Inflammation of the eye resulting from an allergic reaction to pollen or mold spores is pervasive throughout society, with up to 40% of the general population reporting ocular symptoms consistent with allergic conjunctivitis (AC).1 In the United States alone, approximately 74 million adults suffer from AC.2 The two most common forms are seasonal AC and perennial AC; in almost all cases, IgE antibodies specific to certain allergens are present.3 Other forms include giant papillary conjunctivitis (GPC), vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC).
Pharmacological management of AC encompasses several categories of drugs, including: topical and oral antihistamines; mast cell stabilizers; dual-acting drugs that combine antihistamines and mast cell stabilizers; glucocorticoids; and NSAIDs. However, while many of these options are effective, some are limited by tolerability or risk of side effects with long-term use. This article reviews some of the new drugs currently being investigated.
Zyrtec (cetirizine, Pfizer) is well known as an effective over-the-counter oral antihistamine. Cetirizine is a piperazine derivative and an active metabolite of hydroxyzine. Classified as a non-sedating second-generation medication, it is the most potent of the second-generation options, but also the most likely to cause sedation.
AC-170 (Aciex Therapeutics) is an ophthalmic formulation of cetirizine developed for the treatment of allergic conjunctivitis. Two Phase III studies have thus far been conducted; published results from one are still pending. The second study enrolled 101 subjects who received either cetirizine 0.24% or vehicle and were evaluated using a conjunctival allergen challenge model. The study found cetirizine statistically superior to the vehicle in alleviating the primary endpoint—itching—as well as all secondary endpoints, including hyperemia. Additionally, non-conjunctival manifestations such as eyelid swelling and ear pruritus were significantly improved with cetirizine.4 Nicox, which recently acquired Aciex, is expected to submit an NDA in 2015.
N-acetyl-aspartyl-glutamate (NAAG), known globally as spaglumic acid, is available in Europe for the management of VKC. This drug is multi-mechanistic, simultaneously working as a mast cell stabilizer while reducing production of inflammatory mediators and complement activation, and limiting expression of adhesion molecules involved in recruiting other inflammatory cells. NAAG ophthalmic drops appear to be effective and well-tolerated.5
Nonsteroidal selective glucocorticoid receptor agonists (SEGRA) are currently being evaluated for treatment of AC, dry eye syndrome and inflammation following cataract surgery. These drugs inhibit numerous inflammatory mediators, including cytokines and prostaglandin E2, without the side effects of glucocorticoids.5
Singulair (montelukast sodium, Merck) is a leukotriene blocker used orally for the management of asthma and seasonal allergic rhinitis. An ophthalmic formulation has been shown to improve ocular inflammation in a rabbit model.6
Goblet Cell Secretion
RX-10045 (Auven Therapeutics) is an analog of resolvin E1 (RvEq), an inflammatory mediator derived from omega-3 fatty acids. RX-10045 is currently being investigated for the treatment of dry eye and also for AC. It is thought to alter goblet cell secretion of mucin, which may alleviate an underlying tear film disorder common in AC.7
If successful, this and similar drugs could herald a new approach to allergy management.
Disrupting Binding Molecules
Several adhesion molecules, such as α4β1 and α1β2 (lymphocyte function-associated antigen-1, LFA-1) integrins, along with intracellular adhesion molecule-1 (ICAM-1), mediate inflammatory processes characterized by lymphocyte activation. Binding of LFA-1 and ICAM-1 is necessary for the activation and movement of lymphocytes to the inflamed tissue. It is thought that disrupting this binding would reduce inflammation.
Lifitegrast (Shire) is a small-molecule LFA-1 antagonist that inhibits T-cell activation, adhesion, proliferation and cytokine release. A Phase III study conducted on the efficacy of lifitegrast ophthalmic solution 5.0% in treating dry eye disease determined the drug reduced corneal fluorescein and conjunctival lissamine staining and improved symptoms of ocular discomfort and eye dryness compared with placebo when administered twice daily for 84 days.8 Results from an efficacy study to evaluate the drug’s efficacy in treating allergic conjunctivitis are still pending.9
As we continue to further understand the mechanisms of allergies, investigation of new therapies for the management of AC will continue. Vigilantly keeping up with ongoing research and development is our responsibility and helps us bring the best possible treatment options to our patients.
1. Singh K, Axelrod S, Bielory L. The epidemiology of ocular and nasal allergy in the US, 1988-1994. J Allergy Clin Immunol. 2010;126:778–83.
2. Williams DC, Edney G, et al. Recognition of allergic conjunctivitis in patients with allergic rhinitis. World Allergy Organization Journal. 2013;6:4.
3. Rosa M, Lionetti E, Reibaldi M, et al. Allergic conjunctivitis: a comprehensive review of the literature. Ital J Pediatr. 2013; 39(18).
4. Gomes PJ, Raval Y, Schoemmell E, Welch DL. Evaluation of the Onset and Duration of Action of Topical AC-170 (Cetirizine 0.24%) for the Prevention of Allergic Conjunctivitis. ARVO 2014, Poster number C0010.
5. Baiula M, Spampinato S. Phase II drugs under investigation for allergic conjunctivitis. Expert Opin Investig Drugs. 2014;23(12):1671-1686.
6. El-Hossary GG, Rizk KA, El-Shazly AH, Hanafy LK. Montelukast as a new topical ocular theraptueitc agent for treatment of allergic conjunctivitis: an experimental comparative study. Australian J Basic Appl Sci. 2010;4(1):71-78.
7. Nye M, Rudner S, Bielory L. Emerging therapies in allergic conjunctivitis and dry eye syndrome. Expert Opin Pharmacother. 2013;14(11):1449-1465.
8. Correnti AJ, D’Ambrosio FA, Eiferman RA, et al. Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study. Ophthalmology. 2014;121(2):475-83.
9. Efficacy Study to Evaluate the Effectiveness of 3 Concentrations of SAR 1118 in Allergic Conjunctivitis. Available at: www.clinicaltrials.gov/ct2/show/NCT00882687. Accessed January 29, 2015.