`
`I
`
`of
`
`J “
`
`amoo
`
`:
`
`Give Dry Eye a One-two Punch
`
`Mark B. Abelson, MD and Jason Casavant
`
`PUBLISHED 15 MARCH 2003
`
`Give Dry Eye a One-two
`Punch
`
`Many treatments for dry eye have failed to rise above simply
`
`being palliative. However, a new generation of longer-lasting and
`
`more effective agents is emerging to help. Two of these new
`
`treatments, Restasis (Allergan) and Systane (Alcon) will make
`
`their debut this spring. Here is a look at them.
`
`Restasis Arrives
`
`Dry eye is common, especially among the elderly, where it has
`
`been estimated to affect 4.3 million Americans aged 65 and
`
`older.‘ However, everyone has experienced its symptoms.
`
`Previously, the predominant treatment strategy for dry eye
`
`focused upon replacing tears, and was rooted in simplistic
`
`notions of dry eye's causes. Over the last few decades,
`
`researchers have investigated the mechanisms of dry eye. As a
`
`result of this research, they have sought remedies to the disease
`
`based on new knowledge of its mechanisms.
`
`This research bore fruit when Allergan received approval from
`
`https://www.reviewofophtha|mo|ogy.com/articlelgive-dry-eye-a-one-two-punch
`
`1/12
`
`1
`
`ALL 2037
`MYLAN PHARMACEUTICALS v. ALLERGAN
`|PR2016-01129
`
`1
`
`ALL 2037
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01129
`
`
`
`the U.S. Food and Drug Administration for Restasis
`
`(cyclosporine ophthalmic emulsion, 0.05%) in December of 2002.
`
`This Cyclosporin A (CsA) emulsion is the first treatment in what
`
`could be an expanding arsenal of prescription dry-eye therapies.
`
`It's indicated to increase tear production in patients whose
`
`production is presumed to be suppressed due to ocular
`
`inflammation associated with keratoconjunctivitis sicca? In its
`
`trials, researchers didn't find tear production in patients taking
`topical anti-inflammatory drugs or who had punctal p|ugs.2
`
`.:
`
`Restasis is sterile and preservative-free? The dosage regimen is
`
`b.i.d. and it can be used concomitantly with artificial tears? Its
`
`active ingredients include cyclosporine 0.05%. Its inactive
`
`ingredients are glycerin, castor oil, polysorbate 80, carbomer
`
`1342, purified water and sodium hydroxide? The most frequently
`
`reported adverse event with Restasis is ocular burning (17
`
`percent)?
`
`The indication for Restasis is based upon four multicenter
`
`studies of 1,200 patients with moderate to severe
`
`keratoconjunctivitis sicca. Restasis showed statistically
`
`significant increases over vehicle in Schirmer's strip wetting of 10
`
`mm? This increase was seen at six months in a population who
`
`presumably suffered from suppressed tear production due to
`
`inflammation? The increases in Schirmer's strip wetting were
`
`seen in 15 percent of Restasis treated patients compared to only
`
`2
`
`
`
`5 percent of vehicle-treated subjects.2
`
`Restasis was developed to address dry-eye's inflammatory
`
`cascade. The exact workings of this inflammation are still being
`
`examined, but researchers believe that it involves the activation
`
`of the immune response, release of inflammatory mediators and
`
`apoptosis. Unchecked, the cascade can destroy the lacrimal
`
`glands?
