1. 1 Diabetic macula edema

2. ?  Microaneurysms  CWS  Hard exudates  Beading of vessels  IRMA  NVD/NVE  DME- Types 2

3. Definition of DME  Swelling of the retina due to leaking of fluid from blood vessels within the macula in patients with diabetes  Thickening of the basement membrane and a reduction in the number of pericytes are believed to lead to increased permeability and leakage of plasma constituents in the surrounding retina, resulting in retinal edema 3 http://www.medterms.com/script/main/art.asp?articlekey=16569. Accessed February 2009http://www.medterms.com/script/main/art.asp?articlekey=16569

4. 4 DME: retinal pathology Retinal edema Hard exudates Retinal edema and hard exudates illustrated in a color fundus photography image

5. 5 Factors affecting DME  Incidence of DME increases with  elevated levels of HbA1 C  severity of DR  duration of DM  elevated diastolic blood pressure  gender (more frequent in females)  serum lipid levels Klein et al. Ophthalmology 1998; 105: 1801-1815

6. 6 Classification of DR  Microaneurysms only  Microaneurysms, hemorrhages, hard exudates, and cotton-wool spots  Venous abnormalities (beading, loops), intraretinal microvascular abnormalities (IRMA), increased hemorrhage, and exudation NPDR (non-proliferative diabetic retinopathy) PDR (proliferative diabetic retinopathy) DME (diabetic macular edema)  Hard exudates, retinal thickening  Neovascularization, vitreous hemorrhage, and traction retinal detachment Mild Severe Yam & Kwok. Hong Kong Med J 2007; 13: 46-60 Adapted from: Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005. http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf. Accessed February 2009 http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf

7. 7  Most common complications are microvascular changes 1  Diabetic macula edema (DME) is a common cause of blindness in people of working age 2,3 and can develop in both Type 1 and 2 DM 4  About 8% of diabetic patients develop DME with visual impairment 5 1 King et al. Diabetes Care 1998; 21: 1414-1431; 2 Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005. http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf. Accessed February 2009; 3 Watkins. BMJ 2003; 326: 924-926; 4 Klein et al. Ophthalmology 1998; 105: 1801-1815; 5 Calculated from: Ling et al. Eye 2002; 16: 140-145; Broadbent et al. Eye 1999; 13: 160-165; Knudsen et al. Br J Ophthalmol 2006; 90: 1404-1409; Hove et al. Acta Ophthalmol Scand 2004; 82: 443-448; Romero-Aroca et al. Arch Soc Esp Oftalmol 2007; 82: 209-218; Zietz et al. Dtsch Med Wochenschr 2000; 125: 783-788; Kristinsson. Acta Ophthalmol Scand Suppl 1997; 223: 1-76 http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf Diabetes and vision loss

8. 8 Role of VEGF in DR  Vascular endothelial growth factor (VEGF) plays a major role in patients with DR  mediates active intraocular neovascularization and breakdown of the blood-retinal barrier 1  associated with VEGF gene polymorphism 2 1 Aiello et al. N Engl J Med 1994; 331: 1480-1487 2 Nakamura. Graefes Arch Clin Exp Ophthalmol 2009; 247: 21-26

9. 9 VEGF165 in DR  Retinal VEGF165 levels are elevated in experimental diabetes  Increased VEGF165 levels are found in the vitreous of eyes with proliferative DR  Patients with DR have higher VEGF165 levels in the aqueous Qaum et al. IOVS 2001; 42: 2408-2413; Aiello et al. N Engl J Med 1994; 331: 1480-1487

10. Diagnosis of DR / DME  Diagnosis of DR / DME often occurs during routine eye examinations of patients with DM  Type 1 diabetes (no DR / DME)  first examination 3–5 years after diagnosis of diabetes, recommended yearly follow-up  Type 2 diabetes (no DR / DME)  first examination at time of diagnosis of diabetes, recommended yearly follow-up  Follow-up frequency increases with diagnosis of DR / DME 10 AAO Guidelines. Diabetic Retinopathy. http://www.aao.org/ppp. Accessed February 2009http://www.aao.org/ppp Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005. http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf. Accessed February 2009. Images: National Eye Institute, National Institutes of Health http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf Normal vision DR

11. 11 DME: current treatment  Systemic treatment  glucose control  blood-pressure control  blood-lipid control  multifactorial metabolic interventions  Ocular treatment  laser photocoagulation (standard treatment for DR / DME)  vitrectomy  pharmacologic therapy AAO Guidelines. Diabetic Retinopathy. http://www.aao.org/ppp. Accessed February 2009http://www.aao.org/ppp Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005. http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf. Accessed February 2009 http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf

12. 12  Reduction in vessel hyperpermeability and leakage in macular edema DME: aims of therapy  Treatment of neovascularization in PDR

13. 13 Laser photocoagulation for DME  Standard treatment – helps to slow fluid leakage and reduce the amount of fluid in the retina (macula edema)  Aim of treatment is to stabilize / prevent further vision loss  Limitations of treatment include  does not eliminate possibility of further vision loss  improvement in visual acuity is uncommon  complications including permanent damage to the retinal pigment epithelium and secondary choroidal neovascularization National Eye Institute, National Institutes of Health. Diabetic Retinopathy. http://www.nei.nih.gov/health/diabetic/retinopathy.asp#4a Accessed February 2009http://www.nei.nih.gov/health/diabetic/retinopathy.asp#4a AAO Guidelines. Diabetic Retinopathy. http://www.aao.org/ppp. Accessed February 2009http://www.aao.org/ppp Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005. http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf. Accessed February 2009 http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf

