Conjunctival Allergen Challenge:
`Models in the investigation of
`Ocular Allergy
`
`Marla B. Abelson, M D, and Oliver Loefjler
`
`Address
`Ophthalmic Research Associates. 863 Turnpike Street. North Andovet:
`MA O|845. USA.
`E-mail: mbabelson@otaclinicalcom
`Current Allergy and Asthma Reports 2003. 3:363~368
`Current Science Inc. ISSN “329-7322
`Copyright © 2003 by Current Science lnc.
`
`Recently. the number of agents to treat ocular allergy has
`increased dramatically. from three (pheniramine. antazoline.
`cromolyn) to more than a dozen. A general increase in the
`incidence of atopy in recent years and the fact that patients
`are becoming less tolerant of bothersome signs and symp—
`toms have been driving forces in this increase. As visual
`tasking, such as reading and working on a computer. has
`become more prevalent. there is an increased awareness of
`ocular allergy and the impact it has on quality of life and
`productivity at work and school. VWth the need for more
`effective medications the development of models. such as
`the conjunctival allergen challenge (CAC). has made the
`identification of new agents more efficient. In this article,
`we review the relevant background on the science behind
`allergen challenges in the eye. how models are designed.
`and how models are used in the field today.
`
`Introduction
`it
`is estimated that as many as Rtl million .-'\lilt‘llt'.l|15 are
`alilccted hy octtlar allergy—almost 23% (ii the population
`
`I]. Ul'the lottr types ol‘ allergic coniunctivrtis (atopic
`keratoconiunctivitis. vernal le‘l‘alUCUltiUHCthlIl8, sea
`sonal/pcrennial allergic conjunctivitis (SAC/PAC), and
`drugindttced allergic conjunctivitis). the most prevalent
`lin'ms are SM), triggered by pollens, and PM? triggered by
`dust or dander. [he botherscnnc signs and symptoms
`caused by ocular allergy will cause signilicant decreases in
`quality of lite and ability to l'ttnction, sleep problems,
`decreased ability to visual task, and eliects on social inter,
`actions, all leading to missed time at work, owing to visits
`to the doctor’s office, and decreased productivity. 'l'herc-
`lore, it
`is important not only that therapeutic modalities
`he developed lot ocular allergic sufferers, bttt also that the
`model or methods by which these treatments are identie
`
`lied and tested be accurate and reliable. In the pursuit ol‘
`elilcctiyc therapies,
`the toniunctival allergen challenge
`(ti/\(Il model has been developed. This model has
`allowed precise control ol' conliounding lactors that are
`present in the typical environmental study and has
`helped to evaluate and bring to market ellective medicar
`tiotts tor ocular allergy. Ihe model has also been very
`Ltsel'ul in elucidating the allergic and inllaminatory meclr
`anistns ol' the ocular surface,
`in identiliying the cells and
`mediators that are involved, and in identifying targets tor
`novel therapies. In this artit le, we review the (LN; modcl,
`compare it with the environmental tlt‘sign, and look at
`how it has” ltclpt‘tl contribute litrtlier understanding to
`ocular disease and therapy,
`
`Basic Science of‘ the (Iloniunctival
`(.lhallenge Model
`Olitliosc who suffer from ocular allergic conditions. at
`least {MW/u stiller lrom S.-v'\(L/'l‘1\tl,
`'I hese diseases are trigL
`geted when an allergen comes in contact with coniunctivai
`mast cells containing lgl'. molecules bound to thc cytoplasr
`
`mic tuemln'anc.
`l‘hc crosseliuking of pairs of lgl“. molcctt es
`With allergen initiates a cascade oi intercclhtlar changes
`that result in mastlccll degranulalion. Understanding the
`host olisuhstances released, and how they interact, has
`been driven by use of challenge models.
