Researchers at the Tisch Cancer Institute discovered markers of inflammation that could predict which COVID-19 patients are more likely to respond to therapies such as the cancer drug pacritinib, according to phase 2 study results published in JAMA network open In December.
Pacritinib, approved by the Food and Drug Administration (FDA) as a cancer therapy, is classified as a JAK2 inhibitor; it blocks pathways in the immune system that promote inflammation. Researchers suggested it could serve as a model for selecting several other approved immunotherapies shown to improve outcomes in patients with severe COVID-19, including the JAK2 inhibitor baricitinib and the IL-6 inhibitor tocilizumab.
“Although we have identified subtypes of hyperinflammatory COVID-19 patients that may actually benefit from pacritinib, our study failed to show superiority of pacritinib over standard care in hospitalized COVID-19 adults with acute respiratory distress syndrome for various reasons,” says senior author John Mascarenhas, MD, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Center of Excellence in Blood Cancer and Myeloid Diseases. “We believe one reason may have been that the study was limited by the early discontinuation of participants who actually improved with this agent and therefore did not consider it necessary to continue treatment, and these patients were not included in the analysis Responders have been recorded.”
dr Mascarenhas believes that despite recent advances in immunomodulatory treatment, there is still an unmet need for therapeutic strategies to prevent disease progression in hospitalized patients. “Pacritinib showed an excellent safety profile in our study,” he notes, “which is why more studies are needed to show how pacritinib or other agents might be beneficial for certain hyperinflammatory patient groups who are at 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), which are known to promote inflammation. They do this by relaying signals from proteins known as cytokines, which bind to receptors on immune cells 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 JAK2 and IRAK1 enzymes 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 culminating in NFκB activation, which also regulates the expression of inflammatory cytokines.
The study, known as PRE-VENT, started in June 2020 in 21 centers with 200 patients in the early stages of the pandemic. It was the first to show that certain inflammatory markers, such as 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 receive FDA approval for COVID-19 (in combination with remdesivir), and in June 2021, the IL-6 inhibitor tocilizumab received emergency use approval (EUA) . to treat COVID-19. Both agents directly and indirectly target the IL-6 signaling pathway, supporting the PRE-VENT results that IL-6 elevation may be an important biomarker to determine which COVID-19 patients are most likely to be affected by benefit from certain immunomodulatory agents.
Pacritinib was studied primarily in outpatient oncology facilities and, following the completion of PRE-VENT, was FDA approved for the treatment of patients with myelofibrosis, a chronic leukemia that disrupts the body’s production of blood cells. In addition, according to Dr. Mascarenhas, who led the phase 3 trial that led to the drug’s approval for myelofibrosis, is being evaluated for other hematologic malignancies, including acute myeloid leukemia (AML).