Targeting C5a Doesn’t Help Ventilated COVID Patients … or Does It?

An anti-C5a antibody failed to show a statistically significant mortality reduction in critically ill, ventilated COVID-19 patients in a phase III trial, but investigators say the results still point to a benefit with the investigational therapy.

For the primary endpoint, all-cause mortality at 28 days for patients given vilobelimab along with standard of care was an estimated 32% versus 42% for those given placebo, which missed statistical significance in a Cox model that stratified by site and adjusted for age (HR 0.73, 95% CI 0.50-1.06, P=0.94), reported Alexander Vlaar, MD, of the University of Amsterdam in the Netherlands, and colleagues, which included employees of the company developing the drug.

However, as described in Lancet Respiratory Medicine, a predefined analysis that excluded site-stratification suggested the trial would have been positive as originally designed (HR 0.67, 95% CI 0.48-0.96, P=0.027), leading the group to conclude that “overall, data from this study warrant recommending vilobelimab treatment for patients with COVID-19 who require invasive mechanical ventilation.”

Mortality between the vilobelimab and placebo groups, respectively, showed a high degree of variability based on treatment region:

• Western Europe (n=209): 21% vs 37% (HR 0.51, 95% CI 0.30-0.87)
• South America (n=128): 40% vs 37% (HR 0.94, 95% CI 0.53-1.67)
• South Africa, Russia (n=33): 69% vs 87% (HR 0.62, 95% CI 0.28-1.38)

Conflicting results and all, vilobelimab’s manufacturer InflaRx said it still plans to seek emergency use authorization from the FDA, which recommended the site-specific analysis in the first place, according to the study authors.

An accompanying commentary put the results under scrutiny.

“Given that a Cox model was the primary analysis, the central question remains whether site stratified or unstratified results should be prioritized,” said Andre C. Kalil, MD, of the University of Nebraska Medical Center in Omaha, and Michael Proschan, PhD, a mathematical statistician at the NIH in Bethesda, Maryland.

“The site-stratified Cox model excludes sites with no events or only one patient, which in this study accounted for 61 patients from 23 sites, which could bias results in favour of a treatment effect because excluded sites with no difference in mortality support the null hypothesis,” the duo explained. “Eliminating sites with no events or only one patient increased the P value in PANAMO, which was not statistically significant with vilobelimab.”

While noting various limitations of the trial — slow enrollment, large mortality differences across regions, lack of antiviral use, and a largely unvaccinated patient population — Kalil and Proschan said the study shows “promising benefits” of vilobelimab for ventilated COVID-19 patients “and provides a direction for further investigation of new treatments that target the complement system.”

Why target C5a in the first place?

Poor disease outcomes in COVID-19 “have been associated with activation of the complement system, specifically the C5a-C5aR axis,” according to Vlaar and colleagues, and “C5a was reported as the key mediator in neutrophil-mediated viral lung damage, as shown in viral disease models.”

In preclinical work, vilobelimab had been seen to prevent excessive lung inflammation in mice and showing benefit in monkeys with influenza-related lung injury.

From October 2020 to October 2021, the international phase III PANAMO trial randomized 368 critically ill COVID-19 patients at 46 hospitals in Western Europe, South America, South Africa, and Russia. Given the trial timeframe, a considerable proportion were infected with the Delta variant, the authors noted.

Patients had to have a confirmed SARS-CoV-2 infection and a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 60-200 mm Hg for inclusion.

Median patient age was 58 years, over 60% were white, and 68% were men. Both before and after being randomized, 17% of the patients received anti-interleukin-6 treatments (mostly patients in Western Europe), while glucocorticosteroids and antithrombotics were used in nearly all patients.

Common treatment-emergent adverse events were acute kidney injury (20% in the vilobelimab group, 21% in the placebo group), pneumonia (22% vs 14%, respectively), and septic shock (14% vs 16%).