Safety and Efficacy of Mapracorat Ophthalmic Suspension in the Treatment of Inflammation Following Cataract Surgery: Adaptive Design Study Timothy L. Comstock, OD Oliver D. Schein, MD Tuyen Ong, MD Karen Kesler, PhD Disclosures: T Comstock and T Ong are employees of Bausch & Lomb, Inc. O Schein is consutlant for Bausch & Lomb, Inc. Karen Kesler is an employee of Rho, Inc. which conducted the statistical analysis.

Purpose To identify the most effective drug concentration and dose frequency of mapracorat (BOL-303242-X), a novel selective glucocorticoid receptor agonist (SEGRA), for the treatment of inflammation following uncomplicated cataract surgery.

Methods Phase II, multicenter, randomized, double-masked, parallel-group, vehicle-controlled, dose ranging study. Subjects were aged ≥18 years with postoperative anterior chamber (AC) cells of ≥Grade 2 (6-15 cells) on the day following uncomplicated cataract surgery. Subjects expecting to require concurrent ocular therapy with topical NSAIDs, mast cell stabilizers, antihistamines, or decongestants, or systemic NSAIDs or systemic/ocular corticosteroids were excluded.

Methods Eligible subjects self-administered 1-2 drops of study treatment (mapracorat 1%, 2%, 3% or vehicle) QD, BID, or QID for 14 days and completed 7 visits. Visit 1 [Screening] (≤14 days prior to surgery) Eligibility assessment Clinical assessment of ocular symptoms Eye examination (VA, IOP, biomicroscopy, fundoscopy) AEs & concomitant medications Visit 2 [Surgery] Visit 3 [Post-op Day 1] Eye examination (VA, IOP, biomicroscopy) Determination of eligibility Visit 4 [Day 3 ±1] Visit 5 [Day 8 ±1] Visit 6 [Day 15 ±1] Visit 7 [Day 18 ±1] AEs and concomitant medications Mapracorat Vehicle

Methods Primary efficacy endpoint: Secondary efficacy endpoints: Proportion of subjects with complete resolution of AC cells at visit 5 (postoperative day 8) Secondary efficacy endpoints: Proportion of subjects with Grade 0 pain at visit 5 and at each visit Resolution of AC cells, AC flare and overall AC inflammation at each visit Safety endpoints: Incidence of ocular and non-ocular adverse events (AEs) Change from baseline in intraocular pressure (IOP), visual acuity (VA), and biomicroscopy and ophthalmoscopy findings

Results: Subjects 415 subjects were randomized and included in the ITT population Subjects ranged in age from 22 to 90 years with a mean (SD) age of 67.8 (10.4) years. The median ages and proportion of male and female subjects were similar for all treatment groups Subject Demographics-ITT population Mapracorat Vehicle 1% 2% 3% QD, BID, QID Frequency BID QD QID N (%) 60 (14) 28 (7) 28(7) 59 (14) Age, yr Mean (SD) 65.4 (12.0) 67.9 (10.9) 68.9 (10.5) 69.5 (7.1) 68.2 (10.8) 67.3 (10.7) 68.5 (10.3) 67.1 (10.8) Median 66.5 68.5 70.0 69.0 67.5 Min, max 28, 89 32, 85 42, 87 57, 83 22, 84 44, 90 44, 87 43, 87 Gender, N(%) Male 27 (45.0) 13 (46.4) 26 (43.4) 29 (49.2) 28 (46.7) 29 (48.3) Female 33 (55.0) 15 (53.6) 34 (56.7) 30 (50.8) 32 (53.3) 31 (51.7) Race, N(%) Asian 1 (1.7) 3 (5.1) 2 (3.3) Black 5 (8.3) 3 (10.7) 1 (3.6) 4 (6.8) 3 (5.0) 4 (6.7) White 53 (88.3) 25 (89.3) 27 (96.4) 55 (91.7) 52 (88.1) 57 (95.0) Other

Results: Complete Resolution of AC Cells at Visit 5 (postoperative day 8)—Primary Efficacy Endpoint The mapracorat 2% QID and all 3% dose frequencies were highly significantly better than vehicle for resolution of AC cells (28.3%, 25.4%, 25.0% and 30.0%, respectively vs. 5% for vehicle). † † † † * * % Subjects with complete Resolution *P<0.05, †P<0.0005

Results: Grade 0 Pain at Visit 5 (postoperative day 8) The mapracorat 2% QID and all 3% dose frequencies were significantly better than vehicle for pain resolution (78.3%, 71.2%, 75.0% and 70.0%, respectively vs. 50% for vehicle). * * * * % Subjects with Grade 0 Pain *P<0.05

Results: Adverse Events Serious Adverse Events (SAEs) No non-ocular SAEs 2 treatment-emergent ocular SAEs Cystoid macular edema (CME; 3% QD group, possibly related to the study group and probably related to study procedure) Subretinal neovascularization (3% BID group, unrelated to the study drug or study procedure) Treatment-Emergent and Related Non-Ocular AE’s 3 events total Rash (Vehicle group) Headache (2% QID group) Nausea –(3% QD group)

Results: Adverse Events Ocular Treatment Emergent AEs Related to Study Drug Occuring in >3% of Eyes in Any Treatment Group* Mapracorat Vehicle 1% 2% 3% QD, BID, QID (N=60) Dose Frequency BID QD (N=28) QID (N=59) Total No of AEs* 16 1 4 6 9 7 23 No of subjects with ≥ 1 AE 10 (16.7) 1 (3.6) 3 (10.7) 3 (5.0) 8 (13.6) 9 (15.0) 6 (10.0) 12 (20.0) AC Inflammation 1 (1.7) 2 (3.3) Eye Pain 4 (6.7) Photophobia Eye Pruritis AC Flare Conjunctival Hyperemia Dry Eye Eye Irritation Ocular Hyperemia Eye Inflammation *prior to rescue medication use

Results: Mean IOP for Each Visit, Safety Population Mean IOP did not change from baseline for any treatment. Four reports of increased IOP ≥10 mm Hg (1 vehicle, 2 mapracorat 1% BID, 1 mapracorat 3% BID) were not dose related and none exceeded 30 mm Hg. Mean IOP (mmHg)

Conclusions Mapracorat 2% QID treatment and all 3% dose frequencies (QD, BID, QID) demonstrated statistically significant improvements in both AC cells and Grade 0 pain at visit 5 (postoperative day 8) compared with vehicle. Results for secondary endpoints, including results at visit 6 (day 15) and visit 7 (day 18), were consistent with primary outcomes (data not shown) Treatment related adverse effects were infrequent in all treatment groups IOP effects were similar to vehicle.