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The sky is the limit for allergy pipeline
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Growing patient pool is driving clinical trial investment.
Special to Ophthalmology Times®
Allergic conjunctivitis is reported to affect about 40% of the population,1,2 and its prevalence is increasing. Ocular allergies are associated with a significant economic burden as well as quality-of-life concerns.
The global allergic conjunctivitis market was valued at $2.50 billion in 2019 and is predicted to reach $3.05 billion by the end of 2027 on the strength of a 5.4% growth rate.3
The combination of the condition’s high prevalence, new treatment options, and large investments in clinical trials is driving market growth, according to analysts.
Related: The eyes offer conjunctival clue to COVID-19
They note that with changing weather and worsening air pollution in some areas, the potential patient population will continue to expand.
One trend that has been changing the allergy landscape is the FDA’s Rx-to-over the counter (OTC) switch process. In 2006, Alcon’s ketotifen product Zaditor became the first allergy drop to switch from prescription to OTC status.
All 3 of that manufacturer’s olopatadine formulations are also available without a prescription: Pataday Once Daily Relief Extra Strength (olopatadine 0.7%, formerly prescribed as Pazeo); Pataday Once Daily Relief (olopatadine 0.2%); and Pataday Twice Daily Relief (olopatadine 0.1%).
“Approval of a wider range of nonprescription drugs has the potential to improve public health by increasing the types of drugs consumers can access and use that would otherwise only be available by prescription,” the FDA said in a statement
Novel research is under way, and at the same time, manufacturers are seeking to reformulate available drugs.
Related: Researchers eye cure, diagnostics for adenoviral conjunctivitis
Because the eye’s anatomy presents physiological limitations on drug bioavailability, there is much interest in new drug delivery technology. Here is a review of current drug categories and a selection of agents in the pipeline.
Antihistamines
Antihistamines target a key factor in allergic conjunctivitis and have therefore been widely available on the market.
Systemic antihistamines historically used for ocular allergy control have different affinities to various antihistamine receptors. H1 are largely responsible for pruritus, whereas H2 leads to vasodilation.4
Efficacious antihistaminic treatments continue to be developed; the comfort of topical drops is a key concern. Some patients require the concomitant use of lubricating eye drops and oral antihistamines to maximize control of ocular allergy symptoms.
Related: Amid pandemic, friendly bugs can help protect the eye from infection
Under investigation
Bilastine. Approved for the treatment of allergic rhinitis and urticaria in 2011, bilastine is undergoing allergic conjunctivitis clinical trials as a drop (NCT03479307).
The ophthalmic solution 0.6% is being compared with ketotifen ophthalmic solution 0.025% for the treatment of the signs and symptoms of allergic conjunctivitis.
As a second-generation, selective H1-antihistamine, bilastine avoids the sedative effects of first-generation agents.
Related: New molecule for allergic conjunctivitis makes debut
New approval
Another antihistamine, cetirizine (Zerviate, Eyevance Pharmaceuticals) was recently approved in the United States for topical ophthalmic use. Cetirizine has been used for many years as the oral OTC drug Zyrtec.
Clinical trials of the prescription drop showed significantly decreased ocular itch with a rapid onset of action lasting for 8 hours in moderate and severe patients.5
Mast cell stabilizers
Mast cell stabilizers include drugs like cromolyn or nedocromil; however, they are rarely used as monotherapy.1
This class prevents degranulation of mast cells, the release of preformed inflammatory mediators, and the synthesis of additional inflammatory mediators.
These agents block both early and late phases of the ocular surface’s allergic response, reducing hyperemia, itching, and irritation, with differing efficacy among the various agents.
Related: Where to start with treating OSD patients
Mast cell stabilizers are most effective when administered prophylactically, requiring a several week loading period for optimal benefit which decreases patient compliance.
They are generally safe and have minimal ocular adverse effects, although they can cause transient burning or stinging on application.
Dual-acting agents
Combination mast cell inhibitor, antihistamine agents work via inhibition of mast cell degranulation and competitive binding of the H1 receptor to block histamine binding.
Other cytokines that amplify the inflammatory cascade are also released by mast cells.
Related: Ocular surface inflammation: Vicious cycle of ocular surface disruption
Dual-acting agents usually work quickly, typically within 30 minutes of instillation, have better compliance compared with mast cell-stabilizing agents, and generally provide relief of the itching associated with ocular allergy.2
Combination products are the most commonly prescribed drugs as first-line treatment; side effects are generally mild.
OTC and Rx available
Olopatadine—originally a prescription drop and now OTC—was the first dual-acting eye drop to be FDA approved, and thus considered the “gold standard.” Now it has been joined by prescription agents azelastine, bepotastine (Bepreve, Bausch + Lomb), epinastine, and
alcaftadine (Lastacaft, Allergan). Alcaftadine differs from olopatadine and bepotastine as it possesses an affinity 10 times greater to both H1 and H2 receptors.1
As mentioned earlier, Zaditor (ketotifen, Alcon) was the first dual-acting drop to be switched from prescription to OTC status.
