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`New Thinking Spurs New Products
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`Christopher Glenn, Editor in Chief
`New Thinking Spurs New Products
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`PUBLISHED 15 FEBRUARY 2003
`
`With the market for dry-eye products already huge and growing, the need for effective
`therapy is leading to novel approaches that move beyond tear replacement. This article
`reviews some of those efforts that have come to fruition in recent product introductions.
`Restasis, at Last
`The late-December Food and Drug Administration approval of Allergan's Restasis
`(cyclosporine ophthalmic emulsion 0.5%) ended years of development, testing and regulatory
`hurdles for the company. The drug is the first therapeutic dry eye product approved and may
`have paved the way for other competitors.
`
`The product is a reflection of an evolving understanding of the dry-eye disease process.
`Restasis was designed for patients with inadequate tear production due to ocular
`inflammation associated with keratoconjunctivitis sicca. The inflammatory pathophysiology
`until recent years was thought to be limited to a small subset of dry-eye conditions.
`
`Regulatory fits and starts marked the history of Allergan's cyclosporin product, finally approved in December 2002.
`Peter McDonnell, MD, of the University of California, Irvine, who participated in the Restasis
`clinical trials, explains, "It's been known for some time that that diseases like rheumatoid
`arthritis and Sjögrens are autoimmune conditions in which lymphocytes essentially the attack
`the patient's own lacrimal gland, and there is destruction of tissue and dysfunction of the
`gland. It was thought that this was very much the exception, just one small subset of dry-eye
`patients. The data that has been generated over the last five to 10 years show is that this is
`not really a great exception, that, in fact, a very common phenomenon in a great number of
`patients with dry eye is an underlying local disorder of immunity or inflammation that causes
`this same type of lacrimal dysfunction."
`
`Michael Lemp, MD, a clinical professor of ophthalmology at Georgetown University School of
`Medicine, says the action of cyclosporin-A downregulates the inflammatory response and
`allows those cells to recover their normal activity. "By modulating the immune response,
`which sets up inflammation, [cyclosporin-A] controls the inflammatory response," says Dr.
`Lemp. "That response, particularly in the lacrimal glands, but probably also in the meibomian
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`MYLAN - EXHIBIT 1057
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc. - IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
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`New Thinking Spurs New Products
`glands of the eyelid, leads to a dysfunction of acinar cells, the secreting cells in the lacrimal
`glands that produce the aqueous portion of the tears. Those cells become dysfunctional and
`do not produce tears either of normal quantity or quality."
`
`Allergan calls the product a "partial immunomodulator," though its exact mechanism of action
`is not known.
`
`The Restasis Phase III submission was based on four multicenter, randomized, controlled
`trials of 1,200 patients diagnosed as suffering from moderate to severe keratoconjunctivitis
`sicca. The most common side effects in the trials were ocular burning (approximately 17
`percent of patients), and conjunctival hyperemia, discharge, epiphora, eye pain, foreign body
`sensation, pruritus, stinging and blurring (1 to 5 percent).
`
`It may take up to six months for the product to take full effect, though Dr. Lemp points out that
`this is "not unreasonable when you understand how it works. This is a disease process that
`takes a long time for an inflammation to develop and for the cells to become dysfunctional.
`And to restore the environment in which the cells can recover is going to take some time too."
`
`Dave Power, Allergan's director of Global Pharmaceutical Marketing, points out that the
`emulsion vehicle in which the cyclosporin is dissolved provides some comfort benefits fairly
`quickly. "Certainly in our studies we saw improvements in patient comfort at the first month
`and that continued to get better as the disease heals," he says. "We need to educate the
`doctors on how this drug works and why it takes some time for it to have its full effect. That's
`not a hard sell for the doctor to tell a patient who has been coming to his office for several
`years and not gotten the kind of relief that he's looking for to stick with this product, because
`there's really nothing else out there for him."
`
`With the addition of Endura, intended for moderate to severe cases, the Refresh line extends to all levels of dry eye.
`
`Dr. McDonnell agrees. "I've felt for some time fairly impotent in helping these patients with
`severe dry eye, whose lives are really disordered by this condition," he says. "Now to have
`something where we can finally address the underlying condition is pretty exciting."
`A New Landscape
`Dr. Lemp believes the willingness of the FDA to reconsider data based on the changing
`understanding of dry eye bodes well not just for patients and physicians, but for industry as
`well.
`
`"The data from the first two Phase III clinical trials has been available for several years and
`[Restasis] did not receive approval its first time around," says Dr. Lemp. In addition to the two
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`new trials that supported the drug's FDA submission, this approval "involved the agency's
`willingness to relook at data and reinterpret it in terms of defining efficacy," he says. "There
`has been a gradual increasing awareness that [dry eye] is a difficult nut to crack, a gradual
`recognition that has been coming on for years. So this is absolutely a positive development
`for the agency and entirely appropriate."
`
`That willingness to reconsider dry-eye data may benefit Durham, N.C.'s Inspire
`Pharmaceuticals, which is preparing to seek approval on its own product, diquafosol
`tetrasodium (INS365 Ophthalmic). One Phase II trial and two Phase III trials have been
`conducted, and a Phase IIIb trial is ongoing.
`Inspire announced in October 2002 that the NDA filing would be based on safety and efficacy
`data from the completed Phase II and Phase III trials. As well as safety and tolerability, the
`trials of INS365 have demonstrated statistically significant improvement compared to placebo
`in corneal and conjunctival staining.
