Personalised Management of DME: an Expert Panel discussion Novartis Pharma AG CH-4002 Basel, Switzerland September 2015 © 2015-Novartis Pharma AG GLRET/LUC/0371c

Welcome and introduction Pascale Massin France

Scientific disclaimer and context These presentations are intended for scientific purposes only and may contain information on products or indications currently under investigation and/or development These presentations are accurate at the present time Any data about non-Novartis products are based on publicly available information at the time of presentation unless otherwise indicated

Dr. Patricio Schlottmann Our Panel Prof. Paul Mitchell Westmead Hospital, Sydney, Australia Prof. Pascale Massin Lariboisière hospital, Paris, France Prof. Christian Prünte Kantonsspital Liestal, Switzerland Prof. Nicole Eter University Hospital, Munster, Germany Dr. David Strain University of Exeter Medical School, UK Dr. Patricio Schlottmann Organización Médica de Investigación, Argentina

Financial disclosures P. Massin Allergan (AB; C) Alimera (AB; C) Bayer (AB; C) Novartis (AB; C) Sanofi (AB; C) P. Mitchell Bayer (AB; H; R; T) Novartis (AB; H; R; T) P. Schlottmann Allergan (T) Genentech (C) Novartis (AB; C; S) Roche (S) AB: Advisory Board Member; C: Consultant; H: Honorarium; P: Personal Fees R: Research Grant S: Speaker; T: Travel Grant

Financial disclosures N. Eter Alcon (S) Allergan (C; R; S) Bayer (C; R; S) Heidelberg Engineering (S) Roche (C) D. Strain Bayer (P) Boehringer Ingelheim (P) Bristol Myer Squibb (P) Novartis (P; R; T) Novo Nordisk (P; R; T) Pfizer (P) C. Prünte Alcon (C; S) Allergan (C; S) Bayer (C; S) Novartis (C; S) AB: Advisory Board Member; C: Consultant; H: Honorarium; P: Personal Fees R: Research Grant S: Speaker; T: Travel Grant

Objective and agenda Objective Explore clinical approaches to a personalised management of DME, an interactive discussion of clinical cases encountered in everyday practice Ranibizumab evidence in DME: From clinical trials to clinical practice Paul Mitchell Personalised management with ranibizumab in DME: Panel discussion of clinical cases Patricio Schlottmann, Nicole Eter and Pascale Massin The challenges of managing co-morbid DME patients Panel discussion of a Clinical case David Strain and Christian Prünte Agenda

Ranibizumab evidence in DME: from clinical trials to clinical practice Paul Mitchell Australia

There is a wealth of Phase III evidence supporting the efficacy of anti-VEGF treatments in DME BCVA, best corrected visual acuity; PRN, pro re nata; T&E, treat and extend; VA, visual acuity; VEGF, vascular endothelial growth factor Ranibizumab plus deferred or prompt laser superior to triamcinolone plus prompt laser T&E ranibizumab non-inferior to PRN BCVA gains sustained Sustained VA with reduced injections (PRN) Ranibizumab superior to sham Ranibizumab (RBZ) plus deferred laser superior to RBZ plus prompt laser Year 1 Year 2 Year 3 Year 5 Aflibercept superior to laser Ranibizumab alone/combined with laser superior to laser monotherapy Gains in VA sustained over time with reduced injections Regimen RISE/RIDE1-3 REVEAL11 RETAIN10 RESTORE4-6 Protocol I7-9 VIVID/ VISTA13 RESPOND12 Monthly 3+PRN T&E/ 3+PRN Monthly/ 5+2q8 Trial Parameters* included in Phase III trials Ranibizumab Aflibercept Fixed monthly regimen  Loading (3) + PRN regimen  Loading (5) + fixed bimonthly regimen Loading (3) + T&E regimen Versus laser Versus sham Combination with laser Multi-ethnic populations (Afro-American, Asian, Caucasian) *Parameters not from H2H studies 1. Brown DM, et al. Ophthalmology 2013;120:2013-22; 2. Nguyen QD, et al. Ophthalmology 2012;119:789-801; 3. Morse, LS. 37th Macular Society meeting 2014; 4. Mitchell P, et al. Ophthalmology 2011;118:615-25; 5. Lang GE, et al. Ophthalmology 2013;120:2004-12; 6. Schmidt-Erfurth U, et al. Ophthalmology 2014;121:1045-53; 7. Elman MJ, et al. Ophthalmology 2010;117:1064-77; 8. Elman MJ, et al. Ophthalmology 2011;118:609-14; 9. Elman MJ, et al. Ophthalmology 2015;122:375–81; 10. Prünte C, et al. In press BJO, Sept 2015; 11. Ishibashi T, et al. Ophthalmology. 2015 Jul;122(7):1402-15; 12. Berger A et al. Can J Ophthalmol. 2015;50:209-16; 13. Korobelnik JF, et al. Ophthalmology. 2014;121:2247-54.