14. 14 DR and DME: the unmet treatment needs  Despite the use of standard interventions for DR, vision loss as a result of the disease still occurs in many patients 1  Good metabolic and blood-pressure control are often difficult to achieve in clinical practice, and sight-threatening DR still develops 2  Laser treatment is destructive and cannot restore vision loss that has already occurred; it therefore cannot be regarded as an ideal treatment, and there is a need for better-tolerated and less-destructive therapies 3 1 Comer & Ciulla. Curr Opin Ophthalmol 2004; 15: 508-518 2 The DIRECT Programme Study Group. J Renin Angiotensin Aldosterone Syst 2002; 3: 255-261 3 Fong. Surv Ophthalmol 2002; 47: S238-S245

15. RESTORE study in DME patients: 12- month results Core slide resource

16. Primary objective To demonstrate superiority of ranibizumab (0.5 mg) as monotherapy and/or adjunctive to laser treatment vs. laser therapy based on the mean average change from baseline in BCVA over a 12-month treatment period

17. Key secondary objectives  To evaluate whether ranibizumab (0.5 mg) as monotherapy or adjunctive to laser is superior to laser treatment in the proportion of patients with improvement in BCVA  To evaluate ranibizumab (0.5 mg) monotherapy and adjunctive to laser relative to laser treatment with respect to:  the time course of BCVA change  the effects on central retinal thickness (CRT) and other anatomical changes  the effect on patient-reported outcomes  safety

18. Primary endpoint  The mean average change in BCVA from baseline to Month 1 through Month 12  Mean average change is the mean difference between baseline BCVA and the average BCVA over time (Month 1 to Month 12)

19. RESTORE study design Visual impairment due to DME(n=345) Randomised 1:1:1 Ranibizumab 0.5 mg + active laser Ranibizumab 0.5 mg + sham laser Sham Injection + active laser Active/sham laser treatment was administered before sham/intravitreal injection on the same day (minimum interval between the two treatments was 30 minutes)

20. RESTORE treatment schedule Primary endpoint sham injection Laser (n=111) 0123456789101112 Month 0123456789 ranibizumab Laser (n=118) ranibizumab sham laser (n=116) Treatment Initiation phase Continuous/resumed treatment phase ranibizumab 0.5 mg ranibizumab 0.5 mg PRN* laser laser PRN ≠ * According to pre-defined treatment criteria ≠ According to the judgment of the investigator and in accordance with ETDRS guidelines 2 years extension phase with open-label ranibizumab 0.5 mg Arm 1 Arm 2 Arm 3 Randomized, double-masked, multicenter, laser- controlled Phase III (N=345) RESTORE

21. Re-treatment criteria Ranibizumab: monthly ranibizumab/sham injections suspended when: No further BCVA improvement due to treatment at 2 last consecutive visits OR BCVA >84 letters at 2 last consecutive visits monthly ranibizumab/sham injections reinitiated when: decrease in BCVA due to DME progression in the opinion of the investig ator Laser photocoagulation (active or sham): in accordance with the ETDRS guidelines at intervals of ≥3 months from the last treatment AND if deemed necessary by the evaluating investigator RESTORE

22. Key inclusion criteria  Male/female patients >18 years of age  Type 1 or type 2 diabetes mellitus  HbA1C ≤10.0%  Eligibility criteria for study eye:  BCVA score: 78-39 letters  Decrease in vision is due to DME and not due to other causes (based on investigator opinion)  Medication for the management of diabetes stable within 3 months prior to randomization and expected to remain stable during the course of the study RESTORE

23. Key exclusion criteria  Ocular disorders of the study eye that may confound interpretation of study results  Systemic conditions such as:  history of stroke  renal failure requiring dialysis or renal transplant or renal insufficiency with creatinine levels > 2.0 mg/dl  untreated diabetes mellitus  blood pressure systolic >160 mmHg or diastolic >100 mmHg, untreated hypertension or change in antihypertensive treatment within 3 months preceding baseline  Treatment with anti-angiogenic drugs (study eye) within 3 months prior to randomization, ocular conditions requiring corticosteroid treatment or laser photocoagulati on (study eye) within 6 months prior or during study RESTORE

24. Demographic Variable (Randomized set) Ranibizumab N = 116 Ranibizumab + Laser N=118 Laser N=111 Age (years) Mean (SD)62.9 (9.29)64.0 (8.15)63.5 (8.81) Age group (years), n(%) <5524 (20.7)14 (11.9)13 (11.7) 55 - <6541 (35.3)42 (35.6)53 (47.7) 65 - <7540 (34.5)53 (44.9)31 (27.9) ≥7511 (9.5)9 (7.6)14 (12.6) Gender, n (%) Male73 (62.9)70 (59.3)58 (52.3) Female43 (37.1)48 (40.7)53 (47.7) Predominant race, n(%) Caucasian109 (94.0)111 (94.1)106 (95.5) Others*7 (6.1)7 (5.9)5 (4.5) Patient demographics *Others include: Black, Asian, Pacific islander and missing

25. Characteristics (Randomized set) Ranibizumab N=116 Ranibizumab + Laser N=118 Laser N=111 Diabetes type, n (%) Type I13 (11.2)15 (12.7)13 (11.7) Type II103 (88.8)102 (86.4)97 (87.4) Not stated01 (0.8)1 (0.9) HbA1c (%) Mean (SD)7.23 (1.085)7.50 (1.099)7.28 (1.105) HbA1c group, n (%) <884 (72.4)85 (72.0)80 (72.1) 8 - 1030 (25.9)31 (26.3)28 (25.2) >1001 (0.8)0 Missing2 (1.7)1 (0.8)3 (2.7) Time since first diagnosis of diabetes (years) Mean (SD)15.23 (9.909)14.62 (9.835)12.93 (9.024) Diabetes characteristics at baseline

