CTI BioPharma announced the initiation of PRE-VENT, a Phase 3 study evaluating pacritinib in hospitalized patients with severe COVID-19. PRE-VENT, a randomized, double-blind, placebo-controlled multicenter study, will compare pacritinib plus standard of care (SOC) versus placebo plus standard of care in 358 hospitalized patients with severe COVID-19, including patients with and without cancer. The primary endpoint of the trial will assess the proportion of patients who progress to invasive mechanical ventilation and/or extracorporeal membrane oxygenation or die by Day 28. CTI expects to commence enrollment of PRE-VENT in May at sites in the United States and in Europe with data expected by the end of 2020.

"Patients with severe COVID-19, particularly those with cancer, are at high risk for serious complications from the disease stemming from cytokine storm, an inflammatory response that causes white blood cells to not only fight the viral infection, but also damage tissue, primarily in the lungs," said John Mascarenhas, M.D., Associate Professor, Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York and Chief Investigator of the PRE-VENT Study. "Because pacritinib inhibits JAK2, IRAK-1 and CSF1R, there is real potential for pacritinib to prevent patients from developing an inflammatory response to the coronavirus infection and subsequent pulmonary failure, therefore reducing the need for a ventilator."

"Given the unprecedented medical need to improve outcomes for patients with COVID-19, we have made a commitment to test pacritinib, a JAK2/IRAK-1/CSF-1R inhibitor, in hospitalized patients with severe COVID-19, with the goal of preventing progression to acute respiratory distress syndrome and mechanical ventilation," said Adam R. Craig, M.D., Ph.D., President and Chief Executive Officer of CTI Biopharma. "Emerging evidence suggests that the attenuation of the cytokine storm associated with COVID-19 could be a potential treatment approach for this devastating disease, and it is hypothesized that pacritinib may have a role in treating these patients. We would like to thank the FDA for their expedited review of the PRE-VENT protocol. Enrollment is expected to commence in the coming weeks. With ample supply of pacritinib available, we continue to recruit patients on the pivotal Phase 3 PACIFICA trial of pacrtitnib in myelofibrosis patients with severe thrombocytopenia."

Cytokine storm is a pathological immune reaction that can be triggered by viral infection and can lead to serious complications, including acute respiratory distress syndrome (ARDS). Multiple inflammatory cytokines are upregulated in patients with severe COVID-19, including IL-1 and IL-6, and some patients have evidence of over-active macrophage activation. As a JAK2/IRAK-1 inhibitor, pacritinib may ameliorate the effects of cytokine storm via inhibition of IL-6 and IL-1 signaling. Furthermore, as a CSF-1R inhibitor, pacritinib may mitigate effects of macrophage activation syndrome. Of particular importance in this indication, pacritinib has not been associated with increased risk in infections in prior randomized studies, likely because it does not have inhibitory effects on JAK1.

PRE-VENT is expected to enroll 358 patients randomized 1:1 to receive pacritinib (400 mg once daily on Day 1, then 200 mg twice daily from Day 2 to Day 14) + SOC or placebo + SOC. Assigned treatment will continue for up to Day 14 or until the patient experiences intolerable adverse events, withdraws consent, initiates another investigational therapy, or until the study is terminated. Assigned therapy may be given for an additional 7 days (for a total of 21 days) at the discretion of the investigator. In the event of hospital discharge, patients will complete treatment with the assigned therapy as an outpatient. Severe COVID-19 will be defined as an oxygen saturation (SO2) ≤93% on room air at sea level, respiratory frequency >30 breaths per minute, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300, or lung infiltrates >50% on radiographic imaging.

The primary endpoint is the effect of treatment on the proportion of patients who require invasive mechanical ventilation and/or extracorporeal membrane oxygenation, or die by Day 28. An interim analysis will be conducted for futility after 154 patients have been enrolled. Safety will be assessed through 30 days of follow-up after the last dose of study treatment and assessed by the cumulative incidence, severity and seriousness of treatment-emergent AEs, drug discontinuations, laboratory values, and clinical assessments.

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, IRAK1 and CSF1R. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia and lymphoma. In addition to myelofibrosis, the kinase profile of pacritinib suggests its potential therapeutic utility in inflammatory and immune-mediated disorders such acute graft-versus-host disease (aGVHD) and hemophagocytic lymphohistiocytosis (HLH).

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