Anti-Ige: a Treatment Option in Allergic Rhinitis?

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

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 antibody. 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, 10, 27, 32, 34, 37]. venting the interaction of IgE with the FcεRI receptor and further activation of the subse- quent inflammatory pathways. Omalizumab has a higher affinity to free IgE in the serum Omalizumab: than the FcεRI receptor of effector cells lead- patient profiles in AR ing to a strong reduction in free circulating IgE [43]. This is followed by a migration Omalizumab has been demonstrated to of mast cell and basophilic granulocytes re- be beneficial for patients with moderate to cruitment and activation [39] suppressing the severe intermittent and persistent AR and inflammatory pathways within the nasal mu- insufficient symptom control despite con- cosa after allergen exposure [44]. ventional therapy [38]. Several large clinical However, it should be noted that omali- studies reported a significant improvement zumab, when given at therapeutic doses, in symptom control, reduction in the use of does not bind IgE that is already bound to concomitant anti-allergic medication, and an the FcεRI or FcεRII receptor [41]. Since ba- improvement in the quality of life [10, 23, sophilic granulocytes and mast cells have a 26, 38, 39]. Of note, the baseline values of high binding capacity for IgE, a strong reduc- patients with AR seem to correlate with the tion of free IgE and FcεRI receptors is neces- treatment effect size of omalizumab, indicat- sary to reduce the histaminergic response of ing moderate effects in lower IgE profiles effector cells [45]. In clinical trials on omali- [48]. However, omalizumab is not approved zumab, serum free IgE concentrations were in Germany in this indication. reduced by 84 – 99%, degranulation by up to Further atopic diseases such as allergic 90%, and FcεRI receptor expression on ba- asthma and urticaria are often associated sophilic granulocytes by 73 – 99% [21, 22, with AR [10], which often aggravates these 24, 29, 30, 46]. conditions [26]. Previous study results also indicate that According to a variety of studies, about omalizumab not only suppresses the acute half of all patients with AR also suffer from inflammatory response in allergic rhinitis, allergic asthma, and concomitant AR has a but also may provide a long-term immuno- significant impact on asthma control. Poorly modulatory effect [26]. controlled AR is associated with a higher number of asthma exacerbations and hospi- talizations [49]. Since both atopic diseases are associated with elevated serum IgE lev- Omalizumab in AR: els, efficacy of IgE-lowering measures is ob- practical aspects vious. In a study by Vignola et al. [30] on the efficacy and safety of omalizumab in patients Dosage with comorbid asthma and AR, a significant Early studies on the use of omalizumab improvement in asthma and rhinitis symp- in AR aimed to determine the optimal dos- toms as well as lung function was observed. age. Casale et al. [47] compared doses be- Furthermore, an improvement on patients’ tween 50 and 300 mg every 3 – 4 weeks over quality of life was demonstrated [30]. a period of 8 – 9 weeks with placebo admin- In addition to trials investigating efficacy istration. The 300-mg group was significant- of omalizumab monotherapy, some studies ly superior compared to the placebo group. combined this treatment with AIT aimed to However, symptom improvement was also increase treatment response to AR patients seen in patients receiving lower doses. The [31, 37, 38, 39]. In a clinical study, Kuehr et manufacturer (Novartis Pharmaceuticals, al. [27] were able to demonstrate a 48% better East Hanover, NJ, USA) recommends a dose symptom control with combination therapy Anti-IgE: A treatment option in allergic rhinitis? 123 compared to AIT as a monotherapy, indicating Reducing the need a clinical benefit of this add-on co-treatment. for anti-allergic medication