`Vitrious mediators and cytokines are released from the
`mast cell during degranulation, leading to the clinical signs
`and symptoms oilallcrgy and the propagation ot'the reaction
`(‘l'able I). The primary inflammatory mediator released
`during this process is histamine. as continued by a series ol
`studies [273.60-|. lnstillatiou olihistamine into the eye repro—
`duces in a dose-dependent fashion the signs and symptoms
`ot'allcrgic conjunctivitis: itching, redness, chemosis, tearing,
`and lid swelling. In lact, histamine is the only mediator that
`can reproduce the entire clinical allergic condition in the eye
`|2|. ! urtl'iermorc‘, instillation ol'substanccs known to induce
`degranulalion ol' mast cells (secretagogues) and the release of
`histamine also produce the allergic condition in both animal
`and human eyes |3|. lhe collection of histamine in tears is
`dillicult, however, because the enzyme histaminase is also
`released during mastecell degranulation and works to hrea k
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`|PR2018—01020 and |PR2018—01021, Exhibit 1025, Page 1
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`364
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`Ocular Allergy
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`—_————-—
`
`Table l. Mediators released by the mast cell
`’_—___——
`Preformed mediators
`Histamine
`Chymases
`Heparin
`Proteoglycans
`Newly formed mediators
`Leukotriene B4
`Leukotriene C4. D4, E4
`Prostaglandin D2
`Platelet—activating factor
`Masc—cell—derived cytokines/
`chemokines
`TNF-ti
`|L-lB. |L-3, lL—4.
`lL—ltt.
`|L-6. |L-I0
`MCP
`Interferon-y
`Gmnulocyte-macrophage
`Macrophage-inhibitory
`
`protein colony-stimulating factor
`
`Trypcases
`Serine proteases
`Carboxypeptidase A
`
`Thromboxanes
`HHT
`HPE—l'E/HETE
`
`Eotaxin
`RANTES
`
`lL—S.
`
`
`
`(Loniunctival challenges have also been used to identify
`other mediators that are present in allergic patients.
`'l‘ryptase is a good marker for mast-cell degranulation as the
`mast cell is the only cell in the body that contains this netr
`ropeptidase, ‘l'ryptase levels were found to be increased in
`patients who were symptomatic with SAC and in patients
`after challengingthe conjunctiva with allergens, compound
`48/80, and mechanical rubbing [l0|. implications of this
`study were twofold: it showed that tryptase is a good
`indicator of mastvcell degranulation, and it Showed that
`conjunctival challenges can be used to induce mast-cell
`degranulation. Studies in which the conjunctiva was chal—
`lenged with allergen have shown increases in histamine,
`kinins, prostaglandins, albumin, and ’li\t\lli—esterase [tolu—
`ene—sulfoetrypsin-arginine methyl ester) Ill I; leukotr'ienes
`H4, (.74, D4, and lit |l2j; eosinophil cationic protein (lZCl’)
`[13|; and histaminase l l4|. An understanding olthe release
`of histarninase, the enyyme that breaks down the released
`histamine, following a conjunctival challenge is especially
`important in understanding the time course oisigns and
`symptoms. The challenge models have also been used to
`study ellccts that occur on the epithelium in allergic dis-
`eases. lor example, it has been shown that conjunctiva] epi-
`thelium expresses intracellular adhesion molecules [lCAtvt
`l) lollowirrg challenge | 15].
`During the acute allergic reaction, there are many
`chemotactic factors released from the mast cell; the actual
`cellular inliltrate that would be expeclt‘d to subsequently
`occur in the eye is more ambiguous, Some of. the mediators
`released from the mast cell, such as PAIL llllt‘l'lt‘llklIt-S,
`lil'liui, PUDZ, anti tumor necrosis factor [‘I‘Nl“), Will lK’lP 10
`recruit leukocytes, lympl‘roqrtes, and more mast cells in the
`conjunctiva. However, usually only high doses ofallergen
`in a challenge test will provoke cellular infiltrate ol‘eosino-
`phils, neturophils, basophils, lymphocytes. and mast cells
`in selected patients j16|, with ranges of It) minutes to 6 to
`24 hours lollowing challenge. lr’urtherrnore, not all patients
`have cellular inliltrate in their environment, and SAC gene]:
`ally occurs in the absence of cellular recruitment 1 1700,18],
`A second pealc (or continuation of the acute phase) in
