1. a Novartis company AREDS 2 and U Bruce E. Onofrey, OD, RPh, FAAO, FOGS Professor, University of Houston UEI

2. DISCLOSURES I’M AN ADVISOR TO : KEMIN PHARMA ALCON B AND L ALLERGAN

3. a Novartis company Age-Related Eye Disease Study (AREDS): Rationale and Significance PART 2

4. AREDS 2 The Age Related Eye Disease Study-Part 2 JAMA, May 2013 Lutein (+) Zeaxanthin and Omega 3 fatty acids for age related macular degeneration: AREDS 2 The QUESTIONS: 1. Does adding lutein (+) zeaxanthin, the Omega 3 fatty acids DHA (+) EPA or both to the original AREDS formula decrease the risk of developing advanced AMD?

5. QUESTION #2 Does removal of beta- carotene or reduction in the amount of zinc increase the risk of developing AMD?

6. QUESTION #3 JAMA, JULY 2013 Does L/Z supplementation affect the rate of cataract surgery or cataract associated vision loss?

7. AREDS: NEI Trial Overview Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36. FeatureDescription Objective To evaluate the effect of high-dose vitamin supplementation, age-related macular degeneration (AMD) progression and visual acuity. Design Double-masked, randomized, placebo- controlled trial Population 3640 high risk patients (55-80 years) Duration 6.3 years supplementation and follow up

8. ARED (Age related eye disease) Study results Archives of Ophthalmology-October 2001 Categories 1. NO AMD 2. Mild AMD 3. Moderate AMD 4. Advanced AMD

9. Daily Dosage: Placebo VS AREDS formula SupplementDosage Antioxidants Beta-carotene15 mg Vitamin C500 mg Vitamin E400 IU Essential Trace Elements Copper2 mg Zinc80 mg Supplements were manufactured to have the following minimum contents: Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36.

10. AREDS Rationale: Beta-Carotene Why is it important? ▫ Body unable to synthesize 1 ▫ Antioxidant capability 1 What dose was studied? ▫ 15 mg/day (AREDS) 2 Where can I get it in my diet? ▫ Carrots, broccoli, spinach, kale 3 ▫ 15 mg beta-carotene = 1.6 cups of carrots 3 ▫ 15 mg beta-carotene = 47.1 cups of broccoli 3 1.Paiva SAR, et al. Β-Carotene and Other Carotenoids as Antioxidants. J Am Coll Nutr 1999;18(4):426–33. 2.Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36. 3.USDA National Nutrient Database for Standard Reference, Release 18, Beta-carotene. Available at: http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/nutrlist/sr18w321.pdf. Accessed May 1, 2012.

11. The three beta-carotene intervention trials: the Beta Carotene and Retinol Efficacy Trial (CARET), Alpha-Tocopherol, Beta- Carotene Cancer Prevention Study (ATBC), and Physician's Health Study (PHS) have all pointed to a lack of effect of synthetic beta-carotene in decreasing cardiovascular disease or cancer risk in well-nourished populations. The contribution of beta-carotene supplementation to increased risk of lung cancer in smokers has been raised as a significant concern. Risk increase = approx 30% (avg of 3 studies) DON’T FORGET THE CONTRAINDICATIONS - Beta Carotene and Cancer

12. DON’T SMOKE: Cigarette smoking and retinal carotenoids: implications for age- related macular degeneration. Subjects were matched with respect to age, sex, dietary patterns and overall pigmentation (i.e., eye, skin and hair color). The smoking group had a mean MP of 0.16 (SD = 0.12) compared to a mean MP of 0.34 (SD = 0.15) for nonsmokers (P < 0.0001). MP density and smoking frequency were inversely related (r = -0.498 P < 0.001) in a dose-response relationship.

