1. 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.

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

3. 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.

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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)

10. 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

11. 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)

12. 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.