Whats New in AMD - 2012


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  • Comparison of Age-Related Macular Degeneration Treatment Trial
  • Whats New in AMD - 2012

    1. 1. What’s New in AMD Rick Trevino, OD, FAAO School of Optometry University of the Incarnate Word
    2. 2. What’s New in AMD10. Drug Pipeline
    3. 3. “It is difficult to make predictions, especially about the future.”
    4. 4. Drug Pipeline• Geographic Atrophy – Fenretinide (ReVision) • Visual cycle modulator, Phase 3 clinical trial – ACU-4429 (Acucela) • Visual cycle modulator, Phase 2 clinical trial (ENVISION Clarity Trial) – POT-4 (Potentia/Alcon) • Complement-3 inhibitor (anti-inflammatory), Phase 2 clinical trials – NT-501 (Neurotech) • Ciliary neurotrophic factor (neuroprotection), Phase 3 clinical trials
    5. 5. Drug Pipeline• NT-501 (Neurotech) – Ciliary neurotrophic factor (CNF) is a potent neuroprotective agent that affects the survival of cells in the nervous system, including retinal cells – Human cells genetically modified to secrete CNF are placed within a semipermiable capsule which is then implanted within the vitreous – The sustained release capsule will deliver CNF to the retina for a year or longer neurotechusa.com
    6. 6. Ciliary neurotrophic factor is delivered to the retina via encapsulated cell technology(ECT). ECT implants consist of human cells that have been genetically modified toproduce a specific therapeutic protein and encapsulated in a semi-permeable hollowfiber membrane. The cells continuously produce the therapeutic protein whichdiffuses out of the implant at the target site.
    7. 7. Drug Pipeline• Zhang (2011) – Multicenter, 1yr, double-masked, sham-controlled dose-ranging, phase 2 study – CNTF treatment resulted in a dose-dependent increase in retinal thickness – 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
    8. 8. Effect of intraocularCNTF on visual acuitystabilization.(A) Percentage of subjectslosing <15 letters frombaseline over 12 mo.(B) Significant effect ofCNTF on visual acuitystabilization in thehigh-dose group withbaseline BCVA at 20/63or better.
    9. 9. 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
    10. 10. What’s New in AMD9. Implantable Miniature Telescope10. Drug Pipeline
    11. 11. Implantable Miniature Telescope• The FDA approved the Implantable Miniature Telescope (IMT) in 2010 to improve vision in patients 75yrs and older with stable severe-to- profound vision impairment (20/160 to 20/800) caused by bilateral end-stage AMD• IMT produced by VisionCare Ophthalmic Technologies and marketed as CentraSight
    12. 12. The housing measures 3.6 mm in diameter and 4.4 mm in length in a PMMA carrierwith haptics measuring 13.5 mm in diameter designed to be implanted “in the bag”
    13. 13. Implantable Miniature Telescope• IMT is implanted into one eye only, as determined by patient and doctor (typically the non-dominant or poorer seeing eye)• Functions as a fixed focus 2.2x or 2.7x telescope system (2 models available)• Generates a 20° to 24° field of view (depending on mag)
    14. 14. Implantable Miniature Telescope• The size of the device requires a 12 mm limbal incision and is closed with 10.0 nylon sutures• Most common adverse event is persistent vision- impairing corneal edema (9.2% 5-year cumulative probability)
    15. 15. Implantable Miniature TelescopeImplantable Miniature Telescope Professional Use Information, FDA-approved product labeling.
    16. 16. Implantable Miniature Telescope• Partial contraindications list: – Active CNV or tx for CNV within the past 6 mos – Previous intraocular or cornea surgery – Peripheral vision loss in the fellow eye – Central anterior chamber depth (ACD) <3.0 mm – Myopia > 6.0 D or hyperopia > 4.0 D in the operative eye – Presence of corneal guttata – Failure meet the minimum age (75 yrs) and endothelial cell density requirements • Age 75-84: 2000 cells/mm2 • Age ≥85: 1800 cells/mm2 Implantable Miniature Telescope Professional Use Information, FDA-approved product labeling.
