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Joseph Markoff, MD, PhD1; David Birch, PhD2; Robert C. Sergott, MD1; Petra Kozma, MD, PhD3 1 Thomas Jefferson Medical College and Wills Eye Hospital, Philadelphia, PA; 2 Retina Foundation of the Southwest, Dallas, TX; 3 ThromboGenics NV, Leuven, Belgium

§  Disclosures: J. M. is a consultant for ThromboGenics, D. B. Is a scientific advisor for ThromboGenics, R. S. is a consultant for ThromboGenics, and P. K. is an employee of ThromboGenics.

§  Acknowledgments: Medical writing support was provided by Meridius Health Communications, funded by ThromboGenics.

Presentation # 4050 – C0095

ARVO 2016 Annual Meeting May 1-5, 2016

Seattle, WA

Proposed Mechanism

Subject With Resolution of ERG Amplitude Reductions: Case #1

PURPOSE

BACKGROUND

METHODS: STUDY DESIGN AND OBJECTIVES

RESULTS CONCLUSIONS

DISCLOSURES AND ACKNOWLEDGMENTS

Subject With Resolution of ERG Amplitude Reductions: Case #2

§  Ocriplasmin was approved by the FDA on October 17, 2012 for the treatment of symptomatic vitreomacular adhesion following 2 MIVI-TRUST Phase III clinical trials1

§  In case reports, ocriplasmin has been associated with abnormal full-field electroretinograms (ffERGs) and multifocal ERGs in patients with symptomatic vitreomacular adhesion (VMA)2-4

§  ERGs were not regularly obtained in the MIVI-TRUST trials, making the incidence of ERG reductions following ocriplasmin treatment difficult to calculate5

OASIS Study Design and Objective and and

24-month, Phase IIIb, randomized, sham-controlled, double-masked, multicenter clinical trial evaluating ocriplasmin in subjects with symptomatic VMA

ERG Substudy Objective

Correlation of VMA resolution and BCVA with ffERG from baseline through Month 24

RESULTS

§  Had macular hole >400 µm per central reading center at baseline; not eligible for study (not included in Per Protocol Set)

§  Achieved VMA resolution and developed isoelectric ERG by Day 7 visit §  Subsequent vitrectomy and cataract removal §  Gained 13 letters from baseline, improvement of VFQ-25 scores (+26.7 points for composite

and +40.0 points for general vision)

§  41 ocriplasmin (41/146) §  21 sham (21/74) §  1 ocriplasmin subject with no postinjection ERG

assessment was not included in the analysis

§  The prospective nature of the ERG substudy allowed for standardization and comparison of changes from baseline, not possible with retrospective cases

§  Less than half (40.0%) of ocriplasmin-treated subjects experienced acute ERG reductions

§  92.5% of subjects receiving ocriplasmin had either normal ERGs or resolution of ERG reductions by study end §  Only 1 of 3 subjects not resolved by study end experienced a loss of visual acuity

§  An abnormal ERG is associated with a higher rate of VMA release compared to a normal ERG

§  ERG reductions following VMA release may be related to photoreceptor trauma and may parallel commotio retinae

§  Short-term assessments of ERGs and BCVA do not reflect ultimate visual acuity outcome of treatment with ocriplasmin over a longer time period

§  A proposed mechanism for the observed ERG changes is photoreceptor dysfunction similar to commotio retinae, specifically Berlin’s edema

§  Traction on the macula when acutely released with ocriplasmin may have a “trampoline”-like effect, compressing photoreceptors and causing widespread retinal involvement

§  This effect would be revealed in an abnormal flash ERG

§  All isoelectric ERGs occurred after VMA release

§  The effect appears totally reversible in most patients, paralleling what happens in Berlin’s edema

§  ERG results suggest that it is unlikely that nonspecific enzymatic activity of ocriplasmin is occurring in multiple retinal layers

Acute Expert-Defined ERG Reduction

ERG changes ≥40% compared to baseline, starting at either the Day 7 or Day 28 visit

ERG Substudy Design

§  Assessment made of acute expert-defined ERG reductions (definition below) §  6 sites were certified for ERG evaluations §  Espion E2 console and ColorDome full-field were used for ffERG assessment §  Full-field ERGs were recorded in both eyes at each visit §  Recordings were assessed by a masked central reading center §  24 month follow-up period

