Restasis approval broadens treatment options for chronic dry eye

Issue: March 2003

ByJennifer Byrne

IRVINE, Calif. — The recent Food and Drug Administration approval of the dry eye drug Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) is being applauded by the ophthalmic industry as the first step toward providing new treatment options for chronic sufferers, according to clinicians.

“This is exciting, because many severe dry eye patients are just miserable,” said Peter J. McDonnell, MD, chair of the department of ophthalmology at the University of California-Irvine and a clinical investigator for Restasis. “There is a dramatic negative impact on the quality of life in those with this condition, and all we have had until now were fairly weak palliative treatments that didn’t address the underlying problem.”

Delays in approval

The FDA approval of Restasis had previously suffered several setbacks. The drug was initially denied approval in 1999, after an FDA advisory panel voiced concerns regarding its efficacy.

“Following that, Allergan received an approvable letter from the FDA basically saying that the file was approvable, but that there were still some questions outstanding on the efficacy of the drug vs. the vehicle,” said Dave Power, director of global marketing for Allergan. “And so a reanalysis of the pivotal data ensued, plus submission of some additional data.”

Mr. Power explained that Restasis is formulated in an oil-based emulsion and that such emulsion products tend to have a stabilizing effect on the tear film.

“So the vehicle was not a placebo per se, but was this oil-based emulsion vehicle, which is what the cyclosporine in Restasis is actually dissolved in,” he said. “It became very clear that the vehicle actually had a much stronger effect than was originally expected.”

This led to questions regarding the efficacy of Restasis vs. the vehicle, Mr. Power said.

“But the fact is, the Restasis performed better than the vehicle in every parameter and at every time point,” he said. “It was just a statistical problem, not an efficacy problem — the patients got enormously better. It was a comparison to this emulsion vehicle.”

Difficulty with dry eye studies

According to Dr. McDonnell, studies regarding the efficacy of a dry eye product can be difficult, both to conduct and to interpret.

“There is a real difficulty in doing dry eye studies, in choosing a measure of efficacy, because there is no single test to measure tear production,” he said. “There is no single test that seems to be predictive or that correlates very closely with the severity of the disease, at least from the patients’ perspective.”

Specific benefits of Restasis

According to practitioners, Restasis has its greatest efficacy in treating chronic, severe dry eye.

“The studies show that the expected benefit is probably the highest in severe or moderately severe patients who require frequent artificial tears and are very symptomatic,” Dr. McDonnell said. “With patients who have a milder dry eye, it is more difficult to show more obvious benefits from this medication.”

However, many patients who begin with mild dry eye end up with moderate or severe versions of the disease, Dr. McDonnell maintained. “And so one question that we need to ask ourselves is, at what point should we consider putting our patients on this treatment, so that we can prevent worsening, progression and, down the road, a severe dry eye situation?” he said.

Mr. Power said Restasis is particularly helpful in patients with an inflammatory disease that is causing their chronic dry eye. “Many people suffer from occasional dry eye symptoms but don’t have it on a chronic basis,” he said. “But others have a more chronic problem and require tear supplementation every day. There is an underlying immune-based inflammatory process associated with this.”

Off-label uses

Dr. McDonnell discussed the possible off-label uses of Restasis, although he emphasized that these ideas are speculation.

“Off-label is off-label, so what I say is best put under the heading of conjecture,” he said. “But I would conjecture that it does look like cyclosporine could be useful for other diseases where inflammation plays, or seems to play, a significant role.”

Dr. McDonnell said that atopic keratoconjunctivitis, for example, could possibly show improvement with Restasis. “I think vernal keratoconjunctivitis is something else you could look at,” he said. “Either treatment of or prophylaxis against graft rejection is also an area where cyclosporine could be helpful.”

He said conditions for which corticosteroids are currently used could also benefit from cyclosporine. “Of course, corticosteroids have known risks, and it may be that some of those conditions can be as effectively treated with the topical cyclosporine without some of the potential side effects of chronic steroid therapy,” Dr. McDonnell added.

Although Mr. Power would not directly address Restasis’ off-label uses, he does acknowledge that the drug has potential in other areas. “Cyclosporine is a well-known immunomodulator and an anti-inflammatory drug,” he said. “But, of course, we can’t promote the product for anything other than its label.”

Reactions to approval

According to Mr. Power, the approval of Restasis is a significant accomplishment for Allergan.

“This is a really great time for us,” he said. “We have worked very hard and very long with identifying therapies. We’ve worked with our research and development group to identify the underlying cause of the disease and then tailor specific therapeutics toward treating that disease.”

Henry Perry, MD, is the original clinical investigator in the Restasis phase 3, FDA trial. He reported at the recent Contact Lens and Eyecare Symposium in Orlando that the drug provides more of a long-term benefit than plugs.

“Although patients may get relief immediately with plugs, plugs do not address the pathology of the dry eye,” he said. “This drug does.” Dr. Perry added that punctum plugs also lose their effectiveness over time.

Dr. McDonnell said this drug will help patients live more comfortably and improve quality of life. “These patients, many of whom are women, are often quite young. They are at menopause,” he said. “They have long lives ahead of them. Why should they be miserable for most of that?”

For Your Information:

Peter J. McDonnell, MD, is the chair and professor of the department of ophthalmology at the University of California, Irvine. He can be reached at Department of Ophthalmology University of California, 118 Med Surge 1, Irvine, CA 92697; fax: (949) 824-7645. Dr. McDonnell is a paid consultant for Allergan.

Dave Power is director of global marketing for Allergan. He can be reached at 2525 Dupont Drive, PO Box 19534, Irvine, CA 92623-9534; (714) 246-4500; fax: (714) 246-4220.

Henry Perry, MD, can be reached at 2000 N. Village Ave., Rockville Centre, NY 11570; (516) 766-2519; fax: (516) 766-3714; hankcornea@aol.com. Dr. Perry is a paid consultant for Allergan.