    17. 17. Implantable Miniature Telescope• Requirements prior to surgery: – Evidence of visually significant cataract (>Grade 2) – Confirm geographic atrophy or disciform scar with foveal involvement in both eyes – Undergo training and assessment with low vision specialist in the use of an external telescope for the patient to make an informed decision – Agree to participate in post-operative visual training with a low vision specialist.Implantable Miniature Telescope Professional Use Information, FDA-approved product labeling.
    18. 18. Implantable Miniature Telescope• IMT Treatment Program STEP 1: Patient Diagnosis and Management : Retina Specialist STEP 2: Evaluation (Low Vision Assessment/Eye Selection): Low Vision Optometrist STEP 3: Implantation: Cornea/Cataract Surgeon STEP 4: Visual Training/Rehabilitation: Low Vision Optometrist and Occupational Therapist – All providers must receive training before becoming a CentraSight program provider centrasight.com
    19. 19. 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
    20. 20. 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
    21. 21. What’s New in AMD8. Aspirin9. Implantable Miniature Telescope10. Drug Pipeline
    22. 22. Aspirin & AMD• Four major pharmacologic properties of acetylsalicylic acid (ASA) – Analgesic: Inhibits pain via multiple mechanisms – Antipyretic: Lowers body temperature of persons with fever – Anti-inflammatory: Inhibition of prostaglandins, generation of lipoxins – Antiplatelet: Decreases the aggregability of platelets and the formation of intra-arterial thrombi Schror K. Aspirin Update. International Press Workshop 2008
    23. 23. 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
    24. 24. Aspirin & AMDHarmful 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)• de Jong (2012) • Douglas (2007)Protective Effect • Rudnicka (2010)• Christen (2001)• Christen (2009)
    25. 25. Aspirin & AMD• Antiplatelet effect – Enhance circulation and decrease the risk of vascular events could decrease the risk of AMD – Risk of macular hemorrhage associated with use of anticoagulants and aspirin• Anti-inflammatory effect – Aspirin could decrease the risk of AMD through though its anti-inflammatory effects Christen WG. Ophthalmology. 2009; 116: 2386–2392.
    26. 26. Aspirin & AMD• Christen (2009) – Effect of ASA use on AMD development prospectively studied in a 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 (hazard ratio, 0.82; 95% CI, 0.64 to 1.06). Christen WG. Ophthalmology. 2009; 116: 2386–2392.
    27. 27. Christen WG. Ophthalmology. 2009; 116: 2386–2392.
    28. 28. Aspirin & AMD• de Jong (2012) – Study AMD development in 4691 participants aged 65 years and older in the population-based cross-sectional European Eye 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
    29. 29. de Jong, et al. Ophthalmology. 2012;119:112–118
    30. 30. Aspirin & AMD• Summary – Biologically plausible basis for protective effect (improved circulation, anti-inflammatory) – ASA use does not increase the risk of macular bleeding, but if bleeding occurs it may be more severe if anticoagulants or ASA are being used. – Studies to date do not clearly demonstrate either a beneficial or harmful effect of low-dose ASA use on the development or progression of AMD
    31. 31. What’s New in AMD7. Lifestyle8. Aspirin9. Implantable Miniature Telescope10. Drug Pipeline
    32. 32. 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 – Diabetes & Hypertension – Obesity – Elevated markers of inflammation Mares JA, et al. Arch Ophthalmol. 2011;129:470–480
    33. 33. 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
    34. 34. Chakravarthy (2010): Meta-analysis of studies assessing risk of advanced AMD (combined atrophic and exudative) associated with smoking. CC: case control, CS: cross-sectional, PC: prospective cohort
    35. 35. Warning label on cigarettes sold in Australia
    36. 36. 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 hyperleptinemia- induced 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
    37. 37. Chakravarthy (2010): Meta-analysis of studies assessing risk of advanced AMD (combined atrophic and exudative) associated with BMI.
