Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide range of clinical features, from completely asymptomatic infections to fatal or life-threatening disease.
In moderate to severe coronavirus disease 2019 (COVID-19), the pathophysiology is thought to be a hyperinflammatory response to SARS-CoV-2 that often results in a cytokine storm. This is accompanied by modulation of the T regulatory cell (Treg) response, which leads to adverse outcomes.
Study: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Clinical Trial of AZD1656 In Diabetic Patients Hospitalised With COVID-19: The ARCADIA Trial - Implications for Therapeutic Immune Modulation. Image Credit: Fahroni / Shutterstock.com
A new eClinicalMedicine study examines the potential benefit of the glucokinase activator molecule AZD1656 in the AtRial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial. This investigational drug was developed as a treatment for diabetes.
Diabetes is a high-risk factor for death from COVID-19, while high glycated hemoglobin (HbA1C), which is a biomarker of chronic hyperglycemia, predicts increased mortality. This prompted scientists to test the use of an enzyme activator AZD1656, which accelerates the metabolism of glucose, thereby increasing glucokinase activity by over one hundred-fold.
Prior research, including 25 clinical trials, has been carried out on AZD1656 by AstraZeneca in an effort to identify better drugs for diabetes management. These studies included almost one thousand patients treated with AZD1656 for up to six months. While its tolerability was established, its hypoglycemic effect only lasted for up to four months.
Treg recruitment in inflamed tissues precedes their anti-inflammatory effects. Because this migration is selectively controlled by glycolysis levels caused by glucokinase, enhancement of this enzyme function results in increased tissue localization and reduced Tregs in circulation. In vivo, the use of Tregs in acute lung injury subjects resulted in recovery.
The scientists hypothesized that such a reduction in hyperactive immune responses following the use of AZD1656 through increased Treg numbers at inflamed sites could restore normal immune status. As a result, cardiorespiratory complications would be less likely, with shorter hospitalizations and lower death rates.
In the current study, the researchers assessed the ability of AZD1656 to improve clinical parameters by day 14. The researchers also measured the mortality rate, hospitalization duration, glucose levels, and drug safety while exploring associated immunologic changes.
The double-blind, randomized controlled trial included 153 adult patients who were treated at 28 hospitals in three countries. All participants had suspected or confirmed COVID-19, diabetes, and blood glucose levels above the normal range.
AZD1656 or placebo was given twice a day for 21 days. No patients were expected to require mechanical ventilation within the next day.
The mean patient age was 63 and 65 years for the AZD and placebo groups, respectively. The majority of study participants were White.
All study participants had initial baseline blood glucose levels exceeding 8.5 mmol/L. Both AZD and placebo groups were treated for a mean of one week.
If the discharge date, date of mechanical ventilation, or death occurred prior to these three weeks, this event was considered the end date. Standard of care was provided to all patients according to local protocols. Various tests were carried out for safety, cardiac injury, vital signs, and other laboratory tests.
No significant clinical improvement occurred with the use of this drug.
A pre-planned longitudinal analysis showed that AZD1656 performed approximately twice as well as placebo.”
When only males were considered, the clinical improvement was 80% higher in the AZD group. Comparatively, clinical improvement rose by 60% and three-fold among older patients between the ages of 65-85 years and those with low vitamin D levels at baseline, respectively. Prior research has shown that the protective effect of higher Vitamin D levels was mediated by higher Treg/total T-cell ratios and reduction of the toxic cytokine storm.
The proportion of patients discharged was almost identical in both groups at 80%. Glycemic control was not improved; however, more patients receiving AZD1656 had subnormal glucose levels during the study period.
From day seven onwards, the likelihood of being hospitalized remained higher in the placebo group. Four patients died in the AZD group as compared to nine in the placebo group; however, intubation or mechanical ventilation was used in equal proportions in both groups.
Serious adverse events were lower in the AZD group; however, discontinuation rates were similar in both groups.
Immunologic differences were observed between the two groups. For example, the AZD group had lower levels of inflammatory monocytes and the inflammatory cytokine MIP1α in the circulation. These reduced levels were particularly evident at the end of the drug administration period, thus indicating a modulated innate immune response.
The adaptive immune response was also altered in the AZD group, with increased numbers of activated cMet type 1 T helper cells (Th1) cells producing interferon or tumor necrosis factor (TNF). Both type 2 T helper cells (Th2) cells and B-cells were lower in the placebo group at the end of the drug administration period.
Both groups exhibited fewer cMet Tregs only on day 11. This reduction was greater in the placebo group.
Resting Tregs showed no difference in either group. It is possible that the resting-to-activated Treg ratio changed as a result of an altered production use ratio. This observation requires further clarification.
The evidence presented here suggests that specific activation of Tregs might suppress the inappropriate inflammation which is the prime cause of tissue damage in autoimmune disease.”
A post-hoc analysis revealed shorter times to death in the placebo group during hospitalization. Six patients in this group died by the end of the first week as compared to none in the AZD group. By the time the drug was stopped, one patient in the AZD group, as compared to six in the placebo group died.
Time to discharge was shorter in the AZD group, with about 40% discharged by one week as compared to about 25% of the placebo group. With high levels of the pro-inflammatory cytokine interleukin 6 (IL-6), patients were more likely to be hospitalized for longer periods in the placebo group.
Conversely, patients in the AZD group with high IL-6 levels exhibited a three-day reduction in hospitalization duration, despite being at a higher risk for an adverse outcome as compared to the rest of the group.
The study findings indicate the need for larger studies to confirm the potential benefit of AZD1656 in diabetics with moderate to severe COVID-19. AZD1656 may achieve its effect either by better control of blood sugar levels or modulation of the immune response through increased Treg migration to inflammation sites. The potential role of Treg migration is more likely, which indicates that a new equilibrium is reached between the inflammatory and anti-inflammatory responses.
The ARCADIA trial has produced a new therapeutic concept: specific cell activation by a small molecule whereby the activated cell itself becomes the therapeutic agent within the body (“in vivo activated-cell therapy”).”
AZD1656 treats the viral effect on cells and, as a result, is unlikely to be affected by escape mutations, unlike monoclonal antibodies or antiviral drugs targeting viral enzymes. Nevertheless, a larger study is needed to confirm the benefit of this unique drug.
Although the trial was designed to address COVID-19, these findings might have wide implications for the development of new therapeutics across a spectrum of immune and other diseases.”
- Chorlton, J., Hollowood, Z., Dyer, C., et al. (2022). A Randomised, Double-Blind, Placebo-Controlled, Multicentre Clinical Trial of AZD1656 In Diabetic Patients Hospitalised With COVID-19: The ARCADIA Trial - Implications for Therapeutic Immune Modulation. eClinical Medicine. doi:10.1016/j.eclinm.2022.101604.