Emerging drugs for allergic conjunctivitis.

Review

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Chulalongkorn University on 01/05/15 For personal use only.

Emerging drugs for allergic conjunctivitis Erminia Ridolo†, Marcello Montagni, Marco Caminati, Gianenrico Senna, Cristoforo Incorvaia & Giorgio Walter Canonica

1.

Background

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Medical need

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Existing treatment

4.

Market review

5.

Current research goals

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Scientific rationale

7.

Competitive environment

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Potential development issues

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Conclusion

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Expert opinion

†

University of Parma, Department of Clinical and Experimental Medicine, Parma, Italy

Introduction: Allergic conjunctivitis (AC) is a very common disease, especially in association with allergic rhinitis but may also occur in isolated presentation. The treatment of AC has long been based on antihistamines, cromones and topical corticosteroids, but none of these drugs completely abolishes the clinical expression of AC. Areas covered: The development of new drugs for AC is analyzed highlighting the recent insights into the pathophysiological mechanisms of the disease. The major aim of development of drugs for AC is to have agents able to prevent the inflammatory effects of the interaction between the allergen and the specific IgE antibodies on mast cell surface. This may be obtained by blocking the effects of histamine (the main mediator of early allergic response) by H1-receptor antagonists, inhibiting the release of soluble factors able to recruit inflammatory cells (that sustain prolonged inflammation) by mast-cell stabilizers, inhibiting the effects of single mediators, inducing tolerance to the allergen by specific immunotherapy or even acting on factors related to activation and differentiation of T lymphocytes such as the toll-like receptors. Expert opinion: AC is an underestimated disease for which there is a search of more effective treatments. The availability of the drugs under current evaluation will allow more refined therapeutic strategies to apply according to the characteristics and the clinical severity of AC. Keywords: allergic conjunctivitis, antihistamines, immunotherapy Expert Opin. Emerging Drugs (2014) 19(2):291-302

1.

Background

Clinical forms The term allergic conjunctivitis (AC) includes different disorders affecting the ocular surface caused by an IgE-mediated hypersensitivity reaction. The most common type of AC is seasonal allergic conjunctivitis (SAC) due to airborne pollen allergens, usually occurring during spring or fall. Patients sensitized to perennial allergens instead, like house dust mites or animal epithelia, can suffer from perennial allergic conjunctivitis (PAC) and experience symptoms throughout the year [1]. SAC and PAC are frequently associated with respiratory allergic diseases like rhinitis and asthma. Vernal keratoconjunctivitis (VKC) also frequently recognizes an IgE-mediated pathogenesis and is more common in young people living in areas with warmer climates [2]. Atopic keratoconjunctivitis (AKC) usually affect young patients and is associated with other atopic diseases [3]. The latter two forms of ocular allergy are more serious and require an ophthalmologist evaluation. Giant papillary conjunctivitis does not have an allergic pathogenesis but is rather caused by irritative stimuli such as the use of contact lenses [2]. This review focuses on SAC and PAC, which are the most frequent type of AC affecting about 15 -- 20% (up to 40% in some studies) of the general population in the USA and Europe [4,5]. 1.1

10.1517/14728214.2014.902443 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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1.2

Pathogenesis

Both SAC and PAC involve a type I hypersensitivity reaction and are characterized by the early-phase symptoms that occurs within 1 h after allergen exposure and are due to the linking of allergen-specific IgE to the high-affinity IgE receptor FceRI on the surface of resident mast cells, resulting in their degranulation, and a late-phase inflammation in the conjunctiva due to inflammatory cell infiltration driven by chemokines. In SAC, an increase in the number of mast cells compared with normal cells was found during the pollen season, also with a smaller increase in eosinophils and neutrophils [6]. Allergen challenge with grass pollen, in sensitized patients, results in basophil and eosinophil accumulation and mast cell degranulation in the nasal mucosa [7]. The role of mast cell mediators (histamine, leukotrienes, cytokines and chemokines, proteases) is of primary importance in causing inflammation in SAC and PAC: in an animal model, the early-phase response was almost completely abolished in mast-cells-deficient mice (Kitw/Kitw-v) after injections of the allergen and the eosinophilic infiltration was significantly depressed; both were fully restored after adaptive transfer of isolated conjunctival mast cells from naive wild-type mice [8]. Mast cells degranulation also induces the activation of endothelial cells, which expresses adhesion molecules (like intercellular adhesion molecule-1 [ICAM-1] and e-selectin) [9]. Different chemokines are involved, immediate hypersensitivity reactions in the conjunctiva are ablated in mice deficient in eotaxin-1, despite normal numbers of tissue mast cells and levels of IgE, and chemokine C-C motif receptor 3 (CCR-3) (an eotaxin-1 receptor) blockade significantly suppresses allergen-mediated hypersensitivity reactions as well as IgE-mediated mast cell degranulation [10]. Early-phase reaction and late-phase inflammation are both reduced in CCR3-deficient mice [11]. Moreover, prostaglandin E2 content was found to be increased in the eyelids after allergen challenge, linked to a parallel up-regulation of COX-2 and prostaglandin E synthases, and the expression of the prostaglandin E receptor EP3 by conjunctival epithelial cells was able to regulate the allergic response [12]. Clinical diagnosis Symptoms of SAC and PAC are the same and consist of itching, redness and swelling of the conjunctiva. All these symptoms and signs are bilateral and show a seasonal trend in SAC but not in PAC. As symptoms can be typically seasonal or intermittent, a detailed clinical history should always be collected. Usually, the diagnosis can easily be made on the basis of the history and ocular examination but some differential diagnosis have to be considered, like viral or bacterial conjunctivitis, blepharitis and dry eye. A complete evaluation of the patients must include questions about a previous history of allergy (rhinitis, asthma, atopic eczema), the time course of symptoms, the possible exposure to allergens at home (e.g., house dust mites and 1.3

