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2020-04-14

AstraZeneca: AstraZeneca initiates CALAVI clinical trial with Calquence against COVID-19

Trial will assess the effect of Calquence on the exaggerated immune
response of patients hospitalised with COVID-19 infection

AstraZeneca will initiate a randomised, global clinical trial to
assess the potential of Calquence (acalabrutinib) in the treatment of
the exaggerated immune response (cytokine storm) associated with
COVID-19 infection in severely ill patients.

The trial design is based upon strong scientific evidence supporting
the role of the Bruton's tyrosine kinase (BTK) pathway in the
production of inflammatory cytokines and on encouraging early
clinical data. Calquence is a next-generation, highly selective BTK
inhibitor currently used to treat certain types of blood cancers.

The trial, called CALAVI, is based on early clinical data with
Calquence demonstrating that a decrease in inflammation caused by BTK
inhibition appears to reduce the severity of COVID-19-induced
respiratory distress. The goal of the trial is to evaluate the
efficacy and safety of adding Calquence to best supportive care (BSC)
to reduce mortality and the need for assisted ventilation in patients
with life-threatening COVID-19 symptoms.

This large, multicentre, global, randomised trial uses a two-part
patient-centric design developed in record time to accelerate data
capture and analysis. Part one evaluates the addition of Calquence to
BSC versus BSC alone in patients hospitalised with COVID-19 who are
not in the intensive care unit (ICU). Part two evaluates the addition
of Calquence to BSC in a cohort of patients in the ICU.

José Baselga, Executive Vice President, Oncology R&D, said: "With this
trial we are responding to the novel insights of the scientific
community and hope to demonstrate that adding Calquence to best
supportive care reduces the need to place patients on ventilators and
improves their chances of survival. This is the fastest launch of any
clinical trial in the history of AstraZeneca."

Louis M. Staudt, M.D., Ph.D., Chief of the Lymphoid Malignancies
Branch at the National Cancer Institute (NCI), said: "Given the well
documented role of the protein BTK in regulating inflammation, it is
possible that inhibiting BTK with acalabrutinib could provide
clinical benefit in patients with advanced COVID-19 lung disease. As
with all new treatments, it will be necessary to gather data from
clinical trials in order to understand the best and safest treatment
options for patients."

The CALAVI trial is expected to open for enrolment in the coming days
in the US and several countries in Europe. Wyndham H. Wilson, MD,
PhD, of NCI in the US, will serve as the principal investigator of
the trial. Louis M. Staudt, MD, PhD will serve as senior
investigator.

CALAVI

CALAVI is a large, randomised, open-label, multicentre, global,
two-part trial evaluating the efficacy and safety of Calquence with
BSC versus BSC alone in patients hospitalised with respiratory
complications of COVID-19. Part one is randomised (2:1) and evaluates
the addition of Calquence to current BSC in patients who are
hospitalised but not on assisted ventilation and not in the ICU. Part
two evaluates the addition of Calquence to BSC in a cohort of
patients in the ICU with more severe respiratory complications. The
trial is being conducted in multiple sites around the world. The
primary endpoint measures the use of assisted ventilation or death.

COVID-19

Coronavirus disease 2019 (COVID-19) is a new pandemic disease caused
by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Most COVID-19 cases (~80%) are mild respiratory illnesses. However,
some require hospitalisation, mostly due to pneumonia, and can
progress quickly to severe acute lung injury and acute respiratory
distress syndrome (ARDS), which is associated with high
mortality.[1,2,3,4 ]A viral-induced cytokine storm or "hyperimmune
response" is hypothesised to be a major pathogenic mechanism of ARDS
in these patients through modulation of pulmonary macrophages and
dendritic cells and/or neutrophils.[5,6,7,8]

Calquence

Calquence is a next-generation, selective inhibitor of BTK. Calquence
binds covalently to BTK, thereby inhibiting its activity.[9,10,11,12]
In B-cells, BTK signalling results in activation of pathways
necessary for B-cell proliferation, trafficking, chemotaxis, and
adhesion.[13]

Calquence (acalabrutinib) is approved for the treatment of adult
patients with chronic lymphocytic leukaemia (CLL) in the US and a few
other countries with an active global filing programme. In addition,
Calquence is indicated for adult patients with mantle cell lymphoma
(MCL) who have received at least one prior therapy in the US and
several other countries.

