Whats New in AMD - 2013


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Update on the latest research on age-related macular degeneration

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  • Glaucoma treatment analogy – best to catch them early. Have better chance of stabilizing them
  • the rate of endothelial cell loss after intracapsular extraction has been reported to be between 11.6% and 17.1% compared with 13.6–17.0% following conventional extracapsular surgery
  • Two types of harmful effectsVision loss secondary to macular hemorrhageIncreased risk of development or progression of AMD
  • Sunlight may damage the retina by causing photochemical damage
  • Joe Friday
  • Carotenoids with Coantioxidants in Age-Related Maculopathy
  • Visually significant AMD is defined as AMD severe enough to cause a decline in visual acuity to 20/30 or worse
  • Nutritional AMD Treatment 2 StudyNAT2 is the first randomized double-blind study exploring the potential of a long-term oral PUFA supplement enriched in DHA to prevent or slow down the development of CNV in a homogenous group of patients with a typical and severe form of AMD
  • Using RBC to monitor long-term serum DHA levels (analagous to HbA1C)
  • Whats New in AMD - 2013

    1. 1. What’s New in AMD Rick Trevino, OD, FAAORosenberg School of OptometryUniversity of the Incarnate Word
    2. 2. What’s New in AMD• Online slides – slideshare.net/rhodopsin• Online notes – richardtrevino.net• Email me – rctrevin@uiwtx.edu• Disclosures – None
    3. 3. What’s New in AMD 10. Drug Pipeline
    4. 4. Geographic Atrophy Drug Pipeline• Fenretinide (ReVision) – Visual cycle modulator• ACU-4429 (Acucela) – Visual cycle modulator• POT-4 (Potentia/Alcon) – Complement-3 inhibitor (anti-inflammatory),• NT-501 (Neurotech) – Ciliary neurotrophic factor
    5. 5. Drug Pipeline• NT-501 (Neurotech) – Ciliary neurotrophic factor (CNTF) is a potent neuroprotective agent that affects the survival of cells in the nervous system, including retinal cells – Human cells genetically modified to secrete CNTF are placed within a semipermiable capsule which is then implanted within the vitreous – The sustained release capsule will deliver CNTF to the retina for a year or longer neurotechusa.com
    6. 6. Ciliary neurotrophic factor is delivered to the retina via encapsulated cell technology
    7. 7. Encapsulated Cell Technology
    8. 8. Drug Pipeline• Zhang (2011) – Multicenter, 1yr, double-masked, sham-controlled dose-ranging, phase 2 study of CNTF therapy – Average change in VA • 0.8 mean letter gain in the high-dose group • 9.7 mean letter loss in the combined low-dose/sham group – VA stabilization rates (loss of <15 letters) • 96.3% high-dose, 83.3% low-dose, 75% sham group Zhang K, Proc Natl Acad Sci U S A. 2011;108:6241-5
    9. 9. Effect of intraocularCNTF on visualacuity stabilization.(A) Subjects losing<15 letters(B) Subjects losing<15 letters withbaseline BCVA at20/63 or better.
    10. 10. Drug Pipeline• Conclusion – “These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline” Zhang K, Proc Natl Acad Sci U S A. 2011;108:6241-5
    11. 11. Topical Pazopanib• Topical eye drop for exudative AMD currently in Phase IIb clinical trials• Safety and efficacy of pazopanib is being compared to Lucentis• Pazopanib is a receptor tyrosine kinase inhibitor that targets VEGF, platelet-derived growth factor, and c-kit receptors• Preliminary results find that patients with the low-risk CFH genotype respond best http://clinicaltrials.gov/show/NCT01134055
    12. 12. “This preliminary study suggests that topical treatment with pazopanib 0.5% issafe, well tolerated, and may have a role as an alternative for the treatment of CNV.” Amparo F, et al. IOVS 2013;54:537
    13. 13. Aiello LP. NEJM 2008;359:967
    14. 14. What’s New in AMD 9. Implantable Miniature Telescope 10. Drug Pipeline
    15. 15. Implantable Miniature Telescope• The FDA approved the Implantable Miniature Telescope (IMT) in 2010 for patients 75yrs and older with stable severe-to-profound vision impairment (20/160 to 20/800) caused by bilateral end-stage AMD• Marketed as CentraSight
    16. 16. Implantable Miniature Telescope
    17. 17. Implantable Miniature Telescope• Implanted into one eye only (typically the non-dominant or poorer seeing eye)• Two models available 2.2x or 2.7x• Generates a 20° to 24° FOV
    18. 18. Implantable Miniature Telescope• Most common adverse event is persistent vision-impairing corneal edema• 9.2% over 5yrs
    19. 19. Endothelial cell loss following implantation of IMT leadsto vision-impairing corneal edema in about 9% of patients Another 20% lost over time Immediate 20% cell loss Implantable Miniature Telescope Professional Use Information, FDA-approved product labeling.