While the study designs were consistently Reduction of rhinoconjunctival uniform in recording of nasal and ocular symptoms symptoms, there were notable methodologi- cal differences in the use of concomitant Various endpoints have been used in clin- anti-allergic medications. For example, in ical studies to assess symptom severity. The some studies, this medication was paused most common score used to measure nasal following the study protocol [10], whereas symptoms was the Daily Nasal Symptom allowed in others [34]. Depending on the Severity Score (DNSSS). A large number of study, different anti-allergic medication was studies also considered the ocular symptoms provided for treatment of AR symptoms, of allergic rhinoconjunctivitis (ARC) such as such as systemic and topical antihistamines, the Daily Ocular Symptom Severity Score mast cell stabilizers, naphazoline, and topical (OCSSS) [8, 10, 25, 34, 50]. and systemic corticosteroids [8, 10, 25]. How- A meta-analysis from 2014 by Tsab- ever, an anti-allergic medication sparing ef- ouri et al. [38] evaluated nine randomized fect of ~ 50% was observed with omalizumab controlled trials with regards to the effect therapy in several randomized controlled trials of omalizumab on the DNSSS in AR and [25]. Furthermore, Chervinsky et al. [10] and could demonstrate superiority against pla- Okubo et al. [8] reported a reduction of days cebo during the pollen season in SAR [25, on which an anti-allergic medication had 50]. A study by Chervinsky et al. [10] on to be taken by a third and to a fifth, respec- PAR also showed significantly more symp- tively, while no significant differences were tom improvement in the omalizumab group observed in the placebo group. It should be compared to the placebo group. In this study, noted, however, that other studies came to a 28% of patients treated with omalizumab different conclusion [27, 30]. achieved symptom control, compared with only 10% of patients in the control group [24]. Another study by Nagakura et al. [34] Impact of omalizumab also demonstrated significant superiority of on quality of life omalizumab over an anti-allergic drug (Th2 cytokine inhibitor). To assess the impact of omalizumab ther- In general, a significant improvement apy on quality of life, the standardized and in nasal symptoms was observed in all ran- validated Rhinoconjunctivitis Quality of Life domized controlled trials between 2000 and Questionnaire (RQLQ) has frequently been 2010. A particularly strong treatment effect used in AR trials. This questionnaire contains size of 39% was seen when omalizumab was 28 items relating to activity limitations, sleep combined with AIT [30, 37]. A meta-analysis disturbances, symptoms, practical problems, published in 2020 [40] again confirmed the and emotional functioning [10]. Adelroth et benefit of omalizumab by evaluating 9 origi- al. [25] and Chervinsky et al. [10] found a nal studies regarding nasal symptoms and statistically significant improvement in the 5 studies regarding ocular symptoms. A sig- omalizumab group compared to the placebo nificant reduction in symptoms was demon- group in all seven domains of the RQLQ and strated for both