Study identifies potential approach to treat patients with severe COVID-
19

Date:
June 5, 2020
Source:
NIH/National Cancer Institute
Summary:
Early data from a clinical study suggest that blocking the Bruton
tyrosine kinase (BTK) protein with the cancer drug acalabrutinib
provided clinical benefit to a small group of patients with severe
COVID-19.



FULL STORY ========================================================================== Early data from a clinical study suggest that blocking the Bruton
tyrosine kinase (BTK) protein provided clinical benefit to a small group
of patients with severe COVID-19. Researchers observed that the off-label
use of the cancer drug acalabrutinib, a BTK inhibitor that is approved
to treat several blood cancers, was associated with reduced respiratory distress and a reduction in the overactive immune response in most of
the treated patients.


==========================================================================
The findings were published June 5, 2020, in Science Immunology. The
study was led by researchers in the Center for Cancer Research at the
National Cancer Institute (NCI), in collaboration with researchers from
the National Institute of Allergy and Infectious Diseases (NIAID),
both part of the National Institutes of Health (NIH), as well as the
U.S. Department of Defense's Walter Reed National Military Medical Center,
and four other hospitals nationally.

These findings should not be considered clinical advice but are being
shared to assist the public health response to COVID-19. While BTK
inhibitors are approved to treat certain cancers, they are not approved as
a treatment for COVID-19. This strategy must be tested in a randomized, controlled clinical trial in order to understand the best and safest
treatment options for patients with severe COVID-19.

The BTK protein plays an important role in the normal immune system,
including in macrophages, a type of innate immune cell that can cause inflammation by producing proteins known as cytokines. Cytokines act
as chemical messengers that help to stimulate and direct the immune
response. In some patients with severe COVID-19, a large amount of
cytokines are released in the body all at once, causing the immune
system to damage the function of organs such as the lungs, in addition
to attacking the infection. This dangerous hyperinflammatory state is
known as a "cytokine storm." At present, there are no proven treatment strategies for this phase of the illness. The study was developed to
test whether blocking the BTK protein with acalabrutinib would reduce inflammation and improve the clinical outcome for hospitalized patients
with severe COVID- 19.

This prospective off-label clinical study included 19 patients with a
confirmed COVID-19 diagnosis that required hospitalization, as well as
with low blood- oxygen levels and evidence of inflammation. Of these
patients, 11 had been receiving supplemental oxygen for a median of
two days, and eight others had been on ventilators for a median of 1.5
(range 1-22) days.

Within one to three days after they began receiving acalabrutinib,
the majority of patients in the supplemental oxygen group experienced
a substantial drop in inflammation, and their breathing improved. Eight
of these 11 patients were able to come off supplemental oxygen and were discharged from the hospital.

Although the benefit of acalabrutinib was less dramatic in patients
on ventilators, four of the eight patients were able to come off the ventilator, two of whom were eventually discharged. The authors note that
the ventilator patient group was extremely clinically diverse and included patients who had been on a ventilator for prolonged periods of time and
had major organ dysfunction. Two of the patients in this group died.

Blood samples from patients in the study showed that levels of
interleukin-6 (IL-6), a major cytokine associated with hyperinflammation
in severe COVID-19, decreased after treatment with acalabrutinib. Counts
of lymphocytes, a type of white blood cell, also rapidly improved in
most patients. A low lymphocyte count has been associated with worse
outcome for patients with severe COVID-19.

The researchers also tested blood cells from patients with severe COVID-19
who were not in the study. In comparison with samples from healthy
volunteers, they found that these patients with severe COVID-19 had higher activity of the BTK protein and greater production of IL-6. These findings suggest that acalabrutinib may have been effective because its target,
BTK, is hyperactive in severe COVID-19 immune cells.

The results of this study were used to inform the trial design of the
CALAVI (acalabrutinib) randomized, controlled clinical trial, sponsored by AstraZeneca, which will examine the safety and efficacy of acalabrutinib
in patients with severe COVID-19.


========================================================================== Story Source: Materials provided by NIH/National_Cancer_Institute. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Mark Roschewski, Michail S. Lionakis, Jeff P. Sharman, Joseph
Roswarski,
Andre Goy, M. Andrew Monticelli, Michael Roshon, Stephen
H. Wrzesinski, Jigar V. Desai, Marissa A. Zarakas, Jacob Collen,
Keith Rose, Ahmed Hamdy, Raquel Izumi, George W. Wright,
Kevin K. Chung, Jose Baselga, Louis M. Staudt, Wyndham
H. Wilson. Inhibition of Bruton tyrosine kinase in patients with
severe COVID-19. Science Immunology, 2020; 5 (48): eabd0110 DOI:
10.1126/sciimmunol.abd0110 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200605140516.htm

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