Bandello pharmacological treatment of vitreo macular traction
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This document summarizes pharmacological treatment of vitreo-macular traction using ocriplasmin. It defines vitreo-macular traction and adhesion and describes the natural history if left untreated. It outlines the development of ocriplasmin from autologous plasmin to a recombinant form, and phase I-III clinical trial results demonstrating its safety and ability to resolve vitreo-macular adhesion in 26.5% of cases compared to 10.1% for placebo. Potential indications include focal vitreo-macular traction, symptomatic vitreo-macular adhesion, and small non-full thickness or full thickness macular holes.
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Bandello pharmacological treatment of vitreo macular traction
- 1. Pharmacological Treatment of Vitreo-Macular Traction Francesco Bandello, MD, FEBO Lorenzo Iuliano, MD Department of Ophthalmology University Vita-Salute San Raffaele Scientific Institute Milan, Italy
- 2. Financial Disclosure Advisory Board Member for: • Alcon • Alimera • Allergan • Bausch and Lomb • Bayer • Genentech • Hossmann-La Roche • Novagali Pharma • Novartis • Pfizer • Sanofi-Aventis • Thea • Thrombogenics
- 3. • 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
- 4. 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 2010 Schneider EW et al. Clin Ophthalmol 2011 Sebag J. Graefes Arch Clin Exp Ophthalmol 2004 Hollands H et al. JAMA 2009
- 5. 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 2004 Dugel P. Retina Today 2012
- 6. Pathophysiology of Anomalous PVD Stalmans et al. Retina (2013)
- 7. Stalmans et al. Retina (2013) Pathophysiology of Anomalous PVD
- 8. • Vitreo-macular traction can coexist with other diseases Secondary VMT Bandello F et al. Ophthalmologica 2013
- 9. VMT classification Duker JS et al. Ophthalmology 2013
- 10. Natural History Carpineto P et al. Eur J Ophthalmol 2011 Guyer DR et al. Arch Ophthalmol 1992 Hikichi T et al. Br J Ophthalmol 1995 Kim JW et al. Am J Ophthalmol 1996 VMAVMA Total PVDTotal PVD Spontaneous resolution FTMH 3–12% spontaneous closure VMA, VMT non full thickness MH non FTMHnon FTMH 50–84% PVD
- 11. • 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
- 12. The idea • Standard of care: • “Watchful waiting” • Vitrectomy • Alternative: • Pharmacologic vitreolysis
- 13. • Pharmacological vitreolysis was defined by J Sebag “Weaken or cleave V-R junction before or concurrently with liquefaction of core vitreous” • First animal experience of enzymatic vitreolysis are of 1998 Pharmacologic vitreolysis Sebag J. Retina 1998 Sebag J. Retina 2009
- 14. • Several agents have been tested to achieve vitreolysis • Classified accordingly to their biological effect Different agents Bandello F et al. Ophthalmologica 2013
- 15. • 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
- 16. • 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)
- 17. • 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 1998 Wu WC et al. Am J Ophthalmol 2007 Tsukahara Y et al. Am J Ophthalmol 2007 Wu WC et al. Retina 2008 Wu WC et al. Retina 2007 Trese MT et al. Am J Ophthalmol 2000 Rizzo S et al. Retina 2006 Sakuma T et al. Eur J Ophthalmol 2005 Asami T et al. Ophthalmology 2004 Azzolini et al. Am J Ophthalmol 2004 Sakuma T et al. Eur J Ophthalmol 2006 Hirata A et al. Sakuma T et al. Retina 2006 Udaondo P et al. Arch Ophthalmol 2011 Codenotti M et al. Eye 2013
- 18. Codenotti M et al. Eye 2013 intravitreal APE 7 days 30 days Surgery 24h
- 19. 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 2007 de Smet et al. IOVS 2009
- 20. • 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
- 21. • 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.
- 22. 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
- 23. 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
- 24. p<0.001 p=0.113 VMA resolution at day 28 according to adhesion size Ocriplasmin Placebo n= 123 314 41 102 Patientswith resolutionofVMA(%) ThromboGenics NV. JETREA (ocriplasmin) Summary of Product Characteristics. 2013 Post-hoc studies
- 25. N=35 N=86 N=33 N=98 N=68 N=184 Study 006 Study 007 Study 006 Study 007 Combined data N=72 N=128 N=47 N=142 N=119 N=270 Epiretinal membrane No epiretinal membrane p<0.001 p<0.001 p=0.046 p=0.180 p=0.289 p<0.003 Combined data VMA resolution at day 28 according to epiretinal membrane presence Stalmans P et al. NEJM 2012
- 26. N=35 N=86 N=33 N=98 N=68 N=184 Study 006 Study 007 Study 006 Study 007 Combined data N=72 N=128 N=47 N=142 N=119 N=270 Epiretinal membrane No epiretinal membrane p<0.001 p<0.001 p=0.046 p=0.180 p=0.289 p<0.003 Combined data VMA resolution at day 28 according to epiretinal membrane presence Stalmans P et al. NEJM 2012
- 27. Non-surgical MH closure at day 28 according to MH size Stalmans P et al. NEJM 2012
- 28. p<0.001 n = 4 28 5 28 Day 28 6 Months >250 µm p=0.002 p=0.200p=0.031 n = 1 14 3 14 %Patients %Patients Day 28 6 Months ≤250 µm Non-surgical MH closure at day 28 according to MH size Stalmans P et al. NEJM 2012
- 29. • 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
- 30. • Focal VMT • Symptomatic VMA • Non full thickness macular hole • Full thickness macular hole <400 µm Actual indications
- 31. 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
- 32. 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
- 33. 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 2014 Fahim AT et al. JAMA Ophth 2014 • Judicious use • Careful follow-up Phase IV studies
- 34. • 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
- 35. 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