Blockade of Interleukin Seventeen (IL-17A) with Secukinumab in
Hospitalized COVID-19 patients – the BISHOP study.
Resende, Gustavo Gomes
1
; da Cruz Lage, Ricardo
1
; Lobê, Samara Quadros
2
; Medeiros,
Amanda Fonseca
2
; Costa e Silva, Alessandra Dias
2
; Nogueira Sá, Antônio Tolentino
2
; Oliveira,
Argenil José de Assis
2
; Sousa, Denise
2
; Guimarães, Henrique Cerqueira
2
; Gomes, Isabella
Coelho
2
; Souza, Renan Pedra
3
; Aguiar, Renato Santana
3,4
; Tunala, Roberto.
5
; Forestiero,
Francisco.
5
; Bueno Filho, Julio Silvio Souza.
6
; Teixeira, Mauro Martins
7
1
Rheumatology Unit, Hospital das Clínicas - Universidade Federal de Minas Gerais (UFMG),
Brazil
2
Hospital Risoleta Tolentino Neves, Brazil
3
Dept. of Genetics, Ecology and Evolution -
UFMG, Brazil
4
Instituto D’Or de Pesquisa e Ensino (IDOR), Brazil
5
Novartis Brazil
6
Dept. of
Statistics, Universidade Federal de Lavras (UFLA), Brazil
7
Dept. of Biochemistry and Immunology
UFMG, Brazil.
ABSTRACT
Background: Patients with severe COVID-19 seem to have a compromised
antiviral response and hyperinflammation. Neutrophils are critical players in
COVID-19 pathogenesis. IL-17A plays a major role in protection against
extracellular pathogens and neutrophil attraction and activation. We
hypothesized that secukinumab, an anti-IL17A monoclonal antibody, could
mitigate the deleterious hyperinflammation in COVID-19.
Methods: BISHOP was an open-label, single-center, phase-II controlled trial.
Fifty adults hospitalized Covid-19 patients, confirmed by a positive SARS-CoV-2
RT-PCR, were randomized 1:1 to receive 300mg of secukinumab
subcutaneously at day-0 (group A) plus standard of care (SoC: antiviral drugs,
antimicrobials, corticosteroids, and/or anticoagulants) or SoC alone (group B). A
second dose of 300mg of secukinumab could be administered on day-7,
according to staff judgment. The primary endpoint was ventilator-free days at day-
28 (VFD-28). Secondary efficacy and safety outcomes were also explored.
Findings: An intention-to-treat analysis showed no difference in VFD-28: 23.7
(95%CI 19.6-27.8) in group A vs. 23.8 (19.9-27.6) in group B, p=0.62; There was
also no difference in hospitalization time, intensive care unit demand, the
incidence of circulatory shock, acute kidney injury, fungal or bacterial co-
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NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
infections, and severe adverse events. Pulmonary thromboembolism was less
frequent in group A (4.2% vs. 26.2% p=0.04). There was one death in each group.
Viral clearance, defined by the viral load fold change (2-ΔΔCT) in upper airways,
between day-0 and day-7, was also similar: 0.17 (0.05-0.56) in group A vs. 0.24
(0.10-0.57) in group B.
Interpretation: The efficacy of secukinumab in the treatment of Covid19 was not
demonstrated. No difference between groups in adverse events and no
unexpected events were observed.
Funding: Novartis Brazil supported this research providing expert input in the
development of the project, drug supply, data management, and monitoring.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted July 23, 2021. ; https://doi.org/10.1101/2021.07.21.21260963doi: medRxiv preprint
Blockade of Interleukin Seventeen (IL-17A) with Secukinumab in
Hospitalized COVID-19 patients – the BISHOP study.
1. INTRODUCTION
The new coronavirus (SARS-CoV-2) pandemic, which started in late
2019, has spread with impressive speed across the planet and has threatened
all health systems due to the considerable proportion of patients requiring
inpatient treatment, including intensive care and mechanical ventilation
(1)
. The
most severe patients, who progress to acute respiratory distress syndrome
(ARDS), seem to combine a poor antiviral response and systemic
hyperinflammation
(2-5)
. Their laboratory findings (liver dysfunction,
hyperferritinemia, disseminated intravascular coagulation, high levels of D-dimer,
and C-reactive protein, along with cytopenias) and cytokine responses resemble
those of other Hyperferritinemic Syndromes
(6)
such as the macrophage activation
syndrome (MAS), adult-onset Still’s disease (AOSD), septic shock and
catastrophic antiphospholipid syndrome (CAPS)
(7, 8)
.
