1. Bruce H. Koffler, MD University of Kentucky School of Medicine The author of this poster has received research funding and travel expense reimbursement from Aton Pharma. The author would like to acknowledge Susan Terner, MS, and Donald Nelinson, PhD, for support in preparation of the poster with funding from Aton Pharma. Efficacy and Acceptability of Hydroxypropyl Cellulose Ophthalmic Inserts: Subsets of Patients With Dry Eye Syndrome in a Patient Registry For interactivity go to View and click Slide Show

2. Purpose: To determine efficacy and acceptability of hydroxypropyl cellulose ophthalmic inserts (HCOI) in subsets of patients with dry eye syndrome (DES). Methods: A multicenter, open-label, prospective registry enrolled 520 patients with bilateral moderate-to-severe DES. Clinical examinations and Patient Questionnaires incorporating the OSDI assessed clinical signs, average symptom severity and frequency, limitations in ADL, and ocular discomfort in various environments 1 month before baseline and 1 month of treatment. Inserts were used alone or with existing therapy. Results: There were 418 completers. OSDI scores improved significantly (P<.05) in contact lens (23.2%), prior cataract surgery (29.2%), and prior refractive surgery (19.5%) subgroups. OSDI improvement was not significant in cataracts or glaucoma groups. Discomfort, burning, dryness, grittiness, stinging, and sensitivity to light were significantly reduced (P<.05) for cataracts, and discomfort and dryness improved significantly (P<.05) for glaucoma. Blurred vision was the most commonly reported AE. Conclusions: After 1 month, HCOI as monotherapy or with existing therapy improved symptoms, ADL performance, and quality of life in moderate-to-severe DES subsets. Abstract

3. Introduction Patient subsets Contact lens 1 factors affecting DES 1 –Characteristics of lenses –Protein, lipid and mucin deposits –Intolerance of lens solutions Surgery increases risk of DES, depending on type of procedure –Cataract surgery 2-4 2-4 –Laser surgery 5 5 Glaucoma 6 DES is common, associated with type of treatment 6 –Agents containing benzalkonium chloride and other preservatives Diagnostic clinical testing is limited by lack of consensus regarding appropriate tests 7 7 Ocular Surface Disease Index (OSDI) is a validated patient questionnaire that assesses symptom severity and quality of life 8 8 Artificial lubrication in DES patients is often used Artificial tears require frequent administration and may contain preservatives Hydroxypropyl cellulose ophthalmic inserts (LACRISERT ®, Aton Pharma, Lawrenceville, NJ) are indicated once daily in patients with moderate-to-severe DES 9 9 –Lubricate eye over 24-hour period, stabilizing precorneal tear film and prolonging tear film breakup time Purpose of this analysis Analysis of larger patient registry done to determine efficacy and acceptability of inserts in patient subsets

4. Methods: Study Design 28-day, 2-visit, multicenter, patient registry (Tables 1 Registries Vs. Clinical Trials and 2 Criteria for Study Participation)Registries Vs. Clinical Trials Criteria for Study Participation Visit 1 (baseline, Day 0) –BCVA; Slit-lamp examination; DES evaluation of investigator’s choice (TFBUT, staining, Schirmer’s) –Patient Questionnaire, including OSDI, to assess DES symptoms and functioning under various conditions –Instruction in placement of hydroxypropyl cellulose ophthalmic inserts (HCOI) (Figure 1 Placing Insert)Placing Insert Days 1-28 –Treatment with HCOI as monotherapy, or in addition to current care regimen Day 3 ± 1 day –Telephone contact to assess adverse events (AEs) and proper use of HCOI –Reinstruction, if necessary Visit 2: day 28 ± 3 days –Repeat clinical evaluation, as in Visit 1 –Patient Questionnaires, including OSDI, to assess DES symptoms, functioning under various conditions, and satisfaction –Review of AEs Figure 1Table 1Table 2

5. Results and Limitations OSDI Subgroup analyses found that mean OSDI scores improved significantly (P<0.05) for contact lens wearers (23.2%), patients with prior cataract surgery (29.2%), and those who had undergone prior laser surgery (19.5%), but not for patients with cataracts or glaucoma. Although OSDI scores are normed as a total score, Figures 2 Contact Lens Wearers, 3 Cataract Diagnosis, 4 Cataract Surgery, 5 Laser Surgery, and 6 Glaucoma show changes in specific OSDI parameters for each subset.Contact Lens WearersCataract DiagnosisCataract SurgeryLaser SurgeryGlaucoma Blurred vision was the most frequent cause for discontinuation in the total population and increased here, yet patients reported significant improvement in ADLs that require a high degree of visual acuity: reading, watching TV or movies, working with a computer or ATM, and driving at night. Table 3 Blurred Vision in Subgroups shows the percentage of patients affected by blurred vision.Blurred Vision in Subgroups Study Limitations Lower level of evidence due to registry design No standard of care prescribed by registry protocol Inserts often administered as an adjunct to other therapies, but no specific record of other therapies and their doses was required Investigators were not required to record length of time post-surgery for cataract and refractive surgery patients Status of follow-up calls on Day 3 was not always available; omission of a follow-up call may have affected outcomes Figure 2Figure 3Figure 4Figure 5Figure 6Table 3 Slit Lamp Photos of CL Patient with Inserts Select the View additional images/video link on home screen

