Financial Disclosures Consultant Genentech, Regeneron, Allergan, Thrombogenics, Optos, and ArcticDx Grant Support Regeneron, Allergan Mathew W. MacCumber, MD, PhD Professor & Assoc. Chair for Research Rush University Medical Center Chicago, IL Proliferative diabetic retinopathy (PDR) Proliferative vitreoretinopathy (PVR) Macular pucker & Macular hole Diabetic macular edema (DME) Vitreo-macular traction syndrome (VMT) Exudative age-related macular degeneration (AMD)? Vitrectomy is the current treatment vitreoretinal interface pathology Vitreomacular traction syndrome Macular hole Pharmacologic vitreolysis using microplasmin has demonstrated potential to induce PVD Rapid diffusion of drugs It s mostly water Has relatively few molecular components It s relatively acellular ILM Stain for Fibronectin Vitreous adhesion to ILM is mediated by: Fibronectin Laminin Chondroitin Glycoconjugates G. A. Williams, MD 1
G. Williams M. Trese Hydrolyzing laminin and fibronectin which bridge collagen fibers between the posterior vitreous cortex and the ILM Trese and Williams developed autologous plasmin method Induces PVD, especially in young patients, dose and duration dependent Cumbersome preparation using patients serum Kringle 4 (Fibrin binding site) Kringle 3 Kringle 2 Kringle 1 (Fibrin binding site) Kringle 5 Serine Protease (active part) 88 kda Size 29 kda Size Protein Ribbon Structure Generic name for microplasmin Lacks inactive kringle domains Direct-acting thrombolytic (unlike plasminogen activator) Smaller molecule, allows better retinal penetration Recombinant technology Induces PVD with single 75μg or 125μg injection ThromboGenics Leuven, Belgium ~ Dublin, Ireland ~ New York NY Injection The MIVI Trials MIcroplasmin for VItreous Injection 2
19 Centers 125 Patients without PVD Scheduled for Vitrectomy Sacramento Los Angeles Huntington Beach San Diego Tucson Data Monitoring Board Julia Haller, MD William Mieler, MD Lloyd-Paul Aiello, MD PhD Syracuse Boston Minneapolis Royal Oak Pittsburgh New York Chicago Cleveland New Brunswick Raleigh Houston Winter Haven Ft. Meyers McAllen Control Saline Injection 25μg Injection 75μg Injection 125μg Injection Phase IIb randomized, placebo-controlled, double-masked, parallel-group, dose-ranging US study Pars plana vitrectomy 7 days after injection Primary analysis after 35 days (full follow-up at 6 months) Posterior Vitreous Detachment Avoidance of Surgery V-M traction resolution Macular hole closure Assessed by a masked surgeon at the beginning of vitrectomy If vitrectomy not performed: Based on investigator assessment of OCT or B-Scan Safety Endophthalmitis Uveitis Retinal tears Vision Pre-injection - Baseline /63 3
Day 7 /5 Surgery Cancelled 1 month /32 Ophthalmology 1;117:791 797 Rate of total PVD noted at time of surgery: 1% vs. 125µg 31% VMT resolution at 35 days precluding need for surgery: 3% vs. 125µg 31% Macular hole closed without surgery at 35 days: % vs. 125µg 35% Design: Population: Allocation: Follow-Up: Randomized, placebo-injection controlled, double-masked trial (same for both studies) Symptomatic fvma (Patients with VMT or macular holes < μm) 125µg intravitreal injection vs. placebo (vehicle*) injection 2:1: MIVI 6 (US) 3:1: MIVI 7 (US & Europe) 6 months *Vehicle = Mannitol 3.75 mg/ml, Citric Acid Monohydrate 1.51 mg/ml Primary endpoint (MIVI-6 & -7): nsurgical resolution of fvma by Day 28 (determined by Central Reading Center [CRC]) Key Secondary endpoints (MIVI-6 & -7): Proportion of patients with total posterior vitreous detachment (PVD) at Day 28 (determined by ultrasound by investigators) Proportion of patients with nonsurgical closure of macular hole (determined by CRC) 23 Macular Condition Vitreo-Macular Traction Full Thickness Macular Hole (n=16) (n=2) 74 (69.8%) 163 (74.1%) 32 (3.2%) 57 (25.9%) 4
