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`and produced more mucin, and there was a decrease in the inflammatory markers in the conjunctiva, indicating that there was
`significant increase in the numbers of goblet cells, indicating that the patients who received cyclosporine made more goblet cells
`"From a pathologic perspective, the most exciting finding was that when the conjunctival biopsies were performed there was a
`
`less inflammation there," he added.
`McDonnell
`Dr.
`
`Centre, NY, and associate professor of ophthalmology, New York University Medical Center, New York.
`controls," said Dr. Donnenfeld emphasized. He is also a founding partner of Ophthalmic Consultants of Long Island, Rockville
`and more importantly, there was a global improvement in the patients' assessment of their dry eye symptoms compared with the
`cyclosporine had more tear production documented by increased Schirmer scores, decreased corneal and conjunctival staining,
`"In the more than 800 patients who participated in the Restasis study, a statistically significant number of patients who received
`Donnenfeld
`Dr.
`
`according to Eric D. Donnenfeld, MD, a principal investigator in the multicenter Restasis study.
`dry eye resulting from ocular inflammation, because it is the only therapy that increases tear production and tear quality,
`Therapy significance Cyclosporine is eagerly awaited by members of the ophthalmic community who treat patients with chronic
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`controls.
`treatment to detect inflammatory cells; the results with the two concentrations of cyclosporine were then compared with the
`efficacy of cyclosporine. A small subgroup of patients underwent biopsy of the conjunctiva before and after 6 months of
`The frequency of the use of adjunctive artificial tears to relieve dry eye symptoms was also recorded as a measure of the
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`breakup time tests were repeated at each follow-up visit.
`of the severity of the dry eye at 1, 3, and 6 months after the onset of treatment. Schirmer tests, corneal and conjunctival staining, and tear
`Investigators were masked as to which eye drop the patients instilled twice daily for 6 months. The eyes were evaluated by global assessment
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`eye was defined as the presence of corneal staining, Schirmer scores less than 5 mm, and frank conjunctival and corneal staining.
`concentrations of cyclosporine (0.1% and 0.05%) that were compared with a novel lipid emulsion vehicle (placebo). Moderate to severe dry
`
`The three-arm study of cyclosporine for the treatment of dry eye began about 5 years ago and included two
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`commercially available this spring.
`inflammatory process that causes the condition, and not just its symptoms. Allergan estimates that the product will be
`ophthalmology. The eye drop therapy for moderate to severe keratoconjunctivitis sicca is unique in that it treats the
`The FDA approval of cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan) Dec. 26 marked a landmark for
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`Increased tear production: Restasis approval a milestone for dry eye
`OphthalmologyTimesClinical Pharmacology
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`2/27/2017
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`By Lynda Charters
`February 01, 2003
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`ALL 2040
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
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`progression."
`production when patients reach age 30 to detect early manifestations of dry eye disease, when we have a window of opportunity to prevent
`women, especially, to develop severe debilitating disease, with significant limitation of quality of life. Perhaps we should be testing tear
`and dryness have been allowed to progress. We should consider intervening much earlier in the process, instead of waiting for postmenopausal
`patients who are perhaps considered to have 'mild' or 'moderate' dry eye, but who have been suffering for a long time and the inflammation
`"I believe that historically we have waited far too long to diagnose dry eye disease and treat our patients," he added. "We are now treating
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`the need for treatment or be able to taper the treatment so that they no longer have to use the drug twice a day.
`possible to eliminate the inflammation completely, my hope is that some patients will experience a 'cure.' I hope we will be able to eliminate
`without cyclosporine," Dr. McDonnell said. "I think this result may depend on the point in the disease at which we begin to treat. If it is
`"Although the trial did not allow this type of experimentation, after patients completed the study some reported that their condition stabilized
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`patients rather than having to be used chronically.
`An interesting result of this study, but one whose ultimate outcome is presently unknown, is that cyclosporine may cure dry eye in some
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`lymphocytes to pass through the lacrimal gland and not cause damage, Dr. Donnenfeld explained.
`lacrimal gland instead aggregate in the gland and cause inflammation. Cyclosporine reverses the inflammatory process and allows
`The mechanism by which cyclosporine improves tear production is unclear. In dry eye the lymphocytes that normally pass through the
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`herpetic disease because of the drug's possible effect on lymphocytes. Herpetic disease was an exclusion criterion for these trials.
