Ocular itching drugs are numerous in the pipeline

Key Points

Pittsburgh-Several antihistamine and mast cell stabilizer combinations are in the pipeline for the treatment of ocular itching associated with allergic conjunctivitis, as are oral allergy medications based on other formulations. Researchers also are tackling allergies from other angles, including prevention, examining the potential hazards of urban living, and looking at the link between ocular allergies and surgical outcomes.

New combination antihistamine and mast cell stabilizer drugs have been tested for the treatment of allergic conjunctivitis by two manufacturers (ISTA Pharmaceuticals and Johnson & Johnson's Vistakon division), said Francis S. Mah, MD, assistant professor of ophthalmology, University of Pittsburgh School of Medicine, and co-director, Charles T. Campbell Microbiology Laboratory, University of Pittsburgh Medical Center.

An investigational new drug application has been submitted to the FDA for bepotastine (ISTA Pharmaceutials) for the treatment of allergic conjunctivitis. Bepotastine is a non-sedating, selective antagonist of the histamine 1 receptor; it also has a stabilizing effect on mast cells and suppresses the migration of eosinophils into inflamed tissues. ISTA licensed the rights to an eye-drop formulation of bepotastine from Senju Pharmaceutical Co.

Both concentrations and dosing regimens produced highly statistically significant differences in the rapidity of response and the improvement in total nasal symptoms versus placebo, according to ISTA Pharmaceuticals. In the preliminary evaluation of the second primary endpoint, ocular redness, bepotastine showed a trend toward clinical significance but did not achieve statistical significance.

Bepotastine is a powerful antihistamine with modest mast cell stabilizing properties, Dr. Mah said, adding that he expected it to be on the market within the next year or two.

Also, alcaftadine (also known as R8967 ophthalmic solution, Vistakon), is being investigated in phase III trials. According to the Web site http://www.clinicaltrials.gov/, several safety and efficacy studies are ongoing but not recruiting.

New approaches

"The general trend that we're seeing with all of these different molecules and with research is much more specific," Dr. Mah said. "If you look at the history of allergy systemically and then also ocularly, initially there was kind of a 'hand grenade' approach: let's knock out every inflammatory molecule and every inflammatory cell and in the process we'll also quiet the allergy symptoms."

Steroids exemplified that trend, he added. As some of the first anti-inflammatory drugs developed, they were effective at controlling allergy symptoms but also were very powerful drugs that often caused side effects. Moving away from this overkill approach, more and more specific medications have been developed over the years.

"Through research, we're finding out that the actual target cell is the mast cell, and the actual target site is the histamine site, so now we're getting more specific with our treatments, and, therefore, you're going to have fewer and fewer side effects," Dr. Mah said.

Because the medications in development have much more specific activity and fewer adverse effects, adherence to therapy is likely to improve, he added. Typical patient symptoms are itching and redness, and the newer medications are better at targeting the specific sites where those complaints originate.

Researchers also are examining the causes of allergies, including the reasons some people develop them and others don't. "That is kind of a different tack and different approach: Instead of looking at the symptoms of a disease, why don't we try to prevent it?" Dr. Mah said.

A few years ago, that line of research gave rise to the so-called "hygiene theory"-as societies became more sanitary, air and water pollution were tackled, and childhood vaccinations became routine, children had less exposure to diseases and more poorly developed immune systems, increasing their susceptibility to allergies and asthma.

"Maybe from an earlier age we need to have more exposure to antigens so that our immune systems can become more fully developed," Dr. Mah said. Along those lines, vaccinations have been developed that can help individuals build resistance to certain allergens and lessen the impact of seasonal allergies. This avenue of research could be viable in ocular allergies as well.

Other research

Researchers also are investigating a condition known as nonallergic rhinitis, a syndrome that seems to occur among urban residents and may be caused by exposure to the variety of toxins found in cities. "There is debate as to whether people can have these nonspecific inflammatory symptoms in their eyes and whether potentially it's related to the toxins in the cities or to dry eye," Dr. Mah said.

Another topic garnering more interest in the ophthalmology community, he said, is the effect of allergies on surgery. Studies have shown that patients with a history of ocular allergies are at higher risk for complications from refractive surgery, such as diffuse lamellar keratitis following LASIK or epithelialization with PRK, Dr. Mah said. Also, herpes simplex virus ocular disease seems to be significantly worse in patients with a history of atopy. That association may cause somewhat worse outcomes after cataract surgery-such as a slightly higher incidence of endophthalmitis-in patients with atopic keratoconjunctivitis, he said.