26. Mean average change in BCVA from Month 1 through Month 12 compared to baseline (primary endpoint) 6.1 5.9 0.8 p<0.0001* * Differences in LS means and the two-sided 95% CIs are estimated from pair wise ANOVA (stratified) model Full analysis set/LOCF

27. Mean change in BCVA from baseline over time 0.9 6.4 6.8 RESTORE Full analysis set/LOCF

28. Mean change in CRST from baseline over time *CRST: central retinal subfield thickness -61.3 -128.3 -118.7 RESTORE Full analysis set/LOCF

29. Mean average change in BCVA from baseline over time according to type of DME Numbers in boxes are mean average change of BCVA from baseline to Months 1-12 (primary endpoint) FOCAL* DIFFUSE* * 0.4 6.8 7.0 5.6 0.6 7.0 RESTORE * focal (central reading center definition): >67% of leakage originated from leaking microaneurysms in the whole edema area. If around 30-67% leakage comes from microaneurysms, the edema is focal if in the central subfield >67% of the leakage originates from microaneurysms **diffuse (central reading center definition): <33% of leakage comes from leaking microaneurysms and the rest comes from diffuse leaking capillaries in the whole edema area. If around 30-67% leakage comes from microaneurysms, the edema is diffuse if in the central subfield <33% of the leakage originates from microaneurysms

30. Mean average change in BCVA from baseline over time according to type of diabetes TYPE I DIABETES TYPE II DIABETES 2.8 7.7 6.7 0.7 6.2 6.8 Numbers in boxes are mean average change of BCVA from baseline to Months 1-12 (primary endpoint) RESTORE

31. Mean average change in BCVA from baseline over time according to prior laser treatment status WITH PRIOR LASER TREATMENT WITHOUT PRIOR LASER TREATMENT 1.2 4.5 7.6 0.6 8.0 5.9 Numbers in boxes are mean average change of BCVA from baseline to Months 1-12 (primary endpoint) RESTORE

32. Visual functioning questionnaire (VFQ-25): Mean change from baseline at Month 12 Full analysis set/LOCF QoL, quality of life; VFQ-25, Vision Function Questionnaire 25 *p <0.05; **p <0.001 versus Laser * ** * * * * * Mean change in VFQ-25 score from baseline to month 12 (±SE) *

33. Treatment exposure Safety set Ranibizumab N=115 Ranibizumab + Laser N=120 Laser N=110 Number of injections (ranibizumab/sham) Total800816802 Mean (SD)7.0 (2.81)6.8 (2.95)7.3 (3.22) Frequency of injections, n (%) 1 - 316 (13.9)23 (19.2)19 (17.3) 4 - 637 (32.2)34 (28.3)32 (29.1) 7 - 940 (34.8)35 (29.2)22 (20.0) 10 - 1222 (19.1)28 (23.3)37 (33.6) Number of laser treatments (active/sham) Total217198233 Mean (SD)1.9 (1.07)1.7 (0.89)2.1 (1.04) Frequency of laser treatments, n (%) 157 (49.6)67 (55.8)40 (36.4) 229 (25.2)36 (30.0)30 (27.3) 315 (13.0)10 (8.3)27 (24.5) ≥ 414 (12.2)7 (5.8)13 (11.8)

34. Proportion of patients receiving injections over time Safety set

35. Summary of ocular adverse events (AEs)  Main AEs  eye pain (8.3-11.3%)  conjunctival hyperemia (5.0-7.8%)  conjunctival hemorrhage (0-8.3%)  Low level of intra-ocular pressure (IOP) increased (<1%)  Suspected to be related to study drug and/or ocular injection:  eye pain (8.3-10.4%)  conjunctival hyperemia (3.3-7.0%)  conjunctival hemorrhage (0-7.5%) RESTORE

36. Summary of ocular serious adverse events (SAEs)  No ocular SAEs were reported in the ranibizumab monotherapy arm  Ocular SAEs reported in two patients each in the ranibizumab + laser and laser arms (one patient in the laser arm reported both cataract and maculopathy)  No cases of endophthalmitis were reported in any of the treatment arms  None of the ocular SAEs were suspected to be related to study drug and/or ocular injection RESTORE

37. Proportion of patients with ocular SAEs of the study eye Preferred term (Safety set) Ranibizumab N=115 n (%) Ranibizumab + Laser N=120 n (%) Laser N=110 n (%) Total 0 2 (1.7)2 (1.8) Cataract02 (1.7)2 (1.8) Maculopathy001 (0.9) No ocular SAEs reported in the ranibizumab monotherapy arm

38. Summary of non-ocular SAEs (per system organ class)  Non-ocular SAEs with incidence rates >1% were low  cardiac disorders (3.3-7.0%)  infections and infestations (2.5-5.2%)  metabolism and nutrition disorders (1.7-3.5%)  Suspected to be related to study drug and/or ocular injection:  3 patients in ranibizumab arm (intestinal obstruction, hypoglycemia, pulmonary embolism, dyspnea, arterial thrombosis limb) and  1 patient in ranibizumab+laser arm (coronary artery occlusion)  Two deaths reported in each treatment arm, none suspected to be related to the study drug and/or injection procedure RESTORE