fvma Resolut9ion (%) fvma Resolut9ion (%) fvma Resolut9ion (%) 3/6/14 Ocular Characteristic (n=16) (n=2) Epiretinal Membrane 34 (32.1%) 87 (39.7%) Focal Vitreomacular Adhesion (fvma) diameter >15 μm 19 (17.9%) 47 (21.4%) 5 3 1 26.9% 1.2% 26.9% n = 187 n = 465 45 35 3 25 15 1 5 15.% n = 187 1.7% n = 465 38.1% 8.% - ERM + ERM - ERM + ERM n = 113 n = 6 n = 26 n = 188 45 35 3 25 15 1 5 18.9% n = 16 % n = 2 35.7% 8.9% 15 µm > 15 µm 15 µm > 15 µm n = 74 n = 19 n = 143 n = 45 5
Patients, % fvma Resolut9ion (%) fvma Resolut9ion (%) 3/6/14 5 5.6 %.6% 3 1 3.7% 13.3% 3 1 1.6% n = 187 n = 465 n = 47 n = 16 Optimization of Patient Selection and Expected Outcomes with Ocriplasmin Treatment Different Hole Types and Where to Measure CASE STUDIES: DIAMETER OF FTMH ( µm AND > µm) Baseline After Injection Day 7 After Injection Month 6 /5 /5 /25 < µm > µm Large FTMH, less resolution Source: openi.nlm.nih.gov 33 34 Pharmacologic Closure of FTMH* at Day 28 by FTMH Width at Baseline 8 p<.1 Ocriplasmin 6 58.3 p=.9 36.8 16. * μm with VMA Data on file. ThromboGenics, Inc. 13. n=4 28 5.3 1 14 25 μm >25 to μm > μm N=25 48 19 38 3 19.. 35 6
% Postop Hole Closure Rate (n) (n=19) (n=26) 84.2% (16) 84.6% (22) Adverse event (AE) % (n=17) (n=219) Any ocular AE 55.1 71.7 Any ocular serious AE 1.3 9.6 Vitreous floaters 8.4 19.2 Photopsia 3.7 16.4 Any Any ocular ocular Vitreous AE 55.1% 71.7% serious AE 1.3% 9.6% floaters 8.4% 19.2% Photopsia 3.7% 16.4% Conjunctival hemorrhage 13.1 15.5 Eye pain 5.6 15.1 Vision blurred 3.7 11. Cataract 19.3 1.1 Visual impairment 2.8 9.6 MH 11.2 7.3 Visual acuity reduced 4.7 6.4 Photophobia 6.4 Retinal edema.9 5.9 Anterior chamber cell 3.7 4.6 IOP increase 9.3 4.1 Metamorphopsia 4.1 % Retinal Break During 6 mo. Follow-up (n=17) (n=219) Any Retinal Tear or Retinal Detachment 3.74 % 3.19 % Intra / Post-Operative Retinal Tear or Detachment 3.74 % 2.28 % Retinal Tear Retinal Detachment 1.86 % 1.86 % 1.83 %.46 % n-operative Retinal Tear or Detachment %.91 % Retinal Tear Retinal Detachment % % %.91 % Verteporfin Therapy: All Trials Acute Severe VA Decrease Study TAP Investigation 1 VIP Trial 1 VAM 2 VIM 3 VER 4 JAT 4 VALIO 4 Total n/n % 3/2 1/225 33/4435 1/77 1/323 2/64 3/6 53/5586 1. TAP and VIP Study Groups. Am J Ophthalmol. 4;137:683 696. 2. VAM Study Writing Committee. Retina. 4;24:512-5. 3. VIM Study Group. Arch Ophthalmol. In press. 4. Data on file, vartis Pharma AG..7 4.4.6 1.3.3 3.1 5..9 Prior Stroke CHF Arrhythmias Angioplasty Valve Malfunction Stroke Rate by Potential Risk Factor Rate (n/n) 2.7% (2/73) 9.6% (7/73).5% (6/196).7% (8/1136) 3.3% (2/6) 3.1% (2/65).5% (6/119) 1.1% (13/1144).5% (1/214) 3.5% (7/).7% (7/955).8% (8/19) 1.7% (2/116) 2.4% (3/123).6% (6/153) 1.1% (12/186) 2.3% (2/87) 2.3% (2/87).6% (6/182) 1.2% (13/1122).3 mg ranibizumab.5 mg ranibizumab 5 15 Stroke Rate (%) Error bars = 95% CIs 42 7
/25 OS 1+ NS Clinical Case Dec 5, 12 Vision /1 Scheduled Jetrea April 3, 13 April 1, 13 Jetrea given April 11, 13 Vision /15 Kaleidoscope holes/tears with SD 36deg Vision /8 April 24, 13 Scleral depression Large horseshoe tear 4: with SRF Plan: vitrectomy/el/gfx/ilm peeling 8
Vitrectomy April 26, 13 May 18, 13 /7 Thrombogenics: ORBIT Ocriplasmin Research to Better Inform Treatment Phase 4 prospective clinical study to assess the realworld safety and effectiveness of ocriplasmin treatment for US patients with symptomatic vitreomacular adhesion (VMA) Aim is to collect real-time data on 15 patients at 1 US sites with up to one year follow up Enrollment to begin in early 14 Patient with exudative AMD Age-Related Macular Degeneration Diabetic Retinopathy Macular Edema Proliferative Disease 9