Dupilumab for the treatment of chronic rhinosinusitis with nasal polyposis

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Expert Opinion on Biological Therapy
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Dupilumab for the treatment of chronic rhinosinusitis with nasal polyposis
Wytske Fokkens, Rik Van Der Lans & Sietze Reitsma
To cite this article: Wytske Fokkens, Rik Van Der Lans & Sietze Reitsma (2021) Dupilumab for the treatment of chronic rhinosinusitis with nasal polyposis, Expert Opinion on Biological Therapy, 21:5, 575-585, DOI: 10.1080/14712598.2021.1901881
To link to this article: https://doi.org/10.1080/14712598.2021.1901881
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Published online: 01 Apr 2021.
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Otolaryngologist, Epidemiologist, Department of Otorhinolaryngology, Amsterdam University Medical Centres, Amsterdam, North Holland, AZ, Netherlands
ABSTRACT Introduction: Chronic rhinosinusitis with nasal polyps (CRSwNP) affects 1–2.5% of the population and is associated with significant adverse effects on quality of life (QoL). CRSwNP is strongly correlated with (late onset) asthma with 30–70% of the CRSwNP patients having asthma. Health-care spending in rhinosinusitis is high, especially because of indirect costs. Areas covered: In the last years, the recognition of endotyping as an essential presumption to precision medicine has significantly changed the integrated care pathways in the treatment of chronic rhinosinusitis. Dupilumab is the first biological available for the treatment of CRswNP, since late 2019. Treatment with dupilumab results in a significant improvement of QoL (measured as SNOT-22), rhinosinusitis disease severity, symptoms of rhinosinusitis, and especially sense of smell, nasal polyp score, Lund-Mackay CT score, and asthma outcomes (ACQ5 and FEV1) compared to placebo. Expert opinion: At this moment, the high cost of the treatment requires careful patient selection and within the EUFOREA and EPOS2020 context, experts have tried to give guidance based on today’s data. We now need trials evaluating which patients benefit most from treatment with biologicals and in which patients the treatment is cost-effective.
ARTICLE HISTORY Received 28 August 2020 Accepted 8 March 2021
KEYWORDS Chronic rhinosinusitis; nasal polyps; dupilumab; EPOS2020; biological
1. Introduction
Chronic rhinosinusitis (CRS) is a common condition in most of the world, affecting 5–28% of the general population and leads to a significant burden on society in terms of health-care consumption and productivity loss [1–4]. CRS in adults is defined as an inflammation of the nose and the paranasal sinuses characterized by two or more symptoms, one of which should be either nasal blockage/obstruction/ congestion or nasal discharge (anterior/posterior nasal drip) and/or facial pain/pressure and/or reduction or loss of smell and either endoscopic signs of nasal polyps and/ or abnormalities like discharge and swollen mucosa in the middle meatus and/or mucosal changes within the ostio- meatal complex and/or sinuses on CT scan of the sinuses lasting at least 3 months [5].
When a symptom-based diagnosis is verified by endoscopy and/or CT scan, the prevalence of CRS is reduced to 3–6% [6–9].
CRS has traditionally been classified into chronic rhinosinu- sitis with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP). CRSwNP: chronic rhinosinusitis as defined above and bilateral, endoscopically visualized polyps in middle mea- tus; and CRSsNP: chronic rhinosinusitis as defined above and no visible polyps in middle meatus, if necessary following decongestant.
The prevalence of the CRSwNP phenotype is 1–2.5% of the population [10,11].
CRS is associated with significant adverse effects on the quality of life [12,13]. From this perspective, CRS has a greater impact on social functioning than angina or chronic heart failure [14]. A significant percentage of patients with CRS, and especially those with CRSwNP, continue to experience bothersome symptoms despite adequate treatment. This group with so-called severe chronic upper airway disease (SCUAD) represents a therapeutic challenge [15]. Health-care spending in CRS, and especially in CRSwNP, is considerable and significantly greater than in other respiratory diseases such as acute asthma and hay fever [16]. The annual direct costs for the management of CRS have been reported to be between 1500 and 3400 euro [16–18]. The indirect costs of rhinosinusitis are much greater than the direct costs. Since 85% of patients with rhinosinusitis are of working age (range: 18–65 years old), indirect costs such as missed work- days (absenteeism) and decreased productivity at work (pre- senteeism) significantly add to the economic burden of the disease [19]. As a consequence, rhinosinusitis is in the top 10 of most costly health conditions to US employers [20].
