According to the results of the phase 2 trial published in Open JAMA Network in December.
Pacritinib, which has been approved as a cancer treatment by the Food and Drug Administration (FDA), is classified as a JAK2 inhibitor; it blocks immune system messaging pathways that promote inflammation. The researchers suggested it might serve as a model to guide the selection of several other approved immunotherapies that have been shown to improve outcomes in patients with severe COVID-19, including the JAK2 inhibitor baricitinib and tocilizumab, IL-6 inhibitor.
“Although we identified subtypes of COVID-19 patients with hyperinflammation who might actually benefit from pacritinib, our study failed to show the superiority of pacritinib over standard management of hospitalized COVID-19 adults. suffering from acute respiratory distress syndrome for various reasons. “, says lead author John Mascarenhas, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai and director of the Center of Excellence for Blood Cancers and Myeloid Disorders. “We believe that one reason may have been that the study was limited by early dropout of participants who actually improved on this agent and therefore did not feel it was necessary to continue treatment and these patients were not captured as responders in the analysis.”
Dr. Mascarenhas believes that despite recent advances in immunomodulatory therapy, there is still an unmet need for therapeutic strategies to prevent disease progression in hospitalized patients. “Pacritinib showed an excellent safety profile in our trial,” he notes, “which is why further studies are needed to show how pacritinib or other similar agents might benefit certain populations. of patients with hyperinflammation who are at significant risk of poor outcomes. .”
JAK inhibitors are a class of drugs that inhibit the activity of one or more of the Janus kinase enzymes (JAK1, JAK2, JAK3, and TYK2) known to promote inflammation. They do this by transmitting signals from proteins called cytokines that attach to immune cell receptors to produce pro-inflammatory cytokines. JAK inhibitors interfere with this process by blocking the enzyme signaling pathway and calming the body’s immune system. Pacritinib is a selective JAK inhibitor, meaning it affects the enzymes JAK2 and IRAK1, but spares JAK1. This distinction is important because JAK1 is responsible for the differentiation and activity of immune cells that contribute to antiviral and antitumor responses. IRAK1 or IL-1 receptor-associated kinase 1 is an integral part of an inflammatory signaling pathway that results in the activation of NFκB which also regulates the expression of inflammatory cytokines.
The study, known as PRE-VENT, was launched in June 2020 in 21 centers with 200 patients in the early stage of the pandemic. He became the first to demonstrate that certain inflammatory markers like interleukin 6 (IL-6), a cytokine thought to be a key driver of inflammation, can predict which COVID-19 patients are most likely to respond. to immunotherapy. In May 2022, the JAK1/2 inhibitor baricitinib became the first immunomodulatory drug to gain FDA approval for COVID-19 (in combination with remdesivir), and in June 2021 the JAK1/2 inhibitor tocilizumab IL-6, has been granted Emergency Use Authorization (EUA) for the treatment of COVID-19. Both of these agents directly and indirectly target the IL-6 signaling pathway and thus support PRE-VENT’s finding that elevated IL-6 may be an important biomarker in determining which COVID-19 patients are most likely to benefit from certain immunomodulatory agents.
Pacritinib was primarily studied in outpatient oncology settings and, following the completion of PRE-VENT, was approved by the FDA for the treatment of patients with myelofibrosis, a chronic leukemia that disrupts the production of blood cells by the organism. Additionally, it is being studied for other hematological malignancies, including acute myeloid leukemia (AML), according to Dr. Mascarenhas, who led the Phase 3 study that resulted in the drug’s approval for myelofibrosis.
