1. VMT e Ocriplasmin Francesco Barca Stanislao Rizzo Daniela Bacherini Azienda Ospedaliero Universitaria Careggi Firenze

2. Simpson et al Surv Ophthalmol 2012 VMA: focal adhesion of the vitreous face within the macula region without any associated retinal distortion VMT: VMA causing focal tractional distortion of the macula. This image has been proposed as a photographic standard to define VMT VMT: VMA causing focal tractional distortion of the macula.

3. Goal of therapy … To RELEASE vitreous TRACTION on the macula thereby resolving the underlying condition BEFORE structural retinal damage has occurred! Vision Improvement

4. Microplasmin for Intravitreous Injection Traction Release without Surgical Treatment 2 randomized, placebo-controlled Phase 3 studies: TG-MV-006 and TG-MV007 MIVI-TRUST

5. Ocriplasmin: truncated form of human plasmin Plasmin Ocriplasmin

6. Ocriplasmin acts on Laminin and Fibronectin, molecolar glues between PVC and ILM Posterior vitreous cortex ILM Vitreous Therefore … Release of VMT!

7. Indication Ocriplasmin is a truncated form of Human Plasmin Trattamento della TVM, compresa quella associata a MH di diametro ≤ 400 microns

8. Stalmans P, Benz MS, Gandorfer A, et al; MIVI-TRUST Study Group. N Engl J Med. 2012;367:606-615. n=19123 Placebo o N=188 Ocriplasmin N=464 p<0.001 Jetrea (ocriplasmin) Resolution of VMT at Day 28 Patients, %

9. Placebo N=188 (10.1%) Ocriplasmin N=464 (26.5%) Placebo 1 : 10 Ocriplasmin 1 : 4 Jetrea (ocriplasmin) Resolution of VMT at Day 28

10. Independent Baseline Features Predictive of Pharmacologic VMT Resolution FTMH present VMT diameter ≤1500 μm ERM absent Phakic Age <65 years

11. % with VMA Resolution p-valuePatient TypeOcriplasminPlacebo <0.001 Symptomatic VMT 26.510.1 0.006 + FTMH 50.025.5 0.026 + age <65 years + diameter ≤1500 μm 60.026.2 0.017 + no ERM 66.4 35.0 0.020 + phakic status 70.540.0 Ocriplasmin Placebo 100%

12. Positive Predictors Criteria Enzyme impact on small adhesions is expected to be maximal Focal adhesion (≤1.500 μm)

13. Positive Predictors Criteria Enzyme impact on small adhesions is expected to be maximal Focal adhesion (≤1.500 μm) No epiretinal membrane (ERM) Enzyme does not dissolve membranes Younger age Phakic Probably selection bias: patients pseudophakic or aged>65 years would already have developed a spontaneous PVD, therefore patients enrolled might be more resistant cases of VMA

14. -35 subjects with symptomatic VMA. - Retrospective interventional case series -Resolution of VMT 43% Predictive factors of VMA resolution: age<65 years (p 0.04) Retinal comorbidity absence (p 0.02) Adhesion diameter <1500 micron (p 0.005) VMA duration (p 0.03)

15. Proportion of Patients With FTMH Closure at Day 28 Day 28 Patients With FTMH Closure, % Placebo (n=47) Ocriplasmin (n=106) p<0.001 n=43n=5 Stalmans P, Benz MS, Gandorfer A, et al; MIVI-TRUST Study Group. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med. 2012;367:606-615. < 400: 48.8% < 250: 58.3%

16. safety

17. 1) ACUTE REDUCTION VISUAL ACUITY Visual acuity loss was attributed to: -progression of the associated macular pathology (vitreomacular traction and/or fullthickness macular hole) - or to onset of a subretinal fluid at the fovea despite VMA resolution Premarketing, or clinical trial, data (n = 999 inj.) 6-month study end point. Postmarketing reports through July 16, 2013 (n = 4,387 injections) 26% were ongoing or resolving < 35% resolution status unknown.

