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UrduPacritinib, 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 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 we identified subtypes of COVID-19 patients with hyperinflammation who could actually benefit from pacritinib, our study failed to show superiority of pacritinib to standard-of-care management of hospitalized COVID-19 adults with acute respiratory distress syndrome for a variety of 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 for Blood Cancers and Myeloid Disorders. “We believe one reason may have been that the study was limited by the early dropout of participants who actually improved with 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 treatment, an unmet need still exists 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 agents like it might be beneficial to certain populations of patients with hyperinflammation that are at significant risk for poor outcomes.”
JAK inhibitors are a class of medicines that inhibit the activity of one or more of the Janus kinase enzymes (JAK1, JAK2, JAK3, and TYK2) that are known to promote inflammation. They do this by transmitting signals from proteins known as cytokines that attach 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 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 integral to an inflammatory signaling pathway that culminates in NFκB activation which also regulates expression of inflammatory cytokines.
The study, known as PRE-VENT, was launched in June 2020 across 21 centers with 200 patients in the early stage of the pandemic. It became the first to demonstrate that certain inflammatory markers like Interleukin 6 (IL-6), a cytokine thought to be a main driver of inflammation, may 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 win approval from the FDA for COVID-19 (in combination with remdesivir), and in June 2021 the IL-6 inhibitor tocilizumab was 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 the PRE-VENT finding that IL-6 elevation could 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 was approved by the FDA for the treatment of patients with myelofibrosis, a chronic leukemia that disrupts the body’s production of blood cells. Moreover, 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.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report‘s Best Hospitals, receiving high “Honor Roll” status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children’s Hospital among the country’s best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Report‘s “Best Medical Schools,” aligned with a U.S. News & World Report “Honor Roll” Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.
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