Early diagnosis and treatment of VMT with single Intravitreal Injection of Pharmacologic Vitreolysis. Stratos Gotzaridis MD Athens

Transcription

1 Early diagnosis and treatment of VMT with single Intravitreal Injection of Pharmacologic Vitreolysis Stratos Gotzaridis MD Athens

2 The Vitreous Body Gel composed of 98-99% water 1% macromolecules Glycoproteins (opticin) Proteoglycans Collagens (types II,V, VI, IX, and XI) Glycosaminoglycans (hyaluronan) Other structural proteins (fibrillin) Vitreous gel contains two major network-forming polymeric systems 1. Fibrils: maintain the gel structure 2. Hyaluronan (HA) meshwork: stabilize fibril network Ponsioen TL, van Luyn, MJA, van der Worp, RJ, van Meurs, JC, Hooymans, JM, Los, LI Invest Ophthalmol Vis Sci. 2008;49(9): Bos et al. Micron. 2001; 32:

3 The Vitreoretinal Interface The Inner Limiting Membrane (ILM) attaches the retina to the vitreous Symptomatic VMA. Accessed April 30,

4 The Vitreoretinal Interface (cont d) Vitreous cortex is attached to the inner limiting membrane (ILM) of the retina by macromolecules 1 Strongest attachment to retina At vitreous base At equator Over retinal blood vessels At optic disc and at macula Vitreous cortex distinguishable from central vitreous body 2 Higher concentration of matrix proteins 1. Ponsioen et al. Prog Retinal Eye Res. 2010; 29: Bishop PN. Prog Retin Eye Res. 2000;19(3):

5 Pathology of Posterior Vitreous Detachment (PVD) Vitreous remodelling leads to progressive liquefaction with age 1,2 Complete separation (total PVD) Vitreomacular adhesion (VMA) 1. Le Goff MM, Bishop PN. Eye Oct;22(10): Sebag J. Graefes Arch Clin Exp Ophthalmol 2004; 2004 Aug;242(8): Stalmans P, Duker JS, Kaiser P, et al. Retina July;(0):1-9. 5

6 VMT and Macular Hole VMA VMT Macular Hole Can Progress To Can Progress To Fibronectin, laminin, and collagen bind at macular VRI; contribute to VMA Spontaneous VMT release occurs in 11% of patients 1 6-fold increased risk of macular hole in fellow eye 2 1. Hikichi T, Yoshida A, Trempe CL. Am J Ophthalmol. 1995;119(1): Chan A, Duker JS, Schuman JS, Fujimoto JG. Ophthalmology. 2004;111(11):

7 Clinical Presentation of Symptomatic VMA or VMT VMA Metamorphopsia 1 Deteriorating Visual Acuity (VA) 2 Significant Vision Loss 3 + = Symptomatic VMA 4 or VMT + = Symptomatic VMA or VMT Example of Metamorphopsia OCT image courtesy of Heidelberg Engineering. Amsler grid image courtesy of My Vision Test. Accessed May 9, Jaffe NS. Trans Am Acad Ophthalmol Otolaryngol. 1967;71(4): Irvine SR. Am J Ophthalmol. 1953;35(5): Reese AB, et al. Trans Am Ophthalmol Soc. 1966;64: Schneider EW, Johnson MW. Clin Ophthalmol. 2011;5:

8 Potential for Disease Progression Vitreomacular Adhesion Vitreomacular Traction (VMT) TRACTION Macular Hole With VMT TRACTION 8

9 JETREA (ocriplasmin) Offers an Alternative to Watchful Waiting Time worsening of pathology/symptoms Vitreomacular traction Watchful Waiting Vitrectomy Delayed treatment Invasive Surgical risks and complications Earlier treatment Minimally invasive VMA resolution FTMH closure Improved QoL 9

10 JETREA (ocriplasmin) 0.5 mg/0.2 ml concentrate for solution for injection ENZYMATIC VITREOLYSIS 10

11 JETREA (Ocriplasmin) Is a Truncated Form of Human Plasmin Plasmin 86 kda Ocriplasmin 27.2 kda Produced by recombinant DNA technology in Pichia pastoris expression system Delivered via intravitreal injection Cleaves laminin, fibronectin, and collagen JETREA [summary of product characteristics]. Leuven, Belgium: ThromboGenics NV;

