COVID-19, the disease caused by the novel virus SARS-CoV-2, is a respiratory disease that is easily transmitted between people. Many people experience only mild symptoms or no symptoms at all. Mild symptoms include fever, cough, fatigue, myalgia, breathing difficulties, and loss of smell and taste. However, a significant percentage of patients develop severe pneumonia, which can progress to acute respiratory distress syndrome (ARDS) or multi-organ failure. The infection fatality rate for COVID-19 is likely around 1%, with much higher rates in older patients and patients with certain preexisting conditions.
Severe COVID-19 is characterized by inflammation and thrombosis, in addition to respiratory symptoms and damage to lung tissue. Patients show abnormalities in the coagulation system and elevated levels of proinflammatory cytokines as well as infiltration of macrophages and neutrophils in the lung. Several studies (refs 6-8 from Lancet + Cell paper) have demonstrated widespread complement activation in lungs and kidneys in humans as well as in animal models of the disease. The complement component C5a has been implicated in the pathology of COVID-19 in two ways: C5a can attract and activate neutrophils, which leads to tissue damage, and it can activate the coagulation system via its action on endothelial cells and neutrophils. Thus, C5a might have a central role in the development of ARDS as well as in vascular thrombosis (blood clots in the veins) in COVID-19. (refs Lancet 13-16)
Currently, few treatment options for severe COVID-19 exist. In addition to supportive care, dexamethasone, a corticosteroid with anti-inflammatory and immunosuppressive effects, has been shown to be beneficial in hospitalized patients who require supplemental oxygen. Further, remdesivir, a broad-spectrum antiviral, may shorten the recovery time for people with severe COVID-19.
Based on the involvement of C5a in COVID-19, InflaRx initiated a Phase II/III clinical study in March 2020. The Phase II part of the study evaluated vilobelimab treatment plus best supportive care compared to best supportive care alone for up to 28 days. The Phase II part was randomized and enrolled a total of 30 patients. The 28-day all-cause mortality rate was 13% (n = 2 out of 15) in the vilobelimab treatment arm compared to 27% (n = 4 out of 15) in the best supportive care arm. In the IFX‑1 treatment arm, fewer patients experienced renal impairment assessed by estimated glomerular filtration rates and more patients showed reversal of blood lymphocytopenia and a greater lowering of lactate dehydrogenase concentrations as a sign of reduction in tissue damage. A temporary, but statistically significant increase of D-dimer levels in the first days following vilobelimab administration was noted, as a potential signal for induction of blood clot lysis. No statistically significant group differences on the chosen primary endpoint of relative change (%) from baseline to day 5 in oxygenation index (defined as PaO2/FiO2 ratio) were detected. The Phase II results have been published in the Lancet Rheumatology (Link).
In September 2020, InflaRx initiated the randomized, double-blinded, placebo-controlled Phase III part of the study in the Netherlands and received regulatory approval to start the trial in Germany. The trial is currently enrolling, and patients are undergoing treatment. Additional sites in the US, EU and other regions are planned to be added. InflaRx plans to enroll approximately 360 early intubated, critically ill patients with severe COVID-19. Patients will be randomized 1:1 to receive either vilobelimab or placebo; all patients will receive standard of care. The primary endpoint is 28-day all-cause mortality, and key secondary endpoints include assessment of organ support and disease improvement. An interim analysis is planned after enrollment of 180 patients, with the potential for an early stop for efficacy or futility.