`symptoms has been demonstrated during this late phase at
`(a h |l‘)| lollowing a conjunctival challenge with high doses
`ol' allergen. ‘l‘his reaction at 6 h was accompanied by
`increased histamine and eosinophil cationic PFOIt’ili levels
`(l‘,(.‘,l’ereleased from eosinophils), and upregulated adher
`sion molecules, as compared with pie-challenge baseline
`values [ZtJ-j. Although mast—cell numbers were increased in
`this latter study, interestingly tryptase levels were not during
`this late time point, indicating a potential role for cells
`other than mast cells {such as basophils) during this late
`phase. However, it is important to mention that infiltrate in
`general is not correlated with an increase in clinical signs
`and symptoms, and although an increase might be seen fol-
`lowing CACs on the cellular level, this does not necessarily
`reach the clinical threshold necessary to induce signs and
`symptoms. Nonetheless, the study oi cellular infiltrate is
`
`.:_..c_—
`
`
`
`HETErihydroxyelcosatetraenoic acrd; HHTihydroxyheptadeca-
`U‘ienorc acrd: HPETE-bydroperoxyeicosatetr'aenoic acid:
`ng-interleukin: MCPimouocyte chemozrtrractant protein;
`RANTEsi regulated on activation. normal T-cell expressed and
`secreted: TNFirumor necrosis faccor,
`——————'
`
`lis—
`down the released histamine, which pealcs at 3 minutes. I
`tarni nase levels were found to be lower in patients with vernal
`lteratoconjunctivits resulting in chronically elevated hista»
`mine levels, indicating that this condition is allergic in nature
`[4L Inactivation of histaminase allows the collection and
`measurement ol’ tear histamine levels following instillation of
`allergen in the human eye. Four histamine receptors have
`been identified in the human body, although two, I ll and I ll,
`have been identified in the eye |3|. The binding of histamine
`to the | l] receptors on nerve endings leads to itch, and bind-
`ing to [It and ll; receptors on endothelial vascular smooth
`muscle leads to dilation (redness) and endothelial gaping
`(swelling).‘1’he blocking of these receptors with selective
`antagonists results in a decrease in itching, and redness. l-‘ure
`thennore, more recently it has been shown that by instilling a
`potent mast-cell stabilizer into human eyes prior to allergen
`challenge, histamine levels are reduced. which correlates with
`reduced signs and symptoms [6-- l.
`The effects of many of the mediators were investigated by
`instilli ng each ofthem onto the eye and observing effects clirr
`ically and histologically. lior example, platelet activating, lactor'
`(PM) was iound to be a potent chenroattradant for eosino
`phils and neutrophils, leading to intravascular margination in
`the conjunctiva [7); prostaglandin ”2 resulted in redness,
`ct'rnjur‘rctival chemosis, mums discharge, and eosinophil infile
`irate [8|; and in the human eye leukotriene Bil ([1134) did not
`produce vasodilation; however, biopsy revealed infiltration of
`pt)lymorphonuclear infiltrates (l lnpublished data), whereas
`lil‘liLl and 12104 [9] elicited no observable effect. PAF, leultot-
`rienes, and prostaglandins are all newly formed mediators
`produced in the arachidonic acid pathway during the break-
`down ol‘phospholipids from the mast—cell membrane.
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`|PR2018—01020 and |PR2018—01021, Exhibit 1025, Page 2
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`365
`
`Coniunctival Allergen Challenge 0 Abelson and Media
`
`very important in the complete understanding of the aller-
`gic mechanisms, for severe chronic conditions, and as a sur-
`rogate end point for the release of chemotactic factors from
`mast cells (ft), mastvcell degranulation).
`The earlier discussion was not intended to give a full
`review ofthe allergic mechanisms in the eye; however, the
`compilation of research highlights ways in which conjunc-
`rival challenge rrrodels have been trsed to understand the
`pathophysiology of the ocular surface. ‘l'he clinical rele~
`vance of the coniunctival challenge is validated by the si in:
`ilarities seen between the reactions following a challenge
`with the reactions seen in svrrrptornatic atopic patients
`with allergic conjunctivitis.