18. -Foveolar lucencies observed by OCT are a common finding after macular hole surgery (26%). - They occur with and without ICG-assisted ILM peeling and irrespective of the type of gas used for tamponade in this small group of eyes. -Foveolar lucencies gradually decrease and eventually resolve over 3 to 11 months without further surgical intervention. -Disappearance of the foveolar lucency correlates with further improvement of visual acuity. It remains uncertain as to why the foveolar lucencies took so much time to resolve (3– 11 months) and what the material within lucencies consists of.

19. Retrospective, single-center, observational case series In 38 eyes with VMT (10 with concomitant full-thickness macular hole), - Subretinal fluid in the macular region was observed in 36.8% of eyes 1 day after injection, with resolution by day 42

20. 2) ERG CHANGES 3) DYSCHROMATOPSIA 4) RETINAL TEAR/DETACHMENT

21. RBs in: 1.1% (23/1862 eyes) Retinal Tears in Macular Surgery: 23-25 Gauge Cannula System

22. 2) ERG CHANGES 3) DYSCHROMATOPSIA 4) RETINAL TEAR/DETACHMENT 5) LENS SUBLUXATION/PHACODONESIS

23. Case Reports

24. REVERSIBLE VISION LOSS AND OUTER RETINAL ABNORMALITIES AFTER INTRAVITREAL OCRIPLASMIN INJECTION Thanos et al. Retinal cases and Brief reports 2014 A 55-year-old woman experienced acute severe vision loss 2 days after the treatment with ocriplasmin, recovered over a 3-month period after the injection a 97 year old patient with vision reduction after 1 day ocriplasmin inj; resolution after 56 days A 71-year-old woman with vision loss after ocriplasmin: improvement after 4 months, with persistent discontinuity of the ellipsoid zone a 63-year-old woman with acute panretinal dysfunction after intravitreous ocriplasmin injection for a small macular hole with VMA. A 67-year-old female with VMA, ERM and macular hole. One week following intravitreal ocriplasmin visual acuity had decreased to 20/400. 3 weeks later: persistence of the macular hole

25. ELLIPSOID ZONE INTERDIGITATION ZONE MYOID ZONE

26. OUTER RETINAL FINDINGS  Transient loss or disruption of the ellipsoid zone: discontinuity of the IS/OS layer Diffuse loss of this band Day 2 Strong ellipsoid zone band Day 0 Return of the ellipsoid zone Day 32  Subretinal fluid: often associated with VMT resolution

27. The same isoform of laminin found in the internal limitation membrane is also expressed in the IPM (InterPhotoreceptor Matrix) Ocriplasmin may penetrate through the retina and react with the laminin located within the IPM IPM is known to play a major role in mediating retinal adhesion to the RPE

28. -35 subjects with symptomatic VMA. - Retrospective interventional case series -Resolution of VMT 43% Predictive factors of VMA resolution: age<65 years (p 0.04) Retinal comorbidity absence (p 0.02) Adhesion diameter <1500 micron (p 0.005) VMA duration (p 0.03) Transient outer retinal attenuation: 28.6% Broadest VMA diameter Resolved in all cases at mean 24.2 days after IVI p 0.008

29. VMA Resolution Rate (%) Overall rate of MH Closure (%) Overall VMA Diameter ≤1500 μm No ERM FTMH Present Phase 3 Trials26.534.737.45040.6 Bascom Palmer42.15054.566.750 Cole Eye47.161.550NR80 California Retina56n/a56.572.736.4 NJ Retina3538*41.573.332 Real-World Clinical Experience Summary

30. Real-Italy Clinical Experience Summary VMA Resolution Rate: 57% FTMH Closure Rate: 62.5% Presence of ERM: 45% No ERM: 64.8%

31. Tips For Using Ocriplasmin  Consider injecting as posteriorly as possible – bury the ½-inch needle to the hub  Consider laying the patient back for up to 30 minutes after the injection  Use the predictor of response guidelines

32. Ocriplasmin is not the same as other intravitreal agents we are currently utilizing in clinical practice Who, how and when we inject may be important… Patient selection plays a role in the success rate of therapy The majority of adverse events associated with ocriplasmin therapy: Have an acute onset: Days 0–7 Are mild/moderate in severity Are transient and self-limiting Conclusions

33. JETREA:Classe H farmaci a carico del Servizio Sanitario Nazionale utilizzati o forniti in ambito ospedaliero 05/03/2015

35. grazie