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animal epithelia) and in the workplace (e.g., flour for bakers, animal proteins for laboratory workers).

Allergy tests Allergy testing includes in vivo tests (skin prick test and/or intradermal test) and in vitro tests (measuring IgE-specific antibodies in serum). Conjunctival challenge with the suspected allergen is also possible in order to confirm the etiological diagnosis, especially when negative in vivo and in vitro tests are detected in patients with suggestive clinical history or symptoms [13]. Conjunctival smear and the test for total IgE in tears can be helpful in confirming the diagnosis in doubtful cases as well. Molecular-based diagnosis allows to distinguish, in polysensitized patients, genuine versus crossreactive sensitization thereby increasing the accuracy in allergy diagnosis [14]. An etiological diagnosis is needed as a background for the most appropriate treatment choice. 1.4

2.

Medical need

Quality of life Even though AC is not considered a serious disease, it is a clinically relevant illness as symptoms like tearing, itching and redness may result in an impairment in performance of common daily activities concerning social life, school performance and work productivity. From this point of view, given the frequent coexistence of AC with allergic rhinitis, only few data are available on the quality of life (QoL) of patients considering the AC as a separate entity, whereas much information are available on rhinoconjunctivitis. In order to assess the impact of ocular symptoms on QoL, work productivity and resource utilization in allergic rhinitis patients, an observational cross-sectional study in European countries was performed [15]. The results showed that the presence of ocular symptoms reduces QoL, impairs work productivity and increases resource utilization irrespective of whether differences in severity of nasal symptoms are accounted for between the comparison groups. Patients with nasal and ocular symptoms also require more healthcare consultations. Two studies examined the economic and QoL impact of SAC in English and Spanish patients using validated questionnaires [16,17]. Both studies showed a significant reduction in specific ocular as well as in general QoL. A cross-sectional study of AC patients seen in 16 ophthalmology departments in Portugal during a spring showed a significant impairment of self-rated health status during an ocular allergy episode [18]. Therefore, QoL is a central issue in patients with AC, and it is important that physicians consider the patient’s perceptions of their allergic disease and measures its consequences that could have significant impact on patients and also on society. Moreover, the benefit of proper treatment on QoL should be determined. 2.1

Expert Opin. Emerging Drugs (2014) 19(2)

Emerging drugs for allergic conjunctivitis

Table 1. Currently available topical medications for the treatment of AC. Class H1-antagonists Mast-cell stabilizers Corticosteroids


Decongestants NSAIDs Calcineurin inhibitors

Name Ketotifen fumarate*, Bepostatine besilate*, Azelastine hydrochloride*, Olopatadine hydrochloride*, Alcaftadine*, Epinastine hydrochloride*, Levocabastine hydrochloride, Emedastine difumarate Cromolyn sodium, Nedrocromil sodium, Lodoxamide tromethamine, Pemirolast potassium Loteprednol etabonate, Dexamethasone sodium phosphate, Prednisolone acetate, Betamethasone sodium phosphate, Fluorometholone Acetate Naphazoline, Tetrahydrozoline Ketorolac tromethamine Cyclosporin

*Also mast-cell stabilizers. AC: Allergic conjunctivitis.

Allergen avoidance The complete avoidance of the allergen can lead to the disappearance of symptoms and so this approach is relevant in therapeutic terms but unfortunately in clinical practice is often unsatisfactory or impractical for both indoor and outdoor allergens. The use of artificial tears may improve the function of the ocular surface barrier [1], helping to prevent contact between the allergen and the eye. Obviously, lifestyle modifications like to avoid being outdoors during the days of pollen peak or the avoidance of pet exposure in sensitized patients, which are commonly suggested to allergic patients, are beneficial also in AC, especially in mild disease. A small trial that involved 30 patients with PAC (17 of whom also had asthma) due to house dust mite and with a positive conjunctival provocation test to dust mite extract showed that patients receiving allergen-impermeable mattress covers had statistically significant decrease in ocular symptom score [19]. A protective efficacy of sunglasses on the conjunctival symptoms of seasonal rhinitis has been demonstrated in a small trial on 39 patients over 4 weeks. The study showed that the use of sunglasses resulted in a decrease of ocular symptoms (p = 0.002) and use of antihistamines (p = 0.009) [20]. Thus, some measures to prevent and/or limit the contact with the allergens (including lifestyle modifications) are simple and inexpensive, but only a few data are available regarding their effectiveness. Nevertheless, they are an important part of AC management in the real-life practice. 2.2

