Exploring off-label, investigational approaches for allergic conjunctivitis

Reviewed by Michael B. Raizman, MD

The combination of the newer antihistamine/mast cell stabilizer ophthalmic medications with artificial tears-along with instructions about the avoidance of culprit allergens and eye rubbing-will control signs and symptoms of seasonal and perennial allergic conjunctivitis (SAC/PAC) in most patients.

While the addition of a topical corticosteroid can be helpful for patients with a severe ocular allergy manifestation, there are other strategies ophthalmologists may consider to manage those more-challenging cases, said Michael B. Raizman, MD.

In terms of proper management of SAC/PAC, Dr. Raizman suggested referring patients to an allergist for possible immunotherapy, which is now administered by either the sublingual route or by injection.

“Desensitization has been around for a long time, but the sublingual approach is generally preferred by patients,” said Dr. Raizman, Ophthalmic Consultants of Boston; associate professor of ophthalmology, Tufts University School of Medicine; and director of the cornea and cataract dervice, New England Eye Center, Boston.
 

No solid data

While desensitization has shown to be effective for many of the allergens that cause SAC and PAC, he added, there is not solid clinical trial data on its efficacy for controlling specific ocular signs and symptoms.

“My personal experience is the effects are modest, but it may be helpful for patients with severe SAC and PAC,” he said.

Acting through calcineurin inhibition which may lead directly to mast cell stabilization, topical cyclosporine can also be an effective treatment for severe SAC/PAC and useful as a steroid-sparing agent.

However, the benefit may require dosing cyclosporine 0.05% emulsion (Restasis, Allergan) three or four times daily or use of a compounded preparation containing up to 0.5% of the active ingredient.

Tacrolimus, another calcineurin inhibitor, is available as an ophthalmic product outside of the United States. In addition, topical pimecrolimus may be available in the future, Dr. Raizman noted.

A different mechanism of action

A different mechanism of action

Targeted agents under development for treatment of SAC and PAC act via different mechanisms of action. These agents include inhibition of various chemokines released by the mast cell or modulation of the ocular surface tissues at the site of inflammation responsible for the symptoms of ocular allergy, including the nerves, the corneal and conjunctival epithelium, and the conjunctival vessels.

Discussing a few of these modalities, Dr. Raizman said there is interest in investigating lifitegrast 5% (Xiidra, Shire), the lymphocyte function-associated antigen-1 (LFA-1) antagonist available for the treatment of dry eye disease.

“Based on laboratory work, it has been known for some time that mast cell activation can be modulated by inhibition of LFA-1 binding to intercellular adhesion molecule-1 (ICAM-1),” Dr Raizman explained. “Findings from animal studies indicate that it also appears to occur on the ocular surface in vivo.”

Monoclonal antibodies that inhibit the LFA-1/ICAM-1 interaction are also in development.

“Stabilization of the mast cell is the holy grail for treating allergic conjunctivitis,” he added. “If we could shut down mast cell degranulation, it would take care of this condition. [However,] we have to look at new modalities because the existing dual-acting antihistamine/mast cell stabilizers are relatively weak in their activity for mast cell stabilization.”

In addition, the investigational therapeutic pipeline for allergic conjunctivitis includes a number of targeted therapies acting via a host of different mechanisms, including Syk/JAK kinase inhibitors, an aldehyde trap, leukotriene receptor antagonists, and alpha4beta1 integrin antagonists.

Dr. Raizman observed there are several currently available oral leukotriene antagonists. All of these agents are approved for the treatment of asthma and one is indicated for the treatment of allergic rhinitis.

“For reasons that are unclear, none of the leukotriene antagonists seems to be very effective for treating ocular allergy,” Dr. Raizman explained.

“One of the issues with the targeted therapies is they are all working at a point downstream in the allergic inflammatory cascade,” he added. “For that reason, they are not affecting the inflammatory mediators that are released earlier by other pathways. By getting too sophisticated with these targeted approaches, we may be missing the bigger picture and ultimately leaving patients symptomatic.”

Products using new modes of delivery to provide extended release of existing medications are also being investigated for the treatment of ocular allergy, which would offer better convenience and overcome compliance issues accompanying topical treatment.

These options include a punctal plug releasing dexamethasone (Dextenza, Ocular Therapeutix), which failed to meet the primary endpoint in a phase III trial investigating its use for the treatment of allergic conjunctivitis.

Drug-eluting contact lenses are also now  available which may play a role in treating ocular allergy.

Michael B. Raizman, MD

E: mraizman@tuftsmedicalcenter.org

This article was adapted from Dr. Raizman’s presentation during Cornea Subspecialty Day at the 2016 American Academy of Ophthalmology annual meeting. Dr. Raizman is a consultant to Ocular Therapeutix, Shire, and companies that market and are developing treatments for allergic conjunctivitis.