    38. 38. Risk of offending patients when obesity is discussed
    39. 39. Lifestyle & Behavioral Factors• Exercise – Physical activity lowers cardiovascular disease risk, which is possibly predictive of AMD. • Activity improves various risk factors associated with AMD risk : adiposity and blood pressure. – 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
    40. 40. Williams (2009)Dose-responserelationshipRelative risk ofAMD by averagedistance run perday in 41,708nondiabetic, nonsmoking menand women
    41. 41. Lifestyle & Behavioral Factors What’sGood for the Heart Is alsoGood for the Eye! Don’t smoke Lose weightExercise regularly
    42. 42. What’s New in AMD6. Sunlight and Cataract Surgery7. Lifestyle8. Aspirin9. Implantable Miniature Telescope10. Drug Pipeline
    43. 43. 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
    44. 44. Sunlight & Cataract Surgery• Sunlight exposure – Chesapeake Bay Waterman Study (1992): Subjects exposed to long-term high doses of blue light were found to have a higher incidence of advanced AMD – BMES (1998): Persons with sun-sensitive skin (burning rather than tanning) demonstrated increased risk of neovascular AMD – Hirakawa (2008): Greater total lifetime exposure to sunlight as objectively measured using facial wrinkling associated with greater risk of late AMD
    45. 45. Hirakawa M. Br J Ophthalmol. 2008;92:630-634
    46. 46. Sunlight & Cataract Surgery• BDES (2004) – Ten-year follow-up of 2764 participants in the Beaver Dam Eye Study – Persons exposed to the summer sun for >5 hrs per day in youth or at baseline were at higher risk of early AMD than those exposed <2 hrs per day – 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
    47. 47. Sunlight & Cataract Surgery• Fletcher (2008) – Population-based study of 4700 people in 7 European countries – High sunlight exposure and low serum antioxidant levels associated with 4-fold increased risk of wet AMD – Sunlight not hazardous if antioxidant levels are adequate – Risk greatest with low levels of zeaxanthin, vitamin E, and vitamin C Fletcher AE., et al. Arch Ophthalmol. 2008;126:1396-1403
    48. 48. Sunlight & Cataract Surgery• Cataract Surgery – The adult lens absorbs nearly 100% of light below 400nm – Following cataract surgery increased exposure to short-wavelength light 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
    49. 49. 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 – Absence of any consistent pattern in the direction of harm across models reinforces the conclusion that AREDS data provide little evidence that cataract surgery increases the risk of progression to late AMD. Chew EY, et al. Ophthalmology 2009;116:297–303
    50. 50. Chakravarthy (2010): Meta-analysis of studies assessing risk of advanced AMD (atrophic and exudative) associated with cataract surgery.
    51. 51. Sunlight & Cataract Surgery• Blue-blocking IOL Controversy – Most modern IOLs filter UV radiation below 400nm. – The crystalline lens turns yellow with age, thereby blocking some blue light, while most IOLs are transparent – 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
    52. 52. Turner (2008): Spectral sensitivity of photopic, scotopic and circadian (melatoninsuppression) photoreception
    53. 53. Sunlight & Cataract Surgery• Blue-blocking IOL Controversy – Concerns have been raised that blue-blocking IOLs attenuate visual performance under scotopic conditions, have undesirable effects on color perception, and disrupt circadian entrainment – 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
    54. 54. Sunlight & Cataract Surgery• Summary – There is some evidence that removal of a cataractous lens may increase the risk of AMD progression due to an increase in retinal short wavelength light exposure – This risk could possibly be mitigated if IOLs filtered UV and short wavelength visible light – The theoretical disadvantages of blue-light filtering IOLs may be minimized by filtering only violet light
    55. 55. What’s New in AMD5. Lutein6. Sunlight and Cataract Surgery7. Lifestyle8. Aspirin9. Implantable Miniature Telescope10. Drug Pipeline
    56. 56. Lutein• Macular Pigment – As the major components of macular pigment, lutein and zeaxanthin are concentrated at the macula suggesting a possible role in preventing the onset and progression of macular disease. – Laboratory data suggest an important role for these two carotenoids in protecting the neural retina from photo-oxidative damage by absorbing blue light and by quenching reactive oxygen species through powerful antioxidant activity.
