The IL-5 inhibitors Cinqair (reslizumab), Fasenra (benralizumab), and Nucala (mepolizumab) block IL-5 and help control eosinophils.  How do they work and what are the differences between them?

Why target IL-5? IL-5 is a cytokine, a small signaling molecule.  IL-5 is produced and secreted by T cells and mast cells.  The IL-5 molecules can then signal to other blood cells including eosinophils.  IL-5 binds to the IL-5 receptor present on the surface of eosinophils and activates them.  IL-5 is the major activator of eosinophils so modulating IL-5 is a good way to try to control eosinophils.

Available IL-5 inhibitors.  There are currently three commercially available IL-5 inhibitors in the United States.  These include reslizumab (trade name Cinqair), benralizumab (trade name Fasenra), and mepolizumab (trade name Nucala).  All three of these medications are humanized monoclonal antibodies in the class of medications known as biologics.  The “zumab” at the end of their names stands for humanized monoclonal antibody.  All three medications have been approved by the FDA for the treatment of severe eosinophilic asthma.  In addition, mepolizumab (Nucala) has also been approved for the treatment of EGPA/Churg-Strauss Syndrome, but at a higher dose than the dose used for the treatment of eosinophilic asthma.

Figure legend – Inhibiting the lL-5 pathway.  Left:  IL-5 molecules normally bind to the IL-5 receptor on eosinophils, which causes activation or stimulation of the eosinophils.  Center:  Reslizumab (Cinqair) and mepolizumab (Nucala) bind to the IL-5 molecules and prevent the IL-5 molecules from binding to the IL-5 receptor.  This sequesters the IL-5 molecules and prevents them from activating their target receptor.  Right:  Benralizumab (Fasenra) works by a different mechanism.  Benralizumab (Fasenra) binds to the IL-5 receptor and prevents the IL-5 molecules from binding to the IL-5 receptor.

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What is the effect of inhibiting the IL-5 pathway?  Reslizumab (Cinqair) and mepolizumab (Nucala) bind to IL-5 directly.  Benralizumab (Fasenra) works by a different mechanism by binding to the IL-5 receptor and preventing IL-5 from binding.  The end result is similar in that all three medications inhibit the IL-5 receptor from being activated.  This inhibits eosinophil stimulation and activation. The absence of eosinophil stimulation and activation causes eosinophil levels to decrease.  All three IL-5 inhibitors have been shown to decrease eosinophil levels in the blood of patients with eosinophilia.

Comparing efficacy of IL-5 inhibitors.  There have been no clinical trials comparing these medications to each other for the control of eosinophilia and these trials are not likely in the future.  Decisions on which inhibitor to use for eosinophilic asthma are therefore likely to be empirical.  If one inhibitor does not seem to be effective in controlling eosinophilia, or causes side effects, then patients may have better results with one of the others.  In particular, if reslizumab (Cinqair) or mepolizumab (Nucala) are not effective or cause side effects, then benralizumab (Fasenra) is a possible alternative as it works by a slightly different mechanism.  Side effects can sometimes be caused by the formulation or additives during the manufacturing process, so a patient with side effects when taking mepolizumab (Nucala) may better tolerate the reslizumab (Cinqair), or vice versa.

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