39. Proportion of patients with AEs potentially related to systemic VEGF inhibition Preferred term (Safety set) Ranibizumab N=115 n (%) Ranibizumab + Laser N=120 n (%) Laser N=110 n (%) Arterial thromboembolic events*4 (3.5)4 (3.3)3 (2.7) Arterial thrombosis limb100 Carotid artery stenosis111 Cerebral artery embolism100 Cerebrovascular accident100 Cerebrovascular disorder010 Coronary artery occlusion011 Myocardial infarction110 Peripheral arterial occlusive disease101 Vertebrobasilar insufficiency010 Venous thromboembolic events*2 (1.7) 0 2 (1.8) Axillary vein thrombosis001 Deep vein thrombosis0 0 1 Pulmonary embolism201 Hypertension9 (7.8)6 (5.0)9 (8.2) Non-ocular haemorrhage1 (0.9)0 Epistaxis1 (0.9)0 Proteinuria1 (0.9)1 (0.8)0 * ATEs by defined RMP version 6 “identified risks” RESTORE

40. Summary  The primary objective of the study was met with statistically significant superiority of ranibizumab 0.5 mg monotherapy and ranibizumab 0.5 mg adjunctive to laser compared to laser alone with BCVA improvement from baseline to Month 1 through Month 12 of 5.4 and 4.9 letters, respectively  In contrast to laser monotherapy, ranibizumab alone or in combination with laser leads to a rapid and continuous VA improvement within the initial 3 months followed by VA stabilization under PRN treatment  Patients received on average 6.8-7.3 ranibizumab/sham injections and 1.7-2.1 laser (active or sham) treatments in all treatment arms  No new ocular or non-ocular safety risks were identified

41. Conclusions - Efficacy  Ranibizumab monotherapy or as adjunctive therapy to laser photocoagulation provided superior benefits in BCVA improvement as compared to laser monotherapy at Month 12 (primary endpoint met)  The study shows that 37-43% of ranibizumab-treated patients improved vision by 10 letters or more as compared to 16% with standard laser therapy  Ranibizumab given alone or as adjunctive to laser showed rapid mean average BCVA gain which was sustained over 12 months of treatment at around 6 letters above baseline compared to 0.8 letter with laser therapy alone

42.  Ranibizumab was well tolerated as monotherapy or as adjunctive to laser therapy in patients with visual impairment due to DME  no cases of endophthalmitis  ranibizumab showed low incidence (<1%) of IOP increased  systemic safety: low incidence of hypertension (5.0-8.2%) and ATEs (2.7-3.5%) in all treatment groups Conclusions - Safety

43. TURKEY Prof. Dr. Bora Eldem Assoc.Prof.Dr Ziya Kapran Prof. Dr. Cezmi Akkin Prof. Dr. Mehmet Ergin Dr Berati Hasanreisoglu BELGIUM Dr Joachim Van Calster Dr. Marlene Devriendt FRANCE Dr Pascale MASSIN Dr. Jean- Paul Romanet Pr. Michel Weber Pr Catherine Creuzot-Garche GERMANY Prof. Dr. Antonia Joussen Prof. Dr. med. Karl-Heinz Emmerich Prof. Dr. med.Katrin Engelmann Prof. Dr. med. Lutz Hansen Prof. Dr. med. Helmut Hoeh Prof. Dr. med. Frank Holz Prof. Dr. med. Anselm Kampik Prof. Dr. med. Ulrich Kellner Prof. Dr. med. Bernd Kirchhof Prof. Dr. med. Gabriele Lang Prof. Dr. med. Andreas Mohr Dr. med. Georg Spital Prof. Dr. med. Peter Wiedemann Prof. Dr. med. Salvatore Grisanti Prof. Dr. med. Norbert Schrage GREECE Prof. Miltiadis Tsilibaris Assoc. Prof. Periklis Brazitikos Ass. Prof. Vergados Ioaanis Prof Stavros Dimitrakos Dr Stamatina Kabanarou ITALY Prof. F. Bandello Prof. Ugo Menchini Prof. Carlo Sborgia Prof. Alfredo Reibaldi Prof. Emilio Balestrazzi Dr.ssa Anna Tarantini Prof. Nicola Delle Noci NETHERLANDS Prof. Dr. R.O. Schlingemann Dr. J.P. Martinez Ciriano Dr. B.J. Kleverling SPAIN Dr. Josep Garcia Arumi Dr. Francisco Gomez Ulla Dr. Ramon Torres Imaz Dr. Enrique Cervera Dr. Alfredo Adan Civera Dr. Jose Ruiz Moreno SWITZERLAND Dr. med. Malaika Kurz-Levin Prof. Dr. med Ulrike Schneider Prof. Dr. med. Justus Garweg Dr. med. Christoph Tappeiner Prof. Dr. med Heinrich Gerding Dr. med. Patrik Kloos UK Dr Nicholas Beare Dr. Geeta Menon Dr Clare Bailey HUNGARY Dr. Andras Papp Dr. Andras Seres Dr Andras Berta Dr. Árpád Berecki Dr Ágnes Kerény List of PIs in RESTORE study Slide 1/2

44. AUSTRALIA Prof. Paul Mitchell A/Prof Mark Gillies A/Prof Tien Wong Dr Brendan Vote Dr. Dianne Sharp CANADA Dr John Gonder Dr Peter Kertes Dr David Maberley Dr Shelley Boyd Dr Sébastien Olivier Dr Vladimir Kozousek Dr. John Chen List of PIs in RESTORE study RESTORE Slide 2/2

45. Primary and secondary BCVA endpoints: subset of RESTORE (Baseline VA ≤73 letters, CRT ≥300 μm) vs RESOLVE Primary endpoint: Mean average change in BCVA from baseline to Month 1 through Month 12 Ranibizumab (n=80) Ranibizumab+laser (n=81) Laser (n=75) RESOLVE (n=102) 7.47.21.47.6 Secondary endpoint: Mean change in BCVA from baseline at Month 12 RanibizumabRanibizumab+laserLaserRESOLVE 8.48.01.710.3 RESTORE