BTK Inhibition

In lung macrophages, BTK is a key regulator of the production of
multiple cytokines and chemokines including TNFa, IL-6, IL-10, and
MCP-1, among others. BTK inhibition reduces the production of these
cytokines and is, therefore, a promising strategy to reduce the
respiratory complications of COVID-19.[13]

There is evidence that dysregulated BTK-dependent macrophage
signalling may be central to the exaggerated inflammatory responses
to SARS-COV-2 and play a role in COVID-19 pneumonia and ARDS.[
4,5,6,7] In macrophages, TLR3, TLR7 and TLR8 can recognize single
strand RNA from viruses such as SARS-COV-2 and initiate signalling
through BTK-dependent activation of NF-kB and IRF3, triggering the
production of multiple inflammatory cytokines and chemokines.[
5,6,7,8] In support of the role of BTK inhibition, therapeutic
inhibition of BTK in patients with lymphoid malignancies results in
decreased proinflammatory cytokines and chemokines. Similar findings
have been observed in mouse influenza models, where BTK inhibition
also decreased these inflammatory mediators and rescued mice from
lethal acute lung injury.[ ]

AstraZeneca

AstraZeneca (LSE/STO/NYSE: AZN) is a global, science-led
biopharmaceutical company that focuses on the discovery, development
and commercialisation of prescription medicines, primarily for the
treatment of diseases in three therapy areas - Oncology,
Cardiovascular, Renal and Metabolism, and Respiratory. Based in
Cambridge, UK, AstraZeneca operates in over 100 countries and its
innovative medicines are used by millions of patients worldwide.
Please visit astrazeneca.com (http://www.astrazeneca.com/) and follow
the Company on Twitter @AstraZeneca
(https://twitter.com/AstraZeneca).

Contacts

For details on how to contact the Investor Relations Team, please
click here
(https://www.astrazeneca.com/investor-relations.html#Contacts). For
Media contacts, click here
(https://www.astrazeneca.com/media-centre/contacts.html).

References

1. Huang C, Wang Y, Li X, et al. Clinical features of patients
infected with 2019 novel coronavirus in Wuhan, China. Lancet.
2020;395:497-506.

2. Wu Z, McGoogan JM. Characteristics of and important lessons from
the coronavirus disease 2019 (COVID-19) outbreak in China: summary of
a report of 72 314 cases from the Chinese Center for Disease Control
and Prevention. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648. [Epub
ahead of print]

3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for
mortality of adult inpatients with COVID-19 in Wuhan, China: a
retrospective cohort study. Lancet. 2020; 395:1054-62.

4. Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated type I
interferon and inflammatory monocyte-macrophage responses cause
lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe. 2016;
19:181-93.

5. Huang KJ, Su IJ, Theron M, et al. An interferon-gamma-related
cytokine storm in SARS patients. J Med Virol. 2005; 75:185-94.

6. Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and
chemokines in severe acute respiratory syndrome. Clin Exp Immunol.
2004; 136:95-103.

7. Yoshikawa T, Hill T, Li K, et al. Severe acute respiratory syndrome
(SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS
pathogenesis by modulating intrinsic functions of monocyte-derived
macrophages and dendritic cells. J Virol. 2009; 83:3039-48.

8. Herold S, Becker C, Ridge KM, et al. Influenza virus-induced lung
injury: pathogenesis and implications for treatment. Eur Respir J.
2015; 45:1463-78.

9. Calquence (acalabrutinib) [prescribing information]. Wilmington,
DE; AstraZeneca Pharmaceuticals LP; 2019.

10. Wu J, Zhang M & Liu D. Acalabrutinib (ACP-196): a selective
second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).

11. Khan Y & O'Brien S. Acalabrutinib and its use in treatment of
chronic lymphocytic leukemia. Future Oncol. 2018;15(6).

12. Byrd JC, et al. Acalabrutinib (ACP-196) in Relapsed Chronic
Lymphocytic Leukemia. N Engl J Med. 2016; 374:323-332.

13. Buggy JJ
(https://www.ncbi.nlm.nih.gov/pubmed/?term=Buggy%20JJ%5BAuthor%5D&cauthor...)
& Elias L
(https://www.ncbi.nlm.nih.gov/pubmed/?term=Elias%20L%5BAuthor%5D&cauthor=...).
Bruton tyrosine kinase (BTK) and its role in B-cell malignancy.
International Reviews of Immunology.
(https://www.ncbi.nlm.nih.gov/pubmed/22449073) 2012 Apr;31(2):119-32.
doi: 10.3109/08830185.2012.664797.2012

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