Upside Down with Tocilizumab in COVID-19 Save

Several recent reports offer conflicting views on the potential benefits and adverse outcomes of IL-6 inhibition with tocilizumab (TCZ) therapy in patients with severe COVID-19 infection.

An Italian study grabbed the headlines yesterday with a press release stating TCZ did not improve respiratory symptoms, ICU admissions or mortality rates when given to 126 COVID patients with early disease. The study, supported by the Italian Medicines Agency (Aifa), stopped enrollment (about 1/3 of projections) after an interim analysis found insufficient evidence that TCZ would be effective.  This report has not been published or undergone critical review.

Such findings are analogous to reports last month from Sanofi, wherein usual doses (200mg) of sarilumab (Kevzara) showed no beneft, while higher doses were potentially beneficial. 

Preliminary reports of several other studies may suggest benefit when TCZ was given to SARS-CoV-2 patients.

A study by Perrone et al suggests that TCZ in COVID-19 patients was more effective in patients not requiring mechanical respiratory support with a reduced the 30 day (but not 14 day) mortality rate.  This multicenter, phase 2 trial enrolled 1221 patients from Italy, who were hospitalized with COVID pneumonia and given TCZ 8 mg/kg intravenously, with one or two administrations with 12 hours interval.  Only 301 and 920 cases (respectively) were available for intention-to-treat (ITT) analysis in phase 2 and validation cohorts. In phase 2, 67 patients died; lethality rates were 18.4% (97.5%CI: 13.6-24.0, P=0.52) and 22.4% (97.5%CI: 17.2-28.3, P<0.001) at 14 and 30-days, respectively.  Multivariable logistic regression suggests tocilizumab may be more effective in patients not requiring mechanical respiratory support at baseline. No significant toxicity was reported. 

Another pre-released report suggests better survival when TCZ was used to treat COVID.  Observational data from the Hackensack Meridian Health system in New Jersey analyzed 547 ICU patients, 134 who received tocilizumab in the ICU. They found a trend towards an improved survival rate: 56% survival with TCZ compared to 46% not receiving TCZ (adjusted hazard ratio 0.76 [95% CI, 0.57-1.00]).  Data from this same analysis showed no hydroxychloroquine (HCQ) benefit is a study of 2,512 hospitalized COVID-19 patients, 76% received HCQ and 59% received HCQ with azithromycin. There were no differences in survival based on receiving HCQ or not (hospitalization HR, 0.99 [95% CI, 0.80-1.22]).  

Lastly, a study by Somers et al from the University of Michigan analyzed a single-center cohort of COVID-19 patients requiring mechanical ventilation. A total of 154 patients were included, 78 received TCZ and 76 did not. With a median follow-up was 47 days, they found TCZ was associated with a 45% reduction in hazard of death [hazard ratio 0.55 (95% CI 0.33, 0.90). However, TCZ had an increased number of superinfections (54% vs. 26%; p<0.001), without a difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection [22% vs. 15%; p=0.42].  TCZ treated patients were somewhat younger, with less chronic pulmonary disease and had lower D-dimer levels.