H1-receptor antagonists H1 antihistamines improve the early-phase symptoms such as itching and redness by competitive binding to histamine H1 receptor. Topical antihistamines are effective, with the advantage of delivering the medication to the target area. Levocabastine and emedastine are H1 antihistamines that quickly improve ocular symptoms after topical administration to the eye [21,22]. Moreover, some antihistamines exert multiple pharmacologic effects, because besides H1 histamine receptor antagonism, have a mast-cell stabilizing activity and have anti-inflammatory properties. Among these are ketotifen, bepostatine [23-25], azelastine [26], olopatadine [27], alcaftadine [28] and epinastine [29]. Anti-inflammatory effects include the reduction of ICAM-1 expression on epithelial cells, showed by cetirizine, levocabastine, ketotifen, azelastine and olopatadine (which also inhibits the mediator of inflammation TNF-a [30]), and the inhibition of eosinophils chemotaxis [31-35]. Topical antihistamines are generally very well tolerated, the most common side effects being local burning and stinging, which are usually mild and transient; sedation is very rare [36]. However, the ocular irritant effects can be particularly troublesome in the case of prolonged therapy. Also, systemically administered antihistamines are effective but they can dry the ocular surface. Indeed, firstgeneration antihistamines are no more recommended due to their potential sedative and anticholinergic effects. 3.1

Corticosteroids Corticosteroids are very effective in reducing ocular inflammation and can be used to treat the more severe and chronic forms of AC. Topical corticosterods reduce the production of many different mediators that are produced after reaction to allergens. However, they have some ocular adverse effects such as elevation of ocular pressure and the development of cataract. Thus, corticosteroids must be preferably used for short-course therapy. Loteprednol etabonate, a new C-20 ester-based corticosteroid, seems to have a good safety profile for the treatment of seasonal allergic rhinitis (SAR) and persistent allergic rhinitis and also was found to be noninferior to olopatadine for the treatment of SAC [37,38]. Moreover, 3.2

3.

Existing treatment

As mentioned, allergen avoidance and appropriate lifestyle factors, aimed to minimize the contact of allergens with the eye, are theoretically relevant in therapeutic terms because the complete avoidance of causative allergen may lead to the disappearance of symptoms, but they are often insufficient to adequately control the symptoms and troublesome to apply. Therefore, the use of drugs, topically applied or systemically administered, is needed to manage ocular symptoms (Table 1).


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some corticosteroid nasal spray, like fluticasone and mometasone, used for rhinoconjunctivits have also been shown to improve ocular symptoms when used in monotherapy [39].

been shown to improve symptoms and reduce eosinophils inflammation [46]. Clinical data in patients with AC and dry eye are expected (ClinicalTrials.gov number NCT01203540).

Calcineurin inhibitors Topical cyclosporine was initially successfully used in VKC, but placebo-controlled trials are also available on its efficacy in the treatment of AC. A recent systematic review and meta-analysis included seven placebo-controlled studies incorporating 153 patients with VKC and AKC, assessing scores of composite signs and symptoms, reduction in steroid eye drop use in steroid-dependent patients and safety outcomes (i.e., stinging or burning sensation). At 2 weeks of follow-up or longer, a statistically significant improvement in the composite signs (standardized mean difference [SMD] -1.21) and symptoms (SMD, -0.84) after topical cyclosporine treatment regardless of the dosage of treatment was found. There was also a significant reduction (mean difference: -61.16) in the use of steroid eye drops [40]. Stinging or burning sensation was common in both the cyclosporine and placebo groups. These findings suggest that topical cyclosporine could be an effective and safe treatment method for conjunctivitis forms such as VKC and AKC (generally classified as AC), although further randomized controlled trials with larger sample sizes and standardized outcome measurements are warranted, as well as trials on patients with conjunctivitis caused by inhalant allergens.

3.5


3.3

Mast-cell stabilizers Mast-cell stabilizers act by inhibiting the degranulation of mast cells and so preventing the release of mediators with a consequent inhibition of the allergic cascade. Stabilization of mast cell may improve ocular symptoms by reducing the synthesis and release of mediators such as histamine, leukotrienes and tryptase by mast cells after the binding of IgE antibodies to the FcRI receptor. Currently available agents are cromolyn sodium, nedrocromil sodium, N-acetylaspartyl-glutamic acid (NAAGA), lodoxamide tromethamine and pemirolast potassium. The latter also prevents the activation of human eosinophils to inhibit leukotriene C4 and eosinophil cationic protein releases [41]. In a randomized trial, twice-daily administration of pemirolast potassium was as effective and safe as twice-daily nedocromil sodium in the treatment of SAC [42]. Compared with topical antihistamine, cromolyn sodium has been found to be less potent than levocabastine in conjunctival provocation models [43], whereas the new agent lodoxamide seems to be equally effective [44]. A major limitation of mast-cell stabilizers is the need of 3 -- 4 administrations/day, which significantly affects the adherence to treatment. NAAGA is a mast-cell stabilizer that inhibits the release of preformed mediators, such as histamine, and also exerts a wide range of anti-inflammatory actions that reduce allergic and inflammatory processes by various inhibitory activities shown in vitro [45]. Its efficacy and tolerability have been assessed in patients suffering from VKC, in whom it has 3.4