CRS is strongly associated with asthma, with a prevalence of asthma around 25% in patients with CRS compared to 5% in the general population. In patients with CRSwNP, asthma can be found in 30–70% of the patients [21–23]. Conversely, the presence of nasal polyps is associated with the severity of asthma, ranging from 10–30% in mild asthma to 70–90% in severe asthma [24,25]. CRSwNP comprises a heterogeneous group of patients, who differ with respect to co-existing
CONTACT Wytske Fokkens [email protected] Otolaryngologist, Epidemiologist, Department of Otorhinolaryngology, Amsterdam University Medical Centres, Location AMC, Meibergdreef 9, Amsterdam, North Holland, 1105, AZ, Netherlands.
EXPERT OPINION ON BIOLOGICAL THERAPY 2021, VOL. 21, NO. 5, 575–585 https://doi.org/10.1080/14712598.2021.1901881
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
asthma, allergy, NSAID-exacerbated respiratory disease (N-ERD) [26], smoking, age of onset, and disease severity [21,27,28].
The significant percentage of uncontrolled CRSwNP patients despite optimal medical treatment and repeated sur- gery calls for new treatments [29–32]. The new biological treatments that have been introduced for severe asthma show great promise for the treatment of CRSwNP and repre- sent a potential step forward in providing individualized care for all patients with uncontrolled severe upper airway dis- eases. This review aims to present the data on one of these biological treatments: dupilumab in the treatment of CRSwNP.
2. CRS with nasal polyposis classification
Chronic rhinosinusitis has traditionally been classified as chronic rhinosinusitis with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP).
However, it has become progressively clear that CRS is a complex disease consisting of several disease variants with different underlying pathophysiologies [23,33,34]. The pheno- types do not provide full insight into all underlying cellular and molecular pathophysiologic mechanisms of CRS, which becomes increasingly relevant because of the variable associa- tion with comorbidities such as asthma and responsiveness to different treatments including corticosteroids [35,36], surgery [37]and biological agents [29,38–41].
In the last update of the European Position Paper on Rhinosinusitis and Nasal Polyps: EPOS2020 [42] a new classifi- cation of rhinosinusitis has been proposed (see Figure 1), which divides CRS in terms of primary and secondary disease and further divides primary disease into localized and diffuse disease based on anatomic distribution [42]. In primary CRS, the disease is considered by endotype dominance, either type 2 or non-type 2. CRSwNP is mostly diffuse type 2 inflamma- tion, but some other forms of inflammation can be found [23].
AFRS, allergic fungal rhinosinusitis; CCAD, central compart- ment allergic disease; CRSwNP, chronic rhinosinusitis with nasal polyps; eCRS, eosinophilic chronic rhinosinusitis.
3. Pathophysiology of CRSwNP: the role of type 2 inflammation
The inflammation in CRSwNP can be characterized by a complex host–environmental interaction, with great varia- bility in nature, sequence, and intensity of exogenous stressors [42]. Although the mechanisms of inflammation are not totally understood, it has been suggested that an impaired sinonasal epithelial barrier leads to increased exposure to inhaled patho- gens, antigens and particulates, that could promote chronic inflammation [43].
When the barrier is breached, a self-limited immunodefen- sive response is generated, characterized by a cellular and cytokine repertoire targeting one of the three classes of patho- gens. Generally speaking, type 1 immune responses target viruses, type 2 responses target parasites, and type 3 responses target extracellular bacteria and fungi, all of which in optimal conditions would resolve with elimination of the pathogens and restoration of barrier integrity.