SAR [25, 50] and PAR [10]. in the total score using this questionnaire. However, the extent of symptom reduc- Even in patients who did not previously re- tion varied between the studies. For example, spond to AIT or intranasal steroid treatment, Adelroth et al. [25] observed a smaller effect a significant improvement in the total score of omalizumab on OCSSS than on DNSSS, was demonstrated [10]. These findings are whereas the reduction in ocular symptoms further supported by a recent meta-analysis (50%) exceeded the improvement of nasal by Yu et al. and others [10, 25, 26, 39, 40, symptoms (40%) in the study by Okubo et 51]. al. [8]. Pfaar, Gehrt, Li, et al. 124

Safety aspects of omalizumab blood count, such as thrombocytopenia. In the more recent clinical studies, neither the Omalizumab therapy has been shown to occurrence of such blood count changes nor be safe and well tolerated in routine clini- the formation of antibodies against omali- cal care. This is also confirmed in a meta- zumab could be observed [8, 10]. An evalu- analysis by Yu et al. [40] which found no ation of twelve randomized controlled trials significant difference in the frequency of could also not determine any clinically rele- adverse events between the omalizumab and vant blood count changes under omalizumab placebo groups as also reported by other au- treatment [55]. thors [12, 49]. Due to the lack of interaction A clinical study demonstrated a slight of omalizumab with cell-bound IgE, the risk increase in parasitic infections under anti- of anaphylaxis is generally considered to be IgE therapy [33]. However, an increase in low [34]. This is supported by the results of parasitic infections could not be reproduced the Omalizumab Joint Task Force (OJTF), an in the animal model. In fact, low IgE blood initiative of the American Academy of Aller- serum concentrations showed no influence gy, Asthma & Immunology. The data analy- on the course of parasitic infections or the sis of the OJTF showed that the probability risk of reinfection [57, 58]. Clinical trials of of an anaphylactic event after omalizumab asthma therapy with omalizumab also did administration is ~ 0.09% [52]. The major- not show an increased incidence of para- ity of anaphylactic reactions occur in the first sitic infections, nor did they show refractory 120 minutes and within the first 3 injections. courses of anti-parasitic treatment. [54]. Therefore, patients should be followed 30 minutes after each injection, especially as possible causes and predisposing factors for Conclusion anaphylactic and anaphylactoid reactions are still unclear. A case-control study in 2016 In the treatment of AR, monoclonal an- identified previous anaphylaxis and food al- tibodies to IgE represent a promising thera- lergy as possible risk factors [53]. In general, peutic option for the future by effectively re- anaphylactic reactions were rare in clinical ducing the free IgE antibodies in the serum. trials [5, 29]. Studies on long-term treat- Omalizumab has already been the subject ment with omalizumab in PAR also showed of a large number of clinical studies in AR good tolerability [1]. There seems to be no with supportive evidence from the treatment increased risk of adverse events including of other atopic diseases. In AR, this treat- anaphylactic reactions in repetitive treatment ment has demonstrated clinical efficacy by cycles [28, 36]. reducing the symptomatic burden and need In rare cases, antibodies to the drug may for concomitant allergic medication and by be formed during therapy with humanized improving the quality of