Review Allergologie select, Vol. 5/2021 (119-127) Anti-IgE: A treatment option in allergic rhinitis? Oliver Pfaar*, Francesca Gehrt*, Hansen Li, Stefan A. Rudhart, Alexander Nastev, Boris A. Stuck, and Stephan Hoch Department of Otorhinolaryngology, Head and Neck Surgery, Section of Rhinology ©2021 Dustri-Verlag Dr. K. Feistle and Allergy, University Hospital Marburg, Philipps-Universität Marburg, Marburg, ISSN 2512-8957 Germany DOI 10.5414/ALX02205E e-pub: February 24, 2021 Key words Abstract. Background: Allergic rhinitis bidities. Further clinical trials with other bio- omalizumab – biologics (AR) is the most common IgE-mediated al- logics in the management of AR are needed – allergic rhinitis – anti- lergic disease. Multiple clinical trials have and are expected to follow soon. IgE – allergen immuno- demonstrated promising results on the AR therapy treatment with biologics, in particular with the use of omalizumab – an anti-IgE anti- body. Omalizumab has also been established *The two first authors Introduction have equally contributed in the routine management of allergic asthma to the publication. and chronic idiopathic urticaria. However, Allergic rhinitis (AR) is an IgE-mediated currently there is no approved license for the chronic disease of the nasal mucosa. As a re- use of biologics in AR in Germany. Materials sult of exposure to allergens, typical symp- and methods: A systematic literature review has been completed including randomized toms such as rhinorrhea, nasal obstruction, controlled trials, meta-analyses, and reviews sneezing, or itching in the area of the nose on the treatment of AR with omalizumab. occur [1]. Results: The systematic review demon- In Germany, AR is the most common strates strong evidence supporting the use of allergic disease with a lifetime prevalence omalizumab in the treatment of AR with re- gard to symptom control, safety profile, and of 14.8%, as epidemiological studies of the management of comorbidities. Conclusion: Robert Koch Institute (RKI) have demon- Omalizumab is a good and safe option in the strated [2]. In addition, an overall increase treatment of AR in terms of symptom control of the prevalence of AR has been reported and the management of pre-existing comor- worldwide [3]. Nevertheless, it is often mis- diagnosed, under-diagnosed, and underesti- mated as such [4]. The standard treatment of List of abbreviations: AR is based on three principles: i) avoidance AIT Allergen immunotherapy measures, ii) anti-allergic pharmacotherapy, AR Allergic rhinitis and iii) allergen immunotherapy (AIT) [1, 5, ARC Allergic rhinoconjunctivitis 6]. Nevertheless, in many patients, complete Received DBPC Double-blind placebo-controlled symptom control cannot be achieved with December 2, 2020; DNSSS Daily nasal symptom severity score the established standard therapies, and qual- accepted in revised form IL-4 Interleukin 4 February 10, 2021 ity of life and (work) productivity are often IL-13 Interleukin 13 severely affected and impaired. IAR Intermittent allergic rhinitis Correspondence to In particular, sufficient efficacy of avoid- Prof. Dr. med. MAB Monoclonal antibodies Oliver Pfaar OCSS Ocular symptom severity score ance measures cannot always be realized. Department of Otorhino- OJTF Omalizumab joint task force Furthermore, the administration of anti-aller- laryngology, Head and PAR Perennial allergic rhinitis gic medication cannot provide a thorough Neck Surgery, Section of RCT Randomized controlled trials symptom relief in all patients. This is espe- Rhinology and Allergy, RKI Robert Koch Institute University Hospital cially true for nasal obstruction under anti- Marburg, Philipps- RQLQ Rhinoconjunctivitis quality of life histamine therapy [7, 8]. There is moreover Universität Marburg, questionnaire an association of AR and relevant comor- SAR Seasonal allergic rhinitis Baldingerstraße, bidities such as allergic asthma and rhinosi- 35043 Marburg, SCIT Subcutaneous AIT Germany TLR7 Toll-like receptor-7 nusitis, which additionally impairs patients’ [email protected] conditions [4, 9, 10, 11]. Pfaar, Gehrt, Li, et al. 120 Table 1. Clinical development programs of biologics in allergic rhinitis (most advanced study phase reported). Substance name Mechanism of action Indication Study References Manufacturer phase Talizumab IgE – antagonist * I 1997 [18] Tanox MEDI4212 IgE – antagonist * I 2016 [13] MedImmune LLC Ligelizumab IgE – antagonist A I 2014 [14] Novartis PF-06444753 and AHD and AHD+TLR-9 agonist, * I 2015** Pfizer PF-06444752 vaccine inducing anti-IgE antibodies XmAb7195 IgE – antagonist * I 2017** Xencor, Inc. ICON Early Phase Services, LLC MT-2990 MAB*** * I 2018** Mitsubishi Tanabe Pharma Corporation VAK-694 MAB against interleukin 4 * IIa 2011 [15] Novartis Dectrekumab