To explore the efficacy of treatment of pulmonary cytokine storm induced by SARS-CoV2 with a monoclonal antibody to IL-2 (Basiliximab) in addition to current standard of care vs current standard of care with the primary efficacy endpoint being the proportion of subjects alive and free of ventilator support, defined as intubation and requiring mechanical 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