`
`Environmental Model for Studying
`Allergic Conjunctivitis
`'l he environmental model for testing the effectiveness of
`arrtfallergy agents has been tised extensively throughout the
`world, and was the original manner in which ocular allergy
`was studied. In fact, the ”environmental” concept is used
`throught'rut the medical research field to study almost all dis-
`eases. ‘l‘he idea is that a patient can be given the medication
`to rise at home and either maintains a diary, or returns to the
`oftice for follow up visits. A study using the environmental
`model might be conducted during the course of several
`weeks to months. In ocular allergy, the patient can be given a
`diary to record severity of symptorrrs (itching) and perceived
`signs (redness) on a daily basis. Generally, patients are given
`scales to use as a reference in grading At predetermined time
`inten‘als, the patients return to the office for examinations by
`the investigator. 'l‘hese office visits serve as safety visits—to
`determine efficanf and to review compliance with dosing
`and record keeping in the diary. (Zompliance can also he
`monitored utilizing telephone contacts tirade by study staff
`between office visits,
`
`l’actors Affecting Data in the
`Environmental Model
`
`Although this type ofstudy design rrrost accurately reflects
`what would occur in .i clinical setting in the individual
`patient, several confounding factors might interfere with
`the analysis and combination of data from patients within
`the same office and those seen at different sites in multi-
`
`center studies. Particularly in studying an acute condition
`such as allergic coniunctivitis, the Viability and variability of
`the results and interpretation ofthe data might be difficult.
`These issues relate to five main concepts: 1 ) enrollment of
`sensitized atopic individuals; .2) exposure to offending
`allergens; 3] reliance on subjective data and compliance;
`and 4) placebo effect.
`The environmental model relies on the fact that the
`
`patients enrolled suffer from the condition that is being
`studied. therefore, patients enrolled in environmental
`ocular allergy studies need to be atopic, and specifically
`
`allergic in the eye, lf‘they are not, there is no way to ensure
`that the individual will be allergic to the particular allere
`gens that are in season. ()ften, skirt testing is performed to
`qualify patients, and it
`is assumed they will have ocular
`allergy. However, in our experience, we have found an
`approximately 60% to 70% correlation between positive
`skin tests and positive reaction to allergen instilled in the
`eye; therefore, if skin testing is solely relied on, some
`patients will be enrolled who might not have allergy to the
`pollen in season. Others have also seen a similar correla
`tion |Zl |. Often, entry criteria require a patient to present
`in the office with a positive skin test and positive clinical
`signs and symptoms of ocrrlar allergy. In this case,
`it is
`important to ensure that standard diagnostic criteria are
`being followed.
`The second, and most obvious, problerrr associated
`with the environmental model is the inability to regulate
`each participant's exposure to various allergens. Izach indi-
`vidual is exposed to various degrees and types of allergens
`owing to differences in work habits; life style; natural varia-
`tion in pollen counts between home and workplace;
`indoor pets or plants; rise ofair conditioning, fans, or vene
`tilation ducts that would move airborne allergens through
`otrt the borne/office; density ofplants outside; and natural
`variations in pollen counts. i‘tdditionally. some behavioral
`modifications, such as avoidance of allergen during the
`allergy season. might further complicate the issue. If the
`patient is not experiencing significant signs and symptoms,
`it is more difficult to identify a drug effect Alternatively, if
`a patient reports to the office with few signs or symptoms,
`it could be due to a lack ofexposure to offendingallergens.
`'l he scheduled office visits that are included in the
`
`study design to ensure a degree of objectivity are problemv
`atic owing to the unlikelihood of having patients whose
`worst allergic symptcn'ns are timed synchronously with the
`predetermined scheduled visit. Patient diaries can be used
`to track signs and/or symptoms daily, and the patient’s
`assessment ofexposurc to the outdoors and pollen counts
`are recorded within the get.)graphic area ofthe study site by
`a pollen-counting station. But, patients might be allergic to
`indoor allergens or exposed to other irritants. It is clues,
`tiorrahle, therefore, whether a regional pollen cotrnt [or
`patienterecorcled exposure) is a true measure of personal
`allergen exposure. lnterestingly, clinical signs and syrup
`toms are not always exactly correlated with the absolute
`values of pollen counts [22) I‘ollen counts can vary even
`within the same area and will differ based on the exact
`
`location of the counter itself. Perhaps the fact that pollen—
`counting stations are not validated by standard criteria
`between sites might also play a role.
`’l'he third issue is the reliance on patients diaries to deterw
`mine drug efficacy. The diaries contain a high level ofsubjece
`tivity owing to differences in symptom interpretation among
`people. Although standardized scales can be used. environ-
`mental studies rely on data recorded for primary efficacy var-i7
`ables of itching and redness by the patients themselves.