life in patients with DNA-derived monoclonal antibodies in gen- AR. In addition, it has an impact on comor- eral. However, such events have not been ob- bidities and a convincing safety profile. served with omalizumab [1, 29, 34]. Omalizumab is approved as an add-on therapy for better control of severe persistent Omalizumab is able to form an immune allergic asthma, the severe form of chronic complex with free IgE. Since these complex- rhinosinusitis with polyposis (CRSwNP) and es are present as trimers or hexamers, they the severe form of chronic spontaneous urti- pose a low risk for the development of serum caria. Clinical development programs in AR sickness due to their small size [54]. Based are also very convincing. However, further on available data, a low risk for the occur- clinical studies on omalizumab and other rence of serum sickness can be assumed [54, above-mentioned biologics are needed to 55]. So far, only a few cases have been de- integrate these molecules in common treat- scribed in the literature. ment concepts of AR. Large clinical studies showed no increased risk for the occurrence of malignant tumors with omalizumab [56]. In animal Funding studies, omalizumab in higher doses some- times caused pronounced changes in the None. Anti-IgE: A treatment option in allergic rhinitis? 125

Conflict of interest with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008; 63 (Suppl 86): Oliver Pfaar reports grants and personal 8-160. CrossRef PubMed [2] Langen U, Schmitz R, Steppuhn H. [Prevalence of fees from ALK-Abelló, grants and personal allergic diseases in Germany: results of the Ger- fees from Allergopharma, grants and person- man Health Interview and Examination Survey al fees from Stallergenes Greer, grants and for Adults (DEGS1)]. Bundesgesundheitsblatt personal fees from HAL Allergy Holding Gesundheitsforschung Gesundheitsschutz. 2013; 56: 698-706. CrossRef PubMed B.V./HAL Allergie GmbH, grants and per- [3] Björkstén B, Clayton T, Ellwood P, Stewart A, sonal fees from Bencard Allergie GmbH/Al- Strachan D, Phase III Study Group ISAAC; lergy Therapeutics, grants and personal fees ISAAC Phase III Study Group. Worldwide time from Lofarma, grants from Biomay, grants trends for symptoms of rhinitis and conjunctivitis: Phase III of the International Study of Asthma and from Circassia, grants and personal fees Allergies in Childhood. Pediatr Allergy Immunol. from ASIT Biotech Tools S.A., grants and 2008; 19: 110-124. CrossRef PubMed personal fees from Laboratorios LETI/LETI [4] Scadding GK. Optimal management of allergic Pharma, personal fees from MEDA Pharma/ rhinitis. Arch Dis Child. 2015; 100: 576-582. MYLAN, grants and personal fees from An- CrossRef PubMed [5] Pfaar O, Angier E, Muraro A, Halken S, Roberts ergis S.A., personal fees from Mobile Cham- G. Algorithms in allergen immunotherapy in al- ber Experts (a GA2LEN Partner), personal lergic rhinoconjunctivitis. Allergy. 2020; 75: fees from Indoor Biotechnologies, grants 2411-2414. CrossRef PubMed and personal fees from Glaxo Smith Kline, [6] Pfaar O, Agache I, de Blay F, Bonini S, Chaker AM, Durham SR, Gawlik R, Hellings PW, Jutel M, personal fees from Astellas Pharma Global, Kleine-Tebbe J, Klimek L, Kopp MV, Nandy A, personal fees from EUFOREA, personal Rabin RL, van Ree R, Renz H, Roberts G, Salapatek fees from ROXALL Medizin, personal fees AM, Schmidt-Weber CB, Shamji MH, et al. Per- from Novartis, personal fees from Sanofi- spectives in allergen immunotherapy: 2019 and beyond. Allergy. 