Although often mixed types can be found, the most dominant endotype of CRSwNP in the Western world demonstrates a non-parasitic derived type 2 mediated inflammatory response which is characterized by a high pre- valence of eosinophils, mast cells, and basophils, as well as elevated type 2 cytokines (IL-4, IL-5, IL-13, IL-25, and IL-33) and type 2 cells [44–46]. The exact pattern of elevated cell types and/or cytokines may vary depending on the presence of allergies, asthma, N-ERD, and other diseases/markers; the immunological background of all the various CRS endotypes is not fully understood yet. The type 2 inflammatory pattern is mainly driven by CD4+ Th2 lymphocytes and type 2 innate lymphoid cells (ILC2). These cells principally produce IL-4 and IL-13, which play a pivotal role in inducing and
Figure 1. Classification of primary rhinosinusitis [42] (with permission).
576 W. FOKKENS ET AL.
expanding the type 2 inflammation [47]. A predominant type 2 protein expression profile is associated with recurrent CRSwNP after ESS [48].
ILCs are a recently identified family of effector cells, which are important early regulators of immune responses at bar- rier surfaces. It has been demonstrated that ILC2s represent the dominant ILC subset in CRSwNP [48–50]. The ILC2 increase in CRSwNP can be explained by tissue enrichment with ILC2-activating cytokines, that is IL-25, IL-33, and TSLP [51]. Under homeostatic conditions, IL-33 is retained in the nucleus of basal epithelial cells and its release is associated with tissue injury or cell death. Alternatively, IL-33 might be released by epithelial cells. Therefore, elevated IL-33 levels may be related to tissue damage or epithelial activation in treatment-recalcitrant CRSwNP, which may drive the perpe- tuating eosinophilic inflammation via ILC2-derived IL-5 [52]. This vicious circle might well be maintained by eosinophil- derived (and/or mast cell-derived) IL-4, a key cytokine required for the maintenance of ILC2 [53].
Thus, type 2 inflammatory involvement in CRSwNP is believed to have a driving role in the disease process. The biological function of IL4 and IL-13 is exerted through the binding of two receptor (IL-4 R) subtypes, both sharing the common IL-4 Rα. This may result in local IgE production induced by IL-4 and IL-13 and eosinophilic inflammation induced by IL-4 and IL-13 as well as by IL-5. IL-13 and IL-4 partly share the same receptor and signaling pathways, and both are deeply involved in IgE synthesis, eosinophil activa- tion, mucus secretion, and airway remodeling. IL-4 is a major differentiation factor driving a type 2 response by initiating T cell differentiation toward the TH2 subtype [54]. IL-4 also induces the production of type 2 associated cytokines and chemokines such as IL-5, IL-9, IL-13, TARC and eotaxin. Furthermore, IL-4 and IL-13 are primarily responsible for isotype class switching of B cells to produce IgE {Punnonen, 1993 #9168;Le Floc’h, 2020 #23,216}
Remodeling of sinonasal tissues in CRS consists most prominently of polyp formation, goblet cell hyperplasia, and epithelial barrier abnormalities, which, in aggregate, may account for many or most of the CRS symptoms [55]. In the case of the barrier remodeling, the result is greater permeability, likely facilitating persistence or recurrence of CRS. All of these changes are most apparent in type 2 CRS, possibly accounting for the observed greater symptomatol- ogy and higher rate of treatment failure. Biologic agents that suppress type 2 inflammation may suppress the inflam- mation, reverse the remodeling and limit recurrence, thereby altering the clinical course of the most severe CRS phenotypes.
4. Dupilumab
As has been indicated above, IL-4 and IL-13 are potent med- iators of type 2 immunity(e.g. pro-inflammatory cytokines, chemokines, IgE and nitric oxide).
There are two types of receptors for IL-4: the type 1 recep- tor, which is composed of the IL-4 chain (IL-4Rα) and a γ chain (γC), and the type 2 receptor, which is composed of the IL-4Rα chain and the α1 chain of the IL-13 receptor (IL-13Rα1).