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`366 Ocular Allergy
`
`Compliance issues affect the quality of results, as one mtrst
`assume that in sortie cases subieds will neglect to enter data
`in a timely fashion, and then later "baclvlill" prior to the next
`office visit.
`Another isstre involved with the use ofthe environmental
`model is the high rate ofplacebo effect seen. A placebo drop,
`many times an artificial tear, can effect allergy treatment, 'lhey
`do this by acting as a barrier to prevent allergen from attacle
`ing the coniunctival surface, helping to diltrte allergen and
`mediators in the tear film, and acting as an eyewash. Such
`environmental stttdies are known to have placebo effect rat
`ings as high as 50% and (io‘lh [23,24]. Althotrgh it is diffictrlt
`to completely eliminate, the placebo effect is a significant fac-
`tor, and it can be expected to play a larger role in environmen
`tal studies in which it acts as an eyewash, compared with
`single-drop studies in the (At) model.
`
`The (Ionitmctival Allergen Challenge Model for
`Studying Allergic Conjunctivitis
`To evaluate anti~allergic agents in a more controlled manner.
`(JACs have been developed. l listarnine produces a dose
`dependent response when instilled in the eye, and thus has
`been used as a model for screening anti—allergic drugs.
`Althotrgh such an agent can help evaluate drugs with antihis-
`taminic properties [25], arid drugs that actively reduce redr
`ness, strch as vasoconstrictors |2trl, this challenge is not
`directly stimulating mast-cell degranulation, as happens with
`allergen. Substances sttcb as compound 48/80, which is a
`secretagogtre that induces mastecell degrantrlation, have also
`been ttsed in human challenge tests [ IO]. i'lowever, because
`the secretagogues do not induce an immunologic reaction
`via an lgliemediated pathway, they might not be appropriate
`for evaluating agents with mast-cell stabilizing activities [he
`(IAC |2’| was developed as the most accurate replication of
`the true allergic reaction, because it is lgli mediated, and
`results in mastacell degr'anulation.
`‘I'he standard controlled (TAC study design includes two
`baseline visits. 'l'he first is a titration visit, and a selected
`
`allergen is instilled into both eyes ofthe patient. Signs and
`symptoms are then graded on standardized scales. Allergen
`is instilled into the eyes at increasing concentrations until a
`prespecified threshold of clinical response is achieved. The
`threshold scores, however, need to be set considering the
`reaction that resembles a natural allergic reaction—in
`other words, one that provides sufficient improvement of
`drug over placebo, btrt does not stimulate such a large reac-
`tion that it cannot be modulated by the drug. The intent of
`the study also needs to be considered when evaluating, this
`threshold and allergen used. for example, a high dose of
`allergen is generally required to stimulate a significant cele
`lular infiltrate and to correlate this infiltrate with clinical
`
`signs and symptoms. However, this reaction might be
`higher than that usually seen in the environment. When
`critically evaluating data from a study, the methodology
`and allergen dose used should be considered in determin—
`ing clinical relevance.
`
`Once the threshold allergen dose is determined in the
`patient, the patient returns for a confirmation visit, At this
`visit, the close that elicited a sufficient reaction at the first
`visit is instilled in both eyes. This second visit confirms the
`consistency and remodttcibility of the reaction in the
`patient. Patients who demonstrate a sufficient and reprodue
`ible response proceed to a third visit.
`Both onset and duration of action ofthe agent can be
`evaluated rising the CALI model. The patient can be dosed
`with the stttdy treatment (placebo in one eye and drug in
`the other; drug in both; or drug A in one and drug ii in the
`contralateral eye) and then challenged with the appropri
`ate dose ofallergen in both eyes, The eyes are then evalte
`ated for signs and symptoms, and the appropriate analysis
`is performed. To evaluate duration of action, the challenge
`can be performed at a specific time following instillation of
`treatment. for example, ifthe patient is challenged (\ hours
`following instillation of the drug, then it is clear that the
`drttg effects last at least 6 hours. Onset and duration of
`action are evaluated at separate office visits.
`Safety during allergen challenge cannot be emphasized
`enough, because coniunctival instillation can produce signifi—
`cant nasal, throat, and respiratory reactions. Having trained
`medical personnel and appropriate emergency equipment
`on»site is critical.
