June 5, 2020 -- Results published in Science Immunology showed that Calquence (acalabrutinib), a Bruton’s tyrosine kinase (BTK) inhibitor, reduced markers of inflammation and improved clinical outcomes of patients with severe COVID-19 disease.1

The peer-reviewed case series of 19 hospitalised patients with COVID-19 disease and severe hypoxia and/or inflammation is a collaboration from investigators across the US, including AstraZeneca scientists, and led by Wyndham Wilson, M.D., Ph.D. and Louis Staudt, M.D., Ph.D. at the National Cancer Institute of the National Institutes of Health in the US.

The publication describes the effects of Calquence administration in patients with severe respiratory illness caused by the SARS-CoV-2 virus.1 A virus-induced hyperimmune response or “cytokine storm” is hypothesised to be a major pathogenic mechanism of respiratory illness in these patients, and evidence suggests that dysregulated BTK-dependent lung macrophage signalling mediates this cytokine storm and plays a role in COVID-19 pneumonia. 2-7

José Baselga, Executive Vice President, Oncology R&D, said: “The science supporting investigation of the use of Calquence in patients with severe COVID-19 is strong. The encouraging preliminary data in this case series has informed the initiation of global phase II trials, notably the CALAVI programme. We look forward to completing recruitment and obtaining data in these trials as soon as possible to further our understanding of what this potential treatment could mean for patients.”

Calquence is a next-generation, selective BTK inhibitor currently approved in the US for the treatment of certain haematological malignancies.8-10 Calquence is not currently approved in any country to treat patients with illnesses related to SARS-CoV-2.

CALAVI

The CALAVI programme comprises two randomised, open-label, multicentre, global trials evaluating the efficacy and safety of Calquence with best supportive care (BSC) versus BSC alone in patients hospitalised with respiratory complications of COVID-19. These trials are evaluating the addition of Calquence to current BSC in patients who are hospitalised but not on assisted ventilation. These trials are being conducted around the world: one trial in the US and one trial ex-US including Europe, Japan and South America. The primary efficacy endpoint measures the number of patients alive and free of respiratory failure following treatment.11,12

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.13,14 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.3,15 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.4,7

Calquence

Calquence is a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity.8-10 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.10

In the US, Australia, the United Arab Emirates, and India, Calquence is approved for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL), and in Canada for CLL. Calquence is also approved in the US and a few other countries for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is approved in the US under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Calquence is not currently approved in any country to treat patients with illnesses related to SARS-CoV-2.

BTK Inhibition

In lung macrophages, Bruton’s tyrosine kinase (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-19.15

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 acute respiratory distress syndrome (ARDS). 3-6 In macrophages, TLR3, TLR7 and TLR8 can recognise 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. 4-7 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 & Metabolism, and Respiratory & Immunology. 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 and follow the Company on Twitter @AstraZeneca.

References

1 Roschewski M, et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Sci Immunol. 2020;5(28). DOI: 10.1126/sciimmunol.abd0110.
2 Conti P, et al., Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34(2):1. doi: 10.23812/CONTI-E.
3 Channappanavar 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(2):181-193. doi: 10.1016/j.chom.2016.01.007.
4 Huang KJ, et al. An Interferon-Gamma-Related Cytokine Storm in SARS Patients. J Med Virol. 2005;75(2):185-94. doi: 10.1002/jmv.20255.
5 Wong CK, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004;136(1): 95–103. doi: 10.1111/j.1365-2249.2004.02415.x.
6 Yoshikawa T, 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(7): 3039–3048. Published online 12 Nov 2008. doi: 10.1128/JVI.01792-08.
7 Herold S, et al. Influenza Virus-Induced Lung Injury: Pathogenesis and Implications for Treatment. Eur Respir J. 2015;45(5):1463-78. doi: 10.1183/09031936.00186214.
8 Wu J, et al. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).
9 Khan Y, et al. Acalabrutinib and its use in treatment of chronic lymphocytic leukemia. Future Oncol. 2019;15(6):579-589.
10 CALQUENCE® (acalabrutinib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020.
11 AstraZeneca. Acalabrutinib Study With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19. (CALAVI). ClinicalTrials.gov. Identifier: NCT04346199. Accessed June 2020.
12 AstraZeneca. Acalabrutinib Study With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19. (CALAVI US). ClinicalTrials.gov. Identifier: NCT04380688. Accessed June 2020.
13 Huang C, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.
14 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.
15 Buggy JJ & Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Intl Rev Immunol. 2012;31(2):119-132. doi: 10.3109/08830185.2012.664797.2012.

Source: AstraZeneca

Posted: June 2020