Age Related Macular Degeneration


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Dr. Torres gives great information on age related macular degeneration. This is a great update not only on the disease but on emerging treatments for this devastating problem.

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Age Related Macular Degeneration

  1. 1. Age Related Macular Degeneration Emerging Technologies Waldemar Torres, MD, FACS
  4. 4. Age-Related Macular Degeneration  Known as macular degeneration, AMD, ARMD  Approximately 15 million people in the USA have AMD  Described more than 80 years ago by Holloway TB, Verhoeff, Trans Am Opth Soc 1928  AMD is a chronic, progressive disease of the macula (central portion of retina) that destroys central vision required for reading, driving, cooking, facial recognition and other common tasks
  5. 5. Leading Cause of Vision Loss  AMD is the leading cause of severe vision loss & blindness in adults over age 50 in the western world [1]  It is a global public health problem  The general consensus is that as the population grows and ages, the incidence will increase as well  The main cause of vision loss in AMD is the development of choroidal neovascularization or abnormal blood vessel growth, also known as wet AMD [1] Early Detection & Treatment of Neovascular AMD, Bressler, JABFP 2002
  6. 6. AMD Types Dry AMD (non-neovascular) Wet AMD (neovascular)
  7. 7. Dry AMD  Accounts for the majority of AMD cases  Early stage can be very mild at first  Progressive degeneration of the RPE ( retinal pigment epithelium) and the photoreceptor loss (the light sensitive cells) and subsequent vision loss  When the patient loses most of the central vision, this central spot or degeneration is called geographic atrophy ( GA) or the end stage of it,  The progression varies between individuals, with vision loss occurring more quickly in some than in others as the tissue in the macula degenerates
  8. 8. Wet AMD: A Rapid Descent Early Intermediate Advanced (dry) (dry) (wet) There are no good predictors for who will develop Wet AMD or when No Vision Loss Today: many are diagnosed after vision loss Wet AMD Severe Vision Loss Blindness TIME
  9. 9. Wet AMD is a debilitating disease that can result in rapid deterioration of your central vision
  10. 10. Wet AMD  Imbalance of:  pro-angiogenic factors that induce new blood vessels formation  angiogenic inhibitory factors that inhibit new blood vessels formation  Excess production of VEGF (vascular endothelial growth factor)  Growth of “ abnormal blood vessels” or a choroidal neovascular membrane leading to scar formation
  11. 11. Wet AMD  New blood vessels grow beneath the retina  Leak blood & fluid  Damage photoreceptors ( the light sensitive cells at the back of the eye) causing permanent vision loss
  12. 12. Risk of Conversion to Wet AMD  43% of patients who already have wet AMD in one eye will develop wet AMD in their other eye within 5 years [1]  26.4% of patients with intermediate (dry) AMD in both eyes will develop wet AMD within 5 years [1]  6.3% of patients with intermediate (dry) AMD in one eye will develop wet AMD within 5 years [1] [1] AREDS Report No. 11, Arch Ophthalmol, 2003
  13. 13. Treatment for advanced dry AMD (GA)  AMD is a complex disease with various pathologic mechanisms  Current strategies pursued by researchers are:  New drugs that aim to prevent damage to the retina or to slow the progression of dry AMD  Anti-inflammatory drugs  Complement inhibition ( inhibition of a immune system pathway)  Alleviation of oxidative stress ( anti oxidants use)  Reduction of accumulation of retinal toxins  Enhancement of choroidal blood perfusion ( improving circulation of retinal circulation)
  14. 14.  Sirolimus ( Rapamycin): anti fungal and immunosupressant agent  Various phase1/2 clinical trials sponsored by National Eye Institute has been completed  Subconjunctival injection every 2 months for dry AMD  Patients with geographic atrophy  Another study is using an oral dose along with other agents for wet AMD  Results will be available shortly
  15. 15.  Fluocilonolone Acetonide Intra-vitreal implant  Synthetic hydrocortisone derivative implant inside the eye  Sustained release for up to 36 months  Ongoing Phase 2 trial is enrolling patients with bilateral GA  Will assess the rate of GA progression in a 2-year span.  This is a medicine secreting implant to protect dying retinal cells