Bausch + Lomb recently received approval for its non-preserved ketotifen formulation, Alaway (OTC), representing the first dual-acting agent approved in the United States as a non-preserved formulation.
Related: Study: Innovative dexamethasone formulation shows efficacy, safety
Under investigation
Drugs delivered via contact lens. Pall and colleagues recently reported on a study of 244 patients evaluating the efficacy and safety of a Johnson & Johnson Vision product consisting of the OTC antihistamine/mast cell inhibitor ketotifen delivered via a contact lens for ocular allergy.6
Results using the Ora-CAC® Conjunctival Allergen Challenge Model were comparable to direct topical drug delivery and suggest that the lens / ketotifen combination can provide a means of simultaneous vision correction and treatment for lens wearers with ocular allergies, the investigators wrote.6
Contact lenses containing epinastine and olopatadine are being studied as well.1
NSAIDs
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) improve ocular itching and reduce mucus secretion, cellular infiltration, erythema, and chemosis. They work by inhibiting the cyclooxygenase pathway, and thus blocking prostaglandin production.2
Related: Antibiotic-steroid combination boosts confidence with delivery
Ketorolac was the first to be approved for quieting the ocular itch associated with allergy; however, it may be associated with discomfort on instillation and is indicated for use for no longer than 2 weeks.
NSAIDs have been associated with cases of corneal melt and are not typically used in clinical practice for allergic conjunctivitis as other drugs remain better options.7,8
Under investigation
PDE4. Drugs which inhibit phosphodiesterase IV are being investigated for their effects on suppressing activation of the inflammatory cascade. Three PDE4 inhibitor drugs currently approved for the treatment of skin or lung diseases are apremilast, crisaborole, and roflumilast.9
RASP. Reproxalap is a novel small-molecule immune-modulating covalent inhibitor of reactive aldehyde species (RASP), which are elevated in ocular and systemic inflammatory disease.
Aldeyra Therapeutics is studying 0.25% reproxalap ophthalmic solution in phase III clinical
trials for the treatment of dry eye disease and allergic conjunctivitis (ClinicalTrials.gov identifier: NCT03404115). The company reported statistically significant and clinically relevant improvements in subject-reported ocular itching and tearing and investigator-assessed ocular redness.10
Corticosteroids
Topical corticosteroids provide the most robust relief from allergic conjunctivitis, effectively relieving a broad range of signs and symptoms.2
Patients who report excessive and persistent signs and symptoms that severely interfere with quality of life can be treated in “bursts.”
Ophthalmic steroids should be used judiciously along with steroid-sparing dual-activity agents, and patients must be monitored for well-known steroid-related side-effects such as elevated IOP and cataract development.
Related: FDA approves topical corticosteroid for treatment of dry eye disease
Better steroids
Newer, safer and C-20 ester-based corticosteroids appear to have an improved IOP side effect profile.1 Loteprednol 0.02% (Alrex; Bausch + Lomb) is indicated for the treatment of seasonal allergic conjunctivitis with only 1% of patients demonstrating an IOP rise of at least 10 mm Hg.1
Under investigation
Drug delivered via intracanalicular insert. Ocular Therapeutix has reported topline results from its phase 3 clinical trial to evaluate the safety and efficacy of Dextenza intracanalicular insert (dexamethasone 0.4 mg) for the treatment of ocular itching associated with allergic conjunctivitis.11
The potential “hands-free” therapy would be administered in the office setting. The bioresorbable insert is designed to release corticosteroid to the ocular surface for up to 30 days.
Dextenza met all pre-specified primary endpoints as demonstrated by a statistically significant mean change in ocular itching from baseline, on a subject-reported 5-point scale, at three time points on day 8, the company stated.11
Immunomodulating agents
Topical immunomodulators are currently used in severe allergic ocular conditions, such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC). The two most well studied and commonly used are cyclosporine A and tacrolimus, available only as compounded agents.12
They work by inhibiting T-cell activation. Other immunomodulatory agents are being investigated; however, use is limited by their low water solubility and lipophilic nature.
Related: Corticosteroids and Immunomodulators for the treatment of dry eye
Immunobiologicals
Immunobiological modulation, to date, has centered on managing asthma and atopic dermatitis. Omalizumab (Xolair; Genentech), not approved for ocular allergy, may show promise for treatment resistant VKC and AKC.13
Under investigation
Dupilumab. An IL-4 and IL-13 pathway inhibitor, dupilumab (Dupixent; Regeneron), is being looked at for the treatment of signs and symptoms of AKC in a multicenter, double-masked, randomized, placebo-controlled, parallel-group, efficacy, safety, and tolerability study (NCT04296864).
In the clinic
The ideal allergic conjunctivitis topical agent is a comfortable drop that has a rapid onset of action, is effective, and long lasting. It is also important that there is not a rebound effect like that seen with long-term use of vasoconstrictors.
Cost considerations will always come into play, although this issue may be shifting as more and more agents move from prescription to over the counter.
While there are many competing first-line, dual-acting agents in this category, the reality is that most eye care specialists stick to 2 or 3 agents in clinical practice that they feel work the best in their hands.