2019; 74 (Suppl 108): 3-25. Aventis and Sanofi-Genzyme, personal fees CrossRef PubMed from Med Update Europe GmbH, personal [7] Simons FE. Advances in H1-antihistamines. N fees from streamedup! GmbH, grants from Engl J Med. 2004; 351: 2203-2217. CrossRef Pohl-Boskamp, grants from Inmunotek S.L., PubMed personal fees from John Wiley and Sons, AS, [8] Okubo K, Ogino S, Nagakura T, Ishikawa T. Omalizumab is effective and safe in the treatment personal fees from Paul-Martini-Stiftung of Japanese cedar pollen-induced seasonal aller- (PMS), outside the submitted work. Stefan gic rhinitis. Allergol Int. 2006; 55: 379-386. A. Rudhart reports personal fees from UV- CrossRef PubMed SMART outside the submitted work. Boris [9] Juniper EF. Quality of life in adults and children with asthma and rhinitis. Allergy. 1997; 52: 971- A. Stuck has received financial support for 977. CrossRef PubMed research, consultant and speaker fees from [10] Chervinsky P, Casale T, Townley R, Tripathy I, the following companies: G. Pohl-Boskamp Hedgecock S, Fowler-Taylor A, Shen H, Fox H. GmbH & Co.KG, GlaxoSmithKlinie GmbH Omalizumab, an anti-IgE antibody, in the treat- & Co KG and R. Cegla GmbH & Co.KG. He ment of adults and adolescents with perennial allergic rhinitis. Ann Allergy Asthma Immunol. has also received financial support (sponsor- 2003; 91: 160-167. CrossRef PubMed ship) for events of the Department of Oto- [11] Brożek JL, Bousquet J, Agache I, Agarwal A, rhinolaryngology, Head and Neck Surgery, Bachert C, Bosnic-Anticevich S, Brignardello- Marburg from: ALK Abello, Merck, Pohl Petersen R, Canonica GW, Casale T, Chavannes NH, Correia de Sousa J, Cruz AA, Cuello-Garcia Boskamp, Bristol Myers Squibb, Sanofi CA, Demoly P, Dykewicz M, Etxeandia-Ikobaltze- Genzyme. The other authors do not report ta I, Florez ID, Fokkens W, Fonseca J, Hellings any conflicts of interest. PW, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines-2016 revision. J Al- lergy Clin Immunol. 2017; 140: 950-958. Cross- Ref PubMed References [12] Guntern P, Eggel A. Past, present, and future of anti-IgE biologics. Allergy. 2020; 75: 2491-2502. [1] Bousquet J, Khaltaev N, Cruz AA, Denburg J, CrossRef PubMed Fokkens WJ, Togias A, Zuberbier T, Baena-Cagnani [13] Sheldon E, Schwickart M, Li J, Kim K, Crouch S, CE, Canonica GW, van Weel C, Agache I, Aït- Parveen S, Kell C, Birrell C. Pharmacokinetics, Khaled N, Bachert C, Blaiss MS, Bonini S, Boulet Pharmacodynamics, and Safety of MEDI4212, an LP, Bousquet PJ, Camargos P, Carlsen KH, Chen Anti-IgE Monoclonal Antibody, in Subjects with Y, et al; AllerGen. Allergic rhinitis and its impact Atopy: A Phase I Study. Adv Ther. 2016; 33: 225- on asthma (ARIA) 2008 update (in collaboration 251. CrossRef PubMed Pfaar, Gehrt, Li, et al. 126

[14] Arm JP, Bottoli I, Skerjanec A, Floch D, Groene [25] Adelroth E, Rak S, Haahtela T, Aasand G, Rosen- wegen A, Maahs S, Owen CE, Jones I, Lowe PJ. hall L, Zetterstrom O, Byrne A, Champain K, Pharmacokinetics, pharmacodynamics and safety Thirlwell J, Cioppa GD, Sandström T. Recombi- of QGE031 (ligelizumab), a novel high-affinity nant humanized mAb-E25, an anti-IgE mAb, in anti-IgE antibody, in atopic subjects. Clin Exp Al- birch pollen-induced seasonal allergic rhinitis. J lergy. 2014; 44: 1371-1385. CrossRef PubMed Allergy Clin Immunol. 2000; 106: 253-259. [15] Chaker AM, Shamji MH, Dumitru FA, Calderon CrossRef PubMed MA, Scadding GW, Makatsori M, Jones I, He QA, [26] Casale TB, Condemi J, LaForce C, Nayak A, Subramanian KK, Arm JP, Durham SR, Schmidt- Rowe M, Watrous M, McAlary M, Fowler-Taylor Weber CB. Short-term subcutaneous grass pollen A, Racine A, Gupta N, Fick R, Della Cioppa G; immunotherapy under the umbrella of anti-IL-4: Omalizumab Seasonal Allergic Rhinitis Trail A randomized controlled trial. J Allergy Clin Im- Group. Effect of omalizumab on symptoms of munol. 