Similar VA scores at 12 months, regardless of the dosing regimen or the anti-VEGF agent RISE* monthly RIDE* monthly DA VINCI 2q8 VIVID 2q8 VISTA 2q4 VISTA 2q8 DA VINCI 2PRN RESOLVE 0.3-1 mg pooled VIVID 2q4 RETAIN T&E Protocol I PRN + deferred laser RETAIN PRN RESTORE PRN monotherapy Aflibercept 2mg Ranibizumab 0.5mg ETDRS letters 12.0 DA VINCI 2q4 1. Nguyen QD, et al. Ophthalmology 2012;119:789-801; 2. Do DV, et al. Ophthalmology 2012;119:1658–65; 3. Korobelnik JF, et al. Ophthalmology. 2014;121:2247-54; 4. Massin P, et al. Diabetes Care 2010;3:2399–405; 5. Prünte C, et al. In press BJO, Sept 2015; 6. Elman MJ, et al. Ophthalmology 2010;117:1064–77; 7. Mitchell P, et al. Ophthalmology 2011;118:615–25 *2-year data Collation of available studies – study designs may vary

Evolution of DME management with ranibizumab RESOLVE Dose finding Ranibizumab approved in DME RETAIN PRN versus T&E P. Massin et al. C Prünte et. al* Nov 2010 Jan 2011 Apr 2011 Jun Sept 2015 Nov Sept 2016 P Mitchell et. al LUMINOUS DME Baseline data 4500 + patients LUMINOUS DME 1 year data 4500 + patients RESTORE H2H versus Laser LUMINOUS Real World Evidence Continued evidence generation to facilitate improved patient outcomes * Prünte C, et al. In press BJO, Sept 2015

8 randomized controlled trials Ranibizumab 0.5 mg clinical use in DME supported by extensive scientific evidence 8 randomized controlled trials RESOLVE 1800 patients Sham and laser as control RIDE RESTORE RISE Duration* of up to 5 years Monthly, PRN and T&E regimens RETAIN PROTOCOL-I RESPOND REVEAL *Duration ranged from 1 to 5 years for the different studies

RESTORE: early treatment provides sustained VA gains with decreasing number of injections over extended periods of time Extension phase (ranibizumab 0.5 mg PRN) Core phase 7.9 7.9 8.0 7.1 6.7 6.7 6.0 Mean change in BCVA from baseline (letters) VA gains sustained at 36 months 5.4 2.3 Ranibizumab 0.5 mg PRN (n=83) Laser (n=74) Ranibizumab 0.5 mg PRN + laser (n-83) Month Mean injection frequency in ranibizumab 0.5 mg PRN arm Year 1 Year 2 Year 3 7.4 3.9 2.9 Schmidt-Erfurth U, et al. Ophthalmology 2014;121:1045–53

All patients received 0.5 mg ranibizumab PRN RISE & RIDE: BCVA gains maintained with ranibizumab 0.5 mg PRN treatment up to 54 months Sham/0.5 mg crossover Sham control Open-label extension 0.5 mg ranibizumab monthly (n=252) Sham (n=257) 0.3 mg ranibizumab monthly* (n=250) 0.5 mg ranibizumab PRN All patients received 0.5 mg ranibizumab PRN 14.5 15.0 14.3 13.2 14.2 13.2 8.1 7.8 5.1 Patients, n* Sham/crossover 0.3 mg ranibizumab 0.5 mg ranibizumab 158 155 159 152 161 115 95 47 168 167 170 172 126 101 39 163 162 164 124 82 35 * Ranibizumab 0.3 mg monthly regimen is not licensed outside the US Ho, AC. 37th Macular Society meeting, 2014