`
`Advantages ofthe Coniunctival Allergen
`Challenge Model
`The (.‘Atl model mimics the signs and symptoms ofan ocular
`allergic response accurately in a controlled setting [28“].
`The instillation of the threshold dose in the subject's eyes
`consistently results in itching and redness.
`liy enrolling patients based on their resprmse to a (ZAC,
`only those patients who actually have ocular allergy are
`being enrolled. 'l'he titration ofallet'gen during the first visit
`provides a method for obtaining the threshold dose needed
`for adequate reactivity. the coupling of the titration with
`the second visit for confirmation ensures reproducibility.
`'l‘he (TAG model contains a level ofinternal control that is
`not seen in the environmental model because the bilateral
`instillation of drug and placebo serves as a highly reproduc—
`ible internal control.
`
`'lhc patient's exposure to offending allergens and
`certainty that the drug is being tested in an allergic eye is
`controlled by precisely instilling allergen in the office, in
`patients who are asymptomatic at baseline when they enter
`the office. 'I‘herelore, variable exposure patterns to allergens
`typically seen between patients in enx-‘ironmental designs is
`controlled. By completing the study in the “olf—season" UP,
`not during the pollen season} with allergens that the
`patients are allergic to, it can be further ensured that any
`environmental exposure will not confound the results.
`By inducing the allergic reaction in the office, a trained,
`masked examiner can be used to evaluate the primary signs
`
`(redness and chemosis). The primary symptoms can also
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`Coniunctival Allergen Challenge I Abelson (Illtil Luefllw
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`be evaluated by the patients using standardized scales in
`the office while being observed by study staff, ensuring
`grading is done properly and that the paiierits correctly
`understand the scales. The tint.) allows a timely and con
`cise evaluation for the effects ofthe investigational drug.
`Also, with the instillation ofthe study treatments in the
`office, compliance is ensured.
`
`Use of the Coniuuctival Allergen Challenge
`Model for Evaluation of Drugs
`Owing to the (IN) model's high level ofintei‘ual control, sen
`sitivity, and reproducibility, it can be used in several ways.
`The (LAC. model is very applicable for studies involving a
`comparison of efficacy between drug and placebo
`[29, 10,3I 0| 'l‘he (EAL? model can also be ttsed to compare a
`drug with an active control. This has been done by many
`groups usingI various agents available for eye allergy
`[3233345390360]. Using the CAC, precise comparisons
`ofonset of action and dtiration of action can be measured,
`which cannot be acmrately evaluated in environmental Slltde
`has, It
`is important to note that in the challenge studies, in
`which standardized scales are used, a specilied tinit change
`between drug and placebo on that scale can be defined as
`being clinically significant. This is different from showing
`statistical significance, which can occur without clinical sig-
`nilicance. for example, typically on the 0—4 scale, a tiiiit
`change is considered by the FDA to be clinically significant.
`I Iowever, even ifa drug might not produce a clinically signif-
`icant response ofone lull unit. the CAC model is still very
`useful for evaluating efficacy and in helping to select agents
`for further testing (cg, dose ranging).
`[Environmental and (MC models can be combined. In
`
`this design, patients are lirst exposed to a (MC. Patients
`who respond sufficiently to an initial (LAC are enrolled
`into the study with an environmental design. This model
`helps to ensure that patients who are enrolled are atopic
`and. more specifically, are sensitive in the eye to the allere
`gen currently iii-season, during which the sttidy is con
`ducted. I‘liis hybrid model has successfully been tised to
`study the llttlserL‘ll stabilizer peiiiirolast [35“].
`/\ unique use of the (MC is to study effects of drugs on
`nasal signs and symptoms. Inllairimatory mediators,
`released during the allergic reaction in the conjunctiva.
`and/or allergen itself, can drain through the nasolacrimal
`duct into the inferior turbinate of the nose and produce
`clinically significant nasal itching, sneezing, congestion,
`and rhinorrhea. Similar to mediators, topical drugs can
`also drain from the eye into the nose. In fact, we have seen
`an effect of potent allergy eye drops on nasal signs and
`symptoms, in both challenge models and environmental
`studies | 300,370].
