Comparison of Difluprenate 4x/day and Prednisolone Acetate 8x/day in Preventing Investigator-Designated Acute Anterior Uveitis Treatment Failures John D. Sheppard, MD, MMSc Professor of Ophthalmology, Microbiology, & Molecular Biology Eastern Virginia Medical School President, Virginia Eye Consultants 241 Corporate Boulevard, Norfolk, VA Disclosure statement Dr Sheppard has served as a consultant to Abbott, Abbvie, Alcon, Alimera, Allergan, Bausch & Lomb, EyeGate Pharma, Gerson Lehrman, Inspire, Ista, Lux Biosciences, Merck, Mimetogen, Omeros, Santen, SarCode, Science Based Health, TearLab, and Vistakon within the past 3 years, is an equity owner of EyeGate, OcuCure, TearLab, Doctors and EyeRx, and also receives research funding from the National Institutes of Health and The Virginia Eye Foundation.

Introduction Uveitis is the third leading cause of preventable blindness in the USA 1 Endogenous anterior uveitis (EAU) is a from of uveitis that is not directly caused by an infectious pathogen o Indicated by inflammation of the anterior segment (iris, ciliary body, and choroid) including iritis, iridocyclitis, and anterior cyclitis 2 o Incompletely characterized etiology, but has been associated with systemic and immune diseases 2 o Can potentially have severe vision-threatening complications including cataract, glaucoma, band keratopathy, and cystoid macular edema 2 Two Phase 3 studies with similar design (NCT , NCT ) were conducted in the USA in patients with EAU 3,4 o Results from these studies were pooled to improve the power of each individual noninferiority trial 1. Siddique SS, et al. Expert Opin Investig Drug. 2011;20:1497–1515; 2. American Optometric Association. Optometric Clinical Practice Guideline: Care of the Patient with Anterior Uveitis. St Louis, MO: American Optometric Association; Reviewed 2004; 3. Foster CS, et al. J Ocul Pharmacol Ther. 2010;26:475–483; 4. Sheppard JD, et al. Invest Opthalmol Vis Sci. 2014;55:2993–3002.

Study design Inclusion criteria EAU in at least one eye* diagnosed within 2 weeks of enrollment >10 cells in the anterior chamber and a flare score of >2 in one eye Aged 2 years or older Key exclusion criteria Intermediate, posterior or pan-uveitis in either eye New use or change in dosage of any corticosteroid or immunosuppressive drug within 2 weeks Use of topical corticosteroid or NSAID in study eye within 7 days History of glaucoma, ocular hypertension or steroid-induced IOP elevations Inclusion criteria EAU in at least one eye* diagnosed within 2 weeks of enrollment >10 cells in the anterior chamber and a flare score of >2 in one eye Aged 2 years or older Key exclusion criteria Intermediate, posterior or pan-uveitis in either eye New use or change in dosage of any corticosteroid or immunosuppressive drug within 2 weeks Use of topical corticosteroid or NSAID in study eye within 7 days History of glaucoma, ocular hypertension or steroid-induced IOP elevations Randomization Difluprednate 0.05% four times daily (QID), n=106 Prednisolone acetate 1% eight times daily, n=94 14-day treatment 14-day tapering† Phase 3, prospective, multicenter, randomized, double-masked noninferiority trials (n=200) EAU, endogenous anterior uveitis; IOP, intraocular pressure; NSAID, non-steroidal anti-inflammatory drug. *If both eyes met the inclusion and exclusion criteria, both eyes were treated with study drug and the worse eye was designated as the study eye for the efficacy evaluations. If both eyes equally met the inclusion and exclusion criteria, then the right eye was designated as the study eye. Both eyes were examined for safety; †The 14-day tapering regimen was provided in the protocol but was ultimately determined at the investigator discretion.

Efficacy and safety endpoints AC, anterior chamber; ANCOVA, analysis of covariance; CI, confidence interval; IOP, intraocular pressure; OCT, optical coherence tomography. 1. Foster CS, et al. Am J Ophthalmol. 1996;122:171–182; 2. Biswas J, et al. Int Ophthalmol. 2004;25:147–153. o Noninferiority was based on the hypothesis that the upper 95% CI of the between–group difference must be less than 0.5 units 1,2

Patient baseline characteristics were comparable between groups *Between group difference, P=0.67. †Based on the per protocol population where n=94 for the difluprednate 0.05% group and n=86 for the prednisolone acetate 1% group.