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Decongestants Vasoconstrictor eye drops are used in the treatment of ocular symptoms such as redness, itching and edema. Their mechanism of action is related to the activation of a-adrenergic receptor that results in vasoconstriction in the mucosa. Although they are effective in reducing symptoms [47], decongestants have short duration of action and several side effects and contraindications (i.e., glaucoma). If administered orally, they are burdened by several side effects (like insomnia, headache, tachycardia, hypertension, nervousness) that may occur, although to a lesser extent, after topical administration. Also, the possibility of a rebound of symptoms after the suspension limits their use. In a randomized trial comparing different topical antiallergic eye drops, naphazoline had lower tolerability than the other study treatments [48]. Nonsteroidal anti-inflammatory drugs Currently, only ketorolac tromethamine 0.5% has been approved for the treatment of AC, whereas all other NSAIDs are only used for the reduction of inflammation and postoperative pain after cataract surgery but not for AC. When compared with topical antihistamines, ketorolac was significantly less effective than olopatadine in reducing ocular itching in patients with SAC [49]. Compared with steroid fluorometholone, ketorolac was less effective in relieving redness, chemosis, mucus secretion and eyelid edema but was equally effective in attenuating itching, burning and tearing [50]. Adherence to these agents can be reduced by the discomfort that they cause after instillation [51]. 3.6

Allergen-specific immunotherapy Nowadays allergen-specific immunotherapy (AIT), performed in the initial phase by administering an increasing amount of an allergen extract and then a maintenance dose for 3 -- 5 years, represents the only treatment for allergic diseases acting on the causes of allergy. Different from the other available treatment options, it has been shown that its effect persists after treatment withdrawal [52], because AIT has the exclusive ability to induce clinical tolerance to the causative allergens by modifying allergic immune response and consequently the natural history of allergy. AIT mechanism of action relies on the complex interaction of innate and adaptive immunity processes, which involve inflammatory cells, cytokines and chemokines [52]. As a result, immunologic modifications such as the decrease in specific IgE, the increase in specific IgG1 and IgG4 and ultimately, the inhibition of inflammatory cells (mast cells, basophils and eosinophils) occur. Both sublingual and subcutaneous routes have been shown to be safe and effective in patients affected by respiratory allergy [53-58]. Concerning AC, systematic reviews and meta-analyses are available on both subcutaneous immunotherapy (SCIT) and sublingual 3.7




immunotherapy (SLIT). For SCIT, the authors concluded for a high-grade evidence to reduce conjunctivitis symptoms and to improve rhinoconjunctivitis disease-specific QoL in comparison to placebo or usual care and moderate evidence that SCIT decreases rhinitis/rhinoconjunctivitis medication usage [55]. For SLIT, a Cochrane meta-analysis included double-blind, placebo-controlled, randomized clinical trials evaluating its efficacy in patients with symptoms of allergic rhinoconjunctivitis or AC. Authors concluded that “Overall, SLIT is moderately effective in reducing total and individual ocular symptom scores in participants with ARC and AC”… and “The pooled estimates suggested, however, that SLIT is likely to have a small to moderate effect in AC-related ocular symptoms” [56]. As far as pediatric population is concerned, 13 trials on SCIT and 18 trials on SLIT have been recently reviewed. The strength of evidence was low that SCIT improves conjunctivitis symptoms, whereas the strength of evidence was moderate that SLIT improves conjunctivitis symptoms and medications scores [57]. It is apparent that some observations from these meta-analyses are contrasting, but it must be considered that the heterogeneity of the included studies (that is regarded as a limitation of systematic reviews and meta-analyses) significantly influences the results [59]. 4.

Market review

AC is a burdening disease and represents a health problem for both children and adults on a global basis, but data about epidemiology are scarce as survey studies have been directed primarily on allergic rhinitis, while epidemiology of ocular allergic diseases has been poorly investigated. In the US and in Europe about 15 -- 40% of population suffer from AC, and SAC accounts for 90% of all AC [60,61]. Also in the developing countries, although the allergic diseases have a lower incidence, up to 20% of population suffers from AC [62]. Of note, only about 10% of subjects affected by AC seek medical attention. As a result, the disease is largely underdiagnosed and potentially not correctly treated. AC raises social and healthcare costs because of the impairment in performance of common daily activities affecting patients of all ages and their relatives. There are both direct cost, related to outflows during the disease period, and indirect cost, derived from missing work/school and decreased productivity. In European population, two studies were conducted in order to assess the economic impact of SAC [16,17]. The first study, conducted in Oxfordshire by Pitt et al., compared a group of public healthcare patients with SAC to a control group. The authors concluded that the annual total of both the public healthcare and private out-of-pocket costs of SAC per patient ranged between 64.61£ and 123.69£ [16]. The second study was carried out in patients recruited from four private eye clinics and one public hospital in Spain; the estimated annual cost per patient was 348.50e [17]. The daily cost of various ophthalmic solutions (nine anti-allergic drugs and