Essentially, IL-4Rα is a component shared by the IL-4 and IL- 13 receptor complexes and is ubiquitously expressed on both innate and adaptive immune cells to promote the signaling of IL-4 and IL-13 [54]. The type I receptor is primarily expressed on lymphocytes and controls Th2-cell differentiation, whereas the type II receptor is mostly found across resident and mye- loid cells. Dupilumab is a human monoclonal antibody direc- ted against IL-4Rα [54]. By inhibiting IL-4R signaling of both IL- 4 and IL-13 it effectively downregulates the molecular path- ways that drive type 2 inflammation (e.g. pro-inflammatory cytokines, chemokines, IgE and nitric oxide).
Dupilumab has been registered in Europe and the US for the treatment of moderate to severe atopic dermatitis that is not adequately controlled with topical prescription therapies or when those therapies are not advisable and/or for severe asthma with type 2 inflammation that is not properly controlled by a combination of high-dose corticosteroids taken by inhalation plus another medicine used for the prevention of asthma. In 2019 Dupilumab has been approved in Europe and the US for the treatment of CRSwNP with type 2 inflammation (box 1).
5. Possible mechanisms of action of Dupilumab in CRSwNP
Dupilumab has potentially multiple sites of action that remain to be fully established. It can target fundamental mechanisms in type 2 cell inflammatory diseases by blocking type 2 cell differentiation and IgE production by B cells. Moreover, it can act on the vascular endothelium to potentially reduce cellular trafficking in inflamed tissues and attenuate vascular leakage.
Dupilumab treatment in patients with CRSwNP was shown to decrease type 2 biomarker levels, like eosinophil cationic protein (ECP), eotaxin-2 and 3, pulmonary and activation-regulated che- mokine (PARC), IgE,and IL-13 in nasal polyp tissue [56]. Also, blood levels of biomarkers of type 2 inflammation like ECP, eotaxin-3, total IgE, thymus and activation-regulated chemokine (TARC), and periostin have been shown to decline with the addition of dupilumab to intranasal corticosteroid treatment in adults with CRSwNP [57,58]. Serum TARC suppression was max- imal at the first post-baseline level and sustained over the treat- ment period, while serum total IgE suppression was gradual, with a greater effect seen with a longer duration of therapy.
Box 1. Drug summary box Drug name: dupilumab Phase: approved by FDA and EMA Indication: To treat adults with nasal polyps (growths on the inner lining of the
sinuses) accompanied by chronic rhinosinusitis (prolonged inflamma- tion of the sinuses and nasal cavity)(FDA)
As an add-on therapy with intranasal corticosteroids for the treatment of adults with severe CRSwNP for whom therapy with systemic corticoster- oids and/or surgery do not provide adequate disease control (EMA).
Pharmacology description/mechanism of action: dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin- 13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor. Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine- induced responses, including the release of proinflammatory cytokines, chemokines and IgE.
EXPERT OPINION ON BIOLOGICAL THERAPY 577
The reduction of eotaxins potentially blocks eosinophil migration into the tissues and a transient increase in blood eosinophil count was seen in some dupilumab trials [57,59].
In a recent study, using a sensitization and challenging model with house dust mites in mice (electing both IL-4 and IL-13 responses), it was shown that the dual blocking of IL-4 and IL-13 is needed to prevent eosinophil infiltration into lung tissue [54].
In humans, to our knowledge, no data are available on the reduction of (activated) eosinophils in nasal polyps or lung tissues. Data are available on reduction of (activated) eosino- phils in eosinophilic esophagitis after dupilumab treat- ment [60].
Another pathway relevant to chronic rhinosinusitis and nasal polyps involves ALOX15, encoding 15-Lipoxygenase A, whose expression is strictly dependent on IL-4 and IL-13. Loss of function mutations in ALOX15 protects against nasal polyps and chronic rhinosinusitis. Metabolites of ALOX15 activate macrophages toward a M2 phenotype, suggesting that Dupilumab may protect against chronic rhinosinusitis in part by suppressing the IL-4/13-ALOX15/M2 macrophage axis [61].
6. Dupilumab: clinical data in CRSwNP
Dupilumab has been studied in phase 2 and 3 trials in recent years.