    57. 57. Lutein• Weigert (2011) – Dietary lutein supplementation can significantly increase macular pigment optical density (MPOD). – Patients with the lowest MPOD at baseline experience the greatest increase – Patients with high MPOD at baseline experience almost no increase, suggesting that lutein incorporation in the retina is saturable – Increasing MPOD may be associated with improvements in visual function (including improved VA) due to decreased chromatic aberration Weigert A, et al. Invest Ophthalmol Vis Sci. 2011;52:8174–8178
    58. 58. Normal RangeWeigert (2011): Correlation between MPOD at baseline and the change inMPOD after 6 months of lutein supplementation.
    59. 59. Weigert (2011): Correlation between the change in MPOD and the change inVA after 6 months of lutein supplementation.
    60. 60. Lutein• Ma (2012) – Meta-analysis of 6 longitudinal cohort studies evaluating the relationship between dietary intake of lutein and zeaxanthin and AMD risk – 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.
    61. 61. Lutein• Summary – Lutein supplementation will improve MPOD in patients with low levels of macular pigment, and these patients will benefit visually from this intervention – It remains unclear to what extent lutein supplementation or MPOD influences the onset and progression of AMD • This question is being investigated in AREDS 2
    62. 62. What’s New in AMD4. Fish5. Lutein6. Sunlight and Cataract Surgery7. Lifestyle8. Aspirin9. Implantable Miniature Telescope10. Drug Pipeline
    63. 63. Fish• Fish oil is rich in omega-3 long-chain polyunsaturated fatty acids (LCPUFA). – Docosahexaenoic acid (DHA) is the major dietary and structural omega-3 LCPUFA of the retina – Eicosapentaenoic acid (EPA) is a precursor to DHA• LCPUFAs may protect against oxygenic, inflammatory, and age-associated pathology
    64. 64. Fish• Chong (2008) – Meta-analysis of 9 studies finds that consumption of fish twice or more per week and foods rich in omega-3 fatty acids was associated with a reduced risk of both early and late AMD.• AREDS (2009) – Participants reporting the highest consumption of fish oil were approximately 30% less likely to develop advanced AMD than participants reporting the lowest fish oil consumption
    65. 65. Fish• Christen (2011) – Prospective study of 38,000 females over 10 years – Women who consumed 1 or more servings of fish per week, compared with those who consumed less than 1 serving per month, had a relative risk of AMD of 0.58 – 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
    66. 66. FishDiagnosis of Visually Significant Age-Related Macular DegenerationAccording 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) 0.001 Dark-meat fish (salmon, tuna) 0.56 (0.32 – 0.99) 0.01 Canned tuna fish 0.56 (0.40 – 0.80) 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 less than once per month consumption to once per week or greater consumption. Visually significant AMD is defined as AMD severe enough to cause a decline in visual acuity to 20/30 or worse Christen WG, et al. Arch Ophthalmol. 2011;129(7):921-929
    67. 67. 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
    68. 68. What’s New in AMD3. Anti-VEGF medications4. Fish5. Lutein6. Sunlight and Cataract Surgery7. Lifestyle8. Aspirin9. Implantable Miniature Telescope10. Drug Pipeline
    69. 69. Anti-VEGF Medications• Bind to VEGF preventing it from binding to its target receptor on endothelial cells – Decrease growth of and leakage from CNV – Prevents moderate and severe vision loss – Frequently leads to vision improvement• Three anti-VEGF drugs FDA-approved for AMD, plus one used extensively off-label – Pegaptanib sodium (Macugen) – Ranibizumab (Lucentis) – Aflibercept (Eylea, VEGF-Trap) – Bevacizumab (Avastin)
    70. 70. Vascular endothelial growth factor (VEGF) binds to its receptor(VEGFR2) on the surface of vascular endothelial cells and triggersa number of metabolic pathways that promotes and supports thegrowth of new blood vessels, a process known as angiogenesis
    71. 71. Avastin: Humanized mouse anti-VEGF monoclonal antibodyLucentis: Antigen-binding fragment modified to increase affinity for anti-VEGF
