a long track
record of safety and we believe among Th1 cytokine targets, to be a safe target for
inhibition in SARS-COV2 induced cytokine storm.
Additional novel methodologies, including treatment with orally approved FDA approved
JAK-STAT inhibitors (2) sirolimus (19-21) or calcineurin inhibitors (12) may serve as a
broader opportunity to maintain suppression of inflammation following acute phase
cytokine storm intervention with Basilixamab. One new area of interest is in complement
mitigation, and inhibitors (eciluzimab) targeting this more teleologically more primal
cascade may have a role (12, 22).
Drug: Basiliximab Injection
Subjects will be given IV dosing with basiliximab up to a maximum of 2 treatments (day 0
and day 4) for all patients on study. Treatment for patients may stop for unacceptable
side-effects, the Investigator's, or patient's decision to discontinue treatment or other
reasons. Exclusion for second dose is first dose returned patient to SpO2 ≥94% on room
air.
Other Name: Simulect
Drug: Placebo
Subjects will be given IV dosing with placebo (1/2 normal saline) up to a maximum of 2
treatments (day 0 and day 4) for all patients on study. Treatment for patients may stop
for unacceptable side-effects, the Investigator's, or patient's decision to discontinue
treatment or other reasons. Exclusion for second dose is first dose returned patient to
SpO2 ≥94% on room air.
Inclusion Criteria:
Subject Inclusion Criteria
1. Patient or legally authorized representative (LAR) willing and able to provide
written or electronic or otherwise FDA-acceptable informed consent based on current
FDA regulations.
2. Hospitalized male or non-pregnant female
3. RT-PCR confirmed SARS-CoV-2 using WHO consensus or validated primers
4. Meet the Following Criteria:
1. Deficiency in Oxygenation as defined by the Berlin ARDS Criteria (27):
Timing: Within 1 week of onset of symptoms Imaging: Bilateral pulmonary
infiltrates
Oxygenation (any):
Mild: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg Moderate: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg
Severe: PaO2/FiO2 ≤ 100 mmHg and
2. Requiring oxygen support in the form of High Flow Nasal Cannula (HFNC),
non-invasive positive pressure ventilation, intubation and mechanical
ventilation, or initiation of ECMO and
3. Any one or more of the following:
1. Elevated CRP (>10 gm/dL)
2. Elevated Ferritin (>1000)
3. Neutrophil/lymphocyte ratio >3.3
5. Patient will receive current clinical standard of care. This includes inpatient use
of remdesivir, dexamethasone, convalescent plasma, or pre-hospitalization outpatient
treatment with casirivimab and imdevima
6. Age ≥ 18 years
Exclusion Criteria:
1. Off label use of other drugs
2. WOCBP unwilling to use acceptable birth control for 5 weeks, or male partner of a
WOCBP unwilling to use male barrier method (condom) plus effective second method
birth control for partner
3. Pregnant women
4. Pancytopenia
1. Hgb< 8 g/dL (male) or < 7 g/dL (female)
2. WBC<2.0 x 109/L
3. PLT< 50 x 109/L
4) Enrollment in any study using immunomodulatory therapies (monoclonal antibodies,
small molecule inhibitors etc. to interleukins or interleukin-receptor) 5) Any
subjects who have received treatment with immunomodulators or immunosuppressant
drugs, including but not limited to IL-6 inhibitors, TNF inhibitors, anti-IL-1
agents, and JAK inhibitors within 5 half-lives or 30 days (whichever is longer)
prior to randomization.
6) Known/established systemic bacteremia (empiric antibiotics are allowed),
uncontrolled viral infection besides the SARS-CoV-2 study disease, significant
abscess in the opinion of the investigator, or any other finding that, in the
opinion of the investigator, poses undue risk for treatment with basiliximab.
7) Any patient with multi-organ system failure or on intravenous vasopressor support 8)
Do-not-resuscitate status at time of consent, or any contraindication to invasive
mechanical ventilation
mohanakrishnan sathyamoorthy, md
817423-8585
m.sathyamoorthy@tcu.edu
mohanakrishnan sathyamoorthy, Principal Investigator
FWCSWG