Options for treating allergic conjunctivitis are abundant, and both ophthalmologist and patient could use guidance in selecting the best drug from this $816 million dollar market.IMS. April 2014. This article presents a guide for selecting the optimal product, OTC or prescription, for your patient’s needs.
LINGUISTIC NUANCES IN INDICATION
Table 1 shows numerous products offered OTC or by prescription for allergic conjunctivitis. It is interesting to note how the exact wording of the indication changes with these products; some are indicated for prevention, others treatment and still others for relief of signs and/or symptoms. OTC products generally must use the wording “relief” instead of “treatment” per FDA labeling requirements. Yet many prescription products are also approved for “temporary relief” (emedastine,* ketorolac, loteprednol). Cromolyn and lodoxamide are only indicated for vernal keratoconjunctivitis, but they are prescribed for milder allergic disease. The broadest indication was given only to Patanol, or olopatadine 0.1%, approved for the treatment of the signs and symptoms of allergic conjunctivitis; a close second is the steroid loteprednol, approved for temporary relief of signs and symptoms of seasonal allergic conjunctivitis.
Figure 1. Calcium influx provides the link from allergen crosslinking to mast cell
HISTAMINE = ITCHING
The primary symptom of ocular allergy is itching; in fact, it is pathognomonic for this disorder. Abelson MB. Allergic disease of the eye. Abelson MB ed., WB Saunders Co, Philadelphia, 2001. If no itch exists, it isn’t allergy. Recognizing the importance of itching, the FDA has approved most anti-allergic agents for prevention of itching as the indication. Itching is well known as the primary and almost instantaneous result of histamine release from mast cells. Histamine also binds to receptors on vasculature, causing vasodilation and leaky vessels. These lead to the characteristic redness and tearing and, with time, swelling (both lid swelling and chemosis) when fluids build in surrounding tissues. Mediator cascades are triggered that propagate the immediate response and call in other inflammatory cells. If it continues, the inflammatory response worsens. Leonardi A, Motterle L, Bortolotti M. Allergy and the eye. Clin Exp Immunol. 2008 Sep;153 Suppl 1:17-21.,Leonardi A. Allergy and allergic mediators in tears. Exp Eye Res 2013;106:106-117.
If the patient’s primary complaint is itching, one option is an OTC antihistamine or antihistamine/vasoconstrictor combination; while easy to administer and inexpensive, these products are short-acting and associated with stinging and ocular dryness. Included in the first tier are Zaditor, Naphcon-A, Alaway, Opcon-A, Visine-A, Visine A.C. and many generic options of ketotifen.
When the OTC products do not work, and breakthrough itching is significant, the prescription options best serve.
Olopatadine has dominated the ocular allergy market since its arrival in 1996 as Patanol in the 0.1% concentration with BID dosing frequency. Since then it’s been approved in two other concentrations. Pataday, at 0.2%, is a once-daily eye drop for managing symptoms; its approval was based on efficacy in relieving itching at 16 hours after dosing. Abelson MB, Gomes PJ. Olopatadine 0.2% ophthalmic solution: the first ophthalmic anti-allergy agent with once-daily dosing. Expert Opin Drug Metab Toxicol 2008;4:453-461. While the FDA considered this QD approval based on a waking time period, 16 hours might not be enough if the patient is allergic to mites or animal dander.
So enter Pazeo, a 0.7% concentration, which might control ocular itching for the entire 24-hour day. FDA Approves Pazeo. http://www.drugs.com/newdrugs/alcon-receives-fda-approval-pazeo-olopatadine-hcl-ophthalmic-solution-allergic-conjunctivitis-4159.html. Accessed Aug. 4, 2016. Thus, having an indication from your patients as to their hypersensitivity could also dictate which drop you choose.
Table 1.* Products approved to treat or prevent allergic conjunctivitis
Olopatadine maintained superiority against its predecessors in comparative clinical trials for years. Butrus S, Griner JV, Discepola M, Finegold I. Comparison of the clinical efficacy and comfort of Olopatadine hydrochloride 0.1% ophthalmic solution and nedocromil sodium 2% ophthalmic solution in the human conjunctival allergen challenge model. Clin Ther 2000;22:1462-1472., Mah FS, Rosenwasser LJ, Townsend WD, et al. Efficacy and comfort of olopatadine 0.2% versus epinastine 0.05% ophthalmic solution for treating itching and redness induced by conjunctival allergen challenge. Curr Med Res Opin 2007;23:1445-1452., Deschenes J, Discepola M, Abelson M. Comparative evaluation of olopatadine ophthalmic solution (0.1%) versus ketorolac ophthalmic solution (0.5%) using the provocative antigen challenge model. Acta Ophthalmol Scand Suppl 1999;228:47-52. It then fell off its perch against a real challenger.