    72. 72. 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
    73. 73. 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
    74. 74. CATT Study• NIH-sponsored head-to-head comparison of Lucentis and Avastin• The safety and efficacy of Lucentis for wet AMD has been established by clinical trials• Because of it’s significant cost advantage, Avastin has become the most popular drug in the USA for the treatment of wet AMD despite the absence of any large- scale clinical trials supporting it’s use. Martin DF, et al. N Engl J Med. 2011;364:1897–1908
    75. 75. CATT Study• Methods – Multicenter, single-blind, non-inferiority trial – 1208 patients with neovascular AMD were randomly assigned to receive intravitreal Lucentis or Avastin on either a monthly schedule or as needed (PRN) with monthly evaluation x 1yr – 4 study groups: • Lucentis monthly, Lucentis PRN • Avastin monthly, Avastin PRN Martin DF, et al. N Engl J Med. 2011;364:1897–1908
    76. 76. CATT Study• Results: Visual Acuity – Avastin administered monthly was equivalent to Lucentis administered monthly, with 8.0 and 8.5 letters gained, respectively. – PRN Avastin was equivalent to PRN Lucentis, with 5.9 and 6.8 letters gained, respectively – PRN Lucentis was equivalent to monthly Lucentis • 1.7 fewer letters on PRN dosing – The comparison between PRN Avastin and monthly Avastin was inconclusive • 2.6 fewer letters on PRN dosing Martin DF, et al. N Engl J Med. 2011;364:1897–1908
    77. 77. Martin DF, et al. N Engl J Med. 2011;364:1897–1908
    78. 78. CATT Study• Results: Anatomy – The mean decrease in central retinal thickness was greater in the Lucentis-monthly group (196 µm) than in the other groups (P = 0.03) – All other anatomic results also indicate superior efficacy of Lucentis • Resolution of fluid on OCT (P < 0.001) • Cessation of leak on fluorescien angiography (P < 0.001)
    79. 79. A stronger effect on leakage by Lucentis might eventuallylead to actual differences in visual acuity outcomes over time
    80. 80. CATT Study• Results: Safety – The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with Avastin than with Lucentis • Avastin: 24.1% vs. Lucentis 19.0% • Risk ratio, 1.29; 95% CI, 1.01 - 1.66 – Life-threatening or disabling events occurred in 3.51% of the combined Lucentis and 5.61% of the combined Avastin groups (P = 0.04) – 1.5% of patients treated with Lucentis and 2.5% of patients taking Avastin died Martin DF, et al. N Engl J Med. 2011;364:1897–1908
    81. 81. 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
    82. 82. Avastin Safety• Ocular safety concerns – Episodic severe uveitis (sterile endophthalmitis) • Clusters of cases have been documented associated with specific batches of Avastin in the USA, Canada and Japan • Trace endotoxin contamination suspected – Sustained IOP elevation reported much more frequently after Avastin injection than Lucentis • Etiology unknown. • Possibilities include low-grade inflammatory reactions, direct drug toxicity or mechanical obstruction of the trabecular meshwork
    83. 83. Avastin Safety• Systemic safety concerns – Retrospective analysis of 146,942 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 than 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.
    84. 84. Avastin Safety• Summary – Significant safety concerns exist regarding off-label intravitreal Avastin use • Ocular toxicity, compounding practice, systemic effects – Awaiting 2-year results of CATT for clearer evidence of relative safety and efficacy of Avastin and Lucentis – In the meanwhile, intravitreal Avastin should be used with caution
    85. 85. 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 – Attempts to reduce the frequency of injection by employing extended dosing paradigms guided by eye examinations and monitoring • Clinical studies uniformly demonstrate decline in visual acuity gains with less than monthly dosing
    86. 86. Monthly dosing: MARINA studyRosenfield PJ, et al. N Engl J Med. 2006;355:1419-1431
    87. 87. Quarterly dosing: PIER studyRegillo CD, et al. Am J Ophthalmol 2008;145:239–248
    88. 88. As-needed dosing: SAILOR studyBoyer DS, et al. Ophthalmology 2009;116:1731–1739
    89. 89. 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.