    20. 20. Implantable Miniature Telescope• Partial contraindications list – Tx for CNV within the past 6 mos – Anterior chamber depth (ACD) <3.0 mm – Myopia > 6.0 D or hyperopia > 4.0 D – Presence of corneal guttata – Failure meet the minimum age (75 yrs), visually significant cataract and endothelial cell density requirementsImplantable Miniature Telescope Professional Use Information, FDA-approved product labeling.
    21. 21. Patient Diagnosis (RetinalSpecialist) Evaluation & Eye selection (Low vision specialist) Implantation (Cornea/Cataract surgeon) Visual Training & Rehab (Low vision occupational therapist)
    22. 22. Implantable Miniature Telescope• Patient selection – Management of goals and expectations – Visual function questionnaires, cognitive evaluation, and depression screens – Mobility evaluations• Eye selection – Worse eye: Less risk if procedure fails – Better eye: Improved functioning if procedure successful Primo SA. Optometry. 2010;81:86-93
    23. 23. Implantable Miniature Telescope• Summary – Supplements conventional low vision aids for persons with end-stage bilateral AMD – Significant surgical complications and post- operative adverse events can lead to profound vision loss – Strict pre-operative evaluation protocols designed to select those candidates most likely to succeed with IMT and are at lowest risk of adverse events
    24. 24. Retinal Prosthesis
    25. 25. What’s New in AMD 8. Aspirin 9. Implantable Miniature Telescope 10. Drug Pipeline
    26. 26. Aspirin & AMD• Aspirin for the primary prevention of disease – Prevent of cardiovascular events, reduce the risk of some cancers, reduced risk of Alzheimers disease – Approximately 36% of adults take aspirin regularly for primary prevention of disease• Adverse effects of aspirin – Gastrointestinal hemorrhage, worsen hypertension, renal failure, aggravate asthma, hemorrhagic stroke – Each year 16,500 deaths are related to aspirin and NSAID use Seshasai SR, et al. Arch Intern Med. 2012;172:209-16
    27. 27. Aspirin & AMD Harmful Effect No Effect• Feman (1972) • MPS Group (1986)• Bloome (1978) • MPS Group (1990)• Kingham (1988) • Klein (1991)• Lewis (1988) • Hirvela (1996)• AREDS (2000) • Klein (2001)• Klein (2012) • Douglas (2007)• de Jong (2012) • Rudnicka (2010) Protective Effect • Christen (2001) • Christen (2009)
    28. 28. Aspirin & AMD• Christen (2009) – Women’s Health Study: Randomized, double-masked, placebo-controlled trial of 39,876 healthy adult women over an average of 10 years – Low-dose aspirin had a non-significant 18% reduced risk of visually-significant AMD compared to women assigned to placebo Christen WG. Ophthalmology. 2009; 116: 2386–2392.
    29. 29. Aspirin & AMD• de Jong (2012) – European Eye Study: 4691 participants aged 65 years and older in the population-based cross-sectional study in 7 European communities – Frequent aspirin use was associated with early and wet late AMD, and the odds ratios rose with increasing frequency of consumption de Jong, et al. Ophthalmology. 2012;119:112–118
    30. 30. More Associatedfrequent with greaterASA use AMD risk
    31. 31. Aspirin & AMD• Summary – Biologically plausible basis for protective effect (improved circulation, anti- inflammatory) – The literature does not reveal any consistent pattern of benefit or harm of aspirin use on AMD – No scientific basis to advise AMD patients to start or stop ASA
    32. 32. What’s New in AMD 7. Lifestyle 8. Aspirin 9. Implantable Miniature Telescope 10. Drug Pipeline
    33. 33. Lifestyle & Behavioral Factors• Modifiable risk factors related to lifestyle that have been associated with AMD – Smoking – Physical activity – Diet• AMD has been associated with chronic diseases or conditions which can be modified by lifestyle choices – Cardiovascular disease – Hypertension – Obesity – Elevated markers of inflammation Mares JA, et al. Arch Ophthalmol. 2011;129:470–480
    34. 34. Lifestyle & Behavioral Factors• Smoking – Smoking is the most significant modifiable risk factor for AMD – Estimated that 29% of all AMD cases can be attributed to smoking – Dose-response: Increased risk with more pack-years – Reversibility: Risk declines following smoking cessation, but does not return to baseline – Exposure to environmental (second-hand) smoke has not been associated with AMD
    35. 35. Lifestyle & Behavioral Factors• Obesity – Most but not all studies have found a positive association between obesity and AMD – Obesity may have a role in the development of AMD because of its associated oxidative stress – Decreasing abdominal obesity results in a lower risk for AMD. – Suggests a role of weight loss in preventing the development of AMD Peeters A, et al. Arch Ophthalmol. 2008;126(11):1554-1560
    36. 36. LOWER RISK HIGHER RISKChakravarthy (2010): Meta-analysis of studies assessing risk of advanced AMD (combined atrophic and exudative) associated with BMI.