  16. 16.  POT-4  Designed to inhibit the complement activation system ( an immune system pathway)  Intra-vitreal gel sustained release system  Neutralize early AMD inflammatory component  A phase 1 study was completed and a phase 2 study is being pursued
  17. 17.  ARC1905 ( C5 inhibitor aptamer)  Prevents C5a production  Eyes with dry AMD stains for C5a in histopathological studies  Possible benefit in blocking this agent  A phase 1 study was recently completed  Intra-vitreal injection  Results not yet available
  18. 18.  Eculizumab  An antibody against C5  Currently FDA approved for paroxysmal nocturnal hemoglobinuria  Phase 2 study  NT501  Genetically modified RPE intra-vitreal implant  Overexpresses ciliary neurotrophic factor, a growth factor capable of retarding cellular and functional losses in RPE and photoreceptors in neurodegenerative diseases  A phase 2 study reported visual stabilization in 96.3% of treated eyes vs. 75% of control eyes  Improvement in retinal thickness was observed as early as 4 months  It received a FDA fast track designation for the treatment of visual loss associated with GA
  19. 19.  AL-8309A  Has shown capacity to decrease oxidative damage in animal studies of light-induced damage  Similar changes has been found in patients with dry AMD  Potential candidate  Phase 2 study  Topical solution for possible prevention of GA progression as well as visual acuity changes 0ver 2-year span
  20. 20. Reduction of retinal toxins  Studies have shown that there is an accumulation of lipofuscin, a waste product at the leading edge of the lesion in dry AMD  It precedes the spreading of the lesion and death of retinal tissue  To slow or stop progression of GA  ACU-4429 and Fenretinide were developed to prevent the accumulation of lipofuscin  Oral doses  Phase 1 and 2 studies ongoing  Accutane is a possible candidate
  21. 21. Choroidal blood perfusion enhancers  Reduction in choroidal blood flow is more pronounced in patients with AMD  Alprostadil  Intra-venous injection to try to improve macular blood flow  The drug failed to reach the primary outcome  MC-1101  Topical drug that has been shown to increase mean choroidal blood flow  Compelling results from a Phase 1 study have led to a fast track FDA designation for further development of the drug
  22. 22. Other AMD Risk Factors  Age  Genetics  Ethnicity  Gender  Diet - modifiable  Smoking - modifiable
  23. 23. AREDS 2 study  The original AREDS study established that antioxidants, zinc supplements or a combination of both can result in a reduction in risk for AMD progression in patients at high risk  Omega 3 fatty acids in this study population given as a 1gram dose do not appear to have any beneficial effect on preventing progression to wet AMD  Lutein and zeaxanthine , although showing no statistically significant advantage for preventing AMD progression, are reasonable substitutes for beta carotene due the increased risk of lung cancer associated with beta carotene
  24. 24. AREDS 2 supplement Vitamin C 500 mg Vitamin E 400 IU Copper 2 mg Zinc 80 mg Lutein 10 mg Zeaxanthine 2 mg
  25. 25. If you are taking several medications you should consult with your physician The idea that “ more is better” should be avoided
  26. 26. AREDS 2  18 % reduction in the progression to advanced AMD  22% reduction in the risk of progression to neovascular ( wet) AMD  30% reduction in any cataract progression
  27. 27.  Major breakthroughs have been made in the last decade in treating the wet form of AMD  The change in near-term prognosis with 90% chance of stabilizing or increasing vision  Significant price tag of monthly intra-vitreal injections  Injection-related adverse events/ risks  Uncertainty of how long the treatment will last or when it can be stopped without risk of recurrence
  28. 28. Importance of Early Detection On Treatment for Wet AMD Now there are treatments for wet AMD which have proven to be effective in halting the progression of wet AMD in most cases. These treatments consist of injections in the eye. Clinical studies have shown that these new treatments are generally more effective the earlier they begin, when the patient still has good visual acuity and the lesion is still small.
