Bandello pharmacological treatment of vitreo macular traction

Pharmacological Treatment of Vitreo-Macular Traction

Francesco Bandello, MD, FEBO Lorenzo Iuliano, MD

Department of OphthalmologyUniversity Vita-Salute

San Raffaele Scientific InstituteMilan, Italy

Financial DisclosureAdvisory Board Member for:• Alcon• Alimera• Allergan• Bausch and Lomb• Bayer• Genentech• Hossmann-La Roche• Novagali Pharma• Novartis• Pfizer• Sanofi-Aventis• Thea• Thrombogenics

• Vitreomacular adhesion– perifoveal hyaloid detachment with no detectable change in foveal

contour or underlying retinal tissues

• Vitreomacular traction– perifoveal hyaloid detachment associated with distortion of the foveal

surface, intraretinal structural changes, retinal elevation above the RPE, but no full-thickness interruption of all retinal layers

Definition

Physiologic PVD• PVD is the separation of the posterior vitreous from the ILM

• Processes involved– Synchysis

– Syneresis

– Weakening of the V-R adhesion

• PVD can be asymptomatic, although some patients report floaters

Early liquefaction Extensive liquefaction Separation

Johnson MW. Am J Ophthalmol 2010Schneider EW et al. Clin Ophthalmol 2011

Sebag J. Graefes Arch Clin Exp Ophthalmol 2004Hollands H et al. JAMA 2009

Anomalous PVD

• Sufficient weakening at the V-R interface when the critical level of liquefaction has been achieved

• If not, incomplete (anomalous) PVD can arise

Sebag J. Graefes Arch Clin Exp Ophthalmol 2004Dugel P. Retina Today 2012

Pathophysiology of Anomalous PVD

Stalmans et al. Retina (2013)

Stalmans et al. Retina (2013)

Pathophysiology of Anomalous PVD

• Vitreo-macular traction can coexist with other diseases

Secondary VMT

Bandello F et al. Ophthalmologica 2013

VMT classification

Duker JS et al. Ophthalmology 2013

Natural History

Carpineto P et al. Eur J Ophthalmol 2011Guyer DR et al. Arch Ophthalmol 1992

Hikichi T et al. Br J Ophthalmol 1995Kim JW et al. Am J Ophthalmol 1996

VMAVMA

Total PVDTotal PVD Spontaneous resolution

FTMH3–12%

spontaneous closure

VMA, VMTnon full thickness MH non FTMHnon FTMH

50–84%

PVD

• Only 5% will have 20/50 BCVA or better

• 55–58% will have BCVA of 20/100 or better

• Approximately 40% will have BCVA of 20/200 or worse

• If the FTMH closes (rare), BCVA can recover

• Most patients retain a BCVA of 20/100 to 20/400

Macular Hole Prognosis

AAO Retina Panel (2008)Preferred Practice Pattern®

Idiopathic Macular Hole

The idea

• Standard of care:

• “Watchful waiting”• Vitrectomy

• Alternative:

• Pharmacologic vitreolysis

• Pharmacological vitreolysis was defined by J Sebag

“Weaken or cleave V-R junction before or concurrentlywith liquefaction of core vitreous”

• First animal experience of enzymatic vitreolysis are of 1998

Pharmacologic vitreolysis

Sebag J. Retina 1998Sebag J. Retina 2009

• Several agents have been tested to achieve vitreolysis

• Classified accordingly to their biological effect

Different agents

Bandello F et al. Ophthalmologica 2013

• rtPA: safe only for sub-macular hemorrhages in nvAMD

• Nattokinase: only animal models

• Chondroitinase: no significant biological effect

• Dispase: retinal toxicity, PVR• Hyaluronidase (Vitrase®): no FDA approval, just liquefactant

• Collagenase: retinal toxicity, ILM damage

Bandello F et al. Ophthalmologica 2013

• Most studied agent

• Extracted from patient’s plasma-derived plasminogen

• Action• Non-specific serine-protease

• Degrades fibrin, fibronectin and laminin

• Indirectly increases levels of matrix metalloproteinases

• Safety (histology and electrophysiology) at different concentration (0.03-2 IU)

Autologous Plasmin Enzyme (APE)

• Pediatric population:ROP, X-linked retinoschisis, traumatic macular hole

• Assisting surgery

• Diabetic macular edema

• Retinal vein occlusion

• Vitreo-macular traction

Experience with APE

Margherio AR et al. Ophthalmology 1998Wu WC et al. Am J Ophthalmol 2007

Tsukahara Y et al. Am J Ophthalmol 2007Wu WC et al. Retina 2008Wu WC et al. Retina 2007

Trese MT et al. Am J Ophthalmol 2000Rizzo S et al. Retina 2006

Sakuma T et al. Eur J Ophthalmol 2005Asami T et al. Ophthalmology 2004

Azzolini et al. Am J Ophthalmol 2004Sakuma T et al. Eur J Ophthalmol 2006

Hirata A et al. Sakuma T et al. Retina 2006Udaondo P et al. Arch Ophthalmol 2011

Codenotti M et al. Eye 2013

Codenotti M et al. Eye 2013

intravitreal APE

7 days

30 days

Surgery

24h

Form APE to ocriplasmin

• Recombinant truncated form of the active enzyme

• 1/3 molecular weight

• Retains the catalytic activity

Nagai N et al. J Thromb Haemost 2007de Smet et al. IOVS 2009

• Targets fibronectin, laminin and collagen

• Induces vitreous liquefaction and separation of V-R interface

• Cleanly separate hyaloid from ILM

Form APE to ocriplasmin

Collagen

Laminin, Fibronectin

Collagen

Gandorfer et al. IOVS 2004

• Phase I/II, 60 pts

• Safe

• Well tolerated

MIVI studies

• Phase II, 60 pts

• Best dose of 125 µg

• Capable of PVD inducing

de Smet M et al. Ophthalmology 2009

Stalmans P et al. Retina 2010

Stalmans P et al. NEJM 2012

• Phase III, 652 pts

• Dose of 125 µg

• Superior than sham inj.