    37. 37. Lifestyle & Behavioral Factors• Exercise – Physical activity lowers cardiovascular disease risk, which is possibly predictive of AMD. – Seddon (2003): vigorous activity associated with a 25% reduction in progression to advanced AMD – BDES (2006): Regular physical activity reduced the cumulative incidence of exudative AMD
    38. 38. Williams (2009)Dose-responserelationshipFound lowerrisk of AMDwith greaternumber ofkilometers runeach dayRelative risk ofAMD by averagedistance run perday in 41,708nondiabetic,nonsmoking menand women
    39. 39. Lifestyle & Behavioral Factors• Mares (2011) – Cross-sectional study of 1313 women aged 55-74 years in the Women’s Health Initiative Observational Study – Having a combination of 3 healthy behaviors (healthy diet, physical activity, and not smoking) was associated with 71% lower odds for AMD compared with having high risk scores – A combination of healthy lifestyle practices might be more important in reducing AMD risk than a focus on any given one
    40. 40. Lifestyle & Behavioral Factors What’sGood for the Heart Is alsoGood for the Eye! Don’t smoke Lose weightExercise regularly
    41. 41. What’s New in AMD 6. Sunlight and Cataract Surgery 7. Lifestyle 8. Aspirin 9. Implantable Miniature Telescope 10. Drug Pipeline
    42. 42. Sunlight & Cataract Surgery• Photochemical damage occurs when low wavelength light is absorbed by photoreactive pigments in the retina, such as lipofuscin, causing release of reactive oxygen species• Speculate that chronic exposure to low wavelength light may overwhelm normal defense and repair mechanisms• Inconsistent association with AMD risk Chalam KV, et al. Eye & Contact Lens. 2011;37:225–232
    43. 43. Sunlight & Cataract Surgery• BDES (2004) – Ten-year follow-up of 2764 participants in the Beaver Dam Eye Study – Greater sun exposure was associated with higher risk of early AMD – A protective effect of hat and sunglass use was found for those participants with highest amount of sun exposure Tomany SC., et al. Arch Ophthalmol. 2004;122:750-7
    44. 44. Sunlight & Cataract Surgery• Fletcher (2008) – European Eye Study: Cross-sectional study of 4700 people in 7 European countries – Sunlight not hazardous if antioxidant levels are adequate – High sunlight exposure and low serum antioxidant levels associated with 4-fold increased risk of wet AMD – Risk greatest with low levels of zeaxanthin, vitamin E, and vitamin C Fletcher AE., et al. Arch Ophthalmol. 2008;126:1396-1403
    45. 45. Sunlight & Cataract Surgery• Sui (2012) – Meta-analysis of 14 studies investigating sunlight exposure as a risk factor for AMD – Greater sunlight exposure was associated with higher risk of AMD (pooled odds ratio: 1.379) – AMD risk from sunlight exposure significantly decreased as gross domestic product (GDP) per capita increased (p=0.048) – Latitude (p=0.21) was significantly associated with risk Sui GY, et al. Br J Ophthalmol. 2012 Nov 10. [Epub ahead of print]
    46. 46. Sunlight & Cataract Surgery• Cataract Surgery – The adult lens absorbs nearly 100% of light below 400nm – Cataract surgery results in increased exposure to short-wavelength light and this may increase the risk of photochemical damage to the retina – Inconsistent association with AMD risk Bockelbrink A., et al. Surv Ophthalmol 2008;53:359-367
    47. 47. Sunlight & Cataract Surgery• AREDS (2009): – Found no clinically important increased risk of progression to advanced AMD after cataract surgery – AREDS is the only prospective study in which the severity of AMD was documented before and after cataract surgery in a large number of cases with more than 5 years of regular follow-up Chew EY, et al. Ophthalmology 2009;116:297–303
    48. 48. LOWER RISK HIGHER RISKChakravarthy (2010): Meta-analysis of studies assessing risk of advanced AMD (atrophic and exudative) associated with cataract surgery.