`
`In this cascade, the surface of the eye is irritated. When the tear
`
`reflex is inadequate at minimizing the irritation, the nervous
`
`stimulation triggers a mechanism of regulation and repairf‘ T-cells
`
`residing within the ocular surface and its contributory structures,
`
`such as the lacrimal gland, become activated and release
`
`cytokines that can damage host tissues. This affects the quality
`
`and quantity of tears and may affect the neural connections that
`
`drive reflex tearing.“ These effects cause more damage,
`
`resulting in the activation of more T-cells, generating an
`
`inflammatory response that can kill the lacrimal glands and
`
`conjunctival epithelium.4
`
`The exact mechanism of action for Restasis is unknown, though
`
`it's believed to be a partial immunomodulator. The agent possibly
`
`limits T lymphocyte activation by inhibiting the expression of
`
`HLA-DR and other signals that activate the T lymphocytes.5 By
`
`affecting the activation of T-cells, Restasis can modulate
`
`inf|ammation.5
`
`3
`
`
`
`Restasis also is believed to be an anti-inflammatory, by
`
`preventing T-cells from releasing cytokinese Inhibiting cytokine
`
`release leaves the tissue of the lacrimal glands and the ocular
`
`surface intact and prevents further triggering of T lymphocytes by
`
`cytokines.” By affecting the inflammatory cascade, the ocular
`
`surface and the lacrimal gland both recover, promoting normal
`
`tear production.
`
`- Remaining questions. The approval of Restasis as the first
`
`prescription medication for the therapy of the underlying
`
`inflammation associated with chronic dry eye is an important first
`
`step in the development of dry-eye therapies, though it's not the
`
`end of the line. Once Restasis becomes available to physicians,
`
`some questions must be addressed. For example, how does the
`
`clinician identify who would best benefit from the therapy? The
`
`answer is unclear. The subject population during the Phase III
`
`clinical trial was diagnosed as having moderate to severe dry-
`
`eye disease based upon questionnaires, Schirmer's strip wetting
`
`and corneal surface stainingf’ These are commonly used
`
`diagnostic tools of clinical practice. However, only 15 percent of
`
`those subjects selected by these diagnostic criteria and who
`
`received the Restasis formulation had the relevant increase in
`
`Schirmer's strip wetting.
`
`Clinicians should consider additional, and perhaps more
`
`sensitive, diagnostic tests, since we know Schirmer's test can
`
`4
`
`
`
`lack sensitivity. In fact, Michael Lemp, MD, of George
`
`Washington University has suggested taking multiple Schirmer's
`
`in a patient to get a clearer idea of tear production over time. And
`
`Claes Dohlman, former chief of ophthalmology at the
`
`Massachusetts Eye and Ear Infirmary, has suggested ignoring
`
`the reading completely. Since Restasis is thought to act as an
`
`anti-inflammatory, perhaps testing for the presence of some of
`
`the more pronounced dry eye related inflammatory markers like
`
`IL-6 is a necessary step. According to the FDA, the clinical
`
`relevance of such testing still remains to be seen.
`
`‘ nother incentive for us to use better techniques to identify the
`
`best patient population to receive treatment is that Restasis
`
`takes six months to improve Schirmer's strip wetting.
`
`It's also important to consider that 17 percent of the patients
`
`experienced ocular burning, while only 15 percent had a
`
`treatment effect. Before initiating at least a six-month course of
`
`treatment, the clinician should consider whether it's the best
`
`treatment strategy to risk adding discomfort to already moderate
`
`or severe dry eyes without ensuring a better than 15 percent
`
`chance of an effect. In the face of the diagnostic challenges, the
`
`clinician should recommend the patient use artificial tears with
`
`Restasis during the initial six months.
`
`Systane
`
`‘ lso preparing to debut this spring is Systane, a novel sterile
`
`aqueous tear solution preserved with Polyquad, a preservative
`
`5
`
`
`
`many think is safer to the corneal epithelium than benzylkonium
`
`chloride (BAK).9 Polyquad preserves a formulation that includes
`
`monograph demulcents, potassium, calcium, magnesium,
`
`sodium and 0.18% hydroxypropyl guar (HP-guar). Since these
`
`are monograph ingredients, or ingredients that the government
`
`allows to be mixed in any amount to create a new agent, Systane
`
`didn't require an FDA trial for approval. The Systane dry-eye
`
`therapy promotes a healthy corneal epithelium by prolonging tear
`
`film dwell time, maintaining a protective ocular shield.