13. Why is it important? ▫ Body unable to synthesize 1 ▫ Antioxidant capability 1 What dose was studied? ▫ 500 mg/day (AREDS) 2 Where can I get it in my diet? ▫ Citrus fruits and juices 3 ▫ 500 mg vitamin C = 4 cups/32 fl oz of orange juice 3 Why is it important? ▫ Body unable to synthesize 1 ▫ Antioxidant capability 1 What dose was studied? ▫ 500 mg/day (AREDS) 2 Where can I get it in my diet? ▫ Citrus fruits and juices 3 ▫ 500 mg vitamin C = 4 cups/32 fl oz of orange juice 3 AREDS Rationale: Vitamin C 1.Jacob RA, Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin Care 2002;5(2):66-74. 2.Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36. 3.USDA National Nutrient Database for Standard Reference Release 18, Vitamin C. Available at: http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/nutrlist/sr18w401.pdf. Accessed May 1, 2012.

14. AREDS Rationale: Vitamin E Why is it important? ▫ Body unable to synthesize 1 ▫ Antioxidant capability 1 What dose was studied? ▫ 400 IU/day (AREDS) 2 Where can I get it in my diet? ▫ Nuts, fortified cereals, sweet potatoes 3 ▫ 400 IU vitamin E = 182.6 sweet potatoes 3 1.Traber MG, Stevens JF. Vitamins C and E: Beneficial Effects From a Mechanist Perspective. Free Radic Biol Med 2011;51(5):1000-13. 2.Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36. 3.USDA National Nutrient Database for Standard Reference Release 18, Vitamin E. Available at: http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/nutrlist/sr18w323.pdf. Accessed May 1, 2012.

15. AREDS Rationale: Zinc : Early studies suggested ability to slow progression, but not VA loss in AMD Why is it important? ▫ Essential trace element 1 What dose was studied? ▫ 80 mg zinc/day (AREDS) 2 Where can I get it in my diet? ▫ Red meat, poultry, mixed nuts 2 ▫ 80 mg zinc = 55.8 oz of red meat 3 ▫ 80 mg zinc = 50.3 oz of nuts 3 1.Grahn, BH, et al. Zinc and the eye. J Am Coll Nutr 2001;20(2 Suppl):106-18. 2.Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36. 3.USDA National Nutrient Database for Standard Reference Release 18, Zinc. Available at: http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/nutrlist/sr18w309.pdf Accessed May 1, 2012.

16. AREDS Rationale: Copper Why is it important? ▫ Essential trace element 1 ▫ Both an anti-oxidant and pro-oxidant 2 ▫ Body unable to synthesize 2 ▫ High zinc may cause copper deficiency 3 What dose was studied ? ▫ 2 mg/day (AREDS) 4 Where can I get it in my diet? ▫ Seafood, Liver, Nuts, Legumes 2 ▫ 2 mg copper = 1/2 oz of liver 5 ▫ 2 mg copper = 5 cups of beans 5 1.Determinants of Copper Needs Across the Lifespan. Office of Dietary Supplements, National Institutes of Health. Available at: at: http://ods.od.nih.gov/News/Copper.aspx. Accessed August 31, 2011. 2.Copper Overview. University of Maryland Medical Center. Available at: http://www.umm.edu/altmed/articles/copper-000296.htm. Accessed August 31, 2011. 3.NIH Dietary Supplement Fact Sheet: Zinc. National Institutes of Health. Available at: http://ods.od.nih.gov/factsheets/Zinc-HealthProfessional / Accessed 21 July 2011 4.Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36. 5.USDA National Nutrient Database for Standard Reference Release 18, Copper. Available at: http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/nutrlist/sr18w312.pdf Accessed May 1, 2012

17. AREDS 1: THE RESULTS 21 published reports Those likely to benefit from AREDS formula: -extensive intermediate-size drusen -at least one large drusen -noncentral geographic atrophy -advanced AMD -vision loss in one eye

18. ARED Study results Archives of Ophthalmology-October 2001 1. Patients over 55 years should have DFE to be evaluated for risk of AMD. 2. If extensive intermed. Drusen, at least 1 large druse, non-central geographic atrophy in 1 or both eyes or advanced AMD and no contraindications-TX 3. Vit C 500mg, Vit E 400IU, Beta carotene 15mg + Zinc 80mg and Copper 2mg (Oxides) 4. 8% decrease of progression from Catagory 3 to 4 Reduced visual acuity loss by 19% in Catagory 3 and 4

