Summary of Research and Developments in Macular Degeneration, 2012-2013

by Dan Roberts
June 2013
INTRODUCTION
This is a summary of reports about significant research and development in the field of macular degeneration and related diseases presented since June 2012 and May 2013. I will briefly describe the conclusions of 77 studies that have been presented in the areas of therapy, prevention, technology, nutrition and daily living. Reports on the new retinal prosthesis and prevalence of AMD will also be summarized.
For those who wish more detail, references to the original resources are provided. Those sources labeled “ARVO Presentation” refer to reports and posters presented at the May 2013 meeting of the Association for Research in Vision and Ophthalmology and posted on the Web at http://www.arvo.org/webs/am2013/abstract/section/retina.pdf
SURGICAL THERAPY FOR DRY AMD
After targeting the macula with a nano-second pulse laser called 2RT, results suggested a potentially clinically significant reduction in the odds of progression to advanced AMD at 12 months and at 24 months. Researchers concluded that the 2RT laser has the potential to slow the progression of early AMD. A large randomised controlled trial is currently underway.
Source: ARVO Presentation 4146: Novel Laser treatment for Early Age-related Macular Degeneration (Kate Brassington1, et al)
PHARMACEUTICAL THERAPY FOR DRY AMD
In 2008, Acucela Inc. announced that it had begun a Phase I trial for its lead compound ACU-4429, an oral drug developed for the treatment of dry age-related macular degeneration (AMD). It modulates the visual cycle by significantly reducing the accumulation of a by-product of the visual cycle called A2E. which is believed to damage retinal cells.
Phase 1 safety trials were successful, and the results of Acucela’s Phase 2a trial were announced at the ARVO meeting in May 2013. This study demonstrated that ACU-4429 does have the ability to modulate the visual cycle with minimal adverse events. Yhe compound continues to show promise as a treatment for geographic atrophy from dry AMD, and a long-term Phase 2b study is now underway.
Source: A Phase 2 Double-masked, Placebo-controlled, Dose Ranging Study of Emixustat Hydrochloride (ACU-4429) in Subjects with GA Associated with Dry AMD (Pravin U. Dugel1, et al)
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A flavonoid called querectin has been found to protect against oxidative cellular injury and inhibit progression of AMD to the advanced wet form. It may, therefore, be of therapeutic value as an AMD treatment.
Source: ARVO Presentation 4123: Quercetin Protects Hydrogen Peroxide Damaged Human Retinal Pigment Epithelial (hRPE) Cells and Inhibits Vascular Endothelial Growth Factor (VEGF) Production (Andrew Kumar1, et al)
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An antibiotic called minocycline has been seen in cell culture to also protect retinal cells from oxidative damage. This finding suggests that minocycline, too, may play a therapeutic role in the treatment of AMD.
Source: ARVO Presentation 4108: Minocycline protects retinal pigment epithelial cells from hypoxia (Joanna DaCosta)
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A protein called Interleukin-17A (IL17A) is a driving force in chronic inflammation and its overexpression has been linked to AMD. One study found that an injection into the eye of a receptor named sIL17R could neutrilize that damaging protein. Based upon results of the study, the researchers believe this should be considered as another potential treatment for AMD.
Source: ARVO Presentation 1713: Interleukin-17 neutralization ameliorates retinal degeneration in Cx3cr1-/-/Ccl2-/-/Crb1rd8 mice (Daniel Ardeljan1, et al)
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We know that lipid (fatty) deposits in the retina are important factors in development of AMD. Scientists have discovered that a peptide called D-4F, primarily developed to treat arthersclerosis, also reduces lipids in the retina after injection into the eye (Rudolf et al., IOVS 2010, 51: Abstract 2984). Now, this past year, we have learned that D-4F taken orally may be almost as effective as injections, and definitely safer and more pleasant.
Source: ARVO Presentation 1714: Oral administration of Apolipoprotein A-I mimetic peptide D-4F reduces lipid accumulation in murine Bruch’s membrane (BrM) (Martin Rudolf, et al)
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The low vision community has shown an interest in the use of acupuncture as a means of slowing the progression of retinal diseases. No large scale clinical trials have been accomplished to measure safety and efficacy of acupuncture for this purpose, but a small study this past year did show interesting results.