`
`Rather than replacing tears, Systane integrates with the tear film
`
`by using HP-guar as a gelling agent. A water-soluble
`
`polysaccharide even in low concentrations, natural guar
`
`galactomannan causes increased viscosity when dissolved in
`
`solutions. HP-guar is derived from natural guar galactomannan
`
`treated with propylene oxide.” The HP-guar derivative maintains
`
`many of the essential properties of natural guar, but is more
`
`soluble.“
`
`The properties of HP-guar are what place Systane in the new
`
`generation of treatments. When administered topically to the eye,
`
`HP-guar binds to the hydrophobic surface. It also binds to the
`
`borate in the Systane formulation, so that when Systane interacts
`
`ith the pH of the ocular surface, which is approximately 7.4”‘ a
`
`network with a soft, gelatinous consistency is formed. The
`
`increased viscosity of the gelatinous network improves
`
`6
`
`
`
`lubrication, inhibiting mechanical destruction of the ocular
`
`surface. Furthermore, the crosslinking of HP-guar and borate
`
`preferentially adheres to disrupted epithelial cells, so the dwell
`
`time of the highly viscous gelatinous network is improved. These
`
`properties promote corneal and conjunctival healing.
`
`In a comparative environmental trial conducted by Alcon against
`
`a leading tear substitute, Systane reduced the signs and
`
`symptoms of dry eye. In the 87-patient trial, it demonstrated a
`
`very good safety profile and was well-tolerated. Six-week
`
`treatment with Systane reduced conjunctival staining and trends
`
`ere seen towards the reduction in corneal staining. Systane
`
`also demonstrated statistically significant reduction in morning
`
`dryness, end-of-day dryness and foreign body sensation.
`
`Restasis and Systane complement each other. While Restasis
`
`may take six months to show efficacy and is sometimes
`
`accompanied by burning, Systane is well-suited to address
`
`comfort, and dwells long enough to prevent irritation as Restasis
`
`inhibits inflammation. This two-pronged treatment also hedges
`
`against the possibility that Restasis might not be effective in
`
`individual dry-eye patients. Clinicians will ultimately evaluate
`
`these products in their patients, which will establish the agents‘
`
`roles.
`
`Dr. Abelson, an associate clinical professor of ophthalmology at
`
`Harvard Medical School and senior clinical scientist at Schepens
`
`7
`
`
`
`Eye Research Institute, consults in ophthalmic pharmaceuticals.
`
`Mr. Casavant is a clinical researcher in the dry-eye department a
`
`Ophthalmic Research Associates in North Andover.
`
`1. Schein OD, Mu-oz B, Tielsch JM, et al. Prevalence of Dry Eye Among the Elderly. AmerJ of Ophthalmol 1997;124: 723-728.
`
`2. Restasis package insert. 2002 Allergan, Inc.
`
`3. Baudouin, C. The Pathology of Dry Eye. Surv Ophthalmol 2001;45:S211-S220.
`
`. Stern ME, Beuerman RW, Fox RI, et. al. A Unified Theory of the Role of the Ocular Surface in Dry Eye. In: Lacrimal Gland, Tear Film, and Dry Eye Syndromes
`
`2. Sullivan D, ed. Plenum: New York 1998. 643-651.
`
`5. Kunert KS, Tisdale AS, Stern ME. Analysis of topical cyclosporine treatment of patients with dry eye syndrome. Arch Ophthalmol 2000;118:1489-1496.
`
`6. Turner K, Pflugfelder SC, Ji 2, et. al. Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporine ophthalmic
`
`emulsion. Cornea 2000;19:4: 492-496.
`
`7. Rosenbaum JT, Brito B, Han YB, et. al. Cytokines: An Overview. In: Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2. Sullivan D, ed. Plenum: New York,
`
`1998. 441-446.
`
`8. Sail K, Stevenson OD, Mundorf TK, et. al. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to
`
`severe dry eye disease. Ophthalmol 2002;107:4: 631-639.
