Dupilumab: Clinical Efficacy of Blocking IL-4/IL-13 Signalling in Chronic Rhinosinusitis with Nasal Polyps

Abstract

In September 2019, The Lancet published details of two large Phase III double-blind placebo-controlled studies (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52) confirming the clinical efficacy of the biologic dupilumab in simultaneously blocking both IL-4/IL-13 signalling in chronic rhinosinusitis with nasal polyps (CRSwNP). The studies demonstrated that dupilumab (Dupixent^®, Sanofi and Regeneron) 300mg subcutaneously administered was clinically effective when added for patients with moderate to severe CRSwNP already maintained on the standard intranasal steroid mometasone furoate. Duration of treatment ranged from injections either 2 weekly for 24 weeks (SINUS-24) or every 2 weeks for 52 weeks or finally every 2 weeks for 24 weeks stepping down thereafter to every 4 weeks for a further 28 weeks (SINUS-52). Rapid improvements in all important parameters of disease burden were seen with such improvement maintained even where the frequency of injections was decreased. In patients with co-existent asthma, lung function and asthma control scores improved. This is consistent with the one airway hypothesis of shared T2 inflammatory programmes driving both disease syndromes. The studies formed the basis for FDA registration and clinical launch in the US, and EMA approval in Europe. Dupilumab presents a significant new treatment option in an area of urgent unmet therapeutic need in CRSwNP. Should dupilumab prove to be as effective in the real-life clinical environment as it has been in the studies, then a paradigm shift from sinonasal surgery to medical treatment of CRSwNP may need to occur in the ENT community. Questions in relation to best patient selection, combined upper and lower airway therapeutic pathways, long-term safety along with health economics and cost constraints ought now to be addressed.

Keywords: biologic; inflammation; monoclonal antibody; sinusitis; therapeutics.

Figure 1

Summary of key T2 cytokines and cells with established roles in sustaining T2 inflammation and key sources of IL-4 and IL-13. IL-4 and IL-13 are secreted from several cellular sources and along with other key T2 cytokines such as IL-5, IL-33, IL-25 and TSLP can lead to further IL-4 with or without IL-13 secretion depending on the cell type. This leads to immune amplification and auto-inflammatory loops that sustain mucosal disease and contribute to airway disease severity. ILC2 cells, particularly in response to IL-33 secrete large amount IL-13 as well as IL-5.

Figure 2

Summary of IL-4 and IL-13 receptor signalling pathways. The type 1 and type 2 receptor system and the main signalling cascade in relation to specific receptor activation in a cell are illustrated.

Figure 3

(A) and (B) Summary of LIBERTY NP SINUS–24 and LIBERTY NP SINUS–52 study design.

Figure 4

Summary of IL-4 in establishing T2 inflammation. Naive T helper cells (Th0) can only undergo differentiation into Th2 cells upon antigen presentation by dendritic cells in the presence of IL-4. This is a key step in the establishment of Th2 mediated inflammation. Tfh cells in the presence of antigen and IL-4 undergo activation to produce further IL-4 that is essential for the induction of B cell-dependent production of IgE and IgG.