2016; 137: 452-461. PubMed seasonal allergic rhinitis: a randomized controlled [16] Weinstein SF, Katial R, Jayawardena S, Pirozzi G, trial. JAMA. 2001; 286: 2956-2967. CrossRef Staudinger H, Eckert L, Joish VN, Amin N, Maroni PubMed J, Rowe P, Graham NMH, Teper A. Efficacy and [27] Kuehr J, Brauburger J, Zielen S, Schauer U, Kamin safety of dupilumab in perennial allergic rhinitis W, Von Berg A, Leupold W, Bergmann KC, Rolinck- and comorbid asthma. J Allergy Clin Immunol. Werninghaus C, Gräve M, Hultsch T, Wahn U. Ef- 2018; 142: 171-177. PubMed ficacy of combination treatment with anti-IgE [17] Ellis AK, Tsitoura DC, Quint D, Powley W, Lee plus specific immunotherapy in polysensitized LA. Safety and pharmacodynamics of intranasal children and adolescents with seasonal allergic GSK2245035, a TLR7 agonist for allergic rhini- rhinitis. J Allergy Clin Immunol. 2002; 109: 274- tis: A randomized trial. Clin Exp Allergy. 2017; 280. CrossRef PubMed 47: 1193-1203. CrossRef PubMed [28] Nayak A, Casale T, Miller SD, Condemi J, McAlary M, Fowler-Taylor A, Della Cioppa G, Gupta N. [18] Racine-Poon A, Botta L, Chang TW, Davis FM, Tolerability of retreatment with omalizumab, a Gygax D, Liou RS, Rohane P, Staehelin T, van recombinant humanized monoclonal anti-IgE an- Steijn AM, Frank W. Efficacy, pharmacodynam- tibody, during a second ragweed pollen season in ics, and pharmacokinetics of CGP 51901, an anti- patients with seasonal allergic rhinitis. Allergy immunoglobulin E chimeric monoclonal anti- Asthma Proc. 2003; 24: 323-329. PubMed body, in patients with seasonal allergic rhinitis. Clin Pharmacol Ther. 1997; 62: 675-690. Cross- [29] Lin H, Boesel KM, Griffith DT, Prussin C, Foster Ref PubMed B, Romero FA, Townley R, Casale TB. Omalizum- ab rapidly decreases nasal allergic response and [19] Presta LG, Lahr SJ, Shields RL, Porter JP, Gorman FcepsilonRI on basophils. J Allergy Clin Immu- CM, Fendly BM, Jardieu PM. Humanization of an nol. 2004; 113: 297-302. CrossRef PubMed antibody directed against IgE. J Immunol. 1993; [30] Vignola AM, Humbert M, Bousquet J, Boulet LP, 151: 2623-2632. PubMed Hedgecock S, Blogg M, Fox H, Surrey K. Efficacy [20] Milgrom H, Fick RB Jr, Su JQ, Reimann JD, Bush and tolerability of anti-immunoglobulin E therapy RK, Watrous ML, Metzger WJ. Treatment of al- with omalizumab in patients with concomitant aller- lergic asthma with monoclonal anti-IgE antibody. gic asthma and persistent allergic rhinitis: SOLAR. rhuMAb-E25 Study Group. N Engl J Med. 1999; Allergy. 2004; 59: 709-717. CrossRef PubMed 341: 1966-1973. CrossRef PubMed [31] Rolinck-Werninghaus C, Hamelmann E, Keil T, [21] Fox JA, Hotaling TE, Struble C, Ruppel J, Bates Kulig M, Koetz K, Gerstner B, Kuehr J, Zielen S, DJ, Schoenhoff MB. Tissue distribution and com- Schauer U, Kamin W, Von Berg A, Hammermann plex formation with IgE of an anti-IgE antibody J, Weinkauf B, Weidinger G, Stenglein S, Wahn U; after intravenous administration in cynomolgus Omalizumab Rhinitis Study Group. The co-sea- monkeys. J Pharmacol Exp Ther. 1996; 279: sonal application of anti-IgE after preseasonal 1000-1008. PubMed specific immunotherapy decreases ocular and na- [22] MacGlashan DW Jr, Bochner BS, Adelman DC, sal symptom scores and rescue medication use in Jardieu PM, Togias A, McKenzie-White J, grass pollen allergic children. Allergy. 