`
`9. Lopez B, Ubel J. Quantitative evaluation of the corneal epithelial barrier: effect of artificial tears and preservatives. Curr Eye Res 1991;10:7:645-56.
`
`10. Cheng Y, Brown KM, Prud'homme RK. Characterization and intermolecularinteractions of hydroxypropyl guarsolutions. Biomacromolecules 2002;3:456-
`
`A 61.
`
`11. Khurana AK, Chaaudhary R, Ahluwalia BK, Gupta S. Tearfilm profile in dry eye. Acta Ophthalmologica 1991;09:1:79-86.
`
`The Side Effects of Losing a Drug Patent
`
`Mark B. Abelson MD, FRCS (C)
`
`The expiration of a drug's patent has many implications. Though
`
`some of these effects may be beneficial in the short term, there
`
`could be others that are bad in the long run. An example of how
`
`8
`
`
`
`these effects can play out is the recent experience of Schering-
`
`Plough and its $3 billion-per-year anti-allergy drug Claritin, which
`
`lost its patent in 2002.
`
`‘ fter Schering was denied C|aritin's patent extension, it was
`
`allowed to sell the drug over the counter. As the company works
`
`to keep the drug profitable, the atmosphere in pharmaceuticals is
`
`one of intense competition from generic antihistamines, more
`
`conservative attitudes on drug development from Congress and
`
`money-saving tactics from managed care.
`
`In the short term, consumers benefit from a drug's over-the-the
`
`counter availability. However in the future, withdrawing a patent
`
`decreases the number of R&D dollars available to a drug's
`
`maker to re-invest in the development of new drugs. And, as
`
`these dollars diminish, a pharmaceutical company needs more
`
`time to develop drugs. The slowing of the new drug development
`
`process could ultimately be detrimental to consumers.
`
`- Managed care's response. An interesting effect of C|aritin's
`
`OTC status is the decision of some managed-care groups to
`
`deny the use of all other systemic antihistaminics that had been
`
`developed after Claritin, and may even have benefits that
`
`surpass it. Despite the fact that these medications are in the
`
`same class as Claritin, they may not even be on a managed
`
`care's formulary. And if they are on a formulary, a plan's
`
`subscribers are sometimes faced with co-payments of up to $50
`
`for them. Clearly, this is a case of managed care attempting to
`
`tighten its purse strings by dropping the agents.
`
`- Systemic antihistamines extend their claims. With Claritin off
`
`9
`
`
`
`patent, there's the question of how the remaining antihistamines
`
`in the prescription market will respond. Under pressure, they're
`
`scrambling to find a niche in the market to which they have no
`
`real claim. This is behind the recent proliferation of misguided
`
`advertising for agents like Allegra (Aventis), in which the drug is
`
`positioned as adequate for ocular allergy. Such ads are making
`
`unsubstantiated claims of ocular efficacy as a way to differentiate
`
`the drugs and maintain their positions on managed-care
`
`formularies. These claims must seem specious to readers of
`
`both this column and the ophthalmic literature in general, as well
`
`as to those with experience in treating ocular allergy, since no
`
`systemic antihistaminic has ever worked well enough to receive
`
`approval for an ophthalmic indication from the FDA. By utilizing
`
`summed scores of itching, redness and tearing, as well as vague
`
`complaints gleaned from large studies, however, systemic
`
`antihistamines have obtained subtle differences between each
`
`other as far as ocular allergy is concerned. These differences,
`
`though real, don't reach the level of clinical relevance that we
`
`practitioners and the FDA Ophthalmic Division would require for
`
`the approval of an allergic drug such as Patanol, Zaditor,
`
`* lamast and Alrex.
`
`Not only don't the systemic agents work on ocular allergy, but
`
`they all produce ocular drying with a 50-percent decrease in tear
`
`flow and volume.1,2 Tear-film reductions translate into loss of
`
`barrier protection, diluent effect and an inadequate wash over the
`
`eye. The tear film is therefore critical not only in dry-eye patients,
`
`but also in patients with allergy.