All patients received 0.5 mg ranibizumab PRN RISE & RIDE: BCVA gains maintained with ranibizumab 0.5 mg PRN treatment up to 54 months Sham/0.5 mg crossover Sham control Open-label extension 0.5 mg ranibizumab monthly (n=252) Sham (n=257) 0.3 mg ranibizumab monthly* (n=250) 0.5 mg ranibizumab PRN All patients received 0.5 mg ranibizumab PRN 14.5 15.0 14.3 13.2 14.2 13.2 8.1 7.8 5.1 Open-label extension: mean annualized 3.8 injections, ~25% of patients did not require injections * Ranibizumab 0.3 mg monthly regimen is not licensed outside the US Ho, AC. 37th Macular Society meeting, 2014

Mean BCVA change from baseline (letters) Protocol I: better VA outcomes with ranibizumab and deferred laser compared to prompt laser over 5 years 9.8 7.2 Mean BCVA change from baseline (letters) Ranibizumab + prompt laser (n = 124) Ranibizumab + deferred laser (n = 111) Year Elman MJ, et al. Ophthalmology 2015;122:375–81

Ranibizumab + prompt laser Ranibizumab + deferred laser Protocol I: better VA outcomes with ranibizumab and deferred laser compared to prompt laser over 5 years 9.8 7.2 Mean BCVA change from baseline (letters) Median number of injections Ranibizumab + prompt laser Ranibizumab + deferred laser Year 1 8 9 Year 2 2 3 Year 3 1 Year 4 Year 5 Year Elman MJ, et al. Ophthalmology 2015;122:375–81

Greater differences in NEI VFQ-25 QoL subscale scores were observed for ranibizumab 0.5 mg compared to laser monotherapy *p<0.05, **p<0.001 vs laser * * ** * * * * Mean VFQ-25 score Source: Mitchell P et al. Ophthalmology 2011; 118: 615-625 http://www.ncbi.nlm.nih.gov/pubmed/21459215 Supplementary data of VFQ-25 online only at: http://www.sciencedirect.com/science/article/pii/S0161642011000649 The improvement at Month 12 compared to baseline in VFQ-25 composite score, general vision, near activities, and distance activities was numerically greater in the patients treated with ranibizumab and ranibizumab + laser than in patients treated with laser. A positive treatment effect on quality of life of ranibizumab as monotherapy and/or adjunctive with laser treatment on VFQ-25 score was suggested. Full analysis set/LOCF p-values for treatment difference are from the two-sided stratified Cochran-Mantel-Haenszel test NEI-VFQ: national eye institute visual function questionnaire; SE: standard error; LOCF: last observation carried forward; QoL: quality of life Mitchell P, et al. Ophthalmology 2011;118:615–625

Consistent and well-documented long-term safety profile across all 5 indications Incidences of ocular and non-ocular events similar across groups, and similar to previous trials in other indications; no new safety findings or increased safety concerns reported nAMD DME CRVO BRVO mCNV 19,500 patients enrolled in RCTs across all 5 indications 3.1 million patient treatment years of exposure across all 5 indications 18.5 million injections across all 5 indications nAMD Neovascular age-related macular degeneration DME Diabetic macular edema BRVO Branch Retinal vein occlusion CRVO Central Retinal vein occlusion mCNV Myopic choroidal neo-vascularization

Conclusions: ranibizumab in DME Well-established long-term efficacy in RCTs utilizing a monthly, PRN or T&E regimen Early VA gains sustained for up to 5 years in RCTs Injection frequency can be reduced as early as the first year of treatment,* and can be reduced further with continued treatment* Consistent and well-documented safety profile *Treatment is initiated with one injection per month until maximal visual acuity is achieved and/or there are no signs of disease activity. i.e. no change in visual acuity and in other signs and symptoms of the disease under continued treatment. In patients with wet AMD, DME and RVO, initially, three or more consecutive monthly injections may be needed.

How does this evidence apply to real world clinical practice ... With which therapy to initiate treatment? Laser, steroid or anti-VEGF? Should we switch treatments? Which regimen do we use? Monthly, PRN or T&E? Is a "One size fits all" or a personalised approach required in DME management?

Patricio Schlottmann, Nicole Eter and Pascale Massin Personalised management with ranibizumab in DME Patricio Schlottmann, Nicole Eter and Pascale Massin

How does this evidence apply to real world clinical practice ... With which therapy to initiate treatment? Laser, steroid or anti-VEGF? Should we switch treatments? Which regimen do we use? Monthly, PRN or T&E?