Researchers applied electroacupuncture to the forehead and below the eyes, and acupuncture to the bodies of twelve retinitis pigmentosa (RP) patients over a period of two weeks. They found significant and lasting improvement in acuity, contrast, dark adaptation, and visual field, concluding that electro- and standard acupuncture entails minimal risk and may have measurable benefits for patients with RP. Further research may find that it might also be useful as a treatment for similar retinal diseases like macular degeneration. For now, it is still an alternative treatment which should be considered carefully by patients and their physicians.
Source: ARVO Presentation 4017: Visual Function Improvements following Electroacupuncture for Retinitis Pigmentosa (Ava K. Bittner1, et al)
A drug called antifactor D has been in trials since 2011, and results are expected in September of this year. It is injected into the eye to block an enzyme called complement factor D. Factor D is thought to be associated with dry AMD by genetic association.
Source: Genentech, Inc.
ANTI-VEGF THERAPY FOR WET (NEOVASCULAR) AMD
As usual, we have seen a great deal of effort to find more effective therapies for the wet form of macular degeneration in all of its forms, to include age-related MD, myopic degeneration, and diabetic retinopathy. Here, in no particular order, is a quick run down of most of the studies this past year.
Activation of the Stat3 gene is associated with new blood vessel growth (called neovascularization) and inflammation in the retina. An eye drop of an inhibitor of Stat3, called CLT-005, given to rabbit and rodent animal models, has been shown to reduce neovascularization and also prevent dramatic loss of contrast sensitivity in animals with dry AMD. Future studies may support topical CLT-005 as a stand alone therapy or in conjunction with other treatments.
Source: ARVO Presentation 1716: Eyedrop application of CLT-005, a Stat3 inhibitor, is efficacious in animal models of Wet and Dry Age-related Macular Degeneration (Rafal Farjo1, et al)
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A follow up study of Lucentis has shown that the vascular endothelial growth factor, or VEGF, that causes neovascularization was suppressed for 2 months after the initial Lucentis injection in some eyes with AMD. This means that some patients may be able to go as long as two month between injections, rather than the one month originally recommended. (1)
Another study confirmed these results by evaluating the efficacy of bimonthly Lucentis injections. After six months, these researcher also concluded that bimonthly injection may be effective and could be an option. (2)
Sources:
1. ARVO Presentation 3169: Aqueous Vascular Endothelial Growth Factor and Ranibizumab Concentrations after Monthly and Bimonthly Intravitreal Injections of Ranibizumab for Age-Related Macular Degeneration (Xiying Wang1, et al)
2. ARVO Presentation 3804: The efficacy of bimonthly injection of ranibizumab for age-related macular degeneration for six months (Tomoko Sawada, et al)
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One pertinent study was designed to assess the efficacy of retreating proactively or reactively with the anti-VEGF drugs Lucentis or Eylea. In other words, is it better to continue injections on a regular schedule or wait until neovascularization occurs? In the study, a subset of patients lost vision after switching from proactive to reactive treatment with either drug. Since vision lost from nevascularization does not usually return, proactive treatment appeared to result in better visual outcomes than reactive.
Source: ARVO Presentation 3171: Subanalysis of Visual Acuity Outcomes in the Second Year of VIEW Studies (Michaella Goldstein, et al)
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We reported here in 2010 that the Oraya IRay radiation therapy system entered trials to demonstrate the safety and effectiveness of radiation therapy for the treatment of wet AMD. The system delivers a robotically controlled dose of low-energy X-ray radiation to the retina. closing leaking vessels and further stopping inflammation. In this study, the procedure was used in conjunction with anti-VEGF injections. Results showed that patients undergoing radiotherapy may experience about a 50% reduction in the need for anti-VEGF injections, and that their visual acuity may also benefit. Eyes with active leaking and without significant scarring (25-50% of the study population) achieved the greatest benefits from the
treatment.
Source: www.orayainc.com/clinicaltrials.asp
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Phase I trials were completed this past year evaluating another kind of radiation therapy for wet AMD using a novel episcleral brachytherapy device called SMD-1. This easily delivered brachytherapy approach was shown to be safe and tolerable, and it may prove to be an effective therapy alongside anti-VEGF drug injections. Larger phase I/II trials are planned.
