Vilobelimab augments treatment armamentarium for critically ill COVID-19 patients

In the phase III part of the PANAMO trial, the anti-C5a monoclonal antibody vilobelimab, when added to standard of care (SoC), improved survival in COVID-19 patients who required invasive mechanical ventilation (IMV).

The phase II part of PANAMO showed that vilobelimab is safe and effectively suppressed serum C5a concentrations in this population. [Lancet Rheumatol 2020;2:e764-e773; Clin Transl Sci 2022;15:854-858] “[The current] study confirms previous exploratory findings from the phase II PANAMO … [When added to SoC], vilobelimab administration resulted in a reduction in mortality at 28 and 60 days in [this patient setting],” said the researchers. 

At day 28, after site stratification and age adjustments, all-cause mortality rate was lower in the vilobelimab vs the placebo arm (32 percent vs 42 percent; hazard ratio [HR], 0.73; p=0.094). This effect was also evident in the predefined analysis without site stratification (HR, 0.67; p=0.027). [Lancet Respir Med 2022;S2213-2600(22)00297-1]

The mortality advantage of vilobelimab over placebo persisted until day 60, both in the Cox model stratified by site and adjusted for age (37 percent vs 47 percent; HR, 0.74; p=0.082) and the predefined analysis without site stratification (HR, 0.67; p=0.016).

The study included 368 patients (median age 58 years, 68 percent male) from 46 hospitals in South America (Brazil, Mexico, Peru), western Europe (Belgium, France, Germany, the Netherlands), Russia, and South Africa. Participants were on IMV within 48 hours prior to first infusion of study medication, had a PaO₂/FiO₂ ratio of 60–200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days. They were randomized 1:1 to receive IV vilobelimab 800 mg (maximum six* doses) or placebo on top of SoC**.

About a third (31 percent) of participants in the vilobelimab arm died within the first 28 days. In the placebo arm, the corresponding rate was 40 percent.

Regarding treatment-emergent adverse events (TEAEs), the incidence of pneumonia was slightly higher in the vilobelimab vs the placebo arm (22 percent vs 14 percent). The other most common TEAEs - acute kidney injury (20 percent vs 21 percent) and septic shock (14 percent vs 16 percent) - were of similar incidence.

Serious TEAEs also occurred similarly in both arms (59 percent vs 63 percent), as did drug withdrawal owing to TEAEs (3 percent vs 2 percent).

Why target the C5a-C5aR1 axis?

“Poor disease outcomes have been associated with activation of the complement system, specifically the C5a-C5aR axis,” the researchers noted. In viral disease models, C5a was reportedly the key mediator in neutrophil-mediated viral lung damage. Evidence shows that C5a-C5aR1 axis blockade limits myeloid cell infiltration in damaged organs and prevents excessive lung inflammation and endothelialitis. [Nat Rev Immunol 2022;22:77-84; Nature 2020;588:146-150] 

“Vilobelimab selectively blocks C5a, leaving the membrane attack complex function intact. This selective mode of action explains the favourable safety profile of vilobelimab, particularly in terms of infection risk, compared with other upstream complement inhibitors,” they explained.

Enzymes in tissue and during coagulation may directly activate C5 outside of the common complement pathways. As such, the mechanism of action of upstream complement inhibitors may be bypassed, rendering it insufficient to block and control C5a. [Clin Immunol 2017;180:25-32]

“Our findings further show that C5a plays a key role in patients with severe COVID-19 and the PANAMO study is a result of more than 20 years of research on the role of C5a in neutrophil-mediated viral and bacterial septic organ dysfunction,” said the researchers.

“[Hence,] vilobelimab could be considered as an additional therapy for patients in this setting,” the researchers concluded.. “[F]urther research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections.”