    49. 49. Sunlight & Cataract Surgery• Blue-blocking IOL Controversy – All modern IOLs filter UV radiation below 400nm but most do not filter any visible light – Blue-blocking IOLs are designed to simulate transmission characteristics of the adult non-cataractous human lens offering theoretical AMD protection Wong IYH, et al. Int Ophthalmol. 2011;31:73–82
    50. 50. Concerns have been raised that blue-blocking IOLs attenuate visualperformance under scotopic conditions, have undesirable effects oncolor perception, and disrupt circadian entrainmentTurner (2008): Spectral sensitivity of photopic, scotopic and circadian (melatoninsuppression) photoreception
    51. 51. Sunlight & Cataract Surgery• Blue-blocking IOL Controversy – There is currently no evidence of any clinically harmful effects of blue-blocking IOLs – There is currently no evidence of any clinically beneficial effects of blue- blocking IOLs Henderson BA. Surv Ophthalmol 2010;55:284-289
    52. 52. Sunlight & Cataract Surgery• Summary – There is some evidence that cataract removal may increase the risk of AMD – This risk could be mitigated if IOLs filtered UV and blue visible light, but this could cause other problems (impaired night vision) – The theoretical disadvantages of blue-light filtering IOLs may be minimized by filtering only violet light
    53. 53. What’s New in AMD 5. Lutein 6. Sunlight and Cataract Surgery 7. Lifestyle 8. Aspirin 9. Implantable Miniature Telescope 10. Drug Pipeline
    54. 54. Lutein• Macular Pigment – Lutein and zeaxanthin are the major components of macular pigment – Macular pigment may protect the retina from photochemical damage by absorbing blue light and by quenching reactive oxygen species
    55. 55. Lutein• Weigert (2011) – Dietary lutein supplementation can significantly increase macular pigment optical density (MPOD). – Patients with low MPOD at baseline experience the greatest increase – Patients with high MPOD at baseline experience almost no increase – Increasing MPOD is associated with improvements in visual function (including improved VA) due to decreased chromatic aberrationWeigert A, et al. Invest Ophthalmol Vis Sci. 2011;52:8174–8178
    56. 56. Normal Range 50% increase with low baseline MPODWeigert (2011): Correlation between MPOD at baseline and the change inMPOD after 6 months of lutein supplementation.
    57. 57. Expect 3% improvement in VA with 50% increase in MPODWeigert (2011): Correlation between the change in MPOD and the change inVA after 6 months of lutein supplementation.
    58. 58. Lutein• Loughman (2012) – Supplementation with all 3 carotenoids (lutein, zeaxanthin, and meso- zeaxanthin) can produce larger gains in MPOD than supplements not containing meso- zeaxanthin Loughman J, et al. IOVS. 2012;53:7871
    59. 59. Superior performance of supplement containingmeso-zeaxanthin (MZ) Loughman J, et al. IOVS. 2012;53:7871
    60. 60. Lutein• CARMA (2012) – Randomized double-masked placebo-controlled clinical trial of Ocuvite in 433 participants with early AMD over 3 years • Ocuvite: 12 mg lutein, 0.6 mg zeaxanthin, 15 mg vitamin E, 150 mg vitamin C, 20 mg zinc, and 0.4 mg copper – Mean change in BCVA and macular pigment favored the supplemented group – Fewer eyes in the Ocuvite group demonstrated progression of AMD compared with the placebo group, but this did not reach statistical significanceBeatty S, et al. Ophthalmology. 2012 Dec 5. [Epub ahead of print]
    61. 61. Placebo OcuviteProgression of AMD in the CARMA study. The eyes of participants in the activetreatment arm progressed at a slower rate than the placebo arm, but the differencewas not statistically significant
    62. 62. Lutein• Ma (2012) – Meta-analysis of 6 longitudinal cohort studies – Relative risk for early AMD: 0.96 (0.78-1.17) comparing the highest with the lowest category of lutein and zeaxanthin intake – Relative risk for late AMD: 0.74 (0.57-0.97) – Dietary intake of lutein and zeaxanthin may decrease the risk of late but not early AMD Ma L, et al. Br J Nutr. 2012;107:350-9.