46. Treatment regimen concepts / hypotheses  Treatment is individualized  No relevant increase in efficacy upon further treatment in patients who had become stable for at least three consecutive months under ranibizumab treatment  Treatment  Starts and continues until stability of disease  Interruption when disease stabilises  Monitor for disease activity on monthly basis  Restart when disease activity is observed  Continue until disease stability is observed

47. The Diabetic Retinopathy Clinical Research Network Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817 47

48. 48 Study Design Primary outcome: Change in visual acuity from baseline to 1 year (intent to treat analysis) Randomized, multi-center clinical trial At least one eye meeting all of the following criteria: Electronic-ETDRS © best corrected visual acuity letter score of 78 to 24 (~20/32 to 20/320) Definite retinal thickening due to diabetic macular edema involving the center of the macula on clinical examination Central subfield (Stratus OCT™) ≥250 µm

49. Follow-up Schedule 49 Baseline to 1 Year 1 Year to 3 Years 1 Year to 3 Years Every subject has a follow-up visit at 1 year Follow-up every 4 weeks All groups except ranibizumab plus deferred laser group: Additional follow-up visit occurs 3 to 10 days after injection if focal/grid laser also is to be given Every subject has a follow-up visit at 1 year Follow-up every 4 weeks All groups except ranibizumab plus deferred laser group: Additional follow-up visit occurs 3 to 10 days after injection if focal/grid laser also is to be given Every subject has a follow-up visit at 2 years Follow-up every 4 to 16 weeks depending on treatment group, disease progression, and treatment administered Triamcinolone plus prompt laser group only: Additional safety visit every 4 weeks after triamcinolone injection Every subject has a follow-up visit at 2 years Follow-up every 4 to 16 weeks depending on treatment group, disease progression, and treatment administered Triamcinolone plus prompt laser group only: Additional safety visit every 4 weeks after triamcinolone injection

50. Study Enrollment and Completion 50 Ranibizumab +Prompt Laser N = 187 Ranibizumab +Prompt Laser N = 187 Ranibizumab +Deferred Laser N = 188 Ranibizumab +Deferred Laser N = 188 Sham +Prompt Laser N = 293 Sham +Prompt Laser N = 293 Triamcinolone +Prompt Laser N = 186 Triamcinolone +Prompt Laser N = 186 Eyes Randomized: N = 854 (691 Participants) Eyes Randomized: N = 854 (691 Participants) 1 Year Visit Completion: 94%* 2 Year Visit Completion: 87%** * Includes deaths ** Includes deaths and excludes pending and dropped who are not yet in window

51. 51 Baseline Characteristics Sham +Prompt Laser Ranibizumab +Prompt Laser Ranibizumab +Deferred Laser Triamcinolone +Prompt Laser Median age 63626462 Diabetes type Type I 9%6%8% Type II 89%92%90%89% Uncertain 3%2% 3% Median E-ETDRS © visual acuity letter score (Snellen equivalent) 65 (20/50)66 (20/50) Median OCT CSF thickness (µm) 407371382374

52. 52 Injections/Sham Prior to 1 Year Sham +Prompt Laser N = 274 Ranibizumab +Prompt Laser N = 171 Ranibizumab +Deferred Laser N = 178 Triamcinolone +Prompt Laser N =176 Maximal possible # of sham/injections 13 sham*13 drug 9 sham/4 drug Median number of sham/study drug injections to 1 year 11*895 sham/3 drug AE Precluding Study Drug Injection † NA2% 15% Compliance with sham/drug injection when required by protocol 96%95%97% Masked participant with 1 study eye identified correct assignment at 1 year 10%88%90%44% *Excludes 56 eyes among 163 participants with 2 study eyes unmasked at baseline when assigned ranibizumab + deferred laser. † % of visits reported; 12% of eyes in the triamcinolone group compared with 3% and 4% in the ranibizumab groups

53. 53 Laser Treatments Prior to 1 Year Sham +Prompt Laser Ranibizumab +Prompt Laser Ranibizumab +Deferred Laser * (permitted starting at 24- week visit) Triamcinolone +Prompt Laser Median number of laser treatments including baseline 3202 Proportion of eyes receiving laser at 48-week visit 26%16%8%21% No, only 1, only 2 or 3 more lasers after baseline 13%,27%,31%,32%,70%,20%,26%,30%, 40%,20%27%,11%10%,1%28%,15% * 3 eyes deviated from the protocol and received laser prior to 24 weeks (2 were given laser at the 1 week safety visit and 1 at the 20 week visit).

54. 54 Sham +Prompt Laser N = 293 Ranibizumab +Prompt Laser N = 187 Ranibizumab +Deferred Laser N = 188 Triamcinolone +Prompt Laser N = 186 Eyes with alternative treatments (number of treatments) 14 (25)1 (1)0 Per protocol (failure ‡ criteria met) 5101 Deviations from protocol - clinical care 9000 Alternative* Treatments Prior to 1 Year * Alternative treatments include: intravitreal bevacizumab, intreavitreal triamcinolone acetonide, vitrectomy, and intravitreal bevacizumab + intravitreal triamcinolone. ‡ Failure is defined as: ≥10 letter loss from baseline, OCT CSF ≥250 µm, DME present on clinical exam that is cause of visual loss, “complete laser” given AND ≥13 weeks since last laser treatment with no improvement since the last laser treatment

55. Visual Acuity 55

56. Mean Change in Visual Acuity * at Follow-up Visits 56 * Values that were ±30 letters were assigned a value of 30 P-values for difference in mean change in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; and triamcinolone+prompt laser=0.31.