six anti-inflammatory drugs) used to treat AC was estimated in a Japanese survey in 2004 [63]. The impact of ocular symptoms on healthcare resources utilization was assessed in patients with allergic rhinitis in an observational study in European countries [64]. Patients with ocular symptoms were observed to receive a significantly higher number of drugs (p < 0.05) with a consequent higher burden on resource utilization. So, in patients with respiratory allergy it would be very important to quantify the cost of conjunctivitis. A recent systematic review on diagnosis and treatment of conjunctivitis [61] did not include AIT among treatments for AC. The long-term commitment from the patient and/or caregiver in terms of time and economic expense required by AIT could account for such choice. In addition, a strong evidence of its efficacy specifically assessed on AC is still lacking [36]. Thus, current data sustain AIT as a valid treatment option for AC only in patients who suffer from other allergic respiratory comorbidities [36]. It is worth pointing out that the available reviews and meta-analyses on efficacy of AIT for AC suffer from methodological limitations and, as hinted above, heterogeneity of the analyzed studies, and a cost-benefit evaluation has not been specifically addressed to AIT as a treatment for AC. However, recent data concerning, in particular, allergic rhinitis showed significant cost benefits associated with AIT use in affected adults and children [65,66]. On the basis of the growing evidence of cost benefits of AIT, data regarding its efficacy in patients suffering from AC with or without other comorbidities should be implemented and an accurate evaluation of economic advantages and/or monetary savings among the same patients should be provided. 5.

Current research goals

The number of therapeutic options in AC has expanded over the last decades. However, none of the available agents represents the optimal single drug, with each having particular drawbacks. Current research strategies include reformulation of current drugs in an effort to improve their efficacy and reduce their side-effect profile, as well as developing new drugs, fitting AIT to the needs of AC and improving adherence to treatments. Due to the limited role of lifestyle modifications in AC and the possible adverse events related to topical drugs especially when used for a long time [36], the disease-modifying effect of AIT immunotherapy could play a central role [67]. Currently, the evidence of AIT efficacy in AC seems to be weak, but it should be noted that most of the published trials evaluated the impact of AIT on allergic rhinitis, while the efficacy on AC was usually a secondary outcome, assessed in patients who suffer from comorbid ocular symptoms [54,56]. However, to date, no studies have evaluated the effect of SLIT versus standard medications, as subjects involved in clinical trials are generally instructed to use intranasal steroids and systemic antihistamines as rescue medications. In addition, differences in allergen extracts,


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treatment schedule and timing of treatment certainly affect the reviews’ outcomes [54,56,68]. Thus, further studies assessing more specifically and accurately the efficacy and the costbenefit of AIT for AC are needed, including both controlled trials and real-life studies. Also, new routes of administration are being studied concerning their capacity to be less time-consuming and thus to improve adherence to AIT. The compliance and adherence issue, which is crucial in allergic diseases, has only recently been addressed. Many different factors can cause a poor adherence to treatment in chronic diseases like allergic rhinoconjunctivitis, such as cost, side effects, duration of treatment, lack of efficacy and previous treatment failure. In studies on corticosteroids, antihistamines and AIT, it is apparent that also minor details, such as taste and odor of the drug, influence the compliance and that patient education (which is generally recommended in guidelines but is poorly performed) is able to improve compliance [69]. Also, adherence to treatment is inversely related to the number of medications and the number of doses prescribed. A systematic review on this issue found that the mean dose-taking compliance was 79% with 1 dose, 69% with 2 doses, 65% with 3 doses and 51% with 4 doses [70]. Therefore, the development of new drugs fitting with these patient-related aspects may allow reducing treatment failures and the need for complex treatment regimens, finally improving adherence. 6.

Scientific rationale

AC is the clinical expression of allergic inflammation in the eye caused by contact with the responsible allergen(s); thus, the goal of scientific research is to develop new antiinflammatory drugs as well as to improve the effectiveness of the drugs that are already available and their safety and tolerability profile. 7.

Competitive environment

Emerging drugs for AC include a number of agents with antiinflammatory activity, including steroidal and nonsteroidal molecules, mast-cell stabilizers, inhibitors of inflammatory mediators and new topical forms of AIT (Table 2). NSAIDs Prostaglandins, lipid molecules derived from the oxidative metabolism of arachidonic acid by the action of the enzyme COX, are potent mediators of tissue inflammation. Owing to their ability to potently inhibit prostaglandin synthesis and inhibit inflammatory changes, NSAIDs may be an effective practical choice for the treatment of AC. As already said, ketorolac is the only currently approved drug for the treatment of AC, but the efficacy of other NSAIDs was investigated. Bromfenac eye drops were compared with pemirolast in patients with SAC [71]. In 22 patients, for 1 week, one eye was treated with bromfenac eye drops and the 7.1