Baseline

§  VMA present §  VA: 20/40

Day 7

§  VMA release occurred by Day 7 visit §  Loss of scotopic function OS at Day 7 §  VA: 20/40

OS

OD

§  VMA release §  VA 20/25 (10-letter improvement from BL)

Month 24

Subject Enrollment

OASIS Study (N=220)

ERG Substudy (N=62)

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Sub

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ith V

MA

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olut

ion,

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02468101214161820

Sub

ject

s, n

Ocriplasmin 0.125 mg

M3 M6 D0

D28 (Primary Endpoint: Pharmacological VMA Release at Day 28) D7

BL

IVT M9 M12 M15 M18 M21 M24

OASIS Trial Assessment Schedule

Resolution of Acute Expert-Defined ERG Amplitude Reductions in Ocriplasmin and Sham Groups

1/21 (4.8%)

ERG reductions starting at Day 28 – resolved

ERG reductions starting at Day 7 – resolved

ERG reductions starting at Day 7 – unresolved by EOS

Sham Ocriplasmin

n=4 Median time to resolution: 68 days

n=3

n=9 Median time to resolution: 176 days

16/40 (40.0%)

Time to resolution: 66 days

Abbreviations: BCVA, best-corrected visual acuity; BL, baseline; D, day; EOS, end of study; ffERG, full-field electroretinogram; IVT, intravitreal injection; M, month; VMA, vitreomacular adhesion; VFQ-25, 25-item Visual Function Questionnaire.

Sham Ocriplasmin

Without ERG

Reductions

Without ERG

Reductions

With ERG

Reductions

VMA Resolution by Day 7

VMA Resolution by Day 28

10.0% 2/20

0.0% 0/1

With ERG

Reductions

12.5% 3/24

29.2% 7/24

62.5% 10/16

43.8% 7/16

VMA Resolution by ERG Amplitude Reductions in Ocriplasmin and Sham Groups

95% CI values: Day 7 ocriplasmin with ERG changes: 19.8, 70.1; Day 28 ocriplasmin with ERG changes: 35.4, 84.8; Day 7 ocriplasmin without ERG changes: 2.7, 32.4; Day 28 ocriplasmin without ERG changes: 12.6, 51.1; Day 7 and Day 28 sham with ERG changes: 0.0, 97.5; Day 7 and Day 28 sham without ERG changes: 1.2, 31.7

Subjects With Unresolved ERG Amplitude Reductions by Study End Subject #1

Subject #2 §  Unspecified foveal red lesion was reported at baseline §  Did not achieve VMA resolution §  Maintained visual acuity and general vision VFQ-25 score from baseline

Subject #3 §  Macular hole at baseline; worsening noted 6 days after injection §  Achieved VMA resolution by Day 7 visit §  Subject had 4 surgeries after ocriplasmin injection (2 vitrectomies, 1 cataract, 1 other) §  Lost 14 letters by study end (final VA 20/100)

OS

OD

OS

OD

OS

OD

OS

OD

OS

OD

§  VMA present §  VA: 20/32

§  VMA release occurred by Day 7 visit §  Significant scotopic loss OS at Day 28 §  VA 20/32 at Day 7, 20/25 at Day 28

§  Scotopic ERG now normal §  VA 20/20 at Month 6 and Month 24 §  8-letter VA improvement over baseline

Baseline Day 28 Month 24

REFERENCES

§  To evaluate the relationship of ERG changes with anatomic and visual outcomes for up to 24 months after a single injection of ocriplasmin 0.125 mg in the OASIS trial

§  To review selected patients from the ERG substudy that illustrate the broad spectrum of findings

§  To propose a mechanism to account for these findings

1) FDA approves Jetrea for symptomatic vitreomacular adhesion in the eyes [news release]. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm324369.htm. Accessed April 19, 2016. 2) Fahim AT, Khan NW, Johnson MW JAMA Ophthalmol. 2014;132(4):484-486. 3) Margo JA, Schocket LS, Klima K, Johnson MA. Retin Cases Brief Rep. 2015:1-4. 4) Small KW, Shaya FS, La Fontaine M Ophthalmic Surg Lasers Imaging Retina. 2015;46(9):956-962. 5) Hahn P, Chung MM, Flynn HW, et al. Retina. 2014;0:1-7.