Within the dual-acting agent class, I do not believe that there is a significant benefit to using a prescription product versus an OTC agent, when the former’s superiority has not been proven in the clinic.
I do not think eye care specialists can easily justify using a prescription agent if it costs more than an OTC option. If patients fail to get relief with an OTC combination drop, then I consider alternatives.
Related: Confocal microscopy: Seeing what does not meet the eye
For patients with recalcitrant ocular allergy or other ocular surface disease that is thought to be in part related to preservatives, I favor a preservative-free compounded version of 0.01% dexamethasone that I have been using for more than 10 years. My colleagues and I have reported its safety and efficacy.14
Steroids, in my opinion, are really underutilized in chronic ocular surface disease. The proper use of these agents, particularly low dose and unpreserved, can make a huge difference for our patients.
Conclusion
Although undertreated ocular allergy does not usually pose serious consequences for the patient, it does lead to poorer quality of life and decreased satisfaction with outcomes.
More treatment options have become available for the acute management of ocular allergic symptoms with many agents moving from prescription to OTC and a number more being looked at in clinical trials.
Although most patients with allergic conjunctivitis will find reasonable relief using currently available topical agents; a segment of this population remains unsatisfied.15,16
Therefore, there is a need for the development of safer, more effective anti-inflammatories.
About the author
Ira Udell, MD
e:iudell2@northwell.edu
Udell is the emeritus chairman of ophthalmology at Long Island Jewish Medical Center and North Shore University Hospital, and professor of ophthalmology at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. The author wishes to acknowledge Conni Bergmann Koury for providing editorial assistance.
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References
1. Kimchi N, Bielory L. The allergic eye: recommendations about pharmacotherapy and recent therapeutic agents. Curr Opin Allergy Clin Immunol 2020, 20:414–420. DOI:10.1097/ACI.0000000000000669
2. Kimchi N; Bielory , et al. ICON: Diagnosis and management of allergic conjunctivitis. Ann Allergy Asthma Immunol. 2020;124(2):118-134. doi: 10.1016/j.anai.2019.11.014
3. Allergic Conjunctivitis Market to Exhibit 5.4% CAGR and Reach $3.05 Billion by 2027; Massive Investments in Clinical Trials to Boost Growth. https://tinyurl.com/y3cqryul.
4. Abelson MB, Udell IJ. H2-receptors in the human ocular surface. Arch Ophthalmol. 1981;99(2):302-304. doi: 10.1001/archopht.1981.03930010304018.
5. Meier EJ, Torkildsen GL, Gomes PJ, Jasek MC. Phase III trials examining the efficacy of cetirizine ophthalmic solution 0.24% compared to vehicle for the treatment of allergic conjunctivitis in the conjunctival allergen challenge model. Clin Ophthalmol. 2018:12 2617–2628.
6. Pall B, Gomes P; Yi F, Torkildsen G. Management of ocular allergy itch with an antihistamine-releasing contact lens. Cornea. 2019;38(6):713-717. doi: 10.1097/ICO.0000000000001911
7. Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Case Reports. Ophthalmology. 2001;108(5):936-44. doi: 10.1016/s0161-6420(00)00538-8
8. Maguire JI, Rapuano CJ, Udell IJ. Clinical Update. Cornea. Topical NSAIDs: Best practices for safe use. Eyenet. July 2013. https://www.aao.org/eyenet/article/topical-nsaids-best-practices-safe-use
9. Phillips JE. Inhaled phosphodiesterase 4 (PDE4) inhibitors for inflammatory respiratory diseases. Front Pharmacol. 2020;11:259. doi: 10.3389/fphar.2020.00259
10. Aldeyra to present new reproxalap data from Phase 2 clinical trial in allergic conjunctivitis at American Academy of Ophthalmology 2020 Annual Meeting. https://tinyurl.com/y2z2mle9
11. Ocular Therapeutix announces topline results of Phase 3 clinical trial of Dextenza for the treatment of ocular itching associated with allergic conjunctivitis. https://tinyurl.com/y5y9c9c8
12. Vichyanond P, Kosrirukvongs P. Use of cyclosporine and tacrolimus in treatment of vernal keratoconjunctivitis. Curr Allergy Asthma Rep. 2013;314:308–314.
13. Wiliams PB, Sheppard JD. Omalizumab: A future innovation for treatment of severe ocular allergy? Expert Opin Biol Ther. 2006;5(12):1603-1609. DOI: 10.1517/14712598.5.12.1603
14. Jonisch J, Steiner A, Udell IJ. Preservative-free low-dose dexamethasone for the treatment of chronic ocular surface disease refractory to standard therapy. Cornea. 2010;29(7):723-726. doi: 10.1097/ICO.0b013e3181b765a6
15. Schoemmel E, Raval Y, Gomes PJ. Ocular allergy and quality of life: patient survey 2019. Presented at: ARVO 2020; May 3-7; Virtual
16. Charters L. Examining ocular allergy, quality of life. Sept. 28, 2020. https://www.ophthalmologytimes.com/view/examining-ocular-allergy-quality-of-life