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contralateral eye was treated with pemirolast eye drops and no significant differences in subjective symptoms or objective signs were observed between the two treatments. Similar results were found comparing bromfenac 0.1% ophthalmic solution with the steroid fluorometholone 0.02% ophthalmic suspension [72]. More recently, a randomized trial in 75 patients compared topical pranoprofen and fluorometholone eye drops in patients with chronic AC over 4 weeks of treatment [73]. Pranoprofen was effective, particularly in older patients, but with a slower onset of action. However, the studies are insufficient to indicate if really NSAIDs are scientifically appropriate as a further option to treat AC, because they, acting on COXs, may interfere only on a limited part of the allergic cascade. Selective glucocorticoid receptor agonists Selective glucocorticoid receptor agonists (SEGRAs) are a new class of drugs designed to have an improved therapeutic index associated with a reduced side-effect profile over classic corticosteroids [74]. The new SEGRA mapracorat was largely investigated in animal models and in cultured cells. In rabbit models of ocular disease, mapracorat was compared with dexametasone; mapracorat showed an anti-inflammatory efficacy comparable to dexametasone in experimental models of dry eye and postoperative inflammation, also demonstrating lower effects on intraocular pressure and body weight [75]. In human conjunctival fibroblasts and epithelial cells cultures, mapracorat effectively reduced IL-4 or IL-13 plus TNF-ainduced release of proinflammatory and allergy-related cytokines and chemokines and ICAM-1 [76]. In guinea pig, mapracorat reduced clinical symptoms of AC and conjunctival eosinophil inflammation in a manner comparable to that induced by dexamethasone eye drops [76]. Also, it inhibits the migration of cultured human eosinophils and IL-8 release from eosinophils or the release of IL-6, IL-8, CCL5/RANTES and TNF-a from a human mast cell line with equal potency as dexamethasone [77]. So, mapracorat appears to be a promising candidate for clinical use as a topical treatment of AC. A Phase II trial evaluating the efficacy of this drug on AC symptoms using a conjunctival allergen challenge model was recently completed (ClinicalTrials.gov number NCT012 89431). Controlled trials on the efficacy on eye symptoms from natural exposure to allergens are warranted to establish a role for mapracorat in AC. 7.2

Leukotriene receptor antagonists Leukotriene receptor antagonists (LTRAs) are currently used to treat asthma and allergic rhinitis [78]. Cysteinyl leukotrienes are a group of arachidonic-acid-derived lipid endogenous inflammatory mediators produced by different inflammatory cells that are implicated in the pathogenesis of AC, including eosinophils and mast cells. Leukotriene B4 (LTB4) is a potent itch mediator in the conjunctiva. In mice, a sub-conjunctival injection of LTB4 elicited ocular scratching [79]. LTRAs are frequently used as a systemic treatment in patients with 7.3



Table 2. Drugs that are currently in Phases II and III trials for allergic conjunctivitis.


Compound

Company

Indication

Stage of development for AC

Mechanism of action

Olopatadine punctual plug

Mati therapeutics

AC

Phase II

Olopatadine high-dose

Novartis

AC

Phase III

SUN-1334H Brimonidine tartarate Mapracorat

Sun Pharma Eye Therapies Bausch and Lomb

Phase II Phase II Phase II

ODC-9101

Aopix

Phase II

CRTH2 antagonist

Lifitegrast AC-170 AGN-229666 RX-10045

Shire Aciex theraputics Allergan Auven therapeutics

AC, SAR, PAR, urticaria AC, glaucoma AC, cataract, post-operative pain, eczema, xerophthalmia AC, asthma, eczema, eosinophilic esophagitis, SAR AC, xerophthalmia AC AC AC, xerophthalmia

H1-antagonist, mast-cell stabilizer H1-antagonist, mast-cell stabilizer H1-antagonist a2 adrenoreceptor agonist Steroid receptor agonist

Phase Phase Phase Phase

LFA-1 inhibitor Unidentified Unidentified Unidentified

II III II II

AC: Allergic conjunctivitis; CRTH2: Chemoattractant homologous receptor expressed on TH2 cells; LFA-1: Lymphocyte function-associated antigen-1; PAR: Persistent allergic rhinitis; SAR: Seasonal allergic rhinitis.

allergic diseases such as allergic rhinitis with asthma, in which ocular symptoms are frequently present, but they are not currently approved for the treatment of AC. A recent metaanalysis including six trials using LTRAs in adult patients with SAC found that they are more efficacious than placebo but less efficacious than oral antihistamines [80]. Toll-like receptors targeted treatment Toll-like receptors (TLRs) are a family of evolutionally conserved pattern-recognition receptors expressed by many different cells, particularly those of the innate immune system. TLR signaling enhances the TH1 response [81], this is the reason for their possible role as a target of treatment in allergic diseases. In experimental animal model of AC, the bacterial lipopolysaccharide, which strongly activates immune cells by binding to TLR4, suppresses allergic TH2 responses via the TLR4-dependent pathway [82]. TLR9 binds oligonucleotides sequence containing unmethylated CpG dinucleotides; in a mouse model of SAC systemic or mucosal administration of the TLR9 ligands, before or simultaneously with ragweed challenge, inhibited the immediate hypersensitivity and the late-phase responses and the induction of cellular infiltration in the conjunctiva [83]. The stimulation of TLR2 during the efferent phase of murine AC suppresses eosinophil infiltration [84]. Therefore, there is a large amount of data from animal models supporting the effectiveness of TLR stimulation in treatment of AC, but also of other allergic disease and, actually, a number of TLR agonists are in clinical trials for allergic rhinitis [85]. Concerning AIT, a preparation containing an adjuvant that act as agonist of TLR4 combined with ragweed pollen extract for the treatment of SAR was found to be effective and well tolerated in a placebocontrolled, randomized, double-blind trial showing statistical 7.4