    90. 90. Eylea• Need for a neovascular AMD treatment option that can maintain visual acuity gains with less frequent intravitreal injections – Frequent office visits pose a challenge for patients in terms of travel and visit time – Retinal practices are burdened with frequent visits• Need a wet AMD therapy that can deliver consistent efficacy with a more convenient, predictable, less frequent monitoring and dosing regimen Heier J. Regeneron Investor Briefing. 2/13/2011
    91. 91. 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
    92. 92. Top. A key binding domain of VEGFR1 and a key binding domain of VEGFR2 (left) are fusedfor tight binding affinity for both VEGF-A isomers and PlGF (center). Two dual-domain armsare used for one aflibercept molecule to mimic the natural receptor (right).Bottom. The Fc portion of IgG1 (left) is fused to the two dual-domain arms (center)resulting in the engineered molecule of aflibercept (right).
    93. 93. Eylea• Phase 3 clinical trials – Two identical studies in different geographic regions • VIEW 1: USA and Canada • VIEW 2: Europe, Latin America, and Japan – Test two doses at monthly injection frequency and higher dose at bimonthly frequency for 1 year – PRN dosing, with a dose administered at least every 3 mos (but not more often than monthly), is being evaluated during year 2 of the study Heier J. Regeneron Investor Briefing. 2/13/2011
    94. 94. Heier J. Regeneron Investor Briefing. 2/13/2011
    95. 95. Heier J. Regeneron Investor Briefing. 2/13/2011
    96. 96. Heier J. Regeneron Investor Briefing. 2/13/2011
    97. 97. Heier J. Regeneron Investor Briefing. 2/13/2011
    98. 98. Heier J. Regeneron Investor Briefing. 2/13/2011
    99. 99. Eylea• Safety – No significant difference in rates of ocular or systemic adverse events when compared to Lucentis• Conclusions – All Eylea dosing groups were demonstrated non- inferior to monthly Lucentis – Eylea dosed every two months was similar in efficacy and safety to Lucentis dosed monthly – Potential for a new, more predictable and less burdensome treatment paradigm Heier J. Regeneron Investor Briefing. 2/13/2011
    100. 100. What’s New in AMD2. Genetics3. Anti-VEGF medications4. Fish5. Lutein6. Sunlight and Cataract Surgery7. Lifestyle8. Aspirin9. Implantable Miniature Telescope10. Drug Pipeline
    101. 101. Genetics• Besides age, genetic background is the most significant non-modifiable risk factor for AMD – Smoking is the most significant modifiable risk factor• The degree of heritability and the relative role of genetic and environmental factors is still unknown• Seddon (2005): US Twin Study of AMD – Genetic factors explain 46% - 71% of disease severity – Environmental factors explain 19% - 37%
    102. 102. Genetics• Genes associated with AMD – Alternative complement pathway • CFH, C2, CFB, C3, CFI – ARMS2/HTRA1 region • Function unknown – High density lipoprotein (HDL) cholesterol pathway • LIPC, ABCA1, CETP – Extracellular matrix pathway • TIMP3, COL10A1, COL8A1 – Angiogenesis pathway CFH and ARMS2/HTRA1 • VEGFA account for approximately 40% to 60% of the genetic – Vitamin D pathway risks of AMD in whites • CYP24A1 Yu Y, et al. Invest Ophthalmol Vis Sci. 2012 Jan 12. [Epub ahead of print]
    103. 103. 60 50 AMD ODDS RATIO (%) 40 30 20 10 TT GT 0 ARMS2 TT GG TC CFH CCRisk of AMD based upon ARMS2 and CFH genotype Rivera A, et al. Hum Mol Genet. 2005;14:3227-36
    104. 104. Genetics• Risk modeling – Mathematical models that attempt 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
    105. 105. Risk Models• Use of mathematical models to predict risk of developing advanced AMD based upon genotype and environmental risk factors• A genetic test identifying individuals at high risk of developing CNV holds the promise for earlier detection through risk-based surveillance protocols and improved outcomes from more timely intervention
    106. 106. Genetic testing services are currently available, including tests for AMD