MAB against interleukin-13 * II 2008** Novartis GSK2245035 TLR-7 agonist * II 2015 [17] GlaxoSmithKine Dupilumab MAB against IL-4 and IL-13 A, AD, CRS II 2019 [16] Regeneron Pharmaceuticals receptor Omalizumab MAB against IgE A, CSU III 2018** Novartis A = asthma; AD = atopic dermatitis; AHD = aluminium hydroxide; CRS = chronic rhinosinusitis; CSU = chronic spontaneous urticaria. *Indication pending; **trial results (full publication) unpublished; ***MAB with undefined target. Biologics and modulation II study, a combined therapy with VAK-694 of the inflammatory cascade (IL-4 antagonist) and subcutaneous allergen immunotherapy (SCIT) demonstrated an im- The former underlines the important un- munomodulatory effect on the TH2 memory met need for further improvement of thera- cells; however, a clinical response was lack- peutic approaches. Among others, biologi- ing [15]. In contrast, dupilumab targeting cals are promising therapeutic candidates both the IL-4 and IL-13 receptors showed a directly targeting individual mechanisms of significant improvement in symptoms in pa- the inflammatory cascade. Between 1997 tients with persistent AR (PAR) and comor- and 2019, a large number of phase I and II bid asthma [16]. Furthermore, the toll-like studies were conducted on efficacy and safe- receptor 7 (TLR-7) agonist GSK2245035 ty of biologics in AR (Table 1). A first group was found to be beneficial in AR in a phase of biologics comprise monoclonal antibod- II study. However, further dose-ranging trials ies (MAB) against IgE, such as talizumab, are needed for detecting the optimal dosage MEDI4212, ligelizumab, XmAb7195, and [17]. omalizumab. Though talizumab (CGP51901) Currently, the most advanced biologic in has demonstrated a blunting of serum IgE AR in clinical development is the IgE antag- levels in preliminary studies, further clini- onist omalizumab. It has been approved in cal development programs have been paused the EU since 2005 as an add-on therapy for [12]. In an early phase I trials of MEDI4212, patients with severe persistent allergic asth- a particularly rapid and strong reduction in ma and has been established in routine clini- serum IgE was observed in patients with AR cal care [19]. However, due to its mechanism followed by a rapid rebound of serum IgE of action, omalizumab is also considered a levels after cessation of therapy [13]. Ligeli- promising therapeutic option for the treat- zumab also demonstrated a significant reduc- ment of other IgE-mediated atopic diseases tion of serum IgE in a phase I study which such as AR [20]. This is probably also true could be maintained for a longer period after for its biosimilars currently in development treatment [14]. (CMAB007, STI-004, FB317, GBR310, A second class of biologics targets inter- CTP-39, BP001) [12]. The following is an leukins (IL) such as IL-4 and IL-13, and has overview of the current literature on efficacy been investigated in AR patients. In a phase and safety of omalizumab in AR. Anti-IgE: A treatment option in allergic rhinitis? 121 Figure 1. Clinical trials of omalizumab in AR. SAR = seasonal allergic rhinitis; PAR = perennial allergic rhinitis. Omalizumab in AR: of concomitant (anti-allergic) medications search strategies for symptom relief, disease-specific quality of life, safety of SCIT under omalizumab and The literature search was conducted us- safety/tolerability in general. Figure 1 pro- ing PubMed, clinicaltrialisregister.eu, and vides an overview of trials on omalizumab in clinicialtrialis.gov. The search terms “bio- AR extracted by our search. logicals”, “omalizumab”, and “anti-IgE” in combination with “allergic rhinitis” were used to identify relevant study results. Ran- Omalizumab in AR: domized controlled trials (RCT), placebo mechanism-profile controlled (DBPC) trials, review articles, and meta-analyses from 1997 to 2020 were con- As in other atopic diseases, allergen- sidered for the literature search. The most re- specific IgE is overexpressed in patients with cent literature search was conducted on April AR binding to two different receptors (FcεRI 27, 2020 and aimed to specify the effect of and FcεRII) on effector cells. The binding to omalizumab on symptom control, reduction these receptors results in the initiation of the Pfaar, Gehrt, Li, et al. 122 inflammatory cascade with the typical pat- of 0.016 mg/kg/IgE (IU/mL) subcutaneously tern of AR symptoms. Increased levels of every 4 weeks in adults and adolescents (12 serum allergen specific IgE have been found years of age and older) for the treatment of to correlate with the onset and symptom se- severe persistent asthma [35]. Recent trials verity of AR [26, 42]. in AR with this dosage could demonstrate Omalizumab binds free serum IgE, pre- clinical efficacy [8,