    64. 64. Lutein• Summary – Lutein supplementation will improve MPOD in patients with low levels of macular pigment, and these patients will benefit visually from this intervention – Effect of lutein supplementation on AMD remains unclear • Only beneficial against late AMD? • Being investigated in AREDS 2
    65. 65. Lutein• Eller (2012) – First report of peripheral yellow corneal rings secondary to carotenoid supplementation – Not associated with deduced vision or corneal dysfunction. Long-term implications unknown – Carotenoderma: Also known as “xanthoderma,” is a benign and reversible yellowish-orange discoloration of the skin caused by increased levels of carotenoids . Eller AW, et al. Ophthalmology 2012;119:1011
    66. 66. Eller AW, et al. Ophthalmology 2012;119:1011
    67. 67. What’s New in AMD 4. Fish 5. Lutein 6. Sunlight and Cataract Surgery 7. Lifestyle 8. Aspirin 9. Implantable Miniature Telescope 10. Drug Pipeline
    68. 68. Fish• Fish oil is rich in omega-3 long-chain polyunsaturated fatty acids (LCPUFA). – Docosahexaenoic acid (DHA) – Eicosapentaenoic acid (EPA) is a precursor to DHA• LCPUFAs may protect against oxygenic, inflammatory, and age-associated pathology – Hyperlipidemia, coronary disease, HTN, CVA, others
    69. 69. Fish• Chong (2008) – Meta-analysis of 9 studies finds that consumption of fish twice or more per week reduced risk of both early and late AMD.• AREDS (2009) – Participants reporting the highest consumption of omega-3 LCPUFA were about 30% less likely to develop advanced AMD
    70. 70. Fish• Christen (2011) – Prospective study of 38,000 females over 10 years – Consumption of 1 or more servings of fish per week associated with a 40% lower risk of developing AMD, compared with those who consumed less than 1 serving of fish per month Christen WG, et al. Arch Ophthalmol. 2011;129(7):921-929
    71. 71. Diagnosis of Visually Significant Age-RelatedMacular Degeneration According to Categories of Fish Intake in the Women’s Health Study Intake of Fish Relative Risk (95% CI) P Total fish 0.58 (0.38 – 0.87) 40% 0.001 Dark-meat fish (salmon, tuna) 0.56 (0.32 – 0.99) lower 0.01 Canned tuna fish 0.56 (0.40 – 0.80) risk 0.001 Shrimp / lobster / scallops 1.28 (0.77 – 2.13) 0.69 Other fish 0.72 (0.51 – 1.01) 0.06 Comparing risk associated with once per week or greater consumption to less than once per month consumption. Christen WG, et al. Arch Ophthalmol. 2011;129(7):921-929
    72. 72. Fish• Christen (2011) “Strongest observational evidence to date in support of a possible role for intake of omega-3 long-chain fatty acids and fish in the primary prevention of AMD” Christen WG, et al. Arch Ophthalmol. 2011;129(7):921-929
    73. 73. Fish• NAT2 Study (2013) – Randomized, placebo-controlled, double-blind study of 263 patients between age 55 and 85 years with early AMD in one eye and wet AMD in the fellow eye assigned randomly to receive either fish oil capsules or the placebo for 3 years • 840 mg/day DHA and 270 mg/day EPA – CNV incidence was significantly reduced in fish oil supplemented patients showing a steadily high EPA plus DHA index over 3 years. Souied EH, et al. Ophthalmology. 2013 Feb 7 [Epub ahead of print]
    74. 74. PROTECTION HARMCNV incidence was significantly reduced in fish oilsupplemented patients showing a steadily high EPAplus DHA levels over 3 years.
    75. 75. Fish• Summary – Strong and consistent observational evidence that fish and omega-3 fatty acid consumption is protective against early and late AMD – Value of fish oil supplementation in slowing progression to advanced AMD is being tested in AREDS 2
    76. 76. What’s New in AMD 3. Anti-VEGF medications 4. Fish 5. Lutein 6. Sunlight and Cataract Surgery 7. Lifestyle 8. Aspirin 9. Implantable Miniature Telescope 10. Drug Pipeline
    77. 77. Anti-VEGF Medications• Which is better: Lucentis or Avastin? – Both drugs have the same mechanism of action, but very different structures – Lucentis is much more expensive than Avastin • Lucentis costs $2000 per dose compared to $50 for Avastin• Introduction to Eylea – The newest drug to be FDA approved for AMD, became commercially available in November 2011 – Primary advantage is that it’s recommended dosage is q2mos, compared to q1mo for Lucentis
    78. 78. Avastin is the most popular drug used in the treatment of neovascular AMD, but the vast majority of the cost is for the much more expensive Lucentis Brechner RJ, et al. Am J Ophthalmol 2011;151:887
    79. 79. CATT Study: 2yr Results• Methods – 1208 patients with neovascular AMD were randomly assigned to one of four study groups: • Lucentis monthly, Lucentis PRN • Avastin monthly, Avastin PRN – At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or PRN treatment, without changing the drug Martin DF, et al. Ophthalmology 2012;119:1388
