3/16/2017
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`New Thinking Spurs New Products
`
`Christopher Glenn, Editor in Chief
`
`PUBLISHED 15 FEBRUARY 2003
`
`New Thinking Spurs New
`Products
`
`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
`
`A||ergan'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
`
`https://www.reviewofophtha|mo|ogy.com/article/new-lhinking-spurs-new-products
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`ALL 2036
`MYLAN PHARMACEUTICALS v. ALLERGAN
`|PR2016-01128
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`1
`
`ALL 2036
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
`
`
`
`I
`
`of
`
`J “
`
`amoo
`
`:
`
`New Thinking Spurs New Products
`
`Christopher Glenn, Editor in Chief
`
`PUBLISHED 15 FEBRUARY 2003
`
`New Thinking Spurs New
`Products
`
`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
`
`A||ergan'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
`
`https://www.reviewofophtha|mo|ogy.com/article/new-lhinking-spurs-new-products
`
`1/9
`
`1
`
`ALL 2036
`MYLAN PHARMACEUTICALS v. ALLERGAN
`|PR2016-01128
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`1
`
`ALL 2036
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
`
`
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`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 Al|ergan'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, "lt's been
`
`known for some time that that diseases like rheumatoid arthritis
`
`and Sjogrens 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
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`over the last five to 10 years show is that this is not really a great
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`exception, that, in fact, a very common phenomenon in a great
`
`number of patients with dry eye is an underlying local disorder of
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`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
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`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-
`
`] controls the inflammatory response," says Dr. Lemp. "That
`
`response, particularly in the lacrimal glands, but probably also in
`
`the meibomian glands of the eyelid, leads to a dysfunction of
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`acinar cells, the secreting cells in the lacrimal glands that
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`produce the aqueous portion of the tears. Those cells become
`
`dysfunctional and do not produce tears either of normal quantity
`
`or quality.''
`
`‘ llergan calls the product a "partial immunomodu|ator," 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,
`
`oreign 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
`
`hich the cells can recover is going to take some time too."
`
`Dave Power, A||ergan's director of Global Pharmaceutical
`
`Marketing, points out that the emulsion vehicle in which the
`
`cyclosporin is dissolved provides some comfort benefits fairly
`
`3
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`3
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`
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`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
`
`ull 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. "|'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
`
`here we can finally address the underlying condition is pretty
`
`exciting."
`
`‘ New Landscape
`
`Dr. Lemp believes the willingness of the FDA to reconsider data
`
`based on the changing understanding of dry eye bodes well not
`
`'ust 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 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
`4
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`4
`
`
`
`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 (lNS365
`
`Ophthalmic). One Phase II trial and two Phase III trials have
`
`been conducted, and a Phase lllb 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
`
`lNS365 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
`
`‘ nother new product introduced last year extended the Refresh
`
`(Allergan) line of tear supplements. Refresh Endura. Unlike the
`5
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`5
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`
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`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 i 11.0 years)
`
`ith 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 Sj6gren's. Excluded
`
`ere patients with anterior blepharitis of more than moderate
`
`6
`
`6
`
`
`
`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 theyjust notice that something is there," says Dr.
`
`Simmons. "|t 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
`
`7
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`
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`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.
`L
`LIA
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`L
`LIA
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`Advanced Vision Research has added two products to its TheraTears line.
`
`The Nutritional Route
`
`‘ nother 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.
`
`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.
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`3/16/2017
`
`New Thinking Spurs New Products
`
`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 Sjogren'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.
`
`Copyright © 2017 Jobson Medical Information LLC unless othenNise noted.
`
`All rights reserved. Reproduction in whole or in part without permission is prohibited.
`
`https://www.reviewofophthalmology.com/article/new-thinking-spurs-new-products
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