    107. 107. Risk Models• Two types of models – Genetic only • Risk factors are static through life and not subject to misreporting – Genetic plus other factors • May include phenotype, behavioral and environmental factors in the model • Potential for improvement of short-term risk assessment • Unclear how to account for change over time (smoking behavior, weight loss)
    108. 108. Risk Models• Jakobsdottir (2009) – Genetic only model using 3 SNPs – AUC: 0.79 (a measure of how well a test can distinguish between cases and controls)• Seddon (2009) – Joint gene–environment model using six-SNPs – AUC: 0.81 – Can distinguish between “progressors” and “non- progressors” and between non-disease controls from patients with advanced AMD
    109. 109. Risk Models• Hageman (2011) – Genetics only model using 13 SNPs – AUC: 0.80 – Achieves clinical performance comparable with models with fewer SNPs that include self-reported and/or non-static risk factors• Klein (2011) – Joint gene-environment model using two-SNPs – AUC: 0.87
    110. 110. Hageman (2011): Probability of CNV using genetic-only model. Red barsrepresent controls and blue bars represent patients with CNV.
    111. 111. Are you better off knowing genotype or phenotype?Demographics &genotype known Klein (2011): Genetic information provides little additional Demographics & predictive phenotype known value once the phenotype is known
    112. 112. Risk Models• Summary – Using genetic information alone it is possible to construct a model that achieves performance comparable to models that include self-reported and/or non-static risk factors. – 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.
    113. 113. 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) – Supplementation was associated with a greater risk reduction of AMD progression (68%) among those with the low-risk TT genotype compared with those with the high-risk CC genotype (11%) – This is among the first pharmacogenetic studies to suggest interaction between genotype and treatment response Klein ML, et al. Ophthalmology 2008;115:1019–1025
    114. 114. Response to the AREDS supplement is related to CFH genotype -Low risk Low risk 23% 4% Low risk Persons homozygous for the CFH high-risk allele (CC) have a smaller treatment response than persons homozygous for the CFH low-risk allele (TT)
    115. 115. Pharmacogenomics• CFH & Avastin – 86 patients being treated with bevacizumab (Avastin) were evaluated for associations between treatment response and polymorphisms in the genes CFH and ARMS2. – Patients homozygous for both CFH risk alleles (CC) had worse visual outcomes than those with the CFH TC and TT genotypes. Brantley MA, et al. Ophthalmology. 2007;114:2168-73
    116. 116. Pharmacogenomics• CFH & Lucentis – 156 patients receiving ranibizumab (Lucentis) – Patients homozygous for both CFH risk alleles (CC) had worse visual outcomes than those with the CFH TC and TT genotypes – These results suggest that determining patients CFH genotype may be helpful in the future in tailoring treatment for exudative AMD with intravitreal ranibizumab Lee AY, et al. Br J Ophthalmol. 2009;93:610-3
    117. 117. Shastry BS. Discovery Medicine. Aug 2011
    118. 118. Pharmacogenomics• Summary – Genetic information may be used to tailor strategies for predictive testing, treatment, or prevention. • Who should be treated and with which drug – 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
    119. 119. What’s New in AMD1. Vitamins2. Genetics3. Anti-VEGF medications4. Fish5. Lutein6. Sunlight and Cataract Surgery7. Lifestyle8. Aspirin9. Implantable Miniature Telescope10. Drug Pipeline
    120. 120. 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
    121. 121. 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
    122. 122. The 3 major sources ofvitamin D are:• Sunlight• Milk• Supplements
