CATALYST sparks signals favouring namilumab for COVID-19

In the phase II proof-of-concept CATALYST trial comparing the GM-CSF* inhibitor namilumab and the TNF** inhibitor infliximab against usual care (UC), namilumab, but not infliximab, demonstrated signals for reducing inflammation in hospitalized patients with COVID-19 pneumonia. 

“Despite the advances of dexamethasone and tocilizumab in COVID-19, mortality among patients with severe disease remains high. Therefore, considerable unmet medical need remains,” said the researchers. “We aimed to provide early proof-of-concept signals of the effect of namilumab and infliximab on inflammation in patients with COVID-19 compared with UC to efficiently prioritize these approaches for subsequent testing in larger trials powered for clinical outcomes.”

“Consistent with emerging evidence implicating GM-CSF and inflammatory monocytes and macrophages in the pathogenesis of severe COVID-19, [our findings show that] namilumab improved inflammation as measured by C-reactive protein (CRP) in [this patient setting],” they said.

There was a 97-percent probability that namilumab plus UC was superior to UC alone in reducing CRP concentration over time, with a point estimate of –0.09 for treatment-time interaction. [Lancet Respir Med 2021;doi:10.1016/S2213-2600(21)00460-4]

By contrast, the probability of infliximab being superior to UC alone was 15 percent, with a point estimate for the treatment-time interaction of 0.06. This group was stopped for futility, the researchers noted.

“[A]lthough TNF inhibitors are widely used in inflammatory diseases, not all immune-mediated inflammatory diseases are responsive, and TNF itself might suppress specific pro-inflammatory factors that might be relevant to COVID-19,” the researchers explained. “Inhibition of such cross-regulatory effects might underlie our negative findings, or simply indicate that TNF is not on an essential path to driving inflammatory responses as measured by CRP in patients hospitalized with COVID-19.”

The incidence of adverse events was similar between the namilumab and UC arms (55 percent vs 54 percent). Between the infliximab and UC arms, the former was associated with a higher AE rate than the latter (69 percent vs 50 percent). Six patients on namilumab died as opposed to 10 receiving UC. In the comparison between infliximab and UC, the number of deaths was similar (n=4 and 5).

GM-CSF inhibition takes precedence over TNF inhibition

CATALYST comprised 146 patients admitted to the hospital for COVID-19*** pneumonia who had CRP concentrations of ≥40 mg/L. Patients were randomized to receive UC (n=54), namilumab^# 150 mg given over 1 hour (n=57), or infliximab^# 5 mg/kg given over 2 hours (n=35). About 90 percent of patients were on dexamethasone while half were on remdesivir at baseline. 

For the primary outcome of improvement in inflammation measured by CRP concentration over time, 45 patients in the UC arm were compared with 52 in the namilumab arm, while 29 participants receiving UC were compared against 28 on infliximab. Participants were followed up for 28 days.

The current data underline the potential benefit of GM-CSF inhibition in COVID-19, and aligns with available evidence elucidating the role of other GM-CSF inhibitors in this setting. [Mayo Clin Proc 2020;95:2382-2394; Lancet Rheumatol 2020;2:e465-e473; medRxiv 2021;doi.org/10.1101/2021.04.14.21255475; Lancet Respir Med 2021;doi.org/10.1016/S2213- 2600(21)00494-X] “Our proof-of-concept findings with GM-CSF inhibition are consistent with our hypothesis that recruitment and activation of inflammatory monocytes and macrophages are important in the pathogenesis of severe COVID-19,” said the researchers.

GM-CSF inhibition might have an additional benefit in retarding neutrophil recruitment and activation, which could be essential in the pathogenesis of severe COVID-19 as well as acute respiratory distress syndrome. [Clin Infect Dis 2021;doi.org/10.1093/ cid/ciab437]

“[As such,] targeted GM-CSF inhibitors such as namilumab should be further investigated in hospitalized patients with COVID-19 … The clear divergence in the primary outcome … justifies the prioritization of GM-CSF inhibition over TNF inhibition at this dose for further study,” they concluded.