AstraZeneca initiates CALAVI clinical trial with Calquence against COVID-19

AstraZenecaAstraZeneca 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.

About 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.

About 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)

About 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.

About 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 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.(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.

About 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.

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 & Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. International Reviews of Immunology. 2012 Apr;31(2):119-32. doi: 10.3109/08830185.2012.664797.2012

Most Popular Now

How SARS-CoV-2 mutates to escape antibody binding

In a recurring pattern of evolution, SARS-CoV-2 evades immune responses by selectively deleting small bits of its genetic sequence, according to new research from the Uni...

Anticancer drug may improve outcome for severe COV…

Treating severe COVID-19 patients with the anticancer drug bevacizumab may reduce mortality and speed up recovery, according to a small clinical study in Italy and China ...

Pfizer and BioNTech commence global clinical trial…

Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) announced today that the first participants have been dosed in a global Phase 2/3 study to further evaluate the saf...

One dose of COVID-19 vaccine provokes strong immun…

Although clinical trial data are encouraging, real-world evidence with regard to the COVID-19 vaccine remains scarce. In particular, response to the vaccine among those p...

Johnson & Johnson announces submission of appl…

Johnson & Johnson (NYSE: JNJ) (the Company) announced that Janssen Biotech, Inc., has submitted an application to the U.S. Food and Drug Administration (FDA) requesting E...

GSK and Vir Biotechnology expand coronavirus colla…

GlaxoSmithKline plc (LSE/NYSE: GSK) and Vir Biotechnology, Inc. (Nasdaq: VIR) have signed a binding agreement to expand their existing collaboration to include the resear...

Could a nasal spray prevent coronavirus transmissi…

A nasal antiviral created by researchers at Columbia University Vagelos College of Physicians and Surgeons blocked transmission of SARS-CoV-2 in ferrets, suggesting the n...

European Commission purchases additional 150 milli…

Moderna, Inc. (Nasdaq: MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, today announced that the European Commission purchased an...

Neandertal gene variants both increase and decreas…

Last year, researchers at Karolinska Institutet in Sweden and the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany showed that a major genetic risk ...

CureVac initiates rolling submission with European…

CureVac N.V. (Nasdaq: CVAC), a global biopharmaceutical company developing a new class of transformative medicines based on messenger ribonucleic acid (mRNA), today annou...

Pfizer and BioNTech publish data from in vitro stu…

Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) today announced the publication in Nature Medicine of data from in vitro studies that demonstrate that sera from in...

Johnson & Johnson Announces Submission to Worl…

Johnson & Johnson (NYSE: JNJ) (the Company) announced that Janssen-Cilag International N.V. has submitted for Emergency Use Listing (EUL) to the World Health Organization...