ALCAFTADINE: A SLEEPER?
Alcaftadine, approved in 2010, flew under the anti-allergy radar until recently. Once-daily alcaftadine, active against H1, H2, and H4 receptors, Gallois-Bernos AC, Thurmond RL. Alcaftadine, a new antihistamine with combined antagonist activity at histamine H1, H2, and H4 receptors. J Receptor, Ligand & Channel Research 2012;5:9-20. has been shown to dampen conjunctival eosinophil and late-phase immune responses. Ono SJ, Lane K. Comparison of effects of alcaftadine and olopatadine on conjunctival epithelium and eosinophil recruitment in a murine model of allergic conjunctivitis. Drug Design, Development and Therapy 2011; 5:77-84. 11 Two clinical trials Ackerman S, D’Ambrosio FD, Greiner JV, et al. A multicenter evaluation of the efficacy and duration of action of alcaftadine 0.25% and olopatadine 0.2% in the conjunctival allergen challenge model. J Asthma and Allergy 2013; 6:43-52., McLaurin EB, Marsico NP, Ackerman SL, et al. Ocular itch relief with alcaftadine 0.25% versus Olopatadine 0.2% in allergic conjunctivitis: pooled analysis of two multicenter randomized clinical trials. Adv Ther 2014;31:1059-1071. showed that alcaftadine controlled itching better than olopatadine. Ackerman et al presented the results of one multicenter conjunctival allergen challenge (CAC) trial in 127 subjects. At the peak time post-CAC for itching, alcaftadine treatment resulted in significantly lower mean itching scores than olopatadine 16 hours after dosing (p=0.026). Also, alcaftadine provided significant relief of chemosis at every measured time point 24 hours after dosing. This is a unique finding for ocular anti-allergics that are tailored more for symptom than sign relief.
Table 1.* Products approved to treat or prevent allergic conjunctivitis (continued)
Last year, McLaurin et al. published a pooled analysis of two CAC studies performed in 284 subjects. Again, at 16 hours post-instillation, alcaftadine showed superiority to olopatadine 0.2% for the first explosive itching that occurs at 3 minutes after CAC (0.50 vs 0.87, respectively, p=0.0006). Alcaftadine also demonstrated lower mean itching scores over all measured time points (0.68 vs. 0.92 respectively, p=0.0390) compared with Pataday. Finally, minimal itching (a score < 1) was reported in 76.1% of alcaftadine-treated subjects vs. 58.1% of olopatadine-treated subjects (p=0.0121).
One up-and-coming product that might break through this market by the end of 2016 is an ophthalmic version of cetirizine (AC-170), an icon in allergy treatments. Aciex Therapeutics had developed AC-170 through Phase 3. It is now in the R&D pipeline of Nicox, which acquired Aciex last year. Ophthalmic cetirizine has been evaluated in two pivotal CAC studies. 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. Association for Research in Vision and Ophthalmology (ARVO) 2014, Poster number C0010. Nicox held two positive pre-New Drug Application meetings with the FDA, which has recommended submission. Nicox ophthalmic pipeline. http://www.nicox.com/rd/ophthalmic-pipeline/ac-170/. Accessed Aug. 7, 2015.
. The early phase of the ocular allergic reaction is driven by mast cell degranulation. Pre-formed histamine is released almost instantaneously and binds to receptors on nerves to elicit itching, and blood vessels to elicit vasodilation, and as a result, the lid and conjunctival swelling, tearing and redness that is observed in ocular allergy. Figure 2b
. The late phase of the reaction involves other inflammatory cells called in by chemokines such as ICAM to the tissue. Eosinophils, neutrophils and basophils participate, and their pro-inflammatory cytokines promulgate the reaction.
A NICHE FOR CHRONIC ALLERGY?
The ocular allergy market is saturated with dual-acting antihistamines, all destined to evolve into OTC agents as long as insurers continue giving them their preferential blessing. This crossover will provide an opportunity for a prescription-strength allergic conjunctivitis therapeutic.
The industry has long sought a novel compound that could supplant the corticosteroid for safe, disease-modifying treatment of ocular allergy over prolonged periods. A compound that can demonstrate allergic disease modification instead of just symptom relief has yet to be identified.
At the beginning of the pipeline are interleukin antagonists, kinase inhibitors and other pathway-specific molecules that might dramatically change how we treat ocular allergy. Agents that work upstream from histamine receptor antagonism, blocking degranulation of mast cells, would provide a safe and specific target for allergy, and a powerful addition to the market. A prescription option is essential to balance the many OTC choices with which patients self-medicate through trial and error.