  29. 29. Intra-vitreal injection  It is performed in the office  Using topical anesthesia (eyedrops and gel) or a subconjunctival anesthesia (injection under the capillaries of the eye)  Under aseptic/ sterile conditions  Very low risk of infection, bleeding inside/outside the eye, cataract, retinal detachment or corneal scratch after the injection  Usually is very comfortable
  30. 30. Treatments for advanced wet AMD In wet AMD, too much VEGF ( Vascular endothelial growth factor) is produced in the eye  This causes the growth of unwanted, unhealthy blood vessels  Anti-VEGF drugs block the production of VEGF and stop the development of the blood vessels  Ranibizumab ( Lucentis) Genentech, Novartis.  Approved by FDA in 2006  Antibody fragment that is injected inside the eye ( intra-vitreal injection)  Has proven its benefits in several clinical trials by stabilizing or improving the visual acuity in 95% of patients  Reduces the retinal thickness and promotes sub retinal fluid resorption  A monthly intra-vitreal dose , approximately $ 2000
  31. 31.  Bevacizumab (Avastin, Genentech)  Possibly the anti-angiogenic agent most widely used worldwide  Full length antibody against VEGF  Approved by the FDA for the treatment of metastatic colorectal cancer, metastatic breast cancer and nonsmall cell lung cancer.  Monthly dose ( 1.25 mg)  Approximately $ 17-50 month  Recent infection outbreak in USA ( 2011) was linked to a single compounding pharmacy
  32. 32. CATT trial  1,208 patients were randomized  injections of Lucentis vs Avastin  Monthly vs as needed injections with monthly evaluations  They were found to be equivalent on a monthly injection regimen
  33. 33.  Aflibercept ( Eylea), Regeneron, Bayer  Fusion protein of VEGFR1, VEGFR2 and IgG1 Fc fragment  Every month X 3 then every 2 months  Trials suggest that it is effective for longer periods of time
  34. 34. Combination therapy  Targets formation of new blood vessels, inflammation and prevention of scar formation  Goal is to increase the overall efficacy and reduce the need of monthly injections and side effects by allowing the use of lower doses  Radiotherapy      Selectively targets new blood vessels Attenuates the inflammatory response Decreases scar formation Initial data by different studies was encouraging decreasing the number of current injections CABERNET study( 457 eyes)    Failed to demonstrate a visual acuity benefit The future of this treatment modality is uncertain ORAYA therapy is a combination of anti VEGF plus a single, small dose of radiotherapy, less than 20 minutes total procedure  It significantly reduced the need of multiple anti-VEGF
  35. 35. Photodynamic therapy and steroids  In the year 2000, PDT became the first FDA approved treatment for wet AMD, by being the first treatment to effectively prevent vision loss  Intravenous injection of verteporfin ( light sensitive dye) that travels to the eye  Followed by a laser activation within the lesion  It causes a photochemical reaction, leading to platelet aggregation and local thrombosis ( shutting down the abnormal blood vessels)  Studies showed better visual acuity, stabilization of lesions and less retreatment studies ( PDT with Ranibizumab)
  36. 36.  Dexamethasone and triamcinolone  High rate of cataract and high ocular pressure  Anti scar formation, anti inflammatory and anti new blood vessels formation  Sunitib, FDA approved for the treatment of renal and gastrointestinal tumors  Oral dose that has shown to reduce laser-induced formation of new blood vessels in mice  Topical (eyedrops) effective decreasing formation of new blood vessels in rabbit corneas  Ongoing studies using intra-vitreal injections
  37. 37.  CentraSight lens  Implanted into one eye  Magnifies images, projecting the bigger image onto a healthier part of the retina  Strict screening is necessary
  38. 38.  Second Sight  An implant that attaches to the outside surface of the eye and connects to an electrode placed in the retina  A camera mounted on a pair of glasses communicates with the implant  Is in clinical trials in the USA and is already in use in Europe
  39. 39. Acupunture  The theory is that needles placed at certain points release energy to the liver  In traditional Chinese medicine, the liver and gallbladder are thought to control the eyes  The energy supposedly improves the function of the liver and thereby increases the blood supply to the retina  Rigorous controlled testing on a large number of patients is needed
  40. 40. Rheopheresis Still not a proven therapy for dry AMD In clinical trials it was shown to be safe but the visual results were not conclusive It is similar to kidney dialysis, the patient’s blood is filtered It removes substances that accumulate in the blood as LDL cholesterol, fibrinogen and lipoprotein A to promote an improvement in blood flow and vascular function in the retina and elsewhere
  41. 41. Microelectrical stimulation  Is being promoted as a therapy for early stages of AMD  TENS ( Transcutaneous Electrical Nerve Stimulation)  Routinely used for alleviation of pain  A low voltage current is delivered through electrodes in contact with the skin overlying key nerves around the eye  The theory is that it improves macular function and aids the removal of potentially harmful waste products  One study reported improvements of vision in patients with AMD but the study did not use controls, making the results inconclusive
  42. 42. Genetic testing  There are different laboratory developed genetic tests to evaluate the risk of a patient with early or intermediate AMD progressing to advanced wet AMD within certain period of time  The idea is to be able to customize an approach to monitor and treat each individual based on their reported risk scores for disease progression  This allows for a more effective monitoring of patients
  43. 43. Gene therapy  The idea is to replace or remove a defective gene to stimulate the cell not to die and function properly again  Different abnormal genes related to AMD have been identified  The new gene is introduced into the retina via a virus (vector) , which deliver the genetic information for the rest of the patient’s life  Gene replacement therapy  Studies using animal models are now underway  Several companies are at the forefront of research into the use of gene therapy for wet AMD. These include Genzyme; Avalanche Biotechnologies, working with the Lions Eye Institute of Perth, Australia; and Oxford BioMedica, in partnership with Sanofi.