Source: ARVO Presentation 3787: Novel Minimally-Invasive Episcleral Brachytherapy for the Treatment of Neovascular Age-Related Macular Degeneration (nAMD): Results of a Twelve Month Prospective Phase I Safety and Tolerability Evaluation (Kamaljit S. Balaggan, et al)
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A report in late 2012 suggests that the current practice of injecting anti-VEGF drugs as a treatment for wet AMD may cause vision loss in the long run.
The researchers have shown that vascular endothelial growth factor (VEGF) is important to the health of the cone photoreceptor cells in the macula, and that removing the protein in mice retinas has led to atrophy of those cells.
Anti-VEGF drugs are effective in stopping neovascularization. We have now learned, however, that the drugs might actually be starving healthy cone cells by cutting off their nutrition supply. The researchers stress that this has not been an issue in humans during the seven years the drugs have been on the market, but that long-term safety studies have not yet been completed. In view of their findings, they recommend consideration of methods other than general blocking of VEGF. This is a long term adverse effect that merits further investigation.
Source: Journal of Clinical Investigation., November 2012 (Martin Friedlander, MD PhD, et al. The Scripps Research Institute, La Jolla, California)
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The past several years have seen a confusing mixture of study results about the safety of aspirin use by people with AMD. The most recent input comes from Emily Chew, M.D. of the National Eye Institute. She reported in 2012 that, in spite of recent reports, evidence from observational studies and randomized, controlled clinical trials suggest there is no major harmful effect of aspirin use by AMD patients. She said that results from recent studies have shown no increased hemorrhage risk and no harmful association of aspirin with progression of AMD. Furthermore, she supports that aspirin may actually offer significant protection from the development of the disease.
A recent study supported Dr. Chew’s position by finding that aspirin may help to block unwanted blood vessel growth, and that it may not worsen neovascularization in people with wet AMD. (1)
Another new study, however, has concluded that long-term aspirin use may be found to actually enhance new blood vessel growth by increasing vascular density. (2) Past concern about aspirin has focused on the blood thinning issue, but this recent finding suggests that there may yet be more to consider.
Still, most physicians are recommending that, in light of aspirin’s benefit to the cardiovascular system, the best course of action for AMD patients is to consult with their physicians and take aspirin when it is clinically indicated.
Sources:
1. ARVO Presentation 1715: Effect of Aspirin on human ARPE-19 cells and in Mouse Model of Choroidal Neovascularization (Sunali Goyal, et al)
2. Long-term Use of Aspirin and Age-Related Macular Degeneration. Barbara E. K. Klein, MD, et al. (JAMA. 2012;308(23):2469-2478. doi:10.1001/jama.2012.65406)
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In the ongoing debate about which is the better drug for treating wet AMD, Lucentis or off-label Avastin, The National Institutes of Health has reported that, at the end of a 2-year comparison study, both drugs improve vision when administered monthly or on an as needed basis. Patients receiving Lucentis, however, fully maintained first-year vision gains with an average 5.7 injections in the second year. In contrast, patients treated with Avastin experienced a greater decline in vision despite receiving significantly more
injections over the two year period. In addition, secondary anatomical outcomes were significantly better with Lucentis.
Source: NIH News online at www.nih.gov/news/health/apr2012/nei-30a.htm
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Scientists at Queen’s University in Kingston Ontario have found that patients who have gotten eye injections with Avastin have been 12 times more likely to develop pain and serious inflammation in the eye than those who have received Lucentis. Their study, After studying medical records of more than 1500 patients, they concluded that significant concern still exists regarding the safety of [Avastin], and that “patients receiving [Avastin] should be counselled regarding a possible increased risk for serious adverse events.”
Source: Rate of serious adverse effects in a series of bevacizumab and ranibizumab injections. Sanjay Sharma, MD, MSc, et al. Canadian Journal of Ophthalmology, June 2012)
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A recall notice pertaining to off-label Avastin for wet AMD was posted on March 20, 2013 by the FDA. It applied to people being treated in Georgia, Louisiana, South Carolina, and Indiana. It resulted from contamination at a compounding pharmacy that serves clinics in those areas, where five cases of eye infection were reported. This follows previous contamination issues with Avastin in 2011 that led to stricter controls over the use of compounding pharmacies. It seems that contamination of the drug at the pharmacy level is still a problem calling for closer monitoring.