57. Change in Visual Acuity (LOCF) at 1 Year* 57 Change in Visual Acuity (letters) Sham +Prompt Laser N = 293 Ranibizumab +Prompt Laser N = 187 Ranibizumab +Deferred Laser N = 188 Triamcinolone +Prompt Laser N = 186 Mean+3+9 +4 Difference in mean change from Sham +Prompt Laser [P Value]** +5.8 [P<0.001] +6.0 [P<0.001] +1.1 [P = 0.31] *Visits occurring between 308 and 420 days from randomization were included as 1-year visits. When more than 1 visit occurred in this window, data from the visit closest to the 1-year target date were used. For other eyes with out any 1-year data (19 eyes in the sham+prompt laser group, 16 eyes in the ranibizumab+prompt laser group, 10 eyes in the ranibizumab+deferred laser group, and 10 eyes in the triamcinolone+prompt laser group) the last observation carried forward (LOCF) method was used to impute data for the primary analysis. **Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity

58. Change in Visual Acuity at 2 Years* 58 Change in Visual Acuity (letters) Sham +Prompt Laser N = 163 Ranibizumab +Prompt Laser N = 106 Ranibizumab +Deferred Laser N = 112 Triamcinolone +Prompt Laser N = 103 Mean+2+7+100 Difference in mean change from Sham +Prompt Laser [P Value]** +5.0 [P = 0.01] +7.2 [P<0.001] -1.6 [P = 0.43] *Visits occurring between 616 and 840 days from randomization were included as 2-year visits **Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity

59. Visual Acuity Subgroup Analyses 59

60. Change in Visual Acuity at 1 Year Stratified by Baseline Visual Acuity 60 N=146

61. Change in Visual Acuity at 1 Year Stratified by Baseline CSF 61

62. Change in Visual Acuity at 1 Year Stratified by Prior DME Treatment 62

63. Change in Visual Acuity at 1 Year Stratified by Number of Study Eyes 63 N=130

64. Change in Visual Acuity (LOCF) at 1 Year Stratified by Eyes with Diffuse vs. Focal Edema at Baseline as Graded by Study Ophthalmologist 64

65. Change in Visual Acuity at 1 Year Stratified by Pseudophakic at Baseline 65

66. Mean Change in Visual Acuity at Follow-up Visits among Eyes that were Pseudophakic at Baseline* 66 Visit Week * Values that were ±30 letters were assigned a value of 30

67. Retinal Thickening 67

68. Mean Change in Central Subfield Thickening at Follow-up Visits 68 Visit Week P values are for the difference in mean change in OCT CSF retinal thickness from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001, ranibizumab+deferred laser <0.001, and triamcinolone+prompt laser <0.001.

69. Change in Retinal Thickening at 1 Year* 69 Change in OCT Central Subfield Thickening a Sham +Prompt Laser N = 271 Ranibizumab +Prompt Laser N = 171 Ranibizumab +Deferred Laser N = 175 Triamcinolone +Prompt Laser N = 173 Mean change from baseline (µm) -102-131-137-127 Difference in mean change from Sham Prompt+Laser [P Value]** -55 [P<0.001] -49 [P<0.001] -52 [P<0.001] Thickness <250 µm with at least a 25 µm decrease from baseline 27%53%42%47% *Visits occurring between 308 and 420 days from randomization were included as 1 year visits. When more than 1 visit occurred in this window, data from the visit closest to the 1 year target date were used. **Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyes a Missing data for 22 eyes in the sham+prompt laser group, 16 eyes in the ranibizumab+prompt laser group, 13 in the ranibizumab+deferred Laser, and 13 eyes in the triamcinolone+prompt laser group (includes missing and ungradeable data [3 in sham+prompt laser, 2 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser]

70. Change in Retinal Thickening at 2 Years* 70 Change in OCT Central Subfield Thickening a Sham +Prompt Laser N = 152 Ranibizumab +Prompt Laser N = 99 Ranibizumab +Deferred Laser N = 100 Triamcinolone +Prompt Laser N = 93 Mean change from baseline (µm) -133-144-170-95 Difference in mean change from Sham + Laser [P Value]** -31 [P = 0.01] -36 [P = 0.004] -3 [P = 0.81] Thickness <250 µm with at least a 25 µm decrease from baseline 38%54%55%44% *Visits occurring between 616 and 840 days from randomization were included as 2-year visits. When more than 1 visit occurred in this window, data from the visit closest to the 2-year target date were used. ** Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyes ª Excluding pending- Missing data for 2 eyes in the sham+prompt laser group, 2 eyes in the ranibizumab+prompt laser group, 2 in the ranibizumab +deferred laser, and 6 eyes in the triamcinolone+prompt laser group; Ungradeable data for 1 in the ranibizumab+prompt laser, 1 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser

71. Retinopathy 71

72. Retinopathy Progression During 1 Year of Follow-up 72 Sham N = 293 Ranibizumab N = 375 Triamcinolone N = 186 Reported vitreous hemorrhage OR received PRP 8%3% P Value for comparison with sham --0.0020.02

73. Safety 73

74. 74 Major Ocular Adverse Events During 2-Years of Follow-up 74 Sham +Prompt Laser N = 293 Ranibizumab +Prompt Laser N = 187 Ranibizumab +Deferred Laser N = 188 Triamcinolone +Prompt Laser N = 186 Number of injections 18332140685 Endophthalmitis* 1 (<1%)2 (1%) 0 Pseudoendophthalmitis † 1(<1%)001 (1%) Ocular vascular event ‡ 1 (<1%)1 (1%) 3 (2%) Retinal detachment § 001 (1%)0 Vitrectomy 15 (5%)4 (2%)7 (4%)2 (1%) Vitreous Hemorrhage 27 (9%)6 (3%)8 (4%)7 (4%) * One case unrelated to study drug injection (following cataract extraction) in the sham+prompt laser group; 1 case related to study drug injection and 1 case unrelated to injection (following cataract surgery) in the ranibizumab+prompt laser group; 2 cases related to study drug injection in the ranibizumab+deferred laser group. The 3 cases related to study drug injection in the ranibizumab groups are 0.08% of ranibizumab study drug injections given. † One case unrelated to the study drug injection (vitreous opacity with hypopyon) and one case related to study drug injection in the triamcinolone group. ‡ Includes 2 central retinal vein occlusions and 4 branch retinal vein occlusions. § Includes 1 traction retinal detachment with proliferative diabetic retinopathy and prior panretinal photocoagulation at baseline.

