Expert insights on role of IL-5 inhibition in CRSwNP management

Eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) is a subtype of chronic rhinosinusitis (CRS) characterized by local eosinophilic inflammation. Patients with CRSwNP often require multiple nasal surgeries despite repeated use of antibiotics and systemic corticosteroids and long-term use of intranasal corticosteroids with saline nasal rinse. At a symposium organized by the Hong Kong College of Otorhinolaryngologists, Dr Narinder Singh of the Otolaryngology, Head and Neck Surgery Department of the University of Sydney, Australia, discussed the pathogenesis of CRSwNP and the use of mepolizumab in improving outcomes in CRSwNP. Dr A B John, Specialist in Otorhinolaryngology in private practice in Singapore, shared clinical experience and insights in CRSwNP treatment with mepolizumab.

Roles of eosinophils and IL-5 in eosinophilic respiratory diseases
“Interleukin [IL]-5 is a type 2 [T2] inflammatory cytokine that plays a critical role in eosinophilic nasal polyposis,” Singh said. “IL-5 is primarily produced by T helper 2 cells, but is also produced in large quantities by eosinophils in nasal polyps [NPs] as well as some other cells.” [Int Forum Allergy Rhinol 2022;12:1413-1423; Curr Opin Allergy Clin Immunol 2016;16:186-200]

“Eosinophils are leukocytes [ie, white blood cells] involved in NP formation through epithelial injury, basement membrane thickening, fibrosis, angiogenesis and glandular hyperplasia,” Singh said. [Nat Rev Immunol 2013;13:9-22; J Allergy Clin Immunol Pract 2016;4:565-572]

“IL-5 plays a fundamental role in eosinophil maturation, migration, activation and survival,” Singh added. “In eosinophilic asthma and CRSwNP, eosinophils lead to T2 inflammation that triggers production of IL-5, thereby resulting in further eosinophil stimulation.” [Curr Opin Allergy Clin Immunol 2016;16:186-200]

“In patients with CRSwNP, eosinophilia is associated with increased risk of polyp recurrence and more severe olfactory loss,” said John. [Int Forum Allergy Rhinol 2017;7:957-962]

CRSwNP classification
CRS is a highly heterogeneous disorder with epidemiological, clinical and immunopathological variations. The European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2020 classifies CRSwNP, a phenotype of CRS, as an example of T2 endotype dominance. [Rhinology 2020;Supp 29:1-464]

“In Western populations, 80–90 percent of NPs are eosinophilic predominant, whereas Southeast Asian populations exhibit a higher proportion of neutrophil-predominant NPs,” said John. “An endotype review in 578 CRSwNP patients [Asians, 61 percent; Chinese, 58 percent] found that Asians exhibit less eosinophilic and T2 inflammation [40 percent vs 80 percent] but more mixed T2 inflammation [25 percent vs 15 percent] than Caucasians.” [Clin Exp Allergy 2022;52:231-243]

Current management of CRSwNP
Treatment options for CRSwNP include long-term intranasal corticosteroids, short-term systemic corticosteroids, sinus surgery, and biologics. [Rhinology 2023;61:194-202] “Sinus surgery helps reduce inflammatory mucosal load, restore ventilation and drainage of paranasal sinuses, and give postoperative access for intranasal treatment to minimize the use of systemic corticosteroids,” John noted.

“Nevertheless, NP recurrence following surgery is three times more likely in patients with elevated eosinophils [>4 eosinophils/1,000 μm²] than those without [≤3 eosinophils/1,000 μm²] [81.8 percent vs 25 percent; p<0.0001], and up to 90 percent of recurrent NP cases are driven by eosinophilic inflammation. Therefore, IL-5 or eosinophils are major targets of therapeutic intervention for CRSwNP,” John highlighted. [Ann Otol Rhinol Laryngol 2010;119:455-459; Allergol Int 2019;68:403-412; Rhinology 2016;54:150-159]

Guidelines of EPOS and the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) recommend biologics in CRSwNP patients with uncontrolled disease despite appropriate medical and surgical treatment who fulfil ≥3 of the following criteria: presence of T2 inflammation, regular need for systemic corticosteroids, significant impact on quality of life (QoL), loss of smell and comorbid asthma. [Rhinology 2023;61:194-202]

Efficacy and safety of mepolizumab in CRSwNP
Mepolizumab is a recombinant, humanized, immunoglobulin G1 (IgG1) monoclonal antibody against IL-5 that selectively and effectively inhibits eosinophilic inflammation. First approved as an add-on maintenance treatment for severe eosinophilic asthma, which often coexists with CRSwNP due to their common underlying inflammatory mechanisms, it is also indicated as an add-on therapy with intranasal corticosteroids for adult patients with severe CRSwNP for whom systemic corticosteroids and/or surgery do not provide adequate disease control. [Nucala Hong Kong Prescribing Information]

In the pivotal phase III, randomized SYNAPSE trial (n=414), mepolizumab 100 mg Q4W demonstrated efficacy vs placebo in reducing NP size and nasal obstruction symptoms in terms of total endoscopic NP score (NPS) and nasal obstruction visual acuity scale (VAS) score, respectively, in patients aged ≥18 years with severe, recurrent and refractory CRSwNP who had bilateral NP symptoms and prior nasal surgery and required repeat surgery. After 52 weeks of randomized treatment on top of standard of care, both total endoscopic NPS (adjusted difference in medians, -0.73; 95 percent confidence interval [CI], -1.11 to -0.34; p<0.0001) and nasal obstruction VAS score (-3.14; 95 percent CI, -4.09 to -2.18; p<0.0001) significantly improved from baseline with mepolizumab vs placebo. (Figures 1 and 2) [Lancet Respir Med 2021;9:1141-1153]

Subgroup analyses of SYNAPSE demonstrated similar efficacy of mepolizumab in reducing NP size and improving nasal symptoms in patients with comorbidities, including asthma. In addition, marked improvements in health-related QoL and smell as well as reduction in blood eosinophil counts and need for surgery were observed with mepolizumab vs placebo.

Mepolizumab demonstrated a safety profile similar to that of placebo. The most frequently reported adverse events were nasopharyngitis (25 percent and 23 percent), headache (18 percent and 22 percent), epistaxis (8 percent and 9 percent), and sinusitis (5 percent and 11 percent).

Practical advice for starting mepolizumab for CRSwNP
“Mepolizumab can be started for CRSwNP based on the SYNAPSE inclusion criteria and dosage [ie, 100 mg Q4W]. Patients who have undergone multiple procedures are good candidates [for mepolizumab] as they are usually keen for nonsurgical alternatives. I would recommend offering mepolizumab to patients after their first comprehensive surgery,” Singh advised.

“Routine testing for eosinophilic T2 disease is recommended as it is predictive of treatment response. Eosinophilia can be easily checked by performing a full blood count [eosinophil count, ≥300 μL] and sending a sample of NP tissue for histology [≥10 eosinophils per high-power field],” Singh continued. 

Summary
IL-5 inhibitors, such as mepolizumab, are a key development in treatment of T2 or eosinophilic CRSwNP. In the phase III SYNAPSE trial, mepolizumab has demonstrated reductions in NP size and nasal symptoms in severe recurrent CRSwNP. Real-world experience has also shown mepolizumab as an effective, fast-acting and well-tolerated treatment option in improving nasal symptoms, including sense of smell, in Chinese patients with recurrent CRSwNP with inadequate response to intranasal corticosteroids and surgeries.