19. IMPORTANT TO NOT TAKE AREDS TOO FAR DID NOT PREVENT AMD DID NOT REVERSE AMD

20. WHY AREDS 2? WHY L/Z? WHY OMEGA 3’S?

21. 1.Age-Related Eye Disease Study Research Group. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch Ophthal 2007;125(9):1225-32. 2.Age-Related Eye Disease Study Research Group. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol 2007;125(5):671-9 3.Sangiovanni JP, et al. 6{omega}-3 Long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohort study from the Age-Related Eye Disease Study. Am J Clin Nutr 2009;90(6):1601-7. Lutein/zeaxanthin and omega-3 fatty acid: Intake was independently linked with decreased likelihood of: 1,2 Neovascular AMD (Lutein/zeaxanthin, Omega-3s) Geographic atrophy (Lutein/zeaxanthin, Omega-3s) Large or extensive intermediate drusen Omega-3 fatty acids were of particular benefit in groups at higher risk for neovascular AMD and geographic atrophy 3 AREDS 1: Observations

22. Significance of Lutein and Zeaxanthin Several carotenoids are present in human serum, but only lutein and zeaxanthin are present in macula and provide a yellow color known as macular pigment 1 This macular pigment protects the macula from the damaging photo-oxidative effects of blue light 1 Body cannot synthesize 2 5:1 ratio of lutein to zeaxanthin in the diet 3 Powerful Antioxidant 4 –Reduces free radical damage in the eye 1.Lutein and Zeaxanthin. Alternative Medicine Review 2005;10(2):128-35. 2.Nutritional Supplements for Eye Health. Bausch & Laumb Website. Available at: http://www.preservision.co.uk/. Accessed 3 October 2011 3.Thurnham DI. Macular Zeaxanthins and Lutein—A Review of Dietary Sources and Bioavailability and Some Relationships with Macular Pigment Optical Density and Age-Related Macular Disease. Nutr Res Rev 2007;20:163–79. 4.Subczynski WK, et al. Location of Macular Xanthophylls in the Most Vulnerable Regions of Photoreceptor Outer-Segment Membranes. Arch Biochem Biophys 2010;504:61–6. Yellow macular pigment composed of lutein and zeaxanthin

23. Lutein Antioxidant Supplementation Trial (L.A.S.T.) and Macular Pigment Optical Density (MPOD) 90 patients with AMD (4 females, 86 males): –Mean age: 75 –Mean number of smoking pack years: 7 Treatment arms: –10 mg FloraGLO ® lutein –10 mg FloraGLO ® lutein + antioxidants –Placebo Significant improvements from baseline in visual function 1 –Greatest benefit in patients with lowest baseline MPOD 2 1.Richer S, et al. Double-Masked, Placebo-Controlled, Randomized Trial of Lutein and Antioxidant Supplementation in the Intervention of Atrophic Age- Related Macular Degeneration: the Veterans LAST Study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75(4):216-30. 2.Richer S, et al. LAST II: Differential Temporal Responses of Macular Pigment Optical Density in Patients with Atrophic Age-Related Macular Degeneration to Dietary Supplementation with Xanthophylls. Optometry 2007;78(5):213-9. *FloraGlo is a registered trademark of Kemin Industries, Inc. * * * LuteinLutein + antioxidants Placebo 0 0.6 Right eye 0.5 0.4 0.3 0.2 0.1 Macular pigment optical density BaselineFinal visit *P<0.05 36% improvement 43% improvement Left eye * * *

24. Long-term FloraGLO ® Lutein and Zeaxanthin Supplementation Improves MPOD in patients with AMD LUTEGA S TUDY 172 subjects (50+, AMD) Double-masked, randomized: –10 mg FloraGLO ® Lutein / 1 mg Zeaxanthin / 255 mg Omega-3 QD –10 mg FloraGLO ® Lutein / 1 mg Zeaxanthin / 255 mg Omega-3 BID – Placebo 4 evaluations over 12 months Supplementation in Months Absolute Change in ODU*degree² QD Daily supplementation Placebo MPOD C HANGES Jentsch S, et al. The Lutega-Study: Lutein And Omega- 3- Fatty Acids And Their Relevance For Macular Pigment In Patients with Age-related Macular Degeneration (AMD). Invest Ophthalmol Vis Sci 2011;52:E-Abstract 3632. *FloraGLO is a registered trademark of Kemin Industries, inc.