12 JETREA Is a Vitreolytic Agent JETREA contributes to the release of VMA or VMT by: Cleaving the vitreoretinal interface Liquefying the vitreous body JETREA injection JETREA [summary of product characteristics]. Leuven, Belgium: ThromboGenics NV;

13 Histological Studies: Ocriplasmin Shown to Induce PVD Normal Mouse Eye PVD After Ocriplasmin in Mouse Eye Vitreous Body Vitreous cortex PVD Data on file, ThromboGenics. 13

14 JETREA (ocriplasmin) 0.5 mg/0.2 ml concentrate for solution for injection CLINICAL STUDY DESIGN 14

15 Phase 3 Study Design JETREA 125 μg Investigator could opt for vitrectomy TG-MV-006 (US, 2:1) TG-MV-007 (EU and US, 3:1) Intravitreal therapy (IVT) Day 7 Day 14 Day 28 Month 3 Month 6 Vehicle Primary Endpoint (Alpha Protected) Pharmacologic resolution of VMA Secondary Endpoint (Alpha Protected) Total posterior vitreous detachment (PVD) Exploratory Secondary Endpoints Stalmans P, Benz MS, Gandorfer A, et al. N Engl J Med. 2012;367(7): Data on file, ThromboGenics, Inc

16 Key Inclusion and Exclusion Criteria Inclusion Criteria Vitreomacular traction VMA diagnosed by investigatorread OCT Presence of decreased visual function symptoms (metamorphopsia, decreased visual acuity [VA], or other visual complaint) that in the opinion of the investigator are related to the VMA BCVA 20/25 in study eye Exclusion Criteria In the study eye: History of prior vitrectomy or prior laser photocoagulation to the macula High myopia (> 8 diopters) Macular hole diameter >400 µm Proliferative or neovascular retinal diseases that could affect visual function BCVA 20/800 in fellow eye Stalmans P, Benz MS, Gandorfer A, et al. N Engl J Med. 2012;367(7): Data on file. ThromboGenics, Inc

17 Proportion of Patients With Pharmacologic VMA Resolution Over Course of Study Proportion of Patients With VMA Resolution, % % Proportion of patients with VMA resolution relative to Day 28 JETREA % 73% 15 Vehicle Days Postinjection Primary Endpoint Stalmans P, Benz MS, Gandorfer A, et al. N Engl J Med. 2012;367(7):

18 Summary of Product Characteristics: ERM and VMA Diameter Patients with no ERM at baseline were more likely to achieve VMA resolution at Day 28 compared with those who had ERM at baseline. n=17 n=101 n=1 n=16 n= Patients with a smaller VMA diameter at baseline ( 1500 microns) were more likely to achieve VMA resolution at Day 28 compared with those who had a diameter > 1500 microns. n=18 n=109 n=6 n= JETREA [summary of product characteristics]. Leuven, Belgium: ThromboGenics NV; JETREA [product monograph]. Mississauga, ON, Canada: ThromboGenics NV;

19 Proportion of Patients with Total PVD at Day 28 Key Secondary Endpoint P< % 3.7% n=7 n=62 Vehicle (n=188) JETREA (n=464) Alpha-Protected Secondary Endpoint Odds Ratio (95% CI): 4.27 ( ) Stalmans P, Benz MS, Gandorfer A, et al. N Engl J Med. 2012;367(7):

20 Proportion of Patients With FTMH Closure (Without Vitrectomy) n=43 n=43 n=5 n=8 Odds Ratio (Day 28) (95% CI): 5.94 ( ) Data on file, ThromboGenics, Inc

21 Patients With FTMH Closure at Day 28 by FTMH Size at Baseline (Without Vitrectomy) % of Patients With FTMH Closure Vehicle (N=47) JETREA (N=106) n=28 n=4 n=14 n=1 250 µm >250 to 400 µm >400 µm N= Data on file, ThromboGenics, Inc

22 Summary: JETREA for the Treatment of VMT A single intravitreal dose of 125 µg JETREA achieved clinically significant results in eyes with VMT Proportion of patients with VMA resolution at day % Proportion of patients with total PVD at day % Proportion of patients with FTMH closure (without vitrectomy) at 6 months 40.6% VA gains in patients with VMA resolution 2-line gain at 6 months 28.0% 22

