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PATIENTS suffering from dry eye disorders now have more treatment options as new long-acting products come on stream.
Among the most notable of the new products is Restasis (cyclos porine 0.05% ophthalmic emulsion, Allergan), which recently gained FDA approval as the first prescription medication for dry eye.

The approval followed years of research demonstrating that in many patients, dry eye is a manifestation of an underlying inflammatory ocular surface disorder affecting the lacrimal glands and subconjunctival tissues.

Indeed, cyclosporine is distinguished as the only available drug for treating dry eye which targets the etiology of the disease rather than just its symptoms, US ophthalmologist Steven E Wilson MD said.

The pivotal clinical trials evaluating Restasis enrolled patients with moderate to severe keratoconjunctivitis sicca. The studies found that treated patients showed statistically significant improvements compared with those receiving placebo.

According to the FDA, 15% of patients had an increase of 10mm, which is clinically significant, while 59% may have experienced an improvement of 7.0mm.
“This is remarkable since all of these patients had Schirmer’s levels less than 5.0mm of wetting prior to inclusion in the study,” Dr Wilson said.

Significant treatment benefits for cyclosporine were also observed in terms of reducing corneal staining and increasing the density of mucin-producing goblet cells.
The ophthalmic safety profile was favourable.
Investigators did not detect drugs in the blood of hundreds of cyclosporine-treated patients. Moreover, there was no evidence of increases in the rate of infections or other complications attributable to immunosuppression.

Dr Wilson said that the main use for restasis would be for the management of patients suspected of having dry eye, with an underlying inflammatory etiology.
That includes patients with Sjogren’s syndrome and related conditions. It is not indicated for the treatment of dry eye after Lasik in the absence of pre-existing dry eye prior to surgery.

Potential off-label indications might include the treatment of allergic conjunctivitis, meibomitis and chronic inflammatory disease affecting the ocular surface and eyelids.
The most exciting aspect of topical cyclosporine is that it might be used early after diagnosis of an inflammatory dry eye condition to possibly halt disease progression.
“I see very real potential for being able to cure inflammatory dry eye disease using topical cyclosporine. Just as aggressive early treatment has been shown to be helpful in preventing progression of rheumatoid arthritis and other inflammatory joint diseases, I think we will find the same principle applies to inflammatory dry eye disease,” Dr Wilson said.

A multicentre study is required to refute or confirm that hypothesis. In the meantime, however, based on his personal risk/benefit assessment which takes into account the potential outcome of palliative treatment with artificial tears only, Dr Wilson is already offering cyclosporine as an option to his patients with early disease.

Diquafosol tetrasodium (IN365, Inspire Pharmaceuticals) is another promising treatment which is in the pipeline. The investigational agent was designed to activate P2Y2 receptors in the mucosal cells of the palpebral conjunctiva and thereby stimulate production of a fluid from those cells containing electrolytes, water and mucin. Phase III studies of diquafosol demonstrated significant improvement in corneal staining.

Looking forward to the potential availability of diquafosol as Inspire prepares to file its new drug application, Dr Wilson proposed that it might find a particular role in patients with “burned out dry eye” who have suffered permanent lacrimal gland damage and are therefore unresponsive to anti-inflammatory treatment with cyclosporine.
In addition, diquafosol might be a useful adjuvant therapy for patients with moderate-to-severe disease who are being started on cyclosporine.

“It takes one to three months for patients to benefit from cyclosporine treatment, but diquafosol appears to have a faster onset of action and so it theoretically might provide interim relief until cyclosporine takes effect.
“However, the studies have shown that many patients do experience relief in symptoms within a week of starting restasis,” Dr Wilson said.
With the recent introduction of several new over-the-counter artificial tears, consumers may find themselves more overwhelmed than ever before as they shop for a product to provide relief.

As a general guideline, Dr Wilson noted he likes to recommend a preservative-free agent for any patient who finds it necessary to use artificial tears twice daily or more often.
In addition, he tries to provide his patients with a range of samples so they can try a number of different products and decide on a trial and error basis which they like best.

