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Investigational dry eye drugs address the disease on several levels
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The treatment of dry eye continues to gain momentum and emphasis each year, with new products launched and investigated regularly. Some of the latest drugs in the pipeline tackle the disease at the mucomimetic, hormonal and lacrimal levels.
“We have an active development program for pharmaceutical products to treat the underlying causes of dry eye,” said Doug MacHatton, vice president of investor relations and strategic communications for Alcon (Ft. Worth, Texas), in an interview with Primary Care Optometry News. “In addition to these significant programs, we also have other programs underway at earlier stages to continue to explore this challenging and underserved medical need. As a dry eye sufferer, I can tell you that there is a tremendous need for new therapies.”
Alcon’s emerging products
According to Mr. MacHatton, Alcon has two promising new dry eye drugs in the company’s pipeline, which the company hopes will build on the success of Systane.
He said that 15-HETE (icomucret) is an endogenous molecule produced by human ocular tissues that induces the secretion of membrane-bound mucins from human conjunctival and corneal epithelial cells. “These mucins are integral in the formation of a healthy tear film,” Mr. MacHatton said. “We are conducting a number of phase 2 clinical trials with this drug, and we look forward to analyzing the results when they are available.”
The corticosteroid rimexolone is also being studied for its efficacy in treating dry eye, Mr. MacHatton said. “This is a drug that we are developing to address the inflammatory aspect of dry eye,” he said. “Corticosteroids have been reported to provide some benefit in treating dry eye patients. However, there is some concern about increased IOP as a side effect.”
Mr. MacHatton said rimexolone has not shown a significant IOP increase as compared to other corticosteroids. “We are working with a concentration of it that maintains ocular surface anti-inflammatory activity while not adversely affecting IOP,” he said. “We are in phase 2 of our clinical trials, and, while we have seen some positive effects, we are not yet in a position to report clinical results.
“At this time, we are unable to give a time frame for approval for either drug,” he said.
Inspire’s diquafosol in phase 3 trials
Inspire Pharmaceuticals (Durham, N.C.) announced in February the results of a phase 3 clinical study of its dry eye therapy, diquafosol tetrasodium (INS365). According to Donald Kellerman, PharmD, senior vice president of development for Inspire, diquafosol has been in trials for several years.
“We have been in studies since 1999 for this product, and we filed an NDA in June 2003,” he told Primary Care Optometry News. “We received an approvable letter in December 2003.”
Diquafosol is a P2Y2 receptor agonist that is intended to treat dry eye disease through rehydration of the ocular surface.
According to an article by Dr. Kellerman [Nichols KK, Yerxa B, Kellerman DJ. Invest Drugs. 2004;13(1):47-54.], the drug activates P2Y2 receptors on the ocular surface. This leads to rehydration through the stimulation of the fluid pump mechanism of the accessory lacrimal glands on the conjunctival surface. “It stimulates the fluid transport, mucin secretion and, to an extent, lipid stimulation,” Dr. Kellerman said. “We believe it simply hydrates the ocular surface, so in dry eye, it provides the tear film components.”
According to a company press release, the most recent phase 3 study results reported that diquafosol failed to demonstrate statistically significant improvement as compared to placebo for the primary endpoint of the incidence of corneal clearing. Improvement compared to placebo was accomplished for a number of secondary endpoints, including mean corneal staining, mean conjunctival staining and conjunctival clearing.
Dr. Kellerman said the clinical trial results have generally been positive overall. Inspire submitted an admendment to the U.S. Food and Drug Administration in June 2005. He said a ruling is expected by Dec. 1.
“We’ve tested more than 2,000 patients with this in clinical trials,” he said. “I think we could be close to market, provided that we get the favorable ruling from the FDA.”
Novartis’ pipeline
According to Julie Morrow, PhD, global communications manager for Novartis Ophthalmics (Basel, Germany), two notable new drugs are in the company’s pipeline. “Two of our investigational products for dry eye are rebamipide and pimecrolimus,” she said in an e-mail interview.
In February of this year, Novartis announced that it had in-licensed rebamipide from Otsuka Pharmaceutical Company Ltd. (Chiyoda-ku, Tokyo, Japan). The drug is currently in phase 3 studies in the United States.
According to a Novartis press release, rebamipide is expected to “demonstrate a novel mechanism of action to enhance tear secretion and increase the levels of mucin covering the conjunctiva and cornea of the eye.”
In a study presented at the 2005 Association for Research in Vision and Ophthalmology meeting (Donshik et al.), rebamipide was found to be safe and effective in the treatment of dry eye.
The multicenter, randomized, double-masked, dose-response, placebo-controlled, parallel-group study assessed the safety and efficacy of several doses of rebamipide instilled in both eyes over a period of 12 weeks. A total of 200 subjects suffering from dry eye symptoms were involved in the study and were randomized to four treatment groups.
Fluorescein corneal staining (FCS) was the primary objective endpoint, with secondary objective endpoints of lissamine green conjunctival staining (LGCS) and Schirmer’s test. Each patient’s most unpleasant symptom, designated the primary ocular discomfort (POD), served as the primary subjective endpoint.
The results at week 12 showed that, compared to placebo, subjects taking 2% rebamipide showed an advantage or favorable trend in mean change from baseline (CFB) for FCS score, POD, LGCS and the individual symptom severity scores of gritty/sandy sensation, burning/pain as well as general treatment impression scores. Statistically superior results were found in the rebamipide 2% group over placebo in mean CFB for Schirmer’s test at week 2 and week 8.
While all three concentrations of rebamipide were well tolerated and effective, the concentration of 2% appeared to be the most effective concentration.
Dr. Morrow said pimecrolimus, currently in phase 2 clinical trials, is Novartis’ other investigational dry eye product. This emerging treatment is thought to act through an anti-inflammatory mechanism of action.
Allergan’s Androgen Tears
Allergan Inc. (Irvine, Calif.) is currently approaching dry eye at a hormonal level. For several years, clinicians have been studying the possible link between androgens and the meibomian and lacrimal glands. Researchers have found evidence to support the theory that androgen deficiency may be connected to meibomian gland dysfunction.
According to Allergan spokesperson Heather Katt, the company is currently evaluating the latest data for Androgen Tears, its androgen-based dry eye product.
“Phase 2 data were completed in mid-2005 for Androgen Tears, which addresses the lipid layer,” she said. “Due to the prematurity of this project, we can’t comment more specifically on anything at this time.”
In 2003, Allergan acquired Bardeen Sciences Company, LLC, and stated its intention to continue the development of the company’s key products, among them Androgen Tears.
For Your Information:
- Doug MacHatton is vice president of investor relations and strategic communications for Alcon. He can be reached at 6201 S. Freeway, Ft. Worth, TX 76134-2099; (800) 757-9195.
- Donald Kellerman, PharmD, is senior vice president of development for Inspire Pharmaceuticals. He can be reached at 4222 Emperor Blvd., Ste. 200, Durham, NC 27703; (919) 941-9777; e-mail: Dkellerman@inspirepharm.com.
- Julie Morrow, PhD, is global communications manager for Novartis Ophthalmics. She can be reached at Novartis International AG, CH-4002, Basel, Switzerland; (41) 61 697 98 46; e-mail: julie.morrow@novartis.com.
- Heather Katt is a spokesperson for Allergan. She can be reached at PO Box 19534, Irvine, CA 92623; (714) 246-4500; e-mail: Katt_Heather@Allergan.com.