Difluprednate was associated with significantly fewer discontinuations due to treatment failure Completed the study: n=72 (76.6%) Completed the study: n=96 (90.6%) Completed the study: n=96 (90.6%) n=9 discontinued for reasons unrelated to efficacy n=7 exited before any treatment (randomization unknown) n=7 exited before any treatment (randomization unknown) n=9 discontinued for reasons unrelated to efficacy n=1 (0.9%) discontinued for treatment failure with difluprednate n=13 (13.8%) discontinued for treatment failure with prednisolone acetate P= between groups P= between groups Safety & ITT populations Treated with prednisolone acetate: n=94 Treated with difluprednate: n=106 Screened and randomized: N=207 patients

Difluprednate was noninferior to prednisolone acetate in anterior cell grade reduction on Day 14 95% CI (-0.36, 0.05) P=0.135 CI, confidence interval AC cell grades: 0=≤1 cell, 1=2–10 cells, 2=11–20 cells, 3=21–50 cells, 4=>50 cells. Data from the per protocol population with last observation carried forward are presented. The per protocol population includes patients who received at least one dose of the allocated study medication with no major protocol deviation.

Significantly more difluprednate-treated patients were cleared of anterior chamber cells on Day 21 Data from the per protocol population with last observation carried forward are presented. The per protocol population includes patients who received at least one dose of the allocated study medication with no major protocol deviation. P= P=0.201

Significantly more patients achieved anterior chamber cells Grade 0 with difluprednate on Day 21 Anterior chamber cell grades: 0=≤1 cell, 1=2–10 cells, 2=11–20 cells, 3=21–50 cells, 4=>50 cells. Data from the per protocol population with last observation carried forward are presented. The per protocol population includes patients who received at least one dose of the allocated study medication with no major protocol deviation. P=0.0266

Both treatment groups showed similar outcomes for signs, symptoms and quality of life measures No significant between–group differences at any time point were observed for: o Proportion of subjects with anterior chamber cell grade* ≤1 o Mean change in anterior chamber flare grade † o Total sign scores for posterior synechia, limbal injection, keratic precipitates and hypopyon o Total symptom scores for pain/ocular discomfort, photophobia, blurred vision and lacrimation Significant difference favouring the difluprednate group was seen in the mean change from baseline in physical subscale of the WLQ at Day 42 (P=0.0086) o Other quality of life measures (VFQ-25 subscales and composite scores, and WLQ subscales on time management, mental-interpersonal and output) were comparable between the two groups WLQ, Work Limitation Questionnaire; VFQ-25, 25-item Visual Function Questionnaire. *AC cell grades: 0=≤1 cell, 1=2–10 cells, 2=11–20 cells, 3=21–50 cells, 4=>50 cells; † AC flare grades: 0=none, 1=mild, 2=moderate, 3=marked, 4=severe. Data from the per protocol population with last observation carried forward are presented. The per protocol population includes patients who received at least one dose of the allocated study medication with no major protocol deviation.

Safety Criterion IOP increase* was reported for 11 (10.9%) difluprednate-treated and 8 (8.5%) prednisolone acetate–treated patients AE, adverse event; IOP, intraocular pressure; SAE, serious adverse event. *Criterion IOP increase was defined as an IOP increase of ≥21 mmHg and a change of ≥10 mmHg versus baseline at the same visit.

Conclusions Pooled analysis of two Phase 3 trials in patients with EAU showed that, compared with prednisolone acetate 1% eight times daily, difluprednate 0.05% QID o Showed significantly fewer discontinuations due to treatment failures o Was noninferior to prednisolone acetate in anterior cell grade reduction on Day 14 o Was associated with significantly more patients achieving complete clearing of anterior chamber cells on Day 21 o Was associated with significantly more patients achieving anterior cell Grade 0 on Day 21 o Showed comparable anterior chamber flare grade, total symptom scores, total sign scores, and quality of life indices Pooled safety analysis did not identify any unexpected safety concerns with difluprednate 0.05% QID treatment EAU, endogenous anterior uveitis; QID, four times daily.