2004; 59: Sterbinsky SA, Hamilton RG, Lichtenstein LM. 973-979. CrossRef PubMed Down-regulation of Fc(epsilon)RI expression on [32] Casale TB, Busse WW, Kline JN, Ballas ZK, Moss human basophils during in vivo treatment of atop- MH, Townley RG, Mokhtarani M, Seyfert-Margolis ic patients with anti-IgE antibody. J Immunol. V, Asare A, Bateman K, Deniz Y; Immune Tolerance 1997; 158: 1438-1445. PubMed Network Group. Omalizumab pretreatment de- [23] Casale TB, Bernstein IL, Busse WW, LaForce CF, creases acute reactions after rush immunotherapy Tinkelman DG, Stoltz RR, Dockhorn RJ, Reimann for ragweed-induced seasonal allergic rhinitis. J J, Su JQ, Fick RB Jr, Adelman DC. Use of an anti- Allergy Clin Immunol. 2006; 117: 134-140. IgE humanized monoclonal antibody in ragweed- CrossRef PubMed induced allergic rhinitis. J Allergy Clin Immunol. [33] Cruz AA, Lima F, Sarinho E, Ayre G, Martin C, 1997; 100: 110-121. CrossRef PubMed Fox H, Cooper PJ. Safety of anti-immunoglobu- [24] Saini SS, MacGlashan DW Jr, Sterbinsky SA, Togias lin E therapy with omalizumab in allergic patients A, Adelman DC, Lichtenstein LM, Bochner BS. at risk of geohelminth infection. Clin Exp Allergy. Down-regulation of human basophil IgE and FC 2007; 37: 197-207. CrossRef PubMed epsilon RI alpha surface densities and mediator [34] Nagakura T, Ogino S, Okubo K, Sato N, Takahashi release by anti-IgE-infusions is reversible in vitro M, Ishikawa T. Omalizumab is more effective and in vivo. J Immunol. 1999; 162: 5624-5630. than suplatast tosilate in the treatment of Japanese PubMed cedar pollen-induced seasonal allergic rhinitis. Anti-IgE: A treatment option in allergic rhinitis? 127

Clin Exp Allergy. 2008; 38: 329-337. CrossRef nitis (SAR). Ann Allergy Asthma Immunol. 1999; PubMed 82: A32. [35] Segal M, Stokes JR, Casale TB. Anti-immuno- [48] Bousquet J, Rabe K, Humbert M, Chung KF, globulin e therapy. World Allergy Organ J. 2008; Berger W, Fox H, Ayre G, Chen H, Thomas K, 1: 174-183. CrossRef PubMed Blogg M, Holgate S. Predicting and evaluating [36] Ogino S, Nagakura T, Okubo K, Sato N, Takahashi response to omalizumab in patients with severe M, Ishikawa T. Re-treatment with omalizumab at allergic asthma. Respir Med. 2007; 101: 1483- one year interval for Japanese cedar pollen-in- 1492. CrossRef PubMed duced seasonal allergic rhinitis is effective and [49] Crystal-Peters J, Neslusan C, Crown WH, Torres well tolerated. Int Arch Allergy Immunol. 2009; A. Treating allergic rhinitis in patients with co- 149: 239-245. CrossRef PubMed morbid asthma: the risk of asthma-related hospi- [37] Kopp MV, Hamelmann E, Zielen S, Kamin W, talizations and emergency department visits. J Bergmann KC, Sieder C, Stenglein S, Seyfried S, Allergy Clin Immunol. 2002; 109: 57-62. Cross- Wahn U; DUAL study group. Combination of Ref PubMed omalizumab and specific immunotherapy is supe- [50] Casale TB. Anti-immunoglobulin E (omalizum- rior to immunotherapy in patients with seasonal ab) therapy in seasonal allergic rhinitis. Am J allergic rhinoconjunctivitis and co-morbid sea- Respir Crit Care Med. 2001; 164 (supplement_1): sonal allergic asthma. Clin Exp Allergy. 2009; 39: S18-S21. CrossRef PubMed 271-279. CrossRef PubMed [51] Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. The anti-inflammatory effects of [38] Tsabouri S, Tseretopoulou X, Priftis K, Ntzani EE. omalizumab confirm the central role of IgE in al- Omalizumab for the treatment of inadequately lergic inflammation. J Allergy Clin Immunol. controlled allergic rhinitis: a systematic review 2005; 115: 459-465. CrossRef PubMed and meta-analysis of randomized clinical trials. J [52] Cox L, Lieberman P, Wallace D, Simons FE, Fine- Allergy Clin Immunol Pract. 