On 27 April 2020, Regeneron and Sanofi announced the preliminary results from the Phase II portion of an ongoing Phase II/III clinical trial evaluating Kevzara (sarilumab), an antibody targeting the interleukin-6 (IL-6) receptor, in hospitalised patients with severe or critical respiratory illness caused by Covid-19.
The randomised trial compared Kevzara, administered intravenously at doses of 200 mg and 400 mg, with placebo. Out of 457 hospitalised patients, those categorised as severe (requiring low-level oxygen supplementation and who were not ventilated) received no benefit from Sanofi drug Kevzara in the clinical trial. Conversely, those who required mechanical ventilation, high-flow oxygen, or treatment in intensive care did benefit from Kevzara compared to the placebo, particularly at the higher dose of 400mg. Preliminary analysis showed that Kevzara rapidly lowered C-reactive protein (CRP), a key marker of inflammation, meeting the primary endpoint. Baseline levels of IL-6 were elevated across all treatment arms, with higher levels observed in critical patients compared to severe patients.
Targeting the correct patient population and severity group is vital when conducting any study. However, testing a variety of severity groups has enabled a process of elimination that helped the researchers to understand the relationship between cytokine response in Covid-19 patients, and more importantly when is best to treat with IL-6 inhibitors. In order to draw more conclusive evidence, Sanofi and Regeneron are proceeding with the Phase III portion of the Phase II/III trial, specifically targeting critically ill patients at a dose of 400 mg. GlobalData believes that this will provide a more accurate demonstration of any relationship that may exist between IL-6 modulators and the most severe cases of Covid-19.
Covid-19 can lead to a cytokine response syndrome (CRS), and its management follows a grade- and risk-adapted strategy. Low-grade CRS is treated symptomatically with antihistamines, antipyretics, and fluids, whereas more severe patients require ventilator support due to life-threatening symptoms. Not all patients with CRS will require intensive care. It is therefore important to identify suitable candidates who are most likely to benefit from inhibiting IL-6, which is a central driver for many symptoms of CRS.
Although it is known that IL-6 is a key cytokine mediator in CRS, its onset and peak timing can vary in different diseases. GlobalData believes it is of great importance to evaluate the relationship between the peak level and time of serum cytokines to ultimately optimise the treatment of IL-6 modulators. Sanofi and Regeneron now have some data on that, and the results of the Phase III Kevzara trial will provide a better understanding of this pattern.