Clinical case 1 50-year-old male, laser 2011 14th September 2011 Laser scars visible on a patient with DME previously treated with macular laser Clinical Case: Courtesy of Prof. P. Schlottmann

Clinical case 1 50-year-old male, laser scars 2015 14th September 2011 Laser scars visible on a patient with DME previously treated with macular laser Clinical Case: Courtesy of Prof. P. Schlottmann

Laser photocoagulation prevented vision loss but offered limited improvement in vision1 Suprathreshold focal laser photocoagulation reduced moderate vision loss in DME2 Although laser photocoagulation reduces vision loss, increases in visual acuity after treatment are rare2–4 Laser burns cause retinal lesions, which develop into focal areas of chorioretinal scarring5 1. Mitchell P & Wong T. Am J Ophthalmol 2014;157:505-13; 2. ETDRS Research Group. Arch Ophthalmol 1985;103:1796-806; 3. ETDRS Research Group. Ophthalmology 1991;98:766-85; 4. Shamsi HNA et al. World J Diabetes 2013;4:324-38; 5. Luttrull JK & Dorin G. Curr Diabetes Rev 2012;8:274-8

RESTORE: inferior VA outcomes with laser compared to ranibizumab Mean change in BCVA from baseline (letters) BCVA ≤60 letters BCVA 61–73 letters BCVA >73 letters 8.6 8.2 7.5 6.6 3.9 0.4 Source: CSR: table 14.2-2.14 page 604 Mitchell P et al. Ophthalmology 2011; 118: 615-625 http://www.ncbi.nlm.nih.gov/pubmed/21459215 Patient numbers for RESTORE: ranibizumab 0.5 mg, n = 22; ranibizumab 0.5 mg + laser, n = 19; laser, n = 17 –4.8 Month Month Month Ranibizumab 0.5 mg (n = 38) Ranibizumab 0.5 mg (n = 55) Ranibizumab 0.5 mg (n = 22) Ranibizumab 0.5 mg + laser (n = 44) Ranibizumab 0.5 mg + laser (n = 55) Ranibizumab 0.5 mg + laser (n = 19) Laser (n = 40) Laser (n = 53) Laser (n = 17) Mitchell P, et al. Ophthalmology 2011;118:615-25

Lower overall VA outcomes achieved with dexamethasone than with ranibizumab, even in the pseudophakic population1-7 Mean BCVA at baseline Mean BCVA gain at endpoint Ranibizumab: Dexamethasone: Studies of ranibizumab in patients with DME have demonstrated a similar mean BCVA of about 70 letters at 12 months (plateau effect) Patients treated with dexamethasone achieved a lower mean gain in vision at the end of Year 1 than patients treated with ranibizumab Year 1 Year 1 Year 1 Year 1 Year 1 Year 1 Year 1 Year 1 Year 1 Year 1 1 1 2 2 6 6,7 5 5 3 4 Based on available data – only the Maggiore study is a direct ranibizumab vs dexamethasone head-to-head trial5 Cross-trial comparisons should be interpreted with caution. BCVA, best-corrected visual acuity; DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; PRN, pro re nata (as-needed); T&E, treat and extend; VA, visual acuity. *Values estimated from graph of the original publication; †total population; ‡pseudophakic population. 1. Nguyen QD, et al. Ophthalmology 2012;119:789-801; 2. Prünte C, et al. Presented at WOC, 2-6 April 2014; Tokyo, Japan; 3. Mitchell P, et al. Ophthalmology 2011;118:615–25; 4. DRCR.net, et al. Ophthalmology 2010;117:1064–77; 5. ClinicalTrials.gov. NCT01492400. Available from https://clinicaltrials.gov/ct2/show/NCT01492400?term=NCT01492400&rank=1 [accessed 25 Feb 2015]; 6. Boyer DS, et al. Ophthalmology 2014;121:1904-14; 7. Boyer DS. Personal communication

Panel discussion

How does this evidence apply to real world clinical practice ... With which therapy to initiate treatment? Laser, steroid or anti-VEGF? Should we switch treatments? Which regimen do we use? Monthly, PRN or T&E?