2014; 2: 332-340.e1. gold I, Platts-Mills T, Schwartz L. American PubMed Academy of Allergy, Asthma & Immunology/ [39] Bayar Muluka N, Bafaqeeh SA, Cingi C. Anti-IgE American College of Allergy, Asthma & Immunol- treatment in allergic rhinitis. Int J Pediatr Otorhi- ogy Omalizumab-Associated Anaphylaxis Joint nolaryngol. 2019; 127: 109674. PubMed Task Force follow-up report. J Allergy Clin Im- [40] Yu C, Wang K, Cui X, Lu L, Dong J, Wang M, Gao munol. 2011; 128: 210-212. CrossRef PubMed X. Clinical efficacy and safety of omalizumab in [53] Lieberman PL, Umetsu DT, Carrigan GJ, Rahmaoui the treatment of allergic rhinitis: A systematic re- A. Anaphylactic reactions associated with omali- view and meta-analysis of randomized clinical zumab administration: Analysis of a case-control trials. Am J Rhinol Allergy. 2020; 34: 196-208. study. J Allergy Clin Immunol. 2016; 138: 913- CrossRef PubMed 915.e2. PubMed [41] Okayama Y, Matsumoto H, Odajima H, Takahagi [54] Holgate S, Buhl R, Bousquet J, Smith N, Panahloo S, Hide M, Okubo K. Roles of omalizumab in Z, Jimenez P. The use of omalizumab in the treat- various allergic diseases. Allergol Int. 2020; 69: ment of severe allergic asthma: A clinical experi- 167-177. CrossRef PubMed ence update. Respir Med. 2009; 103: 1098-1113. [42] Casale TB, Racine A, Sallas W, Fowler-Taylor A, CrossRef PubMed Gupta N, Rohane PW. Relationship between clini- [55] Deniz YM, Gupta N. Safety and tolerability of cal efficacy of rhu-MAb-E25 (E25) and serum- omalizumab (Xolair), a recombinant humanized free IgE in seasonal allergic rhinitis [abstract]. J monoclonal anti-IgE antibody. Clin Rev Allergy Allergy Clin Immunol. 2000; 104: 5357. Immunol. 2005; 29: 31-48. CrossRef PubMed [43] Liu J, Lester P, Builder S, Shire SJ. Characteriza- [56] Long A, Rahmaoui A, Rothman KJ, Guinan E, tion of complex formation by humanized anti-IgE Eisner M, Bradley MS, Iribarren C, Chen H, Carri- monoclonal antibody and monoclonal human IgE. gan G, Rosén K, Szefler SJ. Incidence of malig- Biochemistry. 1995; 34: 10474-10482. CrossRef nancy in patients with moderate-to-severe asthma PubMed treated with or without omalizumab. J Allergy [44] Bentley AM, Jacobson MR, Cumberworth V, Clin Immunol. 2014; 134: 560-567.e4. PubMed Barkans JR, Moqbel R, Schwartz LB, Irani AM, [57] Watanabe N, Katakura K, Kobayashi A, Okumura Kay AB, Durham SR. Immunohistology of the na- K, Ovary Z. Protective immunity and eosinophilia sal mucosa in seasonal allergic rhinitis: increases in IgE-deficient SJA/9 mice infected with Nip- in activated eosinophils and epithelial mast cells. postrongylus brasiliensis and Trichinella spiralis. J Allergy Clin Immunol. 1992; 89: 877-883. Proc Natl Acad Sci USA. 1988; 85: 4460-4462. CrossRef PubMed CrossRef PubMed [45] MacGlashan DW Jr. Releasability of human baso- [58] Amiri P, Haak-Frendscho M, Robbins K, McKerrow phils: cellular sensitivity and maximal histamine JH, Stewart T, Jardieu P. Anti-immunoglobulin E release are independent variables. J Allergy Clin treatment decreases worm burden and egg pro- Immunol. 1993; 91: 605-615. CrossRef PubMed duction in Schistosoma mansoni-infected normal [46] Beck LA, Marcotte GV, MacGlashan D Jr, Togias and interferon gamma knockout mice. J Exp Med. A, Saini S. Omalizumab-induced reductions in 1994; 180: 43-51. CrossRef PubMed mast cell Fcepsilon RI expression and function. J Allergy Clin Immunol. 2004; 114: 527-530. CrossRef PubMed [47] Casale TB, Condemi J, Miller SD, McAlary M, Taylor AF, Gupta N, Rohane PW. Anti-IgE (omalizumab) in the treatment of seasonal allergic rhi-