25. Increased MPOD is linked to Positive Effects on Visual Performance 1.Stringham JM, et al. Macular Pigment and Visual Performance in Glare: Benefits for Photostress Recovery, Disability Glare, and Visual Discomfort. Invest Ophthalmol Vis Sci 2011;52(10):7406-15. 2.Loughman J, et al. The Relationship Between Macular Pigment and Visual Performance. Vision Res 2010;50(13):1249-56. 3.Richer S, et al. Double-Masked, Placebo-Controlled, Randomized Trial of Lutein and Antioxidant Supplementation in the Intervention of Atrophic Age-Related Macular Degeneration: the Veterans LAST Study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75(4):216-30. 4.Wenzel AJ, et al. Macular Pigment Optical Density and Photophobia Light Threshold. Vision Res 2006;46:4615-22. Glare tolerance 1 Glare recovery 1 Contrast sensitivity 2 Amsler defect and VA improvement 3 Chromatic aberration 2 Photophobia 4 ICP11003SK

26. Omega-3 Fatty Acids (DHA/EPA) Important for proper visual development and retinal function 1 Docosahexaenoic acid (DHA) is found in the highest concentration in the retina 1 Eicosapentaenoic acid (EPA) is used in DHA biosynthesis 1 1.Essential Fatty Acids. American Optometric Association. Available at: http://www.aoa.org/x11853.xml. Accessed October 3, 2011

27. Omega-3 Fatty Acids (DHA/EPA) Benefits of DHA/EPA –Intake is associated with a decreased risk of progression from bilateral drusen to geographic atrophy 1 Low levels of DHA and EPA associated with chronic eye conditions such as: 2 –Diabetic retinopathy –Age-related macular degeneration (AMD) –Retinopathy of prematurity –Dry eye disease 1.SanGiovanni JP, et al. The Relationship of Dietary -3 Long-Chain Polyunsaturated Fatty Acid Intake Inversely Associated With 12-Year Progression to Advanced Age-Related Macular Degeneration: AREDS Report No. 23. Arch Ophthalmol 2008;127(1):110-2. 2.Essential Fatty Acids. American Optometric Association. Available at: http://www.aoa.org/x11853.xml. Accessed October 3, 2011

28. AREDS2* 1.Age-Related Eye Disease Study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011. 2.AREDS2 Study Overview. Available at: http://clinicaltrials.gov/ct2/show/NCT00345176?term=AREDS2&rank=1. Accessed July 21, 2011. FeatureDescription ObjectiveAssess effect of a alternative combination of vitamins and minerals on the progression of AMD and vision loss DesignNEI 5 year, multi-center, randomized, double-masked, placebo-controlled trial Population4000 patients at higher risk of developing AMD (Men and women; 50-85 years*) 1,2 *Age limit 5 years younger than AREDS

29. PROTOCOL NO NORMALS 1-3 MONTH RUN IN WITH AREDS (+) PLACEBOS IF PATIENT COMPLIES WITH DRUG USE AND SHOWS UP-RANDOMIZED TO TX ANNUAL EXAM (+) FUNDUS PHOTOS ANNUAL BLOOD TESTS FOR ANTI- OXIDANT BLOOD LEVELS

30. AREDS2: To Evaluate… *FloraGlo is a registered trademark of Kemin Industries, Inc. * Optisharp is a registered trademark of DSM IP Assets B.V. Ingredients being studied in AREDS2: FloraGLO ® lutein (10mg) OPTISHARP ® zeaxanthin (2mg) Omega-3 fatty acids (350 mg DHA, 650 mg EPA) With and without β-carotene (15 mg vs 0 mg) High vs low zinc levels (80mg vs 25mg) Patients in the AREDS2 study are assigned to different combinations of ingredients Age-Related Eye Disease Study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011.

