Researchers at the Tisch Cancer Institute discovered inflammatory markers that may predict which COVID-19 patients are most likely to respond to therapies such as the cancer drug pacritinib, according to phase 2 trial results published in JAMA Open Network in December.
Pacritinib, which has been approved as a cancer therapy by the Food and Drug Administration (FDA), 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 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 we identified subtypes of COVID-19 patients with hyperinflammation that might actually benefit from pacritinib, our study failed to demonstrate the superiority of pacritinib in the standard treatment of hospitalized adults with COVID-19 with acute respiratory distress syndrome for a variety of of 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 think one of the reasons may have been that the study was limited by leaving participants early who actually improved on this agent and therefore did not feel a need 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 more studies are needed to show how pacritinib or other similar agents might be beneficial for certain populations of patients with hyperinflammation who are at significant risk of bad results.” .”
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 attach 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, which means that it affects the JAK2 and IRAK1 enzymes, but does not affect 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 the activation of NFκB that also regulates the expression of inflammatory cytokines.
The study, known as PRE-VENT, was launched in June 2020 at 21 centers with 200 patients in the early stage of the pandemic. He became the first to show that certain inflammatory markers such as interleukin 6 (IL-6), a cytokine believed to be the main driver of inflammation, can predict which COVID-19 patients are most likely to respond to the 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 Emergency Use Authorization was granted in June 2021. (USA) to the IL-6 inhibitor tocilizumab. for the treatment of COVID-19. Both agents directly and indirectly target the IL-6 signaling pathway and thus support the PRE-VENT finding that elevated IL-6 could be an important biomarker in determining which COVID-19 patients they are more likely to benefit from certain immunomodulatory agents.
Pacritinib has been studied primarily in outpatient oncology settings, and following the completion of PRE-VENT, the FDA approved the treatment of patients with myelofibrosis, a chronic leukemia that disrupts the body’s production of blood cells. In addition, it is being investigated for other hematologic 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.