23 JETREA 0.5 mg/0.2 ml concentrate for solution for injection Ocriplasmin SAFETY PROFILE 23

24 Adverse Events in MIVI 6 and 7 AEs reported Days Placebo (n=187) Ocriplasmin (n=465) Majority of events were related to VMA resolution or the injection procedure 2 AEs were mainly transient and mild in severity 3 1. Kaiser P. Retina Society 2012:oral; 2. ThromboGenics. Data on file. 2013; 3. Stalmans P et al. N Engl J Med 2012;367:606

25 Adverse Events in MIVI 6 and 7 AEs reported Day 8 to Month 6 Placebo (n=187) Ocriplasmin (n=465) Incidences of AEs were similar between treatment groups Kaiser P. Retina Society 2012:oral

26 VMA Resolution in Patients with Acute Vision Decrease (MIVI 6/7) 20/40 20/80 20/32 Baseline Day 7 Month 6 20/40 20/63 20/40 Baseline Day 7 Month 6 ThromboGenics. Data on file. 2013

27 Patient 1 - VMT: Baseline 20/ Patient 1 Information: Injection Date: 16 Jan 62-year-old female Treated Eye (OD): VMT; cataract; VA= 20/40 Other eye (OS): ERM; macular edema Decreased vision TD-OCT 27

28 Patient 1 - VMT: Day 7 20/ TD-OCT 28

29 Patient 1 - VMT: Day 14 20/ TD-OCT 29

30 Patient 1 - VMT: Day 28 20/ TD-OCT 30

31 Patient 1 - VMT: Month 3 20/ TD-OCT 31

32 Patient 1 - VMT: Month 6 20/ TD-OCT 32

33 Patient 1 VMT: Case Summary Baseline Day 7 Day 14 Day 28 Month 3 20/40 20/80 20/32 20/32 20/25 Patient 1 Information: 62-year-old female Injection Date: 16 Jan Outcome at 6 months: VMT resolved by Day 7 VA at 6 months = 20/32 Month 6 20/32 33

34 Patient 2 VMT and MH 400µm (baseline) 20/63 TD-OCT 0.32 Patient 3 Information: Injection Date: 01 July 80-year-old female Treated Eye (OS): Macular hole with VMT; cataract; VA= 20/63 Other eye (OS): cataract OU: glaucoma Distorted vision and blurriness 34

35 Patient 2 VMT and MH 400µm: Day 7 20/ TD-OCT 35

36 Patient 2 VMT and MH 400µm: Day 14 20/ TD-OCT 36

37 Patient 2 VMT and MH 400µm: Day 28 20/ TD-OCT 37

38 Patient 2 VMT and MH 400µm: Month 3 20/ TD-OCT 38

39 Patient 2 VMT and MH 400µm: Month 6 20/ TD-OCT 39

40 Patient 2 VMT and MH 400µm: Case Summary Baseline 20/63 Day 7 Day 14 Day 28 Month 3 20/50 20/63 20/40 20/40 Patient 3 Information: 80-year-old female Injection Date: 01 July Outcome at 6 months: VMT release and MH closure by Day 7 VA at 6 months = 20/32 Month 6 20/32 40

41 Patient 3 VMT With Epiretinal Membrane: Baseline VA: 20/32 TD-OCT VA: 0.63 Patient 7 Information: Injection Date: 25 June 80-year-old male Treated Eye (OS):VMT; ERM; dry AMD; VA=0.63 Other eye (OD): wet AMD; VA=0.08 Floaters Case study courtesy of Peter Stalmans, MD, PhD. 41

42 Patient 3 VMT With Epiretinal Membrane: Day 1 VA: 20/33 VA: 0.63 TD-OCT Reports floaters Case study courtesy of Peter Stalmans, MD, PhD. 42

43 Patient 3 VMT With Epiretinal Membrane: Day 3 VA: 20/32 VA: 0.63 TD-OCT Case study courtesy of Peter Stalmans, MD, PhD. 43

44 Patient 3 VMT With Epiretinal Membrane: Day 7 VA: 20/32 VA: 0.63 TD-OCT Case study courtesy of Peter Stalmans, MD, PhD. 44

45 Patient 3 ERM: Case Summary Baseline Day 1 Day 3 Day Patient 7 Information: 80-year-old male Injection Date: 25 June Outcome: Although patient had a clear ERM and insisted on trying JETREA, he was not a good candidate VA at Day 7 = 0.7 Surgery for ERM was ultimately scheduled Case study courtesy of Peter Stalmans, MD, PhD. 45

46 46 Ευχαριστώ