advantage in favor of the active treatment for ocular symptoms (p = 0.003) compared with placebo [86]. Antagonists of the prostaglandin receptor Prostaglandin D2 is produced by mast cells during the early phase of the allergic immune response and induces chemotaxis of TH2 lymphocytes and eosinophils through the activation of chemoattractant homologous receptor expressed on TH2 cells (CRTH2) [87]. OC000459 is a new selective CRTH2 antagonist that inhibits mast-cell-dependent activation of TH2 lymphocytes and eosinophils [88]. A doubleblind, randomized, placebo-controlled trial conducted in 35 subjects allergic to grass pollen showed that the treatment with OC000459 200 mg b.i.d. significantly reduced ocular, as well as nasal, symptoms in allergic patients compared with placebo after challenge with grass pollen [89]. 7.5

Chymase inhibitors Chymase is a chymotrypsin-like serine proteinase primarily stored in secretory mast cell granules that induces the recruitment of inflammatory cells [90]. In a guinea pig model of pollen-induced AC, chymase activity was increased in ophthalmic lavage fluid immediately after the pollen challenge and the administration of human recombinant chymase by eye dropping-induced scratching behaviour in a dosedependent manner; these effects were effectively blocked by ketotifen and by the chymase inhibitor ONO-WH-236 [91]. 7.6

Conjunctival immunotherapy The route of administration for AIT is now available as either subcutaneous (SCIT) or sublingual (SLIT). The first is effective, but potential adverse reactions still remain the key drawback, requiring medical supervision; the latter is 7.7


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less demanding than SCIT, considering its safety profile that allows the administration of this treatment outside of the medical oversight. Alongside the classical routes of administration, other routes have been developed for future use in clinical practice in order to improve adherence and tolerability of AIT and in patients with allergic rhinoconjunctivitis. Intralymphatic and epicutaneous administration was found to be effective and safe in randomized controlled trials [92-95]. In patients suffering from AC, local conjunctival allergen immunotherapy (LCIT) is a promising treatment. In LCIT, a small amount of eye drops containing specific allergens is instilled into the conjunctiva. Few studies conducted on small numbers of patients showed improvement in clinical symptoms and laboratory findings [96,97]. A prospective, double-blind, randomized controlled trial was carried out on 18 patients suffering from AC and with positive skin prick test reactions to house dust mites (but most patients were polysensitized) [98]. Patients in active group received diluted house dust mites extract in both eyes once daily for 6 months. After 6 months, although there was no statistically significant difference compared with placebo in symptoms and medication scores, the conjunctival provocation test score reached a statistically significant reduction compared with the control group. Overall, the treatment was well tolerated without any serious adverse events in the active group [98].

Lymphocyte function-associated molecule inhibitors

7.8

Lymphocyte function-associated antigen-1 (LFA-1) is a ligand of the ICAM-1; targeting LFA-1 is a possible therapeutic option in order to reduce T-cell-mediated inflammation. Lifitegrast (SAR-1118) is a small molecule with a LFA-1 antagonist activity that inhibits LFA-1 binding to ICAM-1 [99]. Recently, results from Phase III trial in subjects with dry eye disease were published [100]. Lifitegrast is currently under investigation for the treatment of AC.

9.

Conclusion

AC is a very common disease that, similarly to allergic rhinitis, is often underestimated and under-treated, despite its significant impact on QoL. The disease ranges in severity from mild forms to severe cases characterized by potential impairment of visual function. The traditional treatment of AC has been based on topical corticosteroids, antihistamines and mast-cell stabilizers. Topical corticosteroids are very effective on AC but, differently from allergic rhinitis, must be used for short-course therapy because of their adverse effects. This confers to antihistamines a major therapeutic role in AC. These drugs act by inhibiting the action of histamine on H1 receptors. Oral antihistamines, especially the first-generation agents, cause systemic side effects such as sedation and symptoms related to the anticholinergic activity; thus, topical antihistamines are the most preferred option. A role for H4 receptor antagonists is emerging in histamine-mediated disorders such as atopic dermatitis and rhinitis [101], and studies on binding affinities to histamine receptors suggest a possible utility of H4 antihistamines in ocular allergy [102], which needs to be investigated in controlled trials. Mast-cell stabilizers such as topical sodium cromoglycate and nedocromil are effective but the patient’s adherence is often low because of the need of multiple administrations each day. Allergen immunotherapy, in its two routes of administrations, that is, SCIT and SLIT, is the only treatment working on the cause of allergy and is indicated when AC has a prolonged duration and is poorly controlled with antihistamines. Currently, there is an ongoing research on new treatment options, including new mast-cell stabilizers, SEGRAs, inhibitors of inflammatory mediators, new topical NSAIDs, antagonists of the prostaglandin receptor, TLR-targeted treatments, chymase inhibitors and new topical forms of AIT. It is likely that the treatment of AC in the coming years will include new therapeutic options able to control the disease satisfactorily. 10.