75. 75 Elevated Intraocular Pressure/Glaucoma During 2-Years of Follow-up 75 Elevated Intraocular Pressure/Glaucoma Sham +Prompt Laser N = 293 Ranibizumab +Prompt Laser N = 187 Ranibizumab +Deferred Laser N = 188 Triamcinolone +Prompt Laser N = 186 Increase ≥10 mmHg from baseline 8%9%6%42% IOP ≥30 mmHg 3%2%3%27% Initiation of IOP- lowering meds at any visit* 5% 3%28% Number of eyes meeting ≥1 of the above 11% 7%50% Glaucoma surgery** <1%1%0 *Excludes eyes with IOP lowering medications at baseline **Includes 2 filter and 2 cilliary body destruction

76. 76 Cataract Surgery During 2-Years of Follow-up 76 Sham +Prompt Laser Ranibizumab +Prompt Laser Ranibizumab +Deferred Laser Triamcinolone +Prompt Laser Phakic at baseline N = 192N = 131N = 134N = 124 Eyes that had cataract surgery 12% 13%55%

77. Number of Deaths 77 Sham N = 130 Ranibizumab N = 375 Triamcinolone N = 186 Deaths*7 (5%)15 (4%)6 (3%) *Study participants with 2 study eyes are counted in their injection group.

78. 78 Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’ Collaboration through 2-Years 78 Sham ‡ N * = 130 Ranibizumab N * = 375 Triamcinolone N * = 186 Non-fatal myocardial infarction 3%1%3% Non-fatal cerebrovascular accident-ischemic or hemorrhagic (or unknown) 6%2% Vascular death (from any potential vascular or unknown cause † ) 5%2% Any APTC event 12%5%6% * N=Number of Study Participants. Study participants with 2 study eyes are assigned to the non-sham group. Multiple events within a study participant are only counted once per event. ‡One participant had a non-fatal myocardial infarction and a non-fatal stroke (only counted once in the any cardiovascular event row) †Four of the vascular deaths in the sham group, 1 of the vascular deaths in the ranibizumab group, and 1 of the vascular deaths in the triamcinolone group were from an unknown cause

79. Discussion 79

80. 80 Intravitreal Ranibizumab Summary  Intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser had superior VA and OCT outcomes compared with focal/grid laser treatment alone. ~50% of eyes had substantial improvement (≥10 letters) while ~30% gained ≥15 letters Results were similar whether focal/grid laser was given starting with the first injection or it was deferred >24 weeks 80

81. 81 Intravitreal Ranibizumab Summary  If ranibizumab is to be given as it was in this study, the data indicate a need to follow eyes continuously undergoing this treatment Additional ranibizumab and/or laser were needed in most eyes through ≥2 years, even if ‘success’ criteria were met early in the course of treatment. 81

82. 82 Intravitreal Triamcinolone Summary  Intravitreal triamcinolone combined with focal/grid laser did not result in superior VA outcomes compared with laser alone.  Intravitreal triamcinolone did result in a greater reduction in retinal thickening at 1 year but not 2 years compared with laser alone.  In an analysis limited to pseudophakic eyes, the triamcinolone group’s outcome for VA appeared to be of similar magnitude to that of the 2 ranibizum ab groups. 82

83. 83 Intravitreal Triamcinolone Conclusion  In pseudophakic eyes, intravitreal triamcinolone with prompt focal/grid laser may be equally effective as ranibizumab at improving visual acuity and reducing retinal thickening, but is associated with an increased risk of intraocular pressure elevation. 83

84. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) 84  52 clinical study sites

85. RESOLVE: Study Purpose and Population  Phase II study to evaluate the safety and explore the effect of ranibizumab in patients with diabetic macular edema (DME) with center involvement  Study parts and population  Group A: Pilot  42 patients analyzed in the 6-month interim analysis  Group B: Confirmatory*  109 patients not analyzed at interim  Group A+B (all patients): primarily safety and overall efficacy *Clinical Trial Protocol Amendment 3 released May 29, 2008

86. RESOLVE: Study Objectives and Endpoints  Primary endpoints  Group A: demonstrate superiority of ranibizumab to non-treatment in reducing macular edema from baseline to Month 6 in DME  Group B: confirm the efficacy of ranibizumab on visual acuity (VA) as mean average change from baseline to Month 1 through Month 12 in best-corrected VA (BCVA)  Secondary endpoints  explore the treatment effect on VA, retinal structure, and need for laser photocoagulation  explore the superiority of ranibizumab effect on macular edema compared with sham

87. RESOLVE: Trial Design FA, fluorescein angiography OCT, optical coherence tomography Randomized 1:1:1 Sham Baseline fundus photograph, FA and OCT (reading center) Investigator identifies potential DME patients Photocoagulation after 3 injections if needed Assessment if “increase” is needed Increase to 0.6 mg if needed Ranibizumab 0.3 mg Ranibizumab 0.5 mg Increase to 1.0 mg if needed N = 151