In 2016, Bachert et al. performed a small phase II double- blinded, placebo-controlled parallel-group study, in 60 adult CRSwNP patients (51 completed the trial) of which 35 had comorbid asthma. After a four-week run-in period of treat- ment with mometasone, patients were randomly allocated to add-on therapy with subcutaneous dupilumab (600 mg load- ing followed by 15 weekly doses of 300 mg) or matched placebo for 16 weeks [62]. Patients treated with dupilumab had significant improvement in SNOT-22 (LS mean difference −18.1 [95% CI, −25.6 to −10.6]), rhinosinusitis disease severity (VAS) LS mean difference −2.1 [95% CI, −3.7 to −0.6]), nasal blockage measured by PNIF (LS mean difference 33.1 [95% CI 12.7 to 53.5]), sense of smell assessed by UPSIT (LS mean difference 14.8 [95% CI, 10.9 to 18.7]), nasal polyp score (LS mean difference – 1.6 [95% CI, −2.4 to −0.7]), and Lund- Mackay CT score (LS mean difference −8.8 [95% CI, −11.1 to −6.6]), and asthma outcomes (ACQ5 1.1 [95% CI, −1.5 to −0.6]) compared to placebo.
The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively) and headache (17% vs 20%) (Table 1).
Bachert et al. [57] published the results of two rando- mized double-blind, multicenter, placebo-controlled, paral- lel-group phase 3 trials which evaluated dupilumab added to standard-of-care in adults with severe CRSwNP. In the liberty NP SINUS-24 study, patients were randomized 1:1 to 24 weeks subcutaneous dupilumab 300 mg or placebo every 2 weeks. In Liberty NP SINUS-52, patients were rando- mized 1:1:1 to 52 weeks dupilumab 300 mg every 2 weeks, 24 weeks every 2 weeks, then 28 weeks dupilumab 300 mg every 4 weeks, or 52 weeks placebo every 2 weeks. In both studies, treatment with dupilumab significantly improved LS mean difference vs. placebo [95% CI] of the SNOT-22 SINUS- 24 −21.1 [−25.2 to −17] and SINUS-52 −17.4 [−20.9 to 13.9], total symptoms score (VAS) SINUS 24 −2.6 [−3.0 to −2.2] and SINUS-52 −2.4 [−2.9 to −2.0], nasal congestion score (0–3) SINUS 24 −0.9 [−1.0 to −0.7] and SINUS-52 −0.9 [1.0 to −0.7], sense of smell assessed by UPSIT SINUS 24 10.6 [8.8 to 12.3] and SINUS-52 10.5 [9.0 to 12.0]]; nasal polyp score SINUS 24–2.1 [−2.4 to −1.7] and SINUS-52 −1.8 [9.0 to 12.0], Lund-Mackay CT score SINUS 24–7.4 [−8.4 to −6.5] and SINUS-52 −5.1 [−5.8 to −4.5].
The Bachert studies were very much done in the same way and could be combined into a meta-analysis of the three studies evaluating dupilumab added to standard-of-care treat- ment for patients with CRSwNP [42].
The SNOT-22 score (scale 0–110) at 4–6 months showed a significant and clinically relevant decrease in mean differ- ence (MD) –19.61 (95% CI −22.53 – −16.69); 784 participants; two studies; I2 = 0%) (Figure 2).
The Rhinosinusitis disease severity (VAS) at 4–6 months showed a significant and clinically relevant decrease in MD – 2.54 (95% CI −2.84 – −2.23; 784 participants; two studies; I2 = 40%); and the nasal congestion/obstruction score at 4–6 months showed a significant and clinically relevant decrease in MD –0.86 (95% CI −0.98 – −0.75); 784 participants; two studies; I2 = 0%).
Smell was evaluated using the UPSIT. The UPSIT score at 4–6 months showed a significant and clinically relevant decrease in MD 10.83 (95% CI 9.59–12.08; 784 participants; two studies; I2 = 0%) (Figure 3).
The nasal polyp score was the primary endpoint in these studies. The mean nasal polyp score in these studies was around 6, indicating severe polyp disease. The nasal polyp score…