Researchers seek next class of anti-allergics

Spring is on the horizon, and with it comes the renewal of seasonal allergies. Lately, though, it seems that while allergy seasons come and go, allergy therapies remain the same. For more than 3 decades, antihistamine-based agents have been the standard of care. Although there have been valuable improvements over the years (dual-action agents, once-daily therapies), researchers are still looking for the next class of anti-allergic agents that can address the needs of patients whose symptoms are unresponsive to available therapies.

This unmet need includes those with severe allergy, many of those with perennial allergies, and those with allergy combined with additional ocular surface disease, such as dry eye. Add these patients to individuals whose symptoms are unresponsive to antihistamines, and it may be that as many as 20% to 30% of all allergy sufferers constitute those without an effective treatment option. Here, we consider possible remedies for these patients, as well as new approaches to identifying novel therapeutic alternatives.

Current alternatives to anti-histamine therapy include ste­roids, non-steroidal anti-inflammatory drugs (NSAIDs), and other immunosuppressive agents. Ste­roids such as loteprednol etabonate are effective choices for patients with severe or chronic allergy, but their use must be carefully monitored. As with all ste­roids, ocular use (especially prolonged use) increases the risks of ocular infection (bacterial, fungal, or viral), cataracts, and ocular hypertension.

To address these issues, partial selective glucocorticoid receptor agonists are being evaluated.¹ These compounds retain the anti-inflammatory effects of corticosteroid agonists but have a reduced spectrum of adverse effects. A number of these compounds are in clinical trials for treatment of inflammation, and one or more of these partial steroids may ultimately be used for ocular allergy in the future.

Like corticosteroids, there is evidence that NSAIDS can be effective alternative treatments for symptoms associated with ocular allergies, particularly the itching that is the hallmark symptom of the disease. One NSAID, ketorolac 0.4%, is FDA-approved for relief of itching associated with allergic conjunctivitis. Despite this, head-to-head studies have shown NSAIDs to be substantially less efficacious than dual-action agents, antihistamine agents, or even mast cell stabilizers.^2,3

In addition, NSAIDs often cause a stinging or burning upon instillation that can lead to eye rubbing and eventual exacerbation of allergic symptomatology. Although there is good reason to believe that inflammation is a worthwhile therapeutic target, NSAIDs leave much room for improvement in this disease.

The immunosuppressant cyclosporine has been used for therapy of vernal and atopic keratoconjunctivitis (VKC and AKC) for years, but there are few placebo-controlled studies examining its efficacy in these conditions or other, less severe allergic diseases of the eye. Despite this, there is little question that the drug is an efficacious treatment for the most serious forms of allergic keratitis. A 2009 prospective study confirmed this in a large cohort (n=594) of patients with either VKC or AKC.⁴

There are issues remaining with the use of this drug for less severe allergies, however. Formulation has been a huge hurdle, and, as with steroids, a balance between reductions in inflammation without excessive immune-suppression is key to overall therapeutic efficacy.

In addition to improvements to existing drug classes, a handful of new targets for allergy therapy is on the horizon, including protein kinase inhibitors, cytokine antagonists, and immunomodulators. As with any drug development process, establishing reliable end points will be a critical issue for these new allergy therapies.

To focus on treatments that can minimize the persistent aspects of the disease, we have recently tested a new clinical paradigm that combines the traditional allergen challenge model with exposure to adverse environmental conditions of temperature and humidity.⁵ Our goal is to establish the techniques that can provide a platform for developing therapies capable of filling the gaps in current treatment options.

Confocal video microscopy

In this study we also tracked inflammatory responses in real time, using confocal video microscopy of the conjunctiva. This technique provides a continuous picture detailing the immune status of the ocular surface, from initial allergen exposure to recruitment of immune cells, and then finally to clearing of the immune response.

Clearly visible conjunctival vessels are progressively populated with increasing numbers of opaque cells (leukocytes, basophils, eosinophils); these cells eventually adhere to points along the vascular surface, and then enter the surrounding tissue through a process of transient disruption of the vessel integrity or extravasation. At later time points the white cells become less visible as they migrate deeper into surrounding tissues. Quantitative data can be extracted from these video records using standardized, descriptive scales. It is hoped that techniques such as video microscopy will provide the diagnostic guidance needed to find the next generation of ocular anti-allergic agents. 

References

1. Schäcke H, Berger M, Rehwinkel H, Asadullah K. Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index. Mol Cell Endocrinol. 2007;275:109–117.

2. Shulman DG, Amdahl L, Washington C, Graves A.A combined analysis of two studies assessing the ocular comfort of antiallergy ­ophthalmic agents. Clin Ther. 2003;25:1096–1106.

3. Bielory L, Lien KW, Bigelsen S. Efficacy and tolerability of newer antihistamines in the treatment of allergic conjunctivitis. Drugs. 2005;65:215–228.

4. Ebihara N, Ohashi Y, Uchio E, et al. A large prospective observational study of novel cyclosporine 0.1% aqueous ophthalmic solution in the treatment of severe allergic conjunctivitis. J Ocul Pharmacol Ther. 2009;25:365-372.

5. Gomes PJ, Ousler GW, Welch DL, Smith LM, Coderre J, Abelson MB. Exacerbation of signs and symptoms of allergic conjunctivitis by a controlled adverse environment challenge in subjects with a history of dry eye and ocular allergy. Clin Ophthalmol. 2013;7:157–165.