Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019: A Phase 2a Trial

Abstract

Background Based on studies implicating the type 2 cytokine interleukin (IL)-13 as a potential contributor to critical COVID-19, this trial was designed as an early phase II study to assess dupilumab, a monoclonal antibody that blocks IL-13 and IL-4 signaling, for treatment of inpatients with COVID-19. Methods We conducted a phase IIa randomized double-blind placebo-controlled trial (NCT04920916) to assess the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Results Forty eligible subjects were enrolled from June to November of 2021. There was no statistically significant difference in adverse events nor in the primary endpoint of ventilator free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, there were two deaths in the dupilumab group compared five deaths in placebo (60-day survival 89.5% vs 76.2%, adjusted HR 0.05, 95% CI: 0.004- 0.72, p = 0.03). Among subjects who were not in the ICU at randomization, three subjects in the dupilumab arm were admitted to the ICU compared to six in the placebo (17.7% vs. 37.5%; adjusted HR 0.44, 95% CI: 0.09-2.09, p = 0.30). Lastly, we found evidence of type 2 signaling blockade in the dupilumab group through analysis of immune biomarkers over time. Conclusions Although the primary outcome of day 28 ventilator-free survival was not reached, adverse events were not observed and survival was higher in the dupilumab group by day 60.

Recent developments in the immunopathology of COVID‐19

“…Treatment with dupilumab, a monoclonal antibody against IL‐4 and IL‐13, was associated with less severe COVID‐19, while IL‐13 neutralization reduced hyaluronan deposition and disease severity and death in SARS‐CoV‐2–infected mice 63 . Based on the results of this study, a pilot phase IIA clinical trial observing the safety and efficacy of dupilumab on forty moderate or severe COVID‐19 patients found that dupilumab did not increase the ventilator‐free survival at day 28, but it did reduce the mortality at day 60 when compared to placebo 64 . All these data suggest a complex association among type 2 inflammation, ACE2 expression, IL‐13, SARS‐CoV‐2 infection, and COVID‐19 outcomes.…”

Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection

“…In a recent clinical trial of 19 patients who received dupilumab and 21 controls, there were no differences in the proportion of patients on mechanical ventilation at either 28 or 60 days. There was a difference of 2 deaths in the dupilumab group (2/19; 10.5%) versus 5 deaths in the control group (5/21; 23.8%) at 60 days but this difference was not significant (Unadjusted HR: 0.40 (.08–2.05)) until the data were adjusted for sex and mechanical ventilation as a time-varying predictor (Adjusted HR: 0.05 (.004–.72)) [162] . Larger, better controlled studies are needed to explore dupilumab as a potential therapy in COVID-19.…”

“…Blockade of IL-4/IL-13 signaling with dupilumab led to significantly reduced ventilation and death in COVID-19 patients already on this drug. [162] . However, IL-13 was found to be protective against SARS-CoV-2 infection in vitro [ 163 , 164 ].…”

“…Dupilumab, an IL-13 antagonist and an already approved therapy, is another potential therapeutic option to block HA production [162] . In a recent clinical trial of 19 patients who received dupilumab and 21 controls, there were no differences in the proportion of patients on mechanical ventilation at either 28 or 60 days.…”

Repurposing of drugs targeting the cytokine storm induced by SARS‐CoV‐2

“…The results of this study showed some advantages of dupilumab as a treatment option for COVID-19 (Sasson et al, 2022). However, this study was limited by the small size of the cohort and the potential adverse effects of dupilumab, such as hyper-eosinophilia.…”