It has been suggested that neutrophils are critical players in COVID-
19 pathogenesis. Indeed, COVID-19 severity has been associated with
neutrophilia, increased neutrophil-to-lymphocyte ratio (NLR), and aberrant
neutrophil activation
(9)
. Moreover, neutrophils infiltrate the lungs where diffuse
alveolar damage and microvascular thrombosis have been observed
(10)
. IL-17 is
a cytokine contributing to the pathogenesis of several immune-mediated
diseases, including spondyloarthritis and psoriasis
(11, 12)
. IL-17 drives neutrophil
accumulation in these diseases and can up-regulate several cytokines, including
CXCL8, TGF-, IL-1 TNF , and IL-6
(13-15)
. In the context of COVID-19, some
studies suggest that IL-17 may contribute to the pathogenesis of severe COVID-
19. It was already showed that Th17 count and IL-17 levels were increased in
critically ill COVID-19 patients compared to healthy donors. In addition, the ratio
of Th17/Treg cells, RORt/FoxP3, and IL‐17/IL‐10 were considerably enhanced
in patients who evolved to death compared to recovered cases
(16)
. Higher
concentrations of IL-17A in blood have been associated with a more severe
clinical course in patients with COVID-19. An expansion of tissue-resident
memory-like TH17 cells (TRM17 cells) has been observed in the lungs even after
viral clearance
(17)
. Furthermore, treatment with an IL-17RA antibody decreased
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inflammation in the lungs of mice infected with SARS-CoV-2 pseudovirus
expressing ORF8 virus protein
(18)
. Although these findings, a direct
demonstration of the relevance of IL-17 in the pathogenesis of COVID-19 is
lacking.
Secukinumab is a human IgG1 monoclonal antibody that binds to and
neutralizes IL-17A. It is currently approved in many countries to treat psoriasis,
ankylosing spondylitis, non-radiographic axial spondyloarthritis, and psoriatic
arthritis. We hypothesized that secukinumab could be used in patients with
respiratory failure due to COVID-19 and report here the results of a phase 2 open-
label randomized controlled trial to evaluate the effects of secukinumab in
hospitalized adult COVID-19 patients.
2. METHODS
Study design and participants
BISHOP (Blockade of Interleukin Seventeen in Hospitalized cOvid-19
Patients) is an investigator-initiated, open-label, single-center, phase-II controlled
trial. The study was performed in Hospital Risoleta Tolentino Neves (HRTN),
referral center for treatment of COVID-19 in northern region of Belo Horizonte city
in Brazil. Adult patients (age ≥ 18 years) admitted to the hospital were eligible for
the study if they had SARS-CoV-2 infection confirmed by RT-PCR of
nasopharyngeal swab and severe acute respiratory syndrome (SARS), according
to the Brazilian Ministry of Health criteria (dyspnea / respiratory discomfort OR
persistent chest pressure OR oxigen saturation less than 95% in room air OR
cyanosis of lips or face)
(19)
. Patients were included from September 1
st
to
December 29
th
, 2020.
The exclusion criteria were functional classes III and IV of congestive
heart failure (CHF) or chronic obstructive pulmonary disease (COPD), stages 4
and 5 of chronic kidney disease (GFR <30 mL/min), diabetic ketoacidosis, known
history of HIV/AIDS infection or chronic or acute HBV or HCV infection,
unrestrained bacterial or fungal co-infections (defined by hemodynamic
instability, prior 48h of antimicrobial covering, or at the discretion of the study's
medical coordinator), active tuberculosis, history of malignancy in the last year,
current use (or in the previous 15 days) of other immunosuppressants, baseline
neutrophils count ≤1000/mm3, pregnancy or breastfeeding.
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Randomization and procedures
Enrolled patients were sequentially subjected to block randomization
to receive 300 mg of secukinumab subcutaneously at day-0 plus standard of care
(SoC), hereinafter called group A, or SoC alone (group B) in a 1:1 ratio. A second
dose of 300 mg of secukinumab could be administered at day 7, according to the
judgment of the attending medical team and if theall enrollment criteria still
remained met. Of note, secukinumab dose regimen in COVID-19 patients has not
been assessed previously. The standard of care in Hospital Risoleta Tolentino
Neves, available to all patients, regardless of their allocation, during all the time
of study execution, included antimicrobials (azithromycin and a beta-lactam, at
the time of admission and until bacterial infection of the lungs could be excluded),
corticosteroids (dexamethasone, 6mg daily, during ten days), and prophylactic
anticoagulants (enoxaparin 40mg q12hr, except if thromboembolism was
diagnosed, in which case full anticoagulation was performed). Other
immunobiological agents, such as anti-IL-6R / anti-IL1 / anti-TNF-, was not
allowed. Patients, after hospital discharge, were monitored by phone calls and
messages until day 28.
Outcomes
The primary endpoint was ventilator-free days at day 28 (VFD-28).
VFD-28 is defined as (28 - x), where x is the number of days spent receiving
mechanical ventilation. This outcome focuses on the duration of need for
mechanical ventilation while simultaneously taking mortality into consideration
because it assigns a score of zero if the patient dies before 28 days
(20)
.
Secondary efficacy and safety outcomes also included (all assessed within the
time frame of 28 days): mortality rate; length of hospitalization; need and length
of critical care in the ICU; World Health Organization (WHO) Ordinal Scale for
Clinical Improvement; serious adverse events (any undesirable event associated
at least with prolongation of hospitalization), secondary bacterial and fungal
infections (culture-confirmed); and the incidence of acute renal failure (KDIGO
III), circulatory shock or need for vasopressors, pulmonary thromboembolism
(PTE) and reactions at the injection site. The effects of secukinumab on viral
clearance were explored by longitudinal sampling and RT-PCR for SARS-CoV-2
in the upper airway swab. Data were collected using the Research Electronic
Data Capture (REDCap) database (https://www.project-redcap.org).
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