88. Key Inclusion Criteria Male / female patients >18 years of age Patients with type 1 or type 2 diabetes mellitus HbA 1 C ≤ 12.0% Patients with DME with center involvement in at least one eye (focal or diffuse) Eligibility criteria for the study eye at Visit 1: ►Central macular thickness must be ≥300 µm in the center subfield, as assessed by optical coherence tomography (OCT) and confirmed by the central reading center ►BCVA letter score between 73 and 39

89. RESOLVE Treatment Dosing Schedule Month* Ranibizumab 10 mg/ml Sham 0 Ranibizumab 6 mg/ml 12 Primary endpoint 2 1 Dose may be doubled from 0.5 mg to 1.0 mg after 1 mo if indicated Dose may be doubled from 0.3 mg to 0.6 mg after 1 mo if indicated 34567891011 *Months 3-12 treatment on demand based on success, futility, and safety criteria

90. Treatment Adjustments: Dose Doubling* Criteria  Retinal thickness in the study eye remains >300 µm at the Month 1 visit following baseline injection or  Retinal thickness in the study eye is >225 µm and a reduction in retinal edema from the previous assessment is <50 µm, at any monthly visit after Month 1 following the baseline injection *By doubling the injection volume from 50 to 100 μl ywo formulations of 6 mg/ml and 10 mg/ml have been used 1. Kvanta et al., Invest Ophthalmol Vis Sci 1996; 37: 1929-1934. 2. Jonas JB, Neumaier M. Ophthalmic Res 2007, 39: 139-142.

91. Treatment Adjustments: Success and Re-initiation Criteria Discontinuation because of success if:  Retinal thickness in the study eye is ≤225 µm and  BCVA is ≥79 letters (≥20/25) at any visit following the third injection Re-initiation of treatment if:  Retinal thickness increases by ≥50 μm or  Visual acuity decreases by ≥5 letters and is <74 letters

92. Treatment Adjustments: Futility Criteria - No Borderline Improvement Borderline improvement defined as:  Decrease in retinal thickness of ≥50 µm and represents at least a 20% reduction or  Increase in BCVA of ≥5 letters At the investigator’s discretion: discontinue treatment after 3 consecutive injections if no borderline improvement

93. 000000 62.8 24 27 44 4 3 25 1 (32-84) (47.1) (52.9) (86.3) (7.8) (5.9) (49.0) (2.0) 000000 Baseline Demographics and Ocular Disease Characteristics All patients, Group A+B randomized set Age, years Mean (range) Gender, n (%) Female Male Race, n (%) Caucasian Black Asian Other DME type (RC), n (%) Focal Diffuse Questionable Cannot grade Missing Time since first DME diagnosis, years Mean (range) 63.2 22 29 47 4 21 27 1 2 (37-85) (43.1) (56.9) (92.2) (7.8) (41.2) (52.9) (2.0) (3.9) 000000 1.2 (0-7.2) 65.0 24 25 41 1 5 2 25 24 (41-82) (49.0) (51.0) (83.7) (2.0) (10.2) (4.0) (51.0) (49.0) Ranibizumab 6 mg/mL (n=51) Ranibizumab 10 mg/mL (n=51) Sham (n=49) 1.14 (0-7.2)1.40 (0-19.8)

94. RESOLVE Results: Mean BCVA Change* From Baseline Time (months) Mean VA change from BL ± SE (letters) Pooled ranibizumab (N = 102) Sham (N = 49) 0 *All patients, Group A+B Full analysis set; first VA value post-baseline was assessed at Day 8 BCVA, best-corrected visual acuity; BL, baseline; *LOCF, last observation carried forward SE, standard error of the mean

95. RESOLVE: mean CRT change* from baseline Pooled ranibizumab (N = 102) Sham (N = 49) Mean CRT change from BL ± SE (µm) Time (months) 0 *All patients, Group A+B Full analysis set; first VA value post-baseline was assessed at Day 8 BL, baseline; *LOCF, last observation carried forward SE, standard error of the mean

96. Ocular Adverse Events All patients, Group A+B randomized set Patients experiencing at least one ocular AE Most common ocular AEs Conjunctival hemorrhage Eye pain Ranibizumab 6 mg/mL (n=51) Ranibizumab 10 mg/mL (n=51) Sham (n=49) 38 (74.5) 10 (19.6) 9 (17.6) 42 (82.4) 13 (25.5) 9 (17.6) 28 (57.1) 7 (14.3) 10 (20.4) Adverse event (AE), n (%)

97. Serious Ocular Adverse Events Ranibizumab 6 mg/ml (n=51) Ranibizumab 10 mg/ml (n=51) Sham (n=49) Vitreous hemorrhage 100 Peripheral retinal ischemia 010 Retinal artery occlusion* 010 Endophthalmitis 110 Retinal detachment 001 Total patients 131 * transient post-injection of other non-serious ocular adverse events that occurred, no new or unexpected events were observed for this patient population and treatment

98. Adverse Events Potentially Related to Systemic VEGF Inhibition Ranibizumab 6 mg/ml (n=51) Ranibizumab 10 mg/ml (n=51) Sham (n=49) Arterial thromboembolic events 0 (0.0%)2 *(4.0%)2 (4.1%) Hypertension4 (7.8%)5 (9.8%)5 (10.2%) Total 4 (7.8%)7 (13.8%)6 (12.2%) * 1 Myocardial infarction, 1 Transient ischemic attack All patients, Group A+B. Safety set.

99. RESOLVE: Conclusions  The Phase II RESOLVE study results indicate DME response to treatment with intravitreal ranibizumab  Efficacy in the ranibizumab-treated arms showed clinical and statistical superiority compared with sham treatment in terms of mean average change in BCVA and CRT  The safety profile of ranibizumab in patients with DME was similar to that in patients with AMD  These results provide a sound basis for continuing development of ranibizumab in Phase III trials