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Targeting C5a Doesn't Help Ventilated COVID Patients ... or Does It?

— All-cause mortality results varied depending on how data were stratified

Ƶ MedicalToday
A computer rendering of antibodies attacking covid viruses.

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 researchers 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 , 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 to seek emergency use authorization from the FDA, which recommended the site-stratified analysis, according to the study authors.

An 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 favor 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" with vilobelimab in 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 showed benefit in monkeys with influenza-related lung injury.

From October 2020 to October 2021, the international phase III trial randomized 368 critically ill COVID-19 patients at 46 hospitals in Western Europe, South America, South Africa, and Russia. Within 48 hours of intubation, patients received either vilobelimab (800 mg) or placebo, with up to six doses administered through day 22. 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.

At 28 days, 54 of the 177 patients in the vilobelimab group had died versus 77 of 191 patients in the placebo group. At 60 days, 62 and 87 patients in the two arms had died.

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%).

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    Ingrid Hein is a staff writer for Ƶ covering infectious disease. She has been a medical reporter for more than a decade.

Disclosures

The trial was funded by InflaRx and the German Federal Government.

Vlaar reported receiving consulting fees from InflaRx, paid to his institution. Co-authors included founders of InflaRx and multiple employees of the company. Other co-authors reported grants from the German Research Foundation, and financial relationships with B Braun, 4TEEN4, Adrenomed, and Philips.

Primary Source

The Lancet Respiratory Medicine

Vlaar APJ, et al "Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial" Lancet Respir Med 2022; DOI: 10.1016/S2213-2600(22)00297-1.

Secondary Source

The Lancet Respiratory Medicine

Kalil AC, Proschan M "Complement C5a inhibition: a new form of COVID-19 treatment for mechanically ventilated patients?" Lancet Respir Med 2022; DOI: 10.1016/S2213-2600(22)00365-4.