    123. 123. Vitamin D• Parekh (2007) – Cross-sectional study of serum vitamin D and early and advanced AMD from 7752 participants in NHANES – Highest vs lowest quintile of serum vitamin D • Early AMD: 0.64 (95% CI, 0.5-0.8) odds ratio • Advanced AMD: 1.16 (95% CI, 0.5-3.1) odds ratio – Milk intake ‘less than weekly’ vs ‘daily or more’ • Early AMD: 0.75 (95% CI, 0.6-0.9) odds ratio – Vitamin D supplements protective against early AMD only in individuals who did not consume milk daily Parekh N, et al. Arch Ophthalmol. 2007;125:661-669
    124. 124. 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, having serum vitamin D concentrations >38 nmol/L was 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
    125. 125. 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 • Some UVB exposure, necessary for dermal vitamin D synthesis, may be protective for AMD when the eyes are protected – Serum vitamin D levels were higher in unaffected siblings (not statistically significant) – SNPs in CYP24A1 (enzyme in the vitamin D pathway) increased AMD risk. • First genetic association between vitamin D and AMD risk. Morrison MA, et al. Hum Genomics. 2011;5:538-568
    126. 126. Vitamin D• Summary – Strong evidence that higher serum vitamin D levels associated with reduced risk of early AMD • Suggestion of protective effect for neovascular 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 (UV and blue blocker)
    127. 127. 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
    128. 128. Elevated homocysteine levels lead to increased oxidative stress, inflammation, andincreased thrombotic tendency. These all increase the risk of endothelial injury anddysfunction.
    129. 129. B Vitamins• Close relationship between AMD and CVD – Common risk factors • Smoking, Obesity, HTN, CRP – Common antecedents: • Inflammation, Oxidative stress, Vascular endothelial dysfunction, Genetics – Common interventions • Fish oil, heart-healthy diet, exercise, weight loss – Speculation: AMD and CVD are two manifestations of a single underlying chronic inflammatory disease of aging – Hypothesis: If Hcy is assoc with CVD, and if CVD is assoc with AMD, then Hcy may be assoc with AMD
    130. 130. 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
    131. 131. B Vitamins• Christen (2009) – 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
    132. 132. Cumulative incidence rates of confirmed AMD (left) and visually significant(VS) AMD (right). 137 cases of AMD appeared during follow-up, including 70visually significant (20/30 or worse). After an average 7.3 yrs of follow-upthose women on treatment has a 35% lower risk of any AMD and a 40% lowerrisk of visually significant AMD
    133. 133. B Vitamins• Folic acid is the first identified means, other than cigarette avoidance, to prevent the onset of AMD• 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) Christen WG. Arch Intern Med. 2009;169:335-341
    134. 134. B Vitamins• What should I prescribe? – WAFACS supplement not commercially available • 2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12 – Maximum Hcy-lowering effect: 0.8mg (200% RDA) • RDA: 0.4 mg (400 mcg) – Tolerable upper intake of folic acid: 1mg • From all sources (food, supplements) • B12 not required if upper limit not exceeded – Recommendation: ≥200% RDA folic acid plus ≥100% RDA B12 (2.5 mcg)
    135. 135. If you want to prescribe the WAFACS supplement: 5 pills/dayWAFACS: 2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12
    136. 136. Recommendation ≥200% RDA folic acid ≥100% RDA B12WAFACS: 2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12
    137. 137. B Vitamins• Summary – Elevated serum homocysteine levels associated with increased risk of neovascular AMD – B vitamin supplements demonstrated to be protective against developing AMD – B vitamin supplementation may be recommended for normal patients seeking to reduce their risk of developing AMD
    138. 138. What’s New in AMD1. Vitamins2. Genetics3. Anti-VEGF medications4. Fish5. Lutein6. Sunlight and Cataract Surgery7. Lifestyle8. Aspirin9. Implantable Miniature Telescope10. Drug Pipeline
    139. 139. Thank You!