`
`Conclusions
`We can see how the (LAC model has been a useful tool for the
`
`development of new agents for ocular allergy, and to help fur-
`ther our understanding of the pathophysiology ofocular
`allergy. The controls afforded by the Lise ofthis type ofmodel
`lead to more reliable results and help to mitigate many ofthe
`issues we see with standard environmental studies.
`
`Challenge tests have been used for years in the fields of
`asthma and allergic rhinitis. The ophthalmic division at the
`IDA has been a leader in accepting the CAC model, and has
`helped otir field tremendously by giving us an efficient study
`design in which to evaluate the condition and to pave the way
`for the development of novel pharmacetrticals. With the rec-
`ognition ofthe significance of using the model for the drug
`dc 'clopmcnt process, as a pathway for drug approval, we are
`actually now seeing agents being developed lirst specifically
`for the eye, as a proofofcoiicept for other indications. A thoi:
`ougli understanding of the model is required to ensure that
`acttirate init-‘ipreiaiions are made froin the results, and that
`the study is still designed appropriately, matching the pirate
`inacology ofthe agent, clinically relevant mechanisms ofthe
`disease protess, and the objectives ofthe study.
`
`References and Recommended Reading
`Papers of particular interest, published recently, have been
`highlighted as:
`-
`Of importance
`It
`()fmaiorimportance
`
`
`
`I
`m
`
`1
`
`at
`
`Abelson Mlt (Lhapin Ml: (Zurrent and future topical treatments
`for oullar allergy. ( 'tniip ()plitlirilniiil Update ltltltl, 1:503 ,, it 7.
`Abelson Mil, nllanwnith MR, Histamine and the eye. In fHIflItr
`iiologi' tiiiil liiiniitiiujlritfinlogy oftlir lac. litlilt‘d by Silveisteili AM.
`O'Connor (if. New York: Masson,
`I‘IT‘):_3tv.Ze its}.
`Abelson N-lll, Smith IM. Levocahastine: evaluation in the his
`[amine and compound 48/80 models ofocular allergy in
`humans, ()plitliiiliiiolngy I988,95149471497.
`t Abelson \Ili, l,L‘t)lIt‘|ILll AA, Smith IM, ct tll.: Histamiuase activ-
`ity in patients with vernal keratoconirinctivitis. Upliiliiilninlttqy
`l ‘1‘)3, I02: I 9387 I‘m i.
`Abelson a-III, Allansinith MR: Histamine and the eye. In Irimiii
`iiilfivgy {flit} Iiiiiiiiitin/railiulngy of the Eye. ILtlitetl by Silverstein .-\M,
`(i'tlonnor LII. New York: Masson,‘ I97“): 30 ‘37 364.
`(i 0- ] eoriardi .-\, Abelson M: Mast cell stabilizing effects of
`olopatadine following allergen challenge in humans
`[abstract], ARV“ 200.1, in press.
`Ihis is the first study correlating clinical effects and the indiccs of mast
`cell stabilizing properties, including decreased histamine levels. fol a
`therapeutic agent with multiple actions in ocular allergic subjects.
`7
`tieorgc MA, Smith IM, Herdy (if, ct til, I’latelet activating fac-
`tor induced inflammation following topical ocular challenge
`[abstract [. Invest (Jplitlialiiml Vis Sci I990. 31 (Stippl):tii.
`Abelson MB. Madiwale NA, Weston II I: The role ofprostaglandin
`D2 in allergic ocular disease. In lliml International .‘tyitiptuiiriii a}
`the liiiiiiiiimlngy iiiiil Itiiiiiiiiitipiiilmlt‘gi' nt lfll’ Ifye. lidited by O'Con-
`nor (IR, (:l‘liIIiL'llL‘J‘ [\V. New York; Masson; 1085, ] 637 1 (1h,
`0, Weston [l l, Abelson Mb. Lettkntriene C4 in rabbit and human
`eyes [abstract], lIII'tM (:infllflil'ffiltlf H's ,Kti I'Dlt. 26(Suppl):l‘ll.
`Ilotrus SI, Ochsner Ki, Abelson MR, Schwartz. | Ii: ”H3 level of
`tryptase in human tears: an indicator of activation of con—
`itinctival mast cells. ()plirlitilmttlogy I‘Mt), Okla/"571681.
