Mavrilimumab improves outcomes in nonventilated patients with severe COVID-19, hyperinflammation
The human monoclonal antibody mavrilimumab reduced the rates of mechanical ventilation and death in nonmechanically ventilated patients with severe COVID-19 pneumonia and systemic hyperinflammation, according to a phase II/III study presented at EULAR 2021.
Granulocyte/macrophage-colony stimulating factor (GM-CSF) may contribute to respiratory failure or death in patients with severe COVID-19 pneumonia and hyperinflammation. [Lancet Rheumatol 2020 Aug;2:e465-e473; Lancet Rheumatol 2021;3:e410-e418] “It is hypothesized that GM-CSF receptor alpha blockade may reduce infiltration of pathogenic cells into the lungs and may suppress inflammation in [this patient setting],” said Dr Lara Pupim from Kiniksa Pharmaceuticals Corporation, Lexington, Massachusetts, US, who presented the study findings during the virtual congress.
“Mavrilimumab binds GM-CSF receptor alpha, blocks GM-CSF signalling, and downregulates the inflammatory process … [This may address the] unmet need for treatment alternatives in COVID-19 pneumonia,” said Pupim.
In cohort 1 of this trial, 114 nonmechanically ventilated patients (mean age 57.1 years, 57 percent male) with hypoxia and severe COVID-19 were randomized 1:1:1 to receive IV mavrilimumab 6 or 10 mg/kg or placebo. Of these, 96 percent received corticosteroids, while almost a third received remdesivir as standard of care. [EULAR 2021, abstract LB0001]
Comparing the pooled mavrilimumab results with those observed in the placebo arm, more patients on mavrilimumab were alive and free of mechanical ventilation at day 29 (86.7 percent vs 74.4 percent; p=0.1224). “[This means that] about a quarter of placebo recipients progressed to mechanical ventilation or died over 29 days,” explained Pupim. “[The findings] achieved the prespecified evidentiary standard of a two-sided p value of 0.2 without adjustment for multiplicity.”
Looking at mechanical ventilation-free survival using a time-to-event approach, mavrilimumab recipients had a 65-percent reduction in the risk of mechanical ventilation or death (hazard ratio [HR], 0.35; plog-rank=0.0175). “Separation in the Kaplan-Meier curves was evident very early after study drug administration,” said Pupim.
By day 29, mortality rate was 12.5-percentage points lower in the mavrilimumab vs the placebo arm, corresponding to a 61-percent reduction in the risk of death (8.0 percent vs 20.5 percent; HR, 0.39; p=0.0726).
Regarding other key secondary endpoints, mavrilimumab recipients had a trend towards faster time to two-point clinical improvement (median, 7 vs 11 days) and time to room air (median, 7 vs 9 days) than those who received placebo. However, these did not reach a level of significance.
Safety-wise, mavrilimumab was well-tolerated, with no drug-related serious adverse events (AEs). Secondary infections, which are known COVID-19 complications, occurred less frequently in the mavrilimumab vs the placebo arm (9.8 percent [6 mg/kg] and 11.4 percent [10 mg/kg] vs 22.5 percent). Thrombotic events, another COVID-19 complication, only occurred in the placebo arm (12.5 percent).
One patient in a tuberculosis (TB)-endemic area reported active TB approximately 10 days following the mavrilimumab 10-mg/kg dose. It should be noted that this patient received high-dose corticosteroids prior to receiving mavrilimumab, said Pupim. “[Corticosteroid administration is] a known risk factor for TB reactivation; thus, the potential additive contribution of mavrilimumab, if any, is uncertain.”