Clinical case 2 69 year old male Diabetes for 15 years BCVA RE 0.6 LE 0.6 First injection, both eyes treated on the same day with ranibizumab Clinical Case: Courtesy of Prof. N. Eter

Week 4 BCVA RE 0.6 LE 0.7 Second injection, both eyes treated on the same day with ranibizumab Clinical Case: Courtesy of Prof. N. Eter

Week 8 BCVA RE 0.6 LE 0.7 Third injection, both eyes treated on the same day with ranibizumab Clinical Case: Courtesy of Prof. N. Eter

Week 12 BCVA RE 0.8 LE 0.8 Clinical Case: Courtesy of Prof. N. Eter

Delayed responders Pooled analysis from the RESTORE-extension study1,2 Patients losing ≥4 letters from baseline to Month 1 and/or Month 2 (N = 20) Do we change to another drug here or continue with the current drug? These patients gained 11 letters without switching to another drug +11 letters Mean BCVA gain from baseline , ETDRS letters RESTORE Extension: BCVA letter gain over time in patients who lost >4 letters from baseline to Month 1 and/or Month 2 with ranibizumab PRN ± laser treatment Patients losing ≥4 letters at Month 1 and/or 2 with ranibizumab PRN ± laser treatment gained 11 letters at Month 36 +8.8 letters BCVA, best-corrected visual acuity ETDRS, Early Treatment Diabetic Retinopathy Study PRN, pro re nata 1. Schmidt-Erfurth et.al. Ophthalmology 2014;1201:1045–1053; 2. Staurenghi G. ARVO 2015

No injection at Month 3 or 4 More than 25% of patients did not need any injections at Months 3 and 4 in RESTORE All No injection at Month 3 No injection at Month 3 or 4 % (n) 100% (206) 35.4% (73) 26.7% (55) Mean BCVA gain at Month 12 7.5 (± 8.4) 8.8 (± 8.4) 9.0 (± 8.5) Mean (SD) number of injections at Month 12 7.2 (± 2.8) 4.9 (± 2.3) 4.3 (± 1.9) Pooled PRN ranibizumab and ranibizumab + laser Novartis data on file

No injection at Month 3 or 4 More than 25% of patients did not need any injections at Months 3 and 4 in RESTORE All No injection at Month 3 No injection at Month 3 or 4 % (n) 100% (206) 35.4% (73) 26.7% (55) Mean BCVA gain at Month 12 7.5 (± 8.4) 8.8 (± 8.4) 9.0 (± 8.5) Mean (SD) number of injections at Month 12 7.2 (± 2.8) 4.9 (± 2.3) 4.3 (± 1.9) Pooled PRN ranibizumab and ranibizumab + laser Novartis data on file

No injection at Month 3 or 4 More than 25% of patients did not need any injections at Months 3 and 4 in RESTORE All No injection at Month 3 No injection at Month 3 or 4 % (n) 100% (206) 35.4% (73) 26.7% (55) Mean BCVA gain at Month 12 7.5 (± 8.4) 8.8 (± 8.4) 9.0 (± 8.5) Mean (SD) number of injections at Month 12 7.2 (± 2.8) 4.9 (± 2.3) 4.3 (± 1.9) Pooled PRN ranibizumab and ranibizumab + laser Novartis data on file

DME patients demonstrate wide variability in injection needs to have an improvement in their visual acuity RESTORE1 RETAIN1 DRCR.net Protocol I*2 Proportion of patients (%) Number of injections in 12 months 1. Figueira J. Presented at ESASO 2014, Istanbul, Turkey 2. Elman MJ, et al. Ophthalmology 2010;117:1064–77 *Ranibizumab 0.5mg PRN with deferred laser

Panel discussion

How does this evidence apply to real world clinical practice ... With which therapy to initiate treatment? Laser, steroid or anti-VEGF? Should we switch treatments? Which regimen do we use? Monthly, PRN or T&E?

VA 20/50 Clinical Case: Courtesy of Prof. P. Massin

3 IVT ranibizumab (Oct, Nov, Dec) 20/63 65 October 2012 3 IVT ranibizumab (Oct, Nov, Dec) 20/63 65 January 2013 Clinical Case: Courtesy of Prof. P. Massin

3 IVT ranibizumab (Oct, Nov, Dec) 20/63 63 Oct 2012 3 IVT ranibizumab (Oct, Nov, Dec) 20/63 65 Jan 2013 2 IVT ranibizumab (Jan, Feb ) 20/50 64 March 2013 Clinical Case: Courtesy of Prof. P. Massin

1 IVT Lucentis® every 2 months (May and July) 20/50 64 March 2013 1 IVT Lucentis® every 2 months (May and July) 20/32 71 Sept 2013 Clinical Case: Courtesy of Prof. P. Massin