    80. 80. CATT Study: 2yr Results• Results: Visual Acuity – Monthly Avastin was equivalent to monthly Lucentis, with 7.8 and 8.8 letters gained, respectively. – PRN Avastin was equivalent to PRN Lucentis, with 5.0 and 6.7 letters gained, respectively – Mean gain in vision was greater with monthly dosing than PRN dosing for both drugs • Switching to PRN dosing after 1 year of monthly treatment, with either drug, produced a mean 2.2- letter decrease Martin DF, et al. Ophthalmol. 2012;119:1388–1398
    81. 81. At 104 weeks the visual acuity of both PRN dosing groups aresignificantly lower relative to the monthly groups Martin DF, et al. Ophthalmol. 2012;119:1388–1398
    82. 82. CATT Study: 2yr Results• Results: Anatomy – The mean decrease in central retinal thickness was greater in the Lucentis-treated patients than in the Avastin-treated patients (p=0.08) – All other anatomic results also indicate superior efficacy of Lucentis • Resolution of fluid on OCT (P < 0.0001) • Cessation of leak on fluorescien angiography (P = 0.002) Martin DF, et al. Ophthalmol. 2012;119:1388–1398
    83. 83. Lucentis has a stronger effect on leakage than Avastin Martin DF, et al. Ophthalmol. 2012;119:1388–1398
    84. 84. CATT Study: 2yr Results• Results: Safety – Serious systemic adverse events were more frequent with Avastin than with Lucentis • Avastin: 39.9% vs. Lucentis 31.7% – Thromboembolic events occurred in 4.7% of the combined Lucentis and 5.0% of the combined Avastin groups (P = 0.89) – 5.3% of patients treated with Lucentis and 6.1% of patients taking Avastin died (P = 0.62) Martin DF, et al. Ophthalmol. 2012;119:1388–1398
    85. 85. The cumulative proportion of patients with 1 or more systemic serious adverse events by originally assigned dosing regimen and drug. Martin DF, et al. Ophthalmol. 2012;119:1388–1398
    86. 86. CATT Study: 2yr Results• Does too much anti-VEGF medication cause geographic atrophy? – Monthly Lucentis: 30% with GA at 2yrs – Monthly Avastin: 20% – PRN Lucentis: 16% – PRN Avastin: 14% The possible association of anti-VEGF therapy with GA is “one of the most interesting outcomes” from the entire CATT trial. Retinal Physician. Nov 2012
    87. 87. CATT Study• Two plausible interpretations of CATT results – Avastin is almost as good as Lucentis and costs less • The differences in efficacy are not statistically or clinically significant • The differences in safety signals may be attributable to chance, or imbalances in baseline health status – Avastin is not as good as Lucentis with more adverse reactions • In light of significant anatomic differences it is hard to justify calling the efficacy equivalent • Safety data contain some worrisome and important signals which should not be minimized or ignored
    88. 88. “Conclusion: In contrast to [Lucentis], current safetydata for [Avastin] are incomplete and not yet robust. Ifthe medical community remains committed to usingintravitreal [Avastin], it is critical to establish that ithas an acceptable safety profile, supported byevidenced-based medicine. Considerable furtherresearch is warranted to achieve this.” Mitchell P. Curr Med Res Opin 2011;27:1465
    89. 89. Avastin Safety• Analysis of Medicare records – 11% higher risk in all-cause mortality and 57% higher risk of hemorrhagic stroke with Avastin vs Lucentis• BEAT-ROP study – Higher mortality rate with Avastin vs. laser (6.6% vs 2.6%)• Cancer deaths – Compared with chemotherapy alone, the addition of Avastin was associated with an increased risk of fatal adverse events, with a relative risk of 1.46 Lim LS, et al. Am J Ophthalmol. 2011;152:329-31.
    90. 90. Avastin Safety• Complications may occur due to compounding and storage practices – One study found Avastin users were 12x more likely to develop severe intraocular inflammation – Large particulate matter can obstruct aqueous outflow and lead to prolonged elevation of IOP Sharma S. Presented at the Am Soc Retina Specialists, 2010
    91. 91. Avastin Safety• Summary – Significant safety concerns exist regarding off-label intravitreal Avastin use • Ocular toxicity, compounding practice, systemic effects – Intravitreal Avastin should be used with caution
    92. 92. Eylea• The importance of dosing – Lucentis pivotal clinical trials utilized a monthly monitoring and dosing paradigm – Monthly injections create a significant hardship for patients – Intravitreal injections are not risk free – Clinical studies uniformly demonstrate decline in visual acuity gains with less than monthly dosing
    93. 93. The HORIZON study was a 24-month extension of the FOCUS, MARINAand ANCHOR trials. Treated patients were switched from fixed monthlydosing to as needed upon entering HORIZON. Three groups of patientswere always treated, never treated, and cross-over patients who wereinitially untreated and later treated.
