Unmet need spurs research

Therapy for ocular allergy has shown significant progress in recent years. Topical antihistamine/mast cell stabilizers currently available provide a rapid relief of the primary symptoms of allergy, and the newest of these displays a duration of action that permits once-daily dosing for most allergy sufferers.Abelson MB, McLaughlin JT, Gomes PJ. Antihistamines in ocular allergy: are they all created equal? Curr Allergy Asthma Rep. 2011;11:205-211.

These drugs act both directly (by interfering with the action of histamine released by conjunctival mast cells in response to allergen exposure) and indirectly (by reducing the ability of allergens to stimulate histamine release) to attenuate allergic signs and symptoms.

Despite these improvements, many patients with chronic ocular allergies, particularly those with both seasonal and perennial allergy, do not have a full response to antihistamine therapy and so require anti-inflammatory agents such as topical non-ster oidals or cor ti co steroids. Thus a major focus of current and future anti-allergic drug development is to identify therapies to address this unmet need.

Chronic allergy differs from the more acute forms in that it is primarily mediated by cellular factors, and is dependent upon the activity of immune cells such as basophils and eosinophils that have infiltrated the conjunctiva over the course of prolonged allergen exposure.Choi SH, Bielory L. Late-phase reaction in ocular allergy. Curr Opin Allergy Clin Immunol. 2008;8:438- 444.

Increased prevalence of chronic atopic diseases such as allergic conjunctivitis in recent years is also believed to result from the “modern lifestyle” that includes exposure to exacerbating agents such as air pollutants and volatile chemicals. Pollutants and allergens act to prime the immune response, while at the same time they promote a breakdown of the epithelial barriers that function as the first line of ocular surface defense. This combination acts to accelerate the process of immune cell infiltration and ocular surface damage that is the hallmark of chronic allergy.Riediker M, Monn C, Koller T, Stahel WA, Wüthrich B. Air pollutants enhance rhinoconjunctivitis symptoms in pollen-allergic individuals. Ann Allergy Asthma Immunol. 2001;87:311-318.

Patients who display poor or incomplete response to antihistamine therapy appear to fall into two groups: those with chronic allergies and breakthrough seasonal allergies. Patients in the first group are those with the combination of seasonal and perennial ocular allergies; for these patients, it is always allergy season. The second group exhibits robust responses to seasonal allergens, so that on days with particularly high pollen levels they present an allergic response that simply overwhelms the ability of any topical antihistamine to suppress.

Both patient types are subject to exacerbation of their allergies by environmental pollutants such as auto exhaust and industrial haze, and both show recruitment of immune cells to the conjunctiva. With continued allergen exposure, these examples of chronic allergic conjunctivitis evolve into a pathologic condition dominated by ocular surface inflammation. The goal of any new therapy is to “calm” the conjunctiva, allow the recruited cells time to dissipate, and at the same time reduce the inflammatory features of this “late phase” response.

Currently, the best available treatments for chronic ocular allergy sufferers (estimated to be about 30%) are topical ster oids such as prednisolone acetate or lote pred nol etabonate. While effective, these drugs may only be used for brief periods because of adverse ocular effects such as increases in IOP or risk of cataract. Several recent clinical trialshttp://clinicaltrials.gov/ct2/results?term=vernal+keratoco njunctivitis. Searched Jan. 13, 2012. have been conducted testing the efficacy of other anti-inflammatories in a more severe form of ocular allergy, vernal kerato-conjunctivitis. Similar compounds may also be candidates for therapy of chronic allergic conjunctivitis. As with seasonal allergic disease, the key to developing efficacious therapies is the availability of appropriate clinical models of the disease.

In addressing the need for new treatments for chronic and breakthrough ocular allergy, our most recent efforts have focused on modifications to the well-established conjunctival allergen challenge (CAC) model.Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge. A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol. 1990;108:84- 88. Using a number of different paradigms of allergen exposure, we are able create signs and symptoms that replicate those observed in chronic disease.Gomes PJ, Yunes S, Welch D, Abelson MB. Evaluation of the effect of multiple doses of pred forte (prednisolone acetate 1%) in the prevention of conjunctival allergen challenge–Induced ocular allergic signs and symptoms. Invest Ophthalmol Vis Sci. 2006;47: E-Abstract 4978.

In these and other studies we employ a strategy of combining chronic allergen exposure, optimized inclusion criteria, and the established objective endpoints of the CAC to create a new model for chronic ocular allergy. This approach is an ideal clinical path to assess the efficacy of either new chemical entities or re-purposed drugs as therapies for chronic ocular allergy.