1 IVT ranibizumab every 2 months (May and July) 20/50 64 March 2013 1 IVT ranibizumab every 2 months (May and July) 20/32 71 Sept 2013 1 IVT ranibizumab 3 months later (October 2013) 20/40 71 January 2014 Clinical Case: Courtesy of Prof. P. Massin

Visits in April and September 2014 – No injections 20/32 72 Clinical Case: Courtesy of Prof. P. Massin

20/63 65 6 months 5 injections First year 7 injections 20/50 64 20/63 65 6 months 5 injections First year 7 injections 20/50 64 6 months 2 injections 20/32 71 1 year 1 injection Second year 1 injection 20/32 72 Clinical Case: Courtesy of Prof. P. Massin

Mean change (±SE) in BCVA from baseline (ETDRS letters) RETAIN: T&E regimen is a feasible treatment option for DME patients who require long-term treatment and follow-up Months Mean change (±SE) in BCVA from baseline (ETDRS letters) 8.3 6.5 8.1 BCVA, best-corrected visual acuity; ETDRS, early treatment diabetic retinopathy study; MV/LOCF, mean value interpolation/last observation carried forward; PRN pro re nata; RBZ, ranibizumab; T&E, treat and extend RETAIN: first study to demonstrate non-inferiority of a T&E regimen to PRN dosing in DME CMH test (row mean scores statistic) with the observed values as scores; Full analysis set (MV/LOCF, mean value interpolation/last observation carried forward) * Prünte C, et al. In press BJO, Sept 2015

RETAIN study: T&E regimen may reduce visit burden Injections over 24 months Mean number Prünte C, et al. In press BJO, Sept 2015

RETAIN study: T&E regimen may reduce visit burden Visits between Month 3 and Month 24 Injections over 24 months 40% reduction in patient visits with T&E regimen >70% of patients had a treatment interval of ≥2 months Mean number Prünte C, et al. In press BJO, Sept 2015

Panel discussion

David Strain Christian Prünte The challenges of managing comorbid DME patients David Strain Christian Prünte

Diabetes is a growing worldwide epidemic affecting largely a working age population Millions of cases in 2013 (prevalence) Millions of cases in 2035 (prevalence)* % increase Almost half of all adults with diabetes are between the ages of 40 and 59 years North America & Caribbean 36.7 (9.6%) 50.4 (9.9%) +37% Europe 56.3 (6.8%) 68.9 (7.1%) +22% South & Central America 24.1 (8.2%) 38.5 (8.2%) +60% Western Pacific 138.2 (8.1%) 201.8 (8.4%) +46% South-East Asia 72.1 (8.7%) 123.0 (9.4%) +71% Middle East & North Africa 34.6(10.9%) 67.9 (11.3%) +96% Africa 19.8 (5.7%) 41.4 (6.0%) +110% 2013: 382 million 2035: 592 million 55% global increase by 2035 International Diabetes Federation, Diabetes Atlas 6th Edition, 2013 http://www.idf.org/diabetesatlas *Projections for adults aged 20-79 years

Patients with DME are relatively young and usually present with a complex profile of co-morbidities Diabetic retinopathy1 Stroke1 Patients with DME have an even greater risk of complications than diabetes patients without DME3,4 Cardiovascular disease2 Dyslipidemia2 All images freely available from Microsoft clipart or Wikimedia Commons, or purchased for royalty-free use from Shutterstock Diabetic neuropathy1 Diabetic nephropathy1,2 1. Petrella RJ, et al. J Ophthalmol 2012;159167; 2. International Diabetes Federation, Diabetes Atlas 6th Edition, http://www.idf.org/diabetesatlas; 3 Wong TY, et al. JAMA 2002;288:67-74; 4. Nguyen-Khoa B, et al. BMC Ophthalmol 2012;12:11

Patients’ perceptions of being diagnosed with diabetes Feelings about complications at diagnosis: 3% none of these 63% knew these health problems might affect them in the future, but risk seemed remote 25% were devastated they might develop complications 9% were not really concerned Complications patients were most concerned about: 50% 21% 11% 10% 9% 7% Problems with vision/loss of sight/retinopathy Heart/cardiac disease Kidney/renal problems Circulation problems Problems with feet/legs Other Strain DW et al. Diabetes Research and Clinical Practice; 2014;105;302-12

