An Emory University-led phase 2 study will evaluate whether the the PI3K-gamma/delta inhibitor duvelisib is effective at reducing lung inflammation in patients with severe novel coronavirus 2019, thereby decreasing incidences of mechanical ventilation and death in these patients.
Edmund K. Waller, MD, PhD
An Emory University-led phase 2 study will evaluate whether the the PI3K-gamma/delta inhibitor duvelisib (Copiktra) is effective at reducing lung inflammation in patients with severe novel coronavirus 2019 (COVID-19), thereby decreasing incidences of mechanical ventilation and death in these patients.1,2
Investigators theorize that the agent will not only work to reduce inflammation and pulmonary edema, but could also potentially decrease duration of viremia and prompt a response from immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies that could in turn respond to SARS-Cov-2 spike proteins.
The increase in proteins can lead to a cytokine storm, resulting in severe pneumonitis and acute respiratory distress syndrome (ARDS), and can be fatal.1 Investigators hope to reduce the incidence rate of death or mechanical ventilation intervention, which is 40%, to 15% with the use of duvelisib.
“Duvelisib’s use in COVID-19 comes not from its anti-cancer properties, but its activity in the immune system. Particularly, we found that it can enhance the growth and expansion of T-cells that retain anti-cancer activity,” principal study investigator Edmund K. Waller, MD, PhD, a professor in the Departments of Medicine, Pathology, and Hematology and Medical Oncology at Emory University School of Medicine, as well as the medical director of the Center for Stem Cell Processing and Apheresis Emory University Hospital, said in an interview with OncLive. “Results from clinical trials in patients with lymphoma show that these patients had lower levels of cytokines—the inflammatory proteins we believe are a part of COVID-19 pathology—when they’ve been treated with duvelisib compared with other anticancer therapies.”
In September 2018, the FDA has approved duvelisib for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or relapsed/refractory follicular lymphoma.
Waller added that duvelisib may help T cells grow and potentially fight COVID-19, while simultaneously modulating the inflammation that could lead to fluid accumulation in patients’ lungs.
In the study, duvelisib will be administered to patients with COVID-19 over the course of 2 weeks, and investigators will evaluate the agent’s efficacy in not only reducing the need for mechanical ventilation and the risk of death within 30 days of treatment.
Additional end points include the need for high-flow oxygen devices, supplemental oxygen, and hospitalization with or without ongoing medical care. The targeted enrollment is 80 adults whose ages are 18 years and older who have been confirmed to have severe COVID-19 symptoms, such as pneumonia and difficulty breathing. Patients will then be randomized to either duvelisib (n = 40) or placebo (n = 40). Waller said he hopes to determine whether or not the agent will be effective in managing the virus to prevent patients from being admitted to the intensive care unit. Duvelisib, he added, could provide a valuable third line of defense after the infection has been established.
In a preclinical pharmacology setting, duvelisib was shown to be highly potent, with investigators noting a whole blood IC50 of 0.36 nM for delta subunit inhibition and whole blood IC50 of 19.6nM for gamma subunit inhibition. The agent was shown to double T cells in both patients with CLL, as well as healthy volunteers from 40 nM to 0.4 mM over 9 to 14 days.
Should the study results be positive, Waller said that the data warrant a need for a larger, multicenter study to further confirm the findings. Even in the event of a smaller, but still significant reduction by one-third or more of patients, the research could be expanded to include hundreds of patients with severe COVID-19, he said.
“This is a challenging time,” concluded Waller. “There are more [factors about this virus] that we don’t know than we do know. We have to be cautious as new data become available [to ensure] that it’s rigorously looked at in order to change medical practices based on solid clinical data. Our study is small, and I won’t say that it will change clinical practice, but hopefully it’s a step towards finding better ways to treat these patients.”