The definitive approval

Two multicenter, randomized, double-masked, placebo-controlled, phase III studies

Randomized (N=652)

Ocriplasmin 125 µg (n=464)

Placebo(n=188)

Assessments at baseline, injection day, and Days 7, 14, 28, 90, and 180 after injection

Patients with symptomatic VMA confirmed by optical coherence tomography

Stalmans P et al. NEJM 2012

ocriplasmin placebo

VMT resolution 26.5% 10.1%

PVD induction 13.4% 3.7%

MH closure 40.6% 10.6%

P<0.001 (all)

Stalmans P et al. NEJM 2012

The definitive approval

p<0.001

p=0.113

VMA resolution at day 28 according to adhesion size

Ocriplasmin

Placebo

n= 123 314 41 102

Patie

nts

with

re

solu

tion

of V

MA

(%)

ThromboGenics NV. JETREA (ocriplasmin) Summary of Product Characteristics. 2013

Post-hoc studies

N=35N=86

N=33N=98

N=68N=184

Study 006 Study 007 Study 006 Study 007 Combineddata

N=72N=128

N=47N=142

N=119N=270

Epiretinal membrane No epiretinal membrane

p<0.001p<0.001

p=0.046p=0.180

p=0.289

p<0.003

Combineddata

VMA resolution at day 28 according to epiretinal membrane presence

Stalmans P et al. NEJM 2012

N=35N=86

N=33N=98

N=68N=184

Study 006 Study 007 Study 006 Study 007 Combineddata

N=72N=128

N=47N=142

N=119N=270

Epiretinal membrane No epiretinal membrane

p<0.001p<0.001

p=0.046p=0.180

p=0.289

p<0.003

Combineddata

VMA resolution at day 28 according to epiretinal membrane presence

Stalmans P et al. NEJM 2012

Non-surgical MH closure at day 28 according to MH size

Stalmans P et al. NEJM 2012

p<0.001

n = 4 28 5 28 Day 28 6 Months

>250 µm

p=0.002p=0.200p=0.031

n = 1 14 3 14

% P

atie

nts

% P

atie

nts

Day 28 6 Months≤250 µm

Non-surgical MH closure at day 28 according to MH size

Stalmans P et al. NEJM 2012

• Requirement of vitrectomy at day 180– 17.7% (ocriplasmin) vs 26.6% (sham); p=0.02

• BCVA improvement– >2 lines: 28% (ocriplasmin) vs 17.1% (sham); p=0.003

– >3 lines: 12.3% (ocriplasmin) vs 6.4% (sham); p=0.024

Stalmans P et al. NEJM 2012

• Focal VMT

• Symptomatic VMA

• Non full thickness macular hole

• Full thickness macular hole <400 µm

Actual indications

Side effects

• The difference in the proportion of patients experiencing AEs was driven primarily by those associated with vitreous detachment

• The majority of AEs were transient and mild in severity

Placebo (n=187)

Ocriplasmin (n=465)

p

Any ocular AE, n (%) 100 (53.5) 318 (68.4) <0.001

Any ocular serious AE, n (%) 20 (10.7) 36 (7.7) 0.26

Stalmans P et al. NEJM 2012

Event, n (%)Placebo (n=187)

Ocriplasmin (n=465)

p

Any serious AE 20 (10.7) 36 (7.7) 0.26

Macular hole 16 (8.6) 24 (5.2) 0.15

Retinal detachment 3 (1.6) 2 (0.4) 0.16

Reduced VA 1 (0.5) 3 (0.6) 0.94

Stalmans P et al. NEJM 2012

Side effects

Safety concerns

Kim JE. JAMA Ophth 2014

• ERG abnormalities in 7.8% of pts

• Dyschromatopsia (yellowing vision) in 2% of pts• 1% of these with ERG changes

• Reports of vision loss and panretinal abnormalities

Tibbets M et al. JAMA Ophth 2014Fahim AT et al. JAMA Ophth 2014

• Judicious use

• Careful follow-upPhase IV studies

• Eyes with nvAMD have more than twice chance (OR 2.54) to have concurrent VMT

• Anti-VEGF + ocriplasmin?

Jackson TL et al. Retina 2013

VMT and Neovascular AMD

Conclusion

• “Watchful waiting” of VMT can lead to irreversible retinal damage, cysts and macular hole formation

• Spontaneous separation of VMT occurs rarely

• Vitrectomy indicated if VA loss or disease progression, but surgery is not risk-free

• Pharmacologic vitreolysis may induce VMT resolution and improve vision