The cardiovascular risk associated with diabetes 50% of people with diabetes go on to die of CVD1 CVD death rate* per 10,000 person-years3 Rate, n 50% Number of risk factors† Compared with healthy individuals, patients with diabetes are around 4 times more likely to develop CVD1 and have a life expectancy up to 8 years lower2 Number of risk factors† † Additional risk factors from: cholesterol, hypertension, and smoking *Adjusted for age; CV, cardiovascular CVD, CV disease 1. International Diabetes Federation, Diabetes Atlas 6th Edition, http://www.idf.org/diabetesatlas; 2. Gu K et al. Diab Care 1998;21:1138-45; 3. Stamler J et al. Diab Care 1993;16:434-44

DME patients are at even greater risk of cardiovascular and cerebrovascular diseases than patients with diabetes only Acute myocardial infarction Cerebrovascular accident Rate per 1,000 person years Rate per 1,000 person years Presence of DME is a predictor of cardiovascular morbidity and mortality *Age and gender matched diabetes subjects without ophthalmic manifestations, retinal disorders, or vitreous hemorrhage Nguyen-Khoa B, et al. BMC Ophthalmol 2012;12:11

Systemic VEGF-A benefits to the body have been demonstrated in humans and animals Upregulation of VEGF-A through genetic manipulation improves coronary recovery after myocardial infarction in dogs2 Increasing VEGF-A expression in a mouse model of ischemic cardiomyopathy improves tissue perfusion1 Human trials are underway into the administration of VEGF-A in patients with coronary artery disease3,4 1. Clayton JA, et al. Circ Res 2008;103:1027-36; 2. Ferrarini M, et al. Circ Res 2006;98: 954-61; 3. Rosengart TK, et al. Circulation 1999;100:468-74; 4. Hedman M, et al. Gene Ther 2009;16:629-34

Potential side effects of systemic administration of anti-VEGF treatment in oncology patients1 Angiogenesis Endothelial cell (EC) integrity Vascular tone Prevention of blood cell adherence to EC Kidney filtration function Function VEGF blockade Compromised wound healing Hypertension Thromboembolic events Cardiac dysfunction Proteinuria Outcome The dosage, route of administration and side effect profile of anti-VEGF therapies in oncology patients are different to those in ophthalmology patients2–5 1. Chen HX and Cleck JN, Nat Rev Clin Oncol 2009;6:465-77; 2. LUCENTIS® SmPC. Sept 2014 3. EYLEA® SmPC. www.medicines.org.uk/emc/medicine/27224; 4. ZALTRAP® SmPC. www.medicines.org.uk/emc/ medicine/27413 5. AVASTIN® SmPC. www.medicines.org.uk/emc/medicine/15748

Molecular and kinetic properties of ranibizumab Molecular weight 48 kDa1 Structure Intravitreal elimination half-life 2.88 days (rabbit eye)2 9 days (human eye)3 Systemic elimination half-life ~2 hours4 Mean serum exposure after one injection, AUC (days.nM) 0.25 Fab 1. Genentech. Lucentis prescribing information, 2014; 2. Bakri SJ, et al. Ophthalmology 2007;114:2179-82; 3. Novartis Pharma AG. Lucentis SmPC September 2014; 4. EMA. Lucentis EPAR Scientific Discussion.www.ema.europa.eu/docs/en_GB/document_library/EPAR__Scientific_Discussion /human/ 000715/WC500043550.pdf; 5. Avery RL et al. Data presented at ARVO, Poster 586, 4-8 May 2014, US.

Panel discussion

Q & A

Concluding remarks Paul Mitchell Australia

Concluding Remarks Ranibizumab has demonstrated well-established efficacy in RCTs utilizing a monthly, PRN or T&E regimen Laser may be useful in certain patient types, but in general laser does not provide an improvement in vision and patients can often lose vision, impacting their QoL Personalised regimens seem to be an appropriate approach to clinically manage DME patients Comorbidities need to be an important clinical consideration in therapy selection /decision making LUMINOUS and additional real world evidence will further enhance our understanding of DME management and patient care

Summary of product characteristics for Lucentis® (ranibizumab) is available on request from the hostesses

Personalised management of DME: an expert panel discussion Novartis Pharma AG CH-4002 Basel, Switzerland September 2015 © 2015-Novartis Pharma AG GLRET/LUC/0371c