Failure of ex-US Kevzara phase 3 further dents IL-6 COVID-19 hypothesis

The development of hyperinflammatory syndrome reminiscent of macrophage-activation syndrome or CAR-T-driven cytokine-release syndrome has been a defining characteristic of severe COVID-19 cases since the early days of the outbreak. Recognition of the similarities between COVID-19 and other conditions raised hopes that anti-IL-6 antibodies such as Sanofi’s Kevzara and Roche’s Actemra could be repurposed to treat severe cases of the infectious disease.

A series of phase 3 clinical trials have quashed those hopes. In late July, Roche reported Actemra was no better than placebo at improving survival or clinical status in patients with COVID-19 associated pneumonia. The news came weeks after Sanofi and partner Regeneron Pharmaceuticals disclosed a similar setback to Kevzara.

Sanofi and Regeneron stopped the US clinical trial in response to the setback but continued a study in other regions that was assessing a different dosing regimen. Now, Sanofi has data from that ex-US phase 3 trial.

The ex-US trial found intravenously administering 200 mg or 400 mg doses of Kevzara was statistically no better than providing placebo at improving clinical status or day-29 mortality in 420 severely or critically ill patients hospitalized with COVID-19.

Sanofi highlighted trends that fell short of statistical significance but could indicate Kevzara has some effect. Use of the anti-IL-6 antibody was associated with numerical improvements in the duration of hospital stays and time to better clinical outcomes.

Investigators also identified a trend toward reduced mortality in critically ill patients, but not their severely ill peers, and a two- to three-day reduction in time to discharge among people who received Kevzara within the first two weeks. None of the differences were statistically significant, though.

Having recorded two phase 3 failures, Sanofi and Regeneron have dropped plans to further study Kevzara in the treatment of COVID-19. At this stage in the pandemic, companies may be viewing the value of further investments in COVID-19 programs in light of the potential for effective vaccines and neutralizing antibodies to come to market in the coming months.

Roche is still assessing Actemra in COVID-19. A phase 3 trial of Actemra plus standard of care in people hospitalized with COVID-19 pneumonia finished enrolling subjects last month.

Another phase 3 that is testing the effect of giving Actemra in combination with Gilead Sciences’ antiviral remdesivir is still enrolling subjects. The study has a primary completion date of December 1.