6. Conclusions and References Registries provide an evaluation of a product under real-life conditions The OSDI is a validated instrument that measures DES severity and quality of life Total OSDI scores improved significantly for contact lens wearers, patients with prior cataract surgery, and those who had undergone prior laser surgery, but not for patients with cataracts or glaucoma patients Improvement in the OSDI may reflect better functioning and quality of life Blurred vision increased in this analysis, and is likely due to the thickened precorneal tear film observed after placement of the inserts Blurred vision did not interfere with ADLs that require a high degree of visual acuity When used as monotherapy or with existing therapy, after 1 month of treatment, HCOI use improves symptoms, performance of ADL, and quality of life in patients with moderate-to-severe DES who wear contact lenses, or have had cataract or refractive surgery 1. Sindt CW, Longmuir RA. Contact lens strategies for the patient with dry eye. Ocul Surf 2007;5(4):294-307. 2. The definition and classification of dry eye disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop (2007). The Ocular Surface. 2007;5(2):75-92. 3. Ram J, Sharma A, Pandav SS, et al. Cataract surgery in patients with dry eyes. J Cataract Refract Surg 1998;24:1119-1124. 4. Ram J, Gupta A, Brar GS, et al. Outcomes of phacoemulsification in patients with dry eye. J Cataract Refract Surg. 2002;28:1386-1389. 5. Toda I. LASIK and dry eye. Compr Ophthalmol Update. 2007:8(2):79-85. 6. Leung EW, Medieros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17:350-355. 7. The epidemiology of dry eye disease: Report of the Epidemiology Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf. 2007;5(2):93-107. 8. Schiffman RM, Christianson MD, Jacobsen G, et al. Reliability and validity of the ocular surface disease index. Arch Ophthalmol. 2000;118:615-621. 9. LACRISERT [package insert]. Aton Pharmaceuticals, Inc; Lawrenceville, NJ; 2007.

7. ComparisonRegistriesClinical Trials PurposeTo evaluate a product in the real worldTo evaluate a product under controlled conditions HypothesisMay be in place, but study is not designed or powered based on a specified hypothesis Prior hypothesis in place with statistical analysis anticipated by protocol DesignNo randomization, control arm, or blinding Randomized, usually ≥1 control arm, and blinded EvaluationInvestigators use their own preferred methods* Protocol specifies evaluation procedures for all participants TreatmentInvestigators add product to current treatment regimen or change treatment as they would in professional practice; therefore, change is incremental beyond current treatment Protocol specifies treatment in each arm of study AnalysisAd hoc analysis and post hoc data mining analyses are acceptable Ad hoc analyses rare, and post hoc analyses rarer *In this study, all investigators used the OSDI, a validated measure of disease severity, consistently to grade DES. Table 1. Comparison of Registries and Clinical Trials

8. InclusionExclusion Aged 18 years or older Diagnosis of bilateral DES History of intermittent or regular artificial tear use or desire to use artificial tears within the week prior to study initiation Provided informed consent Willing and able to follow all instructions and attend both visits Clinically significant blepharitis, meibomian gland dysfunction, or lid margin inflammation Currently taking systemic or topical medication used to treat ongoing bacterial, viral, or fungal ocular infection; active ocular inflammation; or pre-auricular lymphadenopathy LASIK surgery within 12 months of Visit 1 or any other ocular surgical intervention within 3 months prior to or during the study period Systemic disease or uncontrolled medical condition, that in the opinion of the investigator, could interfere with study measurements or compliance Use of any new DES therapies throughout the trial that they had not been previously using Taking systemic medications known to cause ocular drying, unless already on a stable dose within 30 days of Visit 1 Known allergy and/or sensitivity to hydroxypropyl cellulose Participation in an investigational drug or device trial within 30 days of Visit 1 Table 2. Criteria for Study Participation

9. Contact Lens Wearers Cataract Diagnosis Cataract Surgery Laser Surgery Glaucoma Visit 1 (n=86) Visit 2 (n=86) Visit 1 (n=83) Visit 2 (n=79) Visit 1 (n=53) Visit 2 (n=52) Visit 1 (n=26) Visit 2 (n=22) Visit 1 (n=21) Visit 2 (n=15) 31.341.949.459.550.959.669.35066.7 Table 3. Percentage of Patients in Subgroups Affected by Blurred Vision from Visit 1 to Visit 2 Half or more of the time (%)

10. Figure 1. Placing the Hydroxypropyl Cellulose Ophthalmic Insert All of the time None of the time SymptomsDifficulty in ADLs Difficulty in Environmental Conditions Score Figure 2. Contact Lens Wearers: Change in OSDI Scores* * P<0.05, Mean Improvement in Total Score

11. All of the time None of the time SymptomsDifficulty in ADLs Difficulty in Environmental Conditions Score Figure 3. Cataract Diagnosis: Change in OSDI Scores All of the time None of the time SymptomsDifficulty in ADLs Difficulty in Environmental Conditions Score Figure 4. Cataract Surgery: Change in OSDI Scores* * P<0.05, Mean Improvement in Total Score

12. All of the time None of the time SymptomsDifficulty in ADLs Difficulty in Environmental Conditions Score Figure 5. Laser Surgery: Change in OSDI Scores* All of the time None of the time SymptomsDifficulty in ADLs Difficulty in Environmental Conditions Score Figure 6. Glaucoma: Change in OSDI Scores * P<0.05, Mean Improvement in Total Score