`study for this reason, because the positive effect of the drug was substantial. He also noted that the drug is contraindicated in patients with
`Dr. McDonnell pointed out that despite that fact that many patients reported stinging and burning upon instillation, none of his patients left the
`
`Cyclosporine is not known to cause cataract or infections, and it does not inhibit wound healing.
`conjunctival hyperemia, discharge, epiphora, eye pain, foreign-body sensation, pruritus, stinging, and visual disturbance (mostly blurring).
`The drug appears to be very safe; 17% of patients reported transient ocular burning after instillation of the drops, and from 1% to 5% reported
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`Dr. McDonnell noted that 75% to 80% of patients who received cyclosporine had improvement.
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`said. "Unfortunately, there is no single test that is considered the single standard for patients with dry eye and the results can vary."
`"In addition, our patients typically had less corneal staining, and in some patients the Schirmer test scores actually increased substantially," he
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`and at the end of the study wanted to continue receiving cyclosporine.
`McDonnell said. "Other measures of efficacy were that a high percentage of our patients generally believed that their condition had improved
`"One measure of efficacy of Restasis was the less frequent use of adjunctive tears, which was certainly apparent in many of our patients," Dr.
`
`the University of California, and a control group of patients received the placebo formulation.
`PhD, and Ramin Pirnazar, MD, principal investigator, tested cyclo-sporine according to the same or similar protocols in about 100 patients at
`Peter J. McDonnell, MD, professor and chair, department of ophthalmology, University of California, Irvine, and colleagues Roy Chuck, MD,
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`equivalent to the advent of phacoemulsification or antiviral therapy."
`"Restasis allows patients to make their own physiologically normal tears," he said. "The availability of this drug is a landmark event that is
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`treatment of chronic dry eye disease."
`pleased about the ability to address this unmet need of both patients and ophthalmologists by offering the first therapeutic option for the
`"This is a culmination of Allergan's research and development team's pioneering work in the field of ocular surface disease. Allergan . . . is
`"Allergan is very excited about the FDA approval of Restasis," said Lester J. Kaplan, PhD, president/research and development, Allergan.
`
`ophthalmologists. He said Allergan will be working closely with patient support groups.
`of dry eye disease in the general public and the availability of cyclosporine so that individuals with symptoms can seek help from
`be marketed to physicians in March and April, but not directly to consumers. Public relations initiatives are being planned to raise awareness
`Marketing approach Regarding marketing, David Power, director of global pharmaceutical marketing, Allergan, explained that the drug will
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`tear supplementation."
`of this drug acknowledges for the first time that dry eye is an inflammatory disease that should be treated with immunomodulation and not just
`"For the first time, we can offer these patients a drug that might reverse their dry eye and help resolve the disease," he concluded. "The advent
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`millions of patients in the United States have dry eye.
`"Dry eye is one of the most common and debilitating diseases that ophthalmologists see in clinical practice," Dr. Donnenfeld said. "Tens of
`
`Dr. McDonnell is eager to begin treating his patients with dry eye who did not meet the inclusion criteria.
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`aggressively, with twice-daily dosing. More patients need to be tested to answer these questions."
`Perhaps the dose could be decreased to once daily in some patients, but those with especially severe disease might have to be treated
`Dr. McDonnell said. "The dosing may have to be adjusted and there is a question about whether the drop would last as long in the tear film.
`"Intuitively, Restasis should be effective in these patients, but it has not specifically been established to be safe and effective in these patients,"
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`Dr. McDonnell also pointed out that the efficacy of cyclosporine was not assessed in patients with punctal plugs.
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`becomes fibrotic and not sustainable."
`reverse the process and allow the patient to produce his or her own tears. We do not want to postpone treatment until the lacrimal gland
`"Patients should be treated with cyclosporine at the onset of the development of dry eye. In the early acute inflammatory process, Restasis can
`"I believe that the patients who are the best candidates for treatment with cyclosporine have not yet been identified," Dr. Donnenfeld said
`
`Dr. Donnenfeld echoed that sentiment.
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