  44. 44. Macular degeneration and stem cells  On January 3, 2011, Advanced Cell Technology received a FDA approval to treat advanced dry AMD using retinal pigment cells (RPE) from human embryonic stem cells  Uses a proprietary technique to extract a single cell from a young embryo allowing the rest to remain intact and develop normally  Phase1/2 study to determine the safety of RPE sub retinal implantation  UCLA, Wills Eye and Ear infirmary, Bascom Palmer Eye Institute and Massachusetts Eye and Ear.  July 9, 2012, FDA approved an increase of stem cell dosage to 100,000 RPE cells derived from human embryonic stem cells
  45. 45.  June, 2012, a total of 16 patients started transplantation with Human Central nervous system stem cells ( non embryonic)  Study criteria:     50 years old or older Have no prior or current choroidal neovascularization Specific degree and extend of geographic atrophy No Diabetic retinopathy, cancer, glaucoma or autoimmune disease  Allogenic cells ( another source other than the patient) and will receive immunosuppressive drugs X 3 months  4 patients have been transplanted with a single dose of 200,000 HuCNSSC  Retina Foundation of the Southwest, Dallas, TX and Byers Eyes Inst., Stanford, Palo Alto, CA
  46. 46.  January 2013 update:  “No significant safety issues with human embryonic stem cells in any of the 18 patients”  “ 2 patients that has been treated showed some signs of visual improvement and those gains in visual acuity have persisted for 18 months”  “ no signs of tumorigenicity, apparent rejection, ectopic tissue formation”  August 8, 2013 - The RIKEN Institute in Japan has started a clinical study for a wet AMD treatment derived from induced pluripotent stem cells (iPSC) — mature cells that have been genetically reprogrammed to a stem cell-like state
  47. 47. Importance of Early Detection Unfortunately, many wet AMD patients suffer irreversible vision loss by the time they are diagnosed.(3) Because wet AMD progresses rapidly, at a rate of 18-20 µ per day (4), frequent monitoring is critical. It is impractical for patients to visit their eye doctor as frequently as needed for earliest detection. The most effective solution for early detection is home-based monitoring in addition to routine eye exams. (3) Olsen, Ophthalmology 2004 (4) Vander, Ophthalmology 1989
  48. 48. Amsler grid To test each eye individually to determine if there are any squiggly lines or distortions in the grid
  49. 49. Early Detection of AMD Our brain will correct the signals received if assumes incomplete or inaccurate, making it extremely difficult for AMD patients to notice that something has gone wrong in their retina until damage is Normal Fundus Fluidprofound and Lipid Hemorrhage 20/25 20/30 20/100 Therapeutic window By the time you notice symptoms or Amsler Grid changes irreversible vision loss often has already occurred
  50. 50. • • • • The first FDA cleared home based telemonitoring system for AMD Personalized patient monitoring, between physician exams Designed for early detection, before noticeable symptoms & vision loss Preferential Hyperacuity Perimetry • Demonstrated sensitivity, specificity • Robust normative database • Quantifies changes in metamorphopsia
  51. 51. The ForeseeHome was designed specifically for easy operation by AMD patients. It has received numerous awards for product design and its user friendly interface.
  52. 52. So what do we have to do? Do not smoke Control your blood pressure Get regular physical activity such walking 30 minutes daily Eat a variety of colors of fruits and vegetables Consider natural sources of omega-3 fatty acids such tuna and wild salmon Take AREDS 2 supplements Protect you eyes with 100 % UV protection sun glasses Use a visor or a hat to block out more of the sun’s rays
  53. 53.