`
`10
`
`
`
`The optimal therapy to treat the ocular component of allergy for
`
`patients with rhinoconjunctivitis is a topical drop. Research
`
`shows that nasal symptoms can also be reduced by topically
`
`treating the eye.3,4 Eyedrops and steroid nasal sprays, used in
`
`combination, are superior against allergic rhinitis when compared
`
`to systemic allergics used in combination with a spray.5 Also,
`
`drops alone are superior to systemic agents for ocular allergy.6-8
`
`Only with a drop do you get the highest concentrations of drug
`
`and the appropriate pharmacokinetics to deliver the maximum
`
`amount of antihistaminic and mast cell stabilizing effects.
`
`Issues of legislative or economic concern should be superceded
`
`by the question of proper selection of agents for patients based
`
`on efficacy. For these studies alone and in total, topical treatment
`
`for ocular allergy is better. It will be interesting to see how the
`
`story unfolds as the might of the managed care formularies runs
`
`head on into clinical reality.
`
`1. Nally L, Emory TB, Welch DL. Ocular drying associated with oral antihistamines (loratadine) in the normal population -effect on tear flow and tear
`
`olume as measured by fluorophotometry. ARVO 2002, Abstract No. 92.
`
`2. Gupta G, Ousler GVlI, Pollard SD, Abelson MB. The comparative ocular drying effects between Claritin and Zyrtec in normal adults. ARVO 2002,
`
`3. Abelson MB, Turner FD, Amin D. Patanol is effective in the treatment of the signs and symptoms of allergic conjunctivitis and allergic
`
`rhinoconjunctivitis. Invest Ophthalmol Vis Sci. 2000;41(S): 4922.
`
`4. Crampton HJ. A comparison of the relative clinical efficacy ofa single dose of ketotifen fumarate 0.025% ophthalmic solution versus placebo in
`
`inhibiting the signs and symptoms ofallergic rhinoconjunctivits as induced by conjunctival allergen challenge. Clinical Therapeutics 2002;24:11:1800-
`
`08.
`
`5. Lanier BQ, Abelson MB, Berger WE, Granet DB, D'Arienzo PA, Spangler DL, Kagi MK. Comparison of the efficacy of combined fluticasone propionate
`
`and olopatadine versus combined fluticasone propionate and fexofenadine for the treatment of allergic rhinoconjunctivitis induced by the conjunctival
`
`11
`
`
`
`3/16/2017
`
`Give Dry Eye a One-two Punch
`
`allergen challenge. Clinical Therapeutics 2002;24:7:1161-74.
`
`6. Abelson MB, Welch DL. An evaluation of onset and duration of action of Patanol (olopatadine hydrochloride ophthalmic solution 0.1%) compared to
`
`Claritin (loratadine 10 mg) tablets in acute allergic conjunctivitis in the conjunctival allergen challenge model. Acta Ophthalmol Scand 2000:78:60-63.
`
`7. Abelson MB, Kaplan AP. A randomized, double-blind, placebo-controlled comparison ofemedastine 0.05% ophthalmic solution with loratadine 10 mg
`
`and their combination in the human conjunctival allergen challenge model. Clinical Therapeutics 2002;24(3):445-56.
`
`8. Crampton HJ. An evaluation of the efficacy of ketotifen fumarate 0.025% ophthalmic solution compared to desloratadine 5 mg compared to ketotifen
`
`fumarate 0.025% ophthalmic solution used with desloratadine 5 mg in inhibiting the signs and symptoms of seasonal allergic rhinoconjunctivitis in the
`
`allergen challenge model [in press].
`
`Copyright © 2017 Jobson Medical Information LLC unless otherwise noted.
`
`All rights reserved. Reproduction in whole or in part without permission is prohibited.
`
`https://wwwreviewofophthalmology.com/article/give-dry-eye-a-one-tvvo-punch
`
`1 2
`
`12/12
`
`12
`
`