Improved laboratory markers of inflammation and decreased oxygen requirements observed in most patients??

Ongoing global trials aim to confirm findings

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 Jos? Baselga, Executive Vice President, Oncology R&D, said: ?The science supporting investigation of the use of?Calquencein 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. Contacts For details on how to contact the Investor Relations Team, please click?here. For Media contacts, click?here.

References

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