8.

Expert opinion

Potential development issues

The major aim of development of drugs for AC is to have agents able to prevent the inflammatory effects of the interaction between the allergen and the specific IgE antibodies on mast cell surface. This may be obtained by blocking the effects of histamine (the main mediator of early allergic response) by H1-receptor antagonists, or inhibiting the release of soluble factors able to recruit inflammatory cells (that sustain prolonged inflammation) by mast-cell stabilizers, or inhibiting the effects of single mediators, or even acting on factors related to activation and differentiation of T lymphocytes such as the TLRs. The availability of these agents will allow more refined therapeutic strategies to apply according to the characteristics and the clinical severity of AC. 298

The term ‘allergic conjunctivitis’ defines hypersensitivity disorders that affect the conjunctiva, the lid and/or the cornea. The characteristics signs and symptoms are itching, redness and lid swelling, and also tearing, mucous discharge and burning may occur [1]. AC includes various clinical forms, the main two being SAC (the most common AC), caused by seasonal exposure to pollens, and PAC, caused by exposure to house dust mites and animal epithelia. AC is associated frequently with rhinitis, being thus defined allergic rhinoconjunctivitis [6], but may also be a localized allergic condition affecting only the eye. Thus far, the mechanisms determining the occurrence of only AC or allergic rhinoconjunctivitis are unknown. Both forms are typically caused by a IgE-mediated reaction to environmental airborne allergens, that triggers an




inflammatory response mainly sustained by mast cells, the degranulation of which induces activation of vascular endothelial cells and the production of cytokines (such as IL-4, IL-6, IL-8, IL-13, TNF-a and TGF-b, chemokines and adhesion molecules [9-12]). These agents induce the recruitment of inflammatory cells in the conjunctival mucosa, which results in the ocular late-phase reaction that clinically corresponds to the persistent inflammation, with mucosal infiltration of eosinophils, neutrophils, basophils and T lymphocytes, characterizing the ocular signs and symptoms of AC. The diagnosis of AC is usually obtained by the combination of data from clinical history and results of skin prick testing or in vitro IgE testing. The treatment of AC is based on, when feasible, allergen avoidance, drug treatment and AIT. The mainstay of drug treatment has long been antihistamines, followed by mastcell stabilizers and, when needed, on short courses of topical corticosteroids. In 2005, in a review article on emerging drugs for ocular allergy, Leonardi stated that in the pharmacotherapy of AC none of the available drugs completely abolishes Bibliography

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Affiliation

Erminia Ridolo†1 MD PhD, Marcello Montagni1, Marco Caminati2, Gianenrico Senna2, Cristoforo Incorvaia3 & Giorgio Walter Canonica4 † Author for correspondence 1 University of Parma, Department of Clinical and Experimental Medicine, via Gramsci 14 Parma 43126, Italy Tel: +39 0521702028; Fax: +39 0521 703920; E-mail: [email protected] 2 Verona University Hospital, Allergy Unit, Piazzale Aristide Stefani 1, 37126 Verona, Italy 3 ICP Hospital, Allergy/Pulmonary Rehabilitation Unit, Milan, Italy 4 University of Genoa, IRCCS AOU San Martino-IST, DIMI, Allergy and Respiratory Diseases Clinic, 16132 Genoa, Italy

Model for Studying Anti- Allergic Drugs for Allergic Conjunctivitis in Animals.

Oral immunotherapy for allergic conjunctivitis.

Advances in pharmacotherapy for allergic conjunctivitis.

Allergic conjunctivitis in Jos-Nigeria.

Allergic conjunctivitis due to diazepam.

Evaluation of allergic conjunctivitis by thermography.

A human model of allergic conjunctivitis.

Allergic conjunctivitis: a survey of new antihistamines.

Allergic conjunctivitis: a cross-sectional study.

DSCG eye drops in allergic rhino-conjunctivitis.

Emerging drugs for acromegaly.

Emerging drugs for osteoporosis.

Emerging drugs for endometrial cancer.

Emerging tools for discovering drugs.

Emerging drugs for hemophilia B.

Emerging drugs for neuropathic pain.

Emerging drugs for urothelial carcinoma.

Emerging drugs for prostate cancer.

Emerging drugs for cystic fibrosis.

Emerging drugs for celiac disease.

Emerging drugs for coeliac disease.

Emerging drugs for biliary cancer.

Optic nerve injury in a patient with chronic allergic conjunctivitis.

Drug treatment of allergic conjunctivitis. A review of the evidence.