What's next in ocular allergy?

Ocular allergy remains one area in which new therapies are continually being developed.

Current prescription therapy for AC includes antihistamines, mast cell stabilizers, dual-action agents, and corticosteroids. First-line therapies include all of the dual-action agents that exhibit both antihistamine and mast-cell stabilizing effects (olopatadine [Patanol, Pataday, Alcon Laboratories], azelastine [Optivar, Meda Pharmaceuticals], epinastine [Elestat, Inspire Pharmaceuticals], bepotastine [Bepreve, ISTA Pharmaceuticals], and alcaftadine [Lastacaft, Allergan]).

This area remains one in which new therapies are continually being tested and developed, because of both the large target population and the limitations of current treatments. AC is an inflammatory condition that can be triggered by a variety of stimuli, including pollens, animal dander, and other environmental allergens. The most common sign and symptom associated with AC is redness (hyperemia) and itching (pruritus), respectively. Other frequent signs include eyelid swelling (edema), swelling of the conjunctiva (chemosis), and tearing.

Targeting the early phase

Of the treatments currently available, most target one or more aspects of the early phase: mast-cell stabilizers prevent degranulation while antihistamines block H1 (and to a lesser extent, H2) receptor activation. Dual-action agents exert both these effects, either directly or indirectly. All of these agents are more efficacious in treating ocular itch than they are at relieving redness or other signs of AC.

In addition, our research shows that symptoms for about 40% of AC sufferers are not adequately controlled by current first-line therapies. For these patients it is necessary to use steroids in addition to, or instead of, dual-action agents to provide sufficient relief from AC symptoms.

Steroids, whether systemic or topical, act primarily by suppressing late phase-associated inflammation. While they are efficacious in providing relief from inflammation, steroids also are associated with significant adverse ocular effects, including increased risk of cataract and increased IOP. One major focus of new therapeutic development, then, is to supplant the steroid with an anti-inflammatory medication that does not exhibit these adverse effects. A number of compounds in varying stages of development are aimed at improving on existing therapies ( http://www.clintrials.gov/).

One way to reduce adverse events is to lower the concentration of active agent-and this is part of the rationale behind prednisporin (Fovea; Sanofi-Aventis). This topical formulation combines a low concentration of the steroid prednisone (1/10 the concentration of that found in the ocular prednisone Pred Forte [Allergan]) with a second anti-inflammatory, immune-suppressive agent cyclosporin A. This combination yielded positive results in a recent proof-of-concept study. Another approach is the development of steroid "partial agonists," drugs that retain the anti-inflammatory action of other steroids without the adverse effects. An example of this is a selective glucocorticoid receptor agonist (SEGRA) (Bausch + Lomb), currently in development for ophthalmic indications that would benefit from its anti-inflammatory action such as AC.

More traditional dual-agent therapies also in development include Ketonaph (Bausch + Lomb), a combination of the antihistamine ketotifen and an alpha-adrenergic agonist, naphazoline. This combination provides effective amelioration of the two hallmarks of AC: redness is reduced via adrenergic vasoconstriction and itch is reduced by ketotifen's anti-H1 receptor activity.

Another new option is alcaftadine, an antihistamine that has made it to the development finish line (FDA approval June 2010). Lastacaft has been approved for once-daily dosing for prevention of itch associated with AC, and it has additional effects on the stability of the conjunctival surface that suggest some additional therapeutic effects on chronic, as well as acute, AC symptoms.

Perhaps a bit farther up the pipeline are drugs that were first developed for blood disorders and rheumatoid arthritis (RA) that may have a more general application for treatment of inflammation, including inflammation associated with chronic allergy. These compounds-small-molecule inhibitors of intracellular protein kinases like JAK (Janus Kinase) and SYK (splenic tyrosine kinase)-represent possible successors to corticosteroids that can suppress chronic AC signs without the steroid side effects. Because they are small molecules (rather than biologics) they exhibit good oral bioavailability, and thus have the potential to be delivered in a topical formulation. Several JAK inhibitors have demonstrated good efficacy and safety in phase II studies of RA, and similar results have been reported for SYK inhibitors as well. Phase III studies are under way, and studies of these drugs for ocular disorders are likely in the not-too-distant future.

Implants and other slow-release technology provide examples of another avenue for new product development, that of new delivery technologies. Clinical trials for transdermal patch delivery of ketotifen (Senju USA) were completed recently, and a contact lens "pre-loaded" with antihistamine is also in development (Vistakon). Even though there are options for both practitioners and patients in terms of therapy for ocular allergies, room for improvements remains, and the demand for new therapies is likely to continue for the foreseeable future.

Paul J. Gomes, MS, is vice president of the Allergy Department at Ora Inc. He has no financial interest in the subject matter.

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