AstraZeneca's BTK Inhibitor Calquence Shows Clinical Benefit in Severe COVID-19 Patients Amid Global Pandemic Surge

June 09, 2020 News /BioValleyBIOON/ -- At present, the COVID-19 epidemic overseas is still spreading rapidly. According to Baidu's "Real-time Data on the Novel Coronavirus Pneumonia Epidemic"Big DataReport, as of 18:00 on June 9, 2020, the global cumulative confirmed cases exceeded 7.217 million, with 7.132 million cumulative confirmed cases and 404,000 deaths outside China. Among them, the United States had 2.026 million cumulative confirmed cases and 113,000 deaths.

The COVID-19 pandemic has reached an unprecedented level of severity, prompting governments worldwide to issue emergency authorizations for the use of promising drugs and therapies in the treatment of severe cases of COVID-19. These interventions include antiretroviral agents, antimalarial drugs, anti-inflammatory medications, and convalescent plasma. Currently, numerous pharmaceutical companies have engaged in the research and development of drugs and vaccines for coronavirus disease 2019 (COVID-19).

Recently,AstraZenecaAnnounced, published in "Science"ImmunologyResearch results published in *Science Immunology* show that the anticancer drug BTK inhibitor Calquence (acalabrutinib) can reduce inflammatory markers and improve clinical outcomes in patients with severe COVID-19. The article is titled:Inhibition of Bruton tyrosine kinase in patients with severe COVID-19。

In this article, a peer-reviewed case series comprising 19 hospitalized patients with COVID-19 and severe hypoxia and/or inflammation was conducted through collaboration among U.S. researchers, including scientists from AstraZeneca, under the leadership of Dr. Wyndham Wilson and Dr. Louis Staudt from the National Cancer Institute (NCI) of the National Institutes of Health (NIH).

The article describes the efficacy of Calquence in treating patients with severe respiratory disease caused by the novel coronavirus (SARS-CoV-2). Virus-induced hyperimmune responses, or “cytokine storms,” are considered the primary pathogenic mechanism underlying respiratory disease in these patients. Evidence suggests that dysregulated BTK-dependent pulmonary macrophage signaling mediates this cytokine storm and plays a role in COVID-19 pneumonia.

According to the article, 19 hospitalized patients with severe COVID-19 (11 receiving supplemental oxygen and 8 on mechanical ventilation) were treated with Calquence off-label, 18 of whom had increased oxygen requirements at baseline.During the 10–14-day treatment course, Calquence improved oxygenation in most patients, typically within 1–3 days, with no significant toxicity.

Inflammatory markers—C-reactive protein (CRP) and interleukin-6 (IL-6)—returned to normal rapidly in most patients, lymphopenia also resolved quickly, with corresponding improvement in oxygenation. At the end of Calquence treatment, 72.7% (8/11) of patients in the supplemental oxygen cohort had discontinued supplemental oxygen and were breathing room air; in the mechanical ventilation cohort, 50% (4/8) of patients had been successfully extubated, and 25% (2/8) were breathing room air.

In vitro analysis revealed that, compared with blood monocytes from healthy volunteers, blood monocytes from patients with severe COVID-19 exhibited significantly elevated BTK activity (autophosphorylation) and increased IL-6 production.

These results suggest that targeting excessive host inflammation with BTK inhibitors is a therapeutic strategy for severe COVID-19. Based on these findings, AstraZeneca has initiated a confirmatory international prospective randomized controlled trialClinical Trial。

AstraZenecaTumorJosé Baselga, Executive Vice President of Research and Development, stated, “There is a strong scientific rationale for investigating the use of Calquence in patients with severe COVID-19. The encouraging preliminary data demonstrated in this case series have informed the initiation of global Phase II trials, particularly the CALAVI program. We look forward to completing enrollment and obtaining data from these trials as soon as possible to further understand what this potential treatment means for patients.”

CALAVI Project:In mid-April this year, AstraZeneca announced the launch of the CALAVI project to evaluate the potential of Calquence in treating hyperimmune responses (cytokine storm) associated with COVID-19 infection in critically ill patients. The project includes two randomized, open-label, multicenter, globalClinical Trials, one conducted in the United States and the other conducted outside the United States (including Europe, Japan, and South America), evaluating Calquence combined with best supportive care (BSC) versus BSC alone in hospitalized patients with COVID-19 who had respiratory complications; the primary efficacy endpoint was the number of patients who survived without respiratory failure after treatment.

COVID-19：This is a novel pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most COVID-19 cases (approximately 80%) present as mild respiratory illness. However, some patients require hospitalization, primarily due to pneumonia, and can rapidly progress to severe acute lung injury and acute respiratory distress syndrome (ARDS), which is associated with high mortality. The virus-induced cytokine storm, or “hyperimmune response,” mediated by the modulation of pulmonary macrophages, dendritic cells, and/or neutrophils, is considered the primary pathogenic mechanism underlying ARDS in these patients.

Calquence：This is a new generation of selective BTK inhibitor that covalently binds to BTK, thereby inhibiting its activity. In B cells, BTK signaling leads to the activation of multiple pathways necessary for B cell proliferation, trafficking, chemotaxis, and adhesion. In the United States and several other countries, Calquence is approved for the treatment of adult chronic lymphocyticLeukemia(CLL) and mantle cell lymphoma (MCL).

BTK Inhibition:In pulmonary macrophages, BTK is a key regulator of the production of various cytokines and chemokines, including TNF-α, IL-6, IL-10, and MCP-1. BTK inhibition reduces the production of these cytokines, making it a promising strategy for mitigating respiratory complications in COVID-19.

Evidence suggests that dysregulated BTK-dependent macrophage signaling may be central to the excessive inflammatory response to SARS-CoV-2 and plays a role in COVID-19 pneumonia and ARDS. TLR3, TLR7, and TLR8 in macrophages recognize single-stranded RNA from viruses such as SARS-CoV-2 and initiate signaling through BTK-dependent activation of NF-kB and IRF3, thereby triggering the production of various inflammatory cytokines and chemokines. In lymph node malignancyTumorIn patients, therapeutic inhibition of BTK led to reduced levels of pro-inflammatory cytokines and chemokines, supporting the role of BTK inhibition. Similar findings were observed in a murine influenza model, where BTK inhibition also decreased these inflammatory mediators and rescued mice from fatal acute lung injury. (Bioon.com)

Original Source: Calquence showed promising clinical improvement in majority of 19 hospitalised COVID-19 patients