Researchers at the Tisch Cancer Institute have uncovered inflammatory markers that can predict which COVID-19 patients are more likely to respond to treatments such as the anti-cancer drug pacritinib, according to phase 2 trial results published in 2019. JAMA Network Open in December.
Approved by the Food and Drug Administration (FDA) as a cancer treatment, pacritinib is classified as a JAK2 inhibitor; It blocks messaging pathways in the immune system that promote inflammation. The researchers suggested that it could 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 the IL-6 inhibitor tocilizumab.
“While identifying the subtypes of COVID-19 patients with hyperinflammation who might actually benefit from pacritinib, our study failed to demonstrate superiority of pacritinib to the standard-of-care management of hospitalized COVID-19 adults with acute respiratory distress syndrome for a variety of reasons,” said senior author John Mascarenhas, Icahn at Mount Sinai. Professor of Medicine at the School of Medicine and Director of the Center of Excellence for Blood Cancers and Myeloid Disorders. “We believe one reason may be that the study was limited to early dropout of participants who had actually recovered with this agent and therefore did not feel it necessary to continue treatment, and that these patients were not caught as responders in the analysis.”
Dr. Mascarenhas believes that despite recent advances in immunomodulatory therapy, there is an unmet need for therapeutic strategies to prevent disease progression in hospitalized patients. “Pacritinib showed an excellent safety profile in our trial,” he notes, “so more studies are needed to show how pacritinib or other similar agents may benefit certain patient populations with hyperinflammation that carry significant risk for 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 known as cytokines that bind to receptors on immune cells to produce proinflammatory 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 does not protect 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 NFκB activation, which also regulates the expression of inflammatory cytokines.
The study, known as PRE-VENT, was initiated in June 2020 at 21 centers with 200 patients in the early phase of the pandemic. It was the first to show that certain inflammatory markers, such as Interleukin 6 (IL-6), a cytokine thought to be the main 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 receive FDA approval for COVID-19 (in combination with remdesivir), and an emergency use authorization (EUA) was granted to the IL-6 inhibitor tocilizumab in June 2021. For the treatment of COVID-19. Both of these agents directly and indirectly target the IL-6 signaling pathway, thus supporting the finding that PRE-VENT may be an important biomarker for determining which COVID-19 patients are most likely to benefit from certain immunomodulatory agents.
Pacritinib has been primarily studied in outpatient oncology settings and following the completion of PRE-VENT it was approved by the FDA for the treatment of patients with myelofibrosis, a chronic leukemia that impairs the body’s blood cell production. Also leading the phase 3 study that resulted in the drug being approved for myelofibrosis, Dr. It is being investigated for other hematological malignancies, including acute myeloid leukemia (AML), according to Mascarenhas.