`
`h,
`
`It)
`
`|PR2018—01020 and |PR2018—01021, Exhibit 1025, Page 5
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1025, Page 5
`
`

`

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`
`
`368 Ortilar Allergy
`
`II.
`
`12
`
`1‘1
`
`Itt.
`
`l‘J‘
`
`I’toud I), Sweet I. Stein l’. at tll ' Inflammatory mediator release
`on conitmt‘tival prt)\"0('dll()l1 of allergic suhieets with aller-
`gen. I v‘\IIt't_x;t'(Jlttt Ittttttttttttl
`I‘M)”, 85:3'lt’ti'ltfi
`Iiisgaard ll, l()|Llrllt1ltfltlllHOlt AW. t ltarlesntt 8. wt all: Prodtte-
`lion ol'leultotrienes in human sltin and coninnt'tival mucosa
`
`alter specific allergen challenge. .lllt'lxl‘ l‘)H‘t.-It):= iTi-t.’ 3.
`liorak I, Ioth I, llimehti'ehr R,
`(’1 ttI.‘ llffet't ol't’ontinuous allerv
`gen challenge on clinical symptoms and mediator release itt
`dustimite-allergie patients..\llt't1e.r [‘198,
`I3 52ti8773
`Irl, Abelson Mll, Leonat‘di .-\.\. Smith IN. N ttl.: ilistaminase at'liv-
`ity in patients with vernal keratot'onitmctivitis, ()ttlttltttltttolttgt'
`1905, It)" | 9557 mm.
`(Ziptandi (2, Host aglia 5, I’este (1, er til ‘ Allergic suhieets
`express intertellnlar adhesion tiltiicClllt‘il [l(‘.x\M-l ot'tLI‘J34)
`on epithelial cells ofeoninnttiva alter allergen challenge.)
`.'\llt‘t‘.t{}'(
`lltt ltttittttttnl
`lll‘l l, ‘)1:'TH§--fi‘).‘
`Honini S, Honini .N, \"ert'htttne -\ er of: Inflammatory changes
`iit eoniunctival scrapings alter allergen provocation in
`humans. I
`.’ltllt’l_g':l'(.ll'll Ittttnttttttl I'lb‘fi. ESL-Italwltt‘)
`it _.. Anderson Ill, Marleod ll).\. Iladdelet SM, rt :1!
`. Seasonal alleiv
`git toniuntlivitis is accompanied by increased mast cell
`ntmthers in the ahsenee of leukocyte infiltration. (Iltti Int
`\tttvrgtv 1W7. 27:1UhlLlLlhtt,
`Results til this study show that inlilttate t-Ieosinotthils and neutro
`phils was not seen in more thatt “30‘!“ 0| \nhterts with seasonal Allt‘h
`glc (onittnrtix'itis lhis suggested the al'tsent'e (it a t‘Iinit'alh‘ relevant
`late phase reartit-n in the mes nl' most patients.
`iH
`\helson Mh'. Madiwale N. Weston H l. (Zonjunetival eosino-
`phils in allergie ()(tll.lr disease. .'\ttlt (lttlttltttltttttl
`I‘lh’ i,
`Illlisqfirfiitt.
`|.eon.ttdl .-\, I‘apa \-', Milano (I, Betthi .\l t; l‘llit’aty altd safely
`0t tlesonide phosphate tor the treatment of allergie roniunt'»
`tiviiis. ( otttm JUIL‘. 2i:-l7(t7-1?ii
`ltl - Haron \. .-\h|uwa|ia IT It'atti a. er til; 'l'ear and eoniunctival
`changes during the allergen-induced early and laterphase
`responses. I .\llt't_qt‘( lirt lttnnttttttl 2mm. Itltiflltlfi- ‘H-l.
`lhts \tttth shows an evident inllux Ul t'ells into the rtttnttnt'tn'a ltll
`lowing a high tlth‘ ofalletgen ihe larlt ot a peaL oi Irytnast' duringt
`the (I'll examination lollowing t'lt.tllt'tttte indit ates that mast tells
`might not he degrannlatint: duttng; this time.
`II
`l.t.'l1llt]l'tll.\.il't'gttlldlt‘\,(=l\lll()ntllhl,t'.ltll. (lorrelation
`hetween ((Jllillntlh‘dl provocation ((.l’l‘) and systemit' allerr
`