    94. 94. Eylea• Aflibercept (Eylea, VEGF-Trap) – Receptor decoy – Recombinant chimeric molecule – Contains the VEGF-binding elements from VEGF receptors 1 and 2 fused to human antibody. – Eylea binds all VEGF-A isoforms and placental growth factor Zampros I, et al. J Ophthalmol. 2012;2012:319728
    95. 95. Heier J, et al. Ophthalmology 2012;119:2537
    96. 96. Heier J, et al. Ophthalmology 2012;119:2537
    97. 97. Heier J, et al. Ophthalmology 2012;119:2537
    98. 98. Heier J, et al. Ophthalmology 2012;119:2537
    99. 99. Eylea• Safety – No significant difference in rates of ocular or systemic adverse events when compared to Lucentis• Conclusions – Eylea dosed every two months was similar in efficacy and safety to Lucentis dosed monthly Heier J, et al. Ophthalmology 2012;119:2537
    100. 100. What’s New in AMD 2. Genetics 3. Anti-VEGF medications 4. Fish 5. Lutein 6. Sunlight and Cataract Surgery 7. Lifestyle 8. Aspirin 9. Implantable Miniature Telescope 10. Drug Pipeline
    101. 101. Genetics• Risk modeling – Attempts to predict the risk of developing advanced AMD based upon genetic, phenotypic and behavioral factors• Pharmacogenomics – Attempts to define the genetic variants that determine variable response to medication. – The ultimate goal is to identify those who respond best and avoid adverse reactions
    102. 102. Genetic testing services use risk models to calculate yourrisk of contracting various disorders based on genotype
    103. 103. Risk Models• Genetic only – Genetic risk factors are static throughout life• Genetic plus other factors – May include phenotype, behavioral and environmental factors in the model – Better short-term risk assessment – May reflect change in risk over time (age, smoking behavior, weight loss)
    104. 104. Risk Models # Genes Environment AUCJakobsdottir (2009) 3 No 0.79AREDS (2009) 6 Yes 0.81Hageman (2011) 13 No 0.80Klein (2011) 2 Yes 0.87 The larger the AUC the greater the accuracy of predictions .90-1 = excellent (A) .80-.90 = good (B) .70-.80 = fair (C) .60-.70 = poor (D) .50-.60 = fail (F)
    105. 105. Model predicts 85% chance of having CNV Model predicts 20% chance of having CNV 50-50 chance of having CNV 0% 100%Hageman (2011): Red bars represent controls and blue barsrepresent patients with CNV.
    106. 106. Are you better off knowing genotype or phenotype? Demographics &Worse genotype known Genetic information provides little additional Value added by genetic Demographics & info once phenotype and predictiveBetter phenotype known demographics is known value once the phenotype is known Klein (2011)
    107. 107. Risk Models• Summary – Once phenotype is known, genetic information is of little additional predictive value. – Risk calculators can identify high-risk individuals for more frequent surveillance and clinical interventions. – May be of greatest value early in life prior to phenotype manifesting itself
    108. 108. Pharmacogenomics• CFH & AREDS Supplement – Persons homozygous for the CFH high-risk allele (CC) have a smaller treatment response to the AREDS vitamin/mineral supplement than persons homozygous for the CFH low-risk allele (TT) – This is among the first pharmacogenetic studies to suggest interaction between genotype and treatment response Klein ML, et al. Ophthalmology 2008;115:1019–1025
    109. 109. Response to the AREDSsupplement is related to CFH genotype -Low risk Low risk Low risk 23% 4% Persons homozygous for the CFH high-risk allele (CC) have a smaller treatment response than persons homozygous for the CFH low-risk allele (TT)
    110. 110. Pharmacogenomics• CFH & Avastin (2007) – Patients homozygous for both CFH risk alleles (CC) had worse visual outcomes• CFH & Lucentis (2009) – Patients homozygous for both CFH risk alleles (CC) had worse visual outcomes
    111. 111. Shastry BS. Discovery Medicine. Aug 2011
    112. 112. Pharmacogenomics• CATT Study (2013) – 834 (73%) of 1149 patients participating in the CATT were genotyped for CFH, ARMS2, HTRA1, and C3 – No statistically significant differences in response by genotype were identified for any of the clinical measures studied (VA, anatomic response, # injections) – Genotype did not predict response to anti–VEGF therapy in the CATT trial
    113. 113. Pharmacogenomics• Summary – Determining patients genotype may be helpful in the future in tailoring treatment for exudative AMD • Higher risk therapies may be suitable for patients with higher risk genotypes if it can be predicted that they will not respond to standard therapy – Concerns regarding loss of privacy, impact on employment and insurance discrimination. • Social, ethical, and economical issues such as genetic discrimination needs to be addressed by regulatory agencies. Shastry BS. Discovery Medicine. Aug 2011
    114. 114. What’s New in AMD 1. Vitamins 2. Genetics 3. Anti-VEGF medications 4. Fish 5. Lutein 6. Sunlight and Cataract Surgery 7. Lifestyle 8. Aspirin 9. Implantable Miniature Telescope 10. Drug Pipeline
    115. 115. Vitamins• Vitamin D – Has antiangiogenic, antioxidant and anti- inflammatory effects – Low vitamin D levels associated with AMD• B vitamins – Capable of significantly lowering serum levels of homocysteine – Elevated homocysteine levels are thought to induce vascular endothelial dysfunction, and has been associated with increased risk of AMD
