Lenzilumab ups survival in hospitalized COVID-19 patients

Adding lenzilumab, a monoclonal antibody targeting GM-CSF, on top of standard supportive care significantly improves survival without the need of invasive mechanical ventilation at 28 days in patients hospitalized with COVID-19 compared with standard care alone, reveals the LIVE-AIR study.

“For very sick [COVID-19] patients who require hospitalization, we now know that targeting the dysregulated host response is of greater value than targeting the virus,” wrote a panel of experts led by Dr Srinivas Murthy of University of British Columbia, Vancouver, Canada, in a linked commentary. [Lancet Respir Med 2022;10:223-224]

In the phase III, double-blind trial, 479 adults (mean age 61 years, 65 percent male) hospitalized with COVID-19 pneumonia who required oxygen but not invasive mechanical ventilation were randomized 1:1 to receive three 600-mg doses of lenzilumab or placebo, delivered intravenously 8 hours between doses, in addition to standard supportive care which included remdesivir and corticosteroids. [Lancet Respir Med 2022;10:237-246]

Significantly more patients in the lenzilumab group survived to 28 days without mechanical ventilation compared with those on placebo (84 percent vs 78 percent; hazard ratio [HR], 1.54; p=0.04).

The difference was mainly driven by reduction in the need of invasive ventilation in the lenzilumab group than the placebo group (11 percent vs 20 percent; HR, 0.52; p=0.0059).

“Importantly, the observed benefit was greater than that provided by standard background care including remdesivir and corticosteroids,” said the researchers. 

Key secondary outcomes including ventilator-free days, need for intensive care, recovery time, and mortality were comparable between the two treatment groups.

In terms of safety profile, lenzilumab was well tolerated and no increase in adverse events (AEs) was seen compared with placebo. There were comparable proportion of patients who experienced at least one AE of grade ≥3 in severity in the lenzilumab vs the placebo groups (27 percent vs 33 percent), as per CTCAE criteria — with those related to respiratory disorders (26 percent) and cardiac disorders (6 percent) being the most common.

“No differences in secondary infection rates were observed with lenzilumab treatment. The potential for pulmonary alveolar proteinosis, a concern with anti-GM-CSF therapeutics, has not been reported with lenzilumab in this or other clinical trials,” the researchers noted.

Who is likely to benefit?

While studies on other anti-GM-CSF agents such as mavrilimumab and otilimab did not lead to improvement in the primary outcome, the researchers believed that the sicker population enrolled in these studies might have explained the inconsistencies in the outcomes compared with lenzilumab.

“The clinical population in LIVE-AIR reflects an earlier stage of disease progression than was studied with otilimab and suggests that GM-CSF inhibition alone might be more beneficial earlier in the disease process,” they pointed out.

The median baseline C-reactive protein (CRP) levels in the LIVE-AIR population was 79 mg/L, a level that was lower than those seen in the RECOVERY and REMAP-CAP cohorts — whereby immune modulation with IL-6-targeted therapy has shown benefits.

“The study contributes to the emerging body of evidence about how CRP concentrations relate to the pathogenesis of COVID-19 and to patient and treatment selection, which warrants further investigation,” the researchers said.

“Exploratory sensitivity analyses suggested greater benefit of lenzilumab in patients with CRP concentrations less than the median value of 79 mg/L,” pointed out Murthy and co-authors. “Whether biomarker-driven immunotherapy with stratification of patients can guide individualized use of immunomodulatory treatments in COVID-19 needs to be explored.”

Nonetheless, with the rapidly evolving treatment landscape for background standard of care for severe COVID-19, the researchers also cautioned that “the added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown.”