`
`The content and format of a New Drug Application for the product submission were agreed to
`with the FDA in a pre-NDA meeting held in January 2003.
`"We believe this overall clinical package is strong, and we now have clarity on FDA
`requirements for the content and format of the NDA submission," said Christy L. Shaffer,
`PhD, CEO of Inspire. "Our top priority is to prepare and submit a high-quality NDA mid-year."
`New in OTC
`Another new product introduced last year extended the Refresh (Allergan) line  of tear
`supplements. Refresh Endura. Unlike the other preserved products in the Refresh line,
`Endura is unpreserved and features an emulsion formula that keeps the product active on the
`eye longer, says the company.
`
`Erika Carlucci, product manager for the Refresh line, says, "Endura is intended for the
`moderate to severe dry-eye patient, the ones who tend to go their eye doctor." She calls the
`product "a new type of technology that the over-the-counter market hasn't seen."
`
`Peter Simmons, PhD, senior scientist at Allergan R&D, explains, "The big difference is this
`oil-based emulsion and the structure of the emulsion is such that it's in a low electrolyte
`formula in the container, then when it hits the eye and interacts with the tears, the electrolytes
`in the tears cause the emulsion to break down, and that releases the oil. So the oil can then
`migrate and supplement the lipid layer in the tears."
`
`Castor oil has been shown to be effective in treating patients with meibomian gland
`dysfunction. A randomized, placebo-controlled Japanese study used a low-concentration
`castor oil mixture in 40 eyes of 20 patients (7 male, 13 female, age 52.1 ± 11.0 years) with
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`noninflamed MGD whose symptoms had not improved with conventional artificial tears,
`antibiotics, and corticosteroids.1 Nine patients demonstrated aqueous tear deficiency of
`Schirmer testing, with four of these diagnosed with Sjögren's. Excluded were patients with
`anterior blepharitis of more than moderate severity, infectious conjunctivitis, acute MGD, and
`excessive expression of meibum. For two separate two-week periods, subjects were
`randomly assigned to receive oil eye drops or placebo six times daily.
`
`Pre- and post-study examination included tear evaporation assessment, rose bengal and
`fluorescein staining, tear breakup time and a subjective patient assessment of comfort.
`Symptom scores, as well as each of the objective measures, showed significant improvement
`in the treatment period vs. the placebo period. The authors postulate several mechanisms for
`the improvement in the tear stability including lipid spreading over the ocular surface, greater
`ease of meibum expression, prevention of tear evaporation and the lubricating effect of the
`oil.
`
`Patients may notice an unusual sensation when they first encounter Endura. "When that
`emulsion breaks down, within a minute or so, some people get a sensation, a very transient
`bit of a sting, or they just notice that something is there," says Dr. Simmons. "It behaves
`differently from most eye drops that are usually very soothing initially and wear off rapidly as
`the fluid tends to drain from the eye. The oil component, we think, will reside on the lower lid,
`float on the tear fluid and stay around a lot longer."
`
`Roanoke, Va., ophthalmologist John Sheppard says he's found the solution especially
`effective for patients with lipid-deficiency dry eye, such as those with blepharitis. "It comes in
`a single-dose unit, so it's preservative free, which is great. Because it's an SDU, it's not as
`cost-effective and a little more inconvenient to use, but in many cases, it's well worth those
`minor adaptations."
`
`He's also adding it with good success to antibiotic therapy for certain patients with meibomian
`disease or rosacea. For the majority of patients who tolerate the doxycyclene he normally
`prescribes, the therapy can take a few months to be fully effective. In the interim, he says,
`Endura can provide symptomatic relief.
`
`Advanced Vision Research has added two products to its TheraTears line.
`
`The Nutritional Route
`Another approach to improving tear film composition, this one through nutritional means, is
`TheraTears Nutrition, one of two new products from Advanced Vision Research, of Woburn,
`Mass. The product contains flaxseed oil, an omega-3 essential fatty acid.
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`In the body, omega-3s are acted on to produce prostaglandin E3 and leukotriene B5. These
`two eicosanoids decrease inflammation. Omega 3s also decrease gene expression of
`proinflammatory interleukins, tumor necrosis factor-alpha and cylooxygenase, as well as
`decreasing the activity of proteoglycan-degrading enzymes.
`
`In addition, the meibomian glands use essential fatty acids in the production of the lipid
`component of the tear film, says Jeffrey Gilbard, MD, founder of Advanced Vision Research.
`He cites studies showing the polar lipid profiles of meibomian gland secretions in female
`Sjögren's patients are controlled by the dietary intake of omega-3 essential fatty acids, as
`well as clinical reports of clearer and thinner oils with omega-3 treatment. EFAs also play a
`role in inhibiting production of arachidonic acid and promoting the production of prostaglandin
`E1, which has been shown to stimulate aqueous tear production.
`
`The company has also introduced TheraTears Liquid Gel, a preservative-free, hypotonic
`electrolyte-balanced liquid gel for dry eye. The gel, for nighttime or daytime use, is designed
`to avoid lid crusting and blurred vision, according to the company. 
`
`1. Goto E, Shimazaki J, Monden, Y, et al. Low-concentration Homogenized Castor Oil Eye Drops for Noninflamed ObstructiveMeibomian Gland Dysfunction. Ophthalmology 109:11;2030-2035.
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`Copyright © 2017 Jobson Medical Information LLC unless otherwise noted.
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