    116. 116. Vitamin D• Vitamin D has many diverse metabolic effects – Bone mineralization and the regulation of Ca2+ and phosphorus – Antiangiogenic, antioxidant and anti-inflammatory effects – Role in cellular proliferation, differentiation and apoptosis• Biologically plausible that vitamin D may influence AMD risk
    117. 117. The 3 major sources ofvitamin D are:• Sunlight• Milk• Supplements
    118. 118. Vitamin D• Parekh (2007) – Cross-sectional study of 7752 participants – Highest vs lowest quintile of serum vitamin D • Early AMD: 0.64 odds ratio 36% lower risk! • Advanced AMD: 1.16 odds ratio – Milk intake ‘less than weekly’ vs ‘daily or more’ • Early AMD: 0.75 odds ratio 25% lower risk! Parekh N, et al. Arch Ophthalmol. 2007;125:661-669
    119. 119. Vitamin D• Millen (2011) – Serum vitamin D levels were assessed 6 years prior to AMD status in 1313 women aged 50-79 at baseline. – In women <75 yo, high serum vitamin D concentrations associated with a 48% decreased odds of developing early AMD – No association found between early AMD and reported time spent outside in direct sunlight Millen AE, et al. Arch Ophthalmol. 2011; 129: 481–489
    120. 120. Vitamin D• Morrison (2011) – Cohort of 481 extremely phenotypically discordant siblings • One sibling has wet AMD and other sibling has no AMD – UV irradiance was protective of wet AMD – Serum vitamin D levels were higher in unaffected siblings (not statistically significant) – Genetic link between the vitamin D pathway and AMD risk (SNPs in CYP24A1 increased risk) Morrison MA, et al. Hum Genomics. 2011;5:538-568
    121. 121. Vitamin D• Summary – Strong evidence that higher serum vitamin D levels associated with reduced risk of early AMD – Increased consumption of milk and vitamin D supplements may decrease AMD risk – Sunlight exposure may be protective against AMD if eye protection is worn
    122. 122. B Vitamins• Among many other effects, B vitamins have the ability to lower serum homocysteine levels• Homocysteine is an amino acid that has been found to promote inflammation and oxidative stress in the body• Elevated homosysteine levels have been associated with higher risk of cardiovascular disease and stroke
    123. 123. B Vitamins• Close relationship between AMD and CVD – Common risk factors (Smoking, Obesity, HTN) – Common antecedents (Inflammation, Oxidative stress) – Common interventions (Fish oil, diet, exercise, weight) – Speculation: AMD and CVD are two manifestations of a single underlying chronic inflammatory disease of aging
    124. 124. Hypothesis AMDCVD Homocysteine
    125. 125. B Vitamins• Observational evidence – Studies finding AMD associated with elevated Hcy 1. Axer-Siegel (2004) wet AMD only 2. Nowak (2005) wet AMD only 3. Vine (2005) wet and dry AMD 4. Coral (2006) wet AMD only 5. Kamburoglu (2006) wet and dry AMD 6. Seddon (2006) intermediate or advanced AMD 7. Rochtchina (2007) advanced AMD in persons <75yo 8. Ates (2009) wet AMD only 9. Javadzadeh (2011) wet AMD only – Studies not finding an association 1. Heuberger (2002) NHANES, few late AMD cases, non-fasting 2. Wu (2007) BMES, few late AMD cases
    126. 126. B Vitamins• Christen (2009) – Women’s Health Study: RCT of 5205 women without AMD at baseline randomized to receive folic acid or placebo for 7.3yr • 2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12 – Women assigned to B vitamin supplementation had a statistically significant 35% to 40% decreased risk of developing AMD Christen WG. Arch Intern Med. 2009;169:335-341
    127. 127. Cumulative incidence rates of confirmed AMD (left) and visuallysignificant (VS) AMD (right). After an average 7.3 yrs of follow-upthose women on treatment had a 35% lower risk of any AMDand a 40% lower risk of visually significant AMD
    128. 128. B Vitamins• Conclusion – “Folic acid is the first identified means, other than cigarette avoidance, to prevent the onset of AMD” Christen WG. Arch Intern Med. 2009;169:335-341
    129. 129. B Vitamins• Should I prescribe this to my patients? – As with any prophylactic therapy, the risk, cost and convenience of the treatment must be weighed against the risk posed by the disease – Should be avoided by cancer patients and those on antifolate medications (eg. methotrexate)
    130. 130. B Vitamins• What should I prescribe? – WAFACS supplement is not commercially available • 2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12 – Recommendation: ≥200% RDA folic acid plus ≥100% RDA B12 (2.5 mcg) • 200% RDA provides maximum Hcy-lowering effect of folic acid • B12 helps to balance effect of folic acid
    131. 131. Recommendation≥200% RDA folic acid ≥100% RDA B12 Take 2 pills per day to get recommended dosage
    132. 132. B Vitamins• Summary – Elevated serum homocysteine levels associated with increased risk of neovascular AMD – B vitamin supplements demonstrated to be effective in the primary prevention of AMD – B vitamin supplementation may be recommended for normal patients seeking to reduce their risk of developing AMD in the future
    133. 133. What’s New in AMD 1. Vitamins 2. Genetics 3. Anti-VEGF medications 4. Fish 5. Lutein 6. Sunlight and Cataract Surgery 7. Lifestyle 8. Aspirin 9. Implantable Miniature Telescope 10. Drug Pipeline
    134. 134. Thank You!