31. AREDS 2 WAS COMPLICATED 16 RANDOMIZED GROUPS NO NORMALS 2 LEVELS OF RANDOMIZATION SPECIAL RULES FOR SMOKERS CENTRUM SILVER FOR THOSE ON A MV SUPPLEMENT STATISTICS LIMITED BY COHORT SIZE AND DURATION OF STUDY

32. 32 | ICP12167SK Ocular Nutrition | May 2012 | Business Use Only AREDS2 Study Design No ATS* AREDS2 Vitamin / Mineral Evaluation ATS* No ß-C & Low Zn No ß-C Low Zn Randomized Participants ~4000 Original ATS* *AREDS type supplements. Placebo DHA/EPA L/ZL/Z+DHA/EPA ATS* Options No smoker can be in an arm with beta-carotene Background multivitamin supplementation is allowed, but is standardized Age-Related Eye Disease study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011. AREDS 2 Study Overview. Available at: http://clinicaltrials.gov/ct2/show/NCT00345176?term=AREDS2&rank=1. Accessed July 21, 2011.

33. NEI AREDS2 Dosage Options 1 10 mg/day Lutein (FloraGLO ® ) 2 mg/day Zeaxanthin (OPTISHARP ® ) 1.Age-Related Eye Disease Study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011. 2.Thurnham DI. Macular Zeaxanthins and Lutein—A Review of Dietary Sources and Bioavailability and Some Relationships with Macular Pigment Optical Density and Age-Related Macular Disease. Nutr Res Rev 2007;20:163–79. FloraGLO is a registered trademark of Kemin Industries, Inc. Optisharp is a registered trademark of DSM IP Assets B.V. 5:1 ratio of lutein to zeaxanthin commonly found in American diet 2

34. Endpoints: Progression to advanced AMD Progression to moderate vision loss Progression of lens opacity Effective Cognitive function Cardiovascular morbidity/mortality AREDS2: To Evaluate… Progression to advanced AMD Progression to moderate vision loss Progression of lens opacity Effective cognitive function Cardiovascular morbidity/mortality Age-Related Eye Disease Study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011.

35. LIES, DAMN LIES AND STATISTICS SPINNING THE AREDS 2 DATA

36. Re-interpretation of results at ARVO 2013 by lead investigator, Emily Chew et al Adding omega 3’s to AREDS: No benefit Adding L/Z to AREDS and evaluating the effect on the total cohort (study population) 1. L/Z reduced advanced AMD by 10% 2. Neovasc. AMD 11% 3. Neovasc AMD 26% in low L/Z diets 4. Cataract progression 30% in low L/Z diets 5. Beta carotene doubles risk of lung cancer in all participants, 0.9% VS 2% W-BC

37. CDC. National Health and Nutrition Examination Survey Data 2001-2002. Available at: http://www.cdc.gov/nchs/about/major/nhanes/nhanes01-02.htm. Accessed July 14, 2011. Consumption of Lutein/Zeaxanthin in the US is LOW Figure courtesy of Kemin Health, Inc. The average American only gets between 1 mg to 2.3mg per day of combined lutein and zeaxanthin in their diet which is below the AREDS2 intake of 10mg 37 | ICP11001SK Ocular Nutrition | October 2011 | Business Use Only

38. The Bottom Line on ARMD/AREDS 1 DON’T BE Northern European DON’T GET OLDER DON’T SMOKE DON’T GIVE SMOKERS ANTIOX CONTROL VASCULAR DISEASE RISK FACTORS SUPPLEMENTS DON’T REPLACE A BAD LIFESTYLE

39. ADDITIONAL RECOMMENDATIONS FROM AREDS 2 NEVER use beta-carotene in ANYBODY INCREASE L/Z foods in patients diet-if not, then supplement OMEGA 3’s have value, but NOT for AMD

40. MY RESEARCH INTEREST WHY DO STUDIES HAVE TO LAST SSSSSOOOOOOOO LONNNGG? WAY TOOOO EXPENSIVE STRUCTURE VS FUNCTION ADAPTIVE OPTICS (Dr. Porter) Supplement X 6 months-evaluate VA, 10-2VF, OCT and retinal cone density and morphology-supplement vs no supplement CAN AO’s predict vision loss Can we take a photo-objective test and measure stability VS progression

41. QUESTIONS?