“There is a lot of inter-patient variation in terms of comfort and response with the use of different artificial tear products. Therefore, I find it helpful to provide patients with several choices, review other options they can consider, and let them determine through personal testing what helps most," Dr Wilson said.
Some of the new over-the-counter (OTC) choices represent new versions of existing products. However, Systane from Alcon Laboratories is a unique formulation, with the reported benefit of longer-lasting comfort.

Systane contains HP-Guar and borate which undergo a cross-linking reaction on contact with the physiological pH of the ocular surface. The result is transformation of the liquid product into a gel-like membrane that spreads over the cornea and conjunctiva and attaches itself to areas of existing epithelial cell damage. The polymerised membrane persists for hours, allowing epithelial repair to occur in a healthy environment.

In clinical trials, Systane reduced corneal staining by 51%. Compared with a commercially available artificial tear product, it was better in relieving morning dryness, evening dryness and foreign body sensation.

“Systane fulfills a previously unmet need for a dry eye product that provides durable ocular surface protection. Ophthalmologists who encourage their patients to try this new product might find it will become their recommendation of choice for an OTC agent to manage dry eye,” Boston-based specialist Mark Abelson MD said.

Although its name would suggest that Refresh Endura is a modification of existing products in the Refresh line from Allergan, it is actually a unique lubricant eye drop derived from the vehicle used as the control in the Restasis trial.
“The surprising efficacy observed in the vehicle arm was one of the factors which delayed approval of Restasis. Although it had no benefit in improving measures of the underlying inflammation, the study results revealed the vehicle itself was quite effective in improving comfort,” Dr Wilson explained.

Refresh Endura is a preservative-free emulsion with ingredients which treat all three layers of the tear film. In addition to an aqueous component, Refresh Endura contains a demulcent that enhances the mucin layer of the tears along with a lipid component, castor oil. It too seems to provide long-lasting relief.

“Some of my dry eye patients who have been instilling other products up to eight times a day report that they are able to use Refresh Endura much less often, and approximately 90% of my post-Lasik dry eye patients are happy with the relief it provides,” Dr Wilson said.

By providing lipid supplementation, Refresh Endura may also have a particular role in treating patients with meibomian gland dysfunction who are affected by tear lipid deficiency.

That concept is supported by the results of a recent study in patients with non-inflamed obstructive meibomian gland dysfunction which showed that a homogenised castor oil eye drop improved tear stability, tear evaporation, tear interface images, corneal staining and meibomian gland orifice obstruction.

“Current interventions for meibomian gland dysfunction consist of lid hygiene and warm compression to melt the obstructed lipid in the gland. Treatment with a lipid-containing agent such as Refresh Endura provides a more convenient and direct treatment for the underlying lipid tear deficiency.
“With optimal surface tension after instillation, that product can form a stable lipid layer to increase lubrication efficacy and decrease symptomatology,” Japanese investigator Eiki Goto MD said.

Advanced Vision Research recently introduced two new products for patients suffering dry eye problems. TheraTears Gel provides longer lasting protection than the original TheraTears product but without causing crusting and blurring which can be an unwanted consequences of using more viscous ophthalmic topical agents.
TheraTears Nutrition, an oral nutraceutical, is the company’s second entry. Its key ingredient, flaxseed oil, is an excellent source of omega-3 essential fatty acids, which have been reported in various studies to decrease meibomian gland dysfunction and enhance both the lipid and aqueous fractions of tears.

Novartis Ophthalmics has also expanded its GenTeal dry eye product line with GenTeal PF, a single-dose, preservative-free agent containing 0.3% hydroxypropyl methylcellulose.

Steven E Wilson MD
University of Washington School of Medicine, Seattle, US.
Email: sewilson@u.washington.edu

Mark Abelson MD
Schepens Eye Research Institute,
Harvard Medical School, Boston, US.
Email: abelson@vision.eri.harvard.edu

Eiki Goto MD
Tokyo Dental College, Chiba, Japan.
Email: eikigoto@nifty.com

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