Source: www.fda.gov/Safety/MedWatch/SafetyInformation/…/ucm344664.htm
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In August 2012, the FDA recommended Lucentis for treatment of diabetic macular edema (DME). DME is an eye condition in people with diabetes characterized by retinal swelling and blurred vision. It is a major cause of vision loss and blindness estimated to affect more than 560,000 people in the United States. The current standard of care for DME in the U.S. is laser surgery, which primarily serves to slow the progression of vision loss and help stabilize vision. Lucentis was first approved by the FDA for treatment of wet age-related macular degeneration in 2006 and for macular edema following retinal vein occlusion in 2010.
Source: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315130.htm
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We know that our bodies can sometimes become resistant to long term use of certain drugs. We also know that not all systems react positively to the same drugs. For these reasons, doctors may consider switching from one product to another, and it is useful for them to share reports about how patients will respond.
In one study this past few months, Eylea, the newest drug treatment for wet MD, was been found to be effective in 20 patients who were unresponsive to Lucentis and Avastin.
Source: “The Effect of Eylea (Aflibercept) in Exudative AMD Patients Recalcitrant to Ranibizumab and Bevacizumab”. Vincent S Hau MD, et al. (Published online at
http://meeting2012.asrs.org/Annual-Meeting/Details/1080@Session=15&dayId=3%23dayContent3)
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Another study compared increases in intraocular pressure (IOP) from injections of ucentis and Eylea, and found that Eylea patients had a lower incidence of increased IOP than Lucentis patients.
Source: IOP in Patients With Neovascular AMD Receiving Intravitreal Aflibercept or Ranibizumab Injection. K Bailey Freund, et al. (Published online at www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=2866&sKey=aa3d0ab1-c373-4ac8-9953-1825cc2a538b&cKey=bf3fcd14-a17c-4206-b585-f7f967bbaf59&mKey=%7BF0FCE029-9BF8-4E7C-B48E-9FF7711D4A0E%7D
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Further research assessed the effect of switching from Avastin and/or Lucentis to Eylea in AMD patients. One group found that, on average, 41% had improved visual acuity, and 57% had a decrease in swelling of the retina. (1)
Another group found that, in the first twelve months after switching from Lucentis to Eylea, a patient on Eylea would likely experience more injections than on Lucentis, but there should be a large reduction in monitoring visits. (2)
A third group found that Eylea injections are a prudent alternative to Lucentis and Avastin where a patient has become unresponsive. This retrospective case study suggested that beginning Eylea rescue therapy can resolve blood vessel growth in 25% of eyes previously nonresponsive to the other drugs. The data also showed that 70% of eyes undergoing rescue therapy had maintained or gained acuity following the three rescue injections. Neovascularization, however, is unlikely to stop if it does not do so during the initial three rescue injections. (3)
Sources:
1. ARVO Presentation 3827: The effects of aflibercept following bevacizumab or ranibizumab on visual acuity and central macular thickness in patients with age-related macular degeneration (Ambar Faridi, et al)
2. ARVO Presentation 3813: Impact of using the aflibercept dosing regimen for wet macular degeneration on numbers of injections and monitoring visits over three years (Niro Narendran, et al)
3. ARVO Presentation 3806: Eylea Rescue Therapy in Eyes with Proven Non-Response to Other anti-VEGF Molecules (Benjamin Guidry, et al)
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Some researchers are finding that antibiotics may not be necessary after drug injections into the eyeball. One retinal surgeonreported that, after administering 15,029 injections using an antiseptic, but no topical antibiotic, only one case of infection occurred. The antiseptic Betadine was used in conjunction with all of the treatments.
Source: Eliminating Antibiotic Prophylaxis for Intravitreal Injections: A
Consecutive Series of 15,029 Injections by a Single Surgeon. Abdhish R Bhavsar MD (Published online at
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=2866&sKey=ce12315b-3ddb-4eae-bb79-cae6ff5b8bcc&cKey=4ae3de2c-9fd4-4a0e-978e-2fea44a84d5e&mKey=%7BF0FCE029-9BF8-4E7C-B48E-9FF7711D4A0E%7D
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A vitrectomy is a surgical operation that involves removal and replacement of the vitreous gel from the inside of the eyeball. Patients with wet AMD who have undergone vitrectomies have been noted to have a reduced response to anti-VEGF injections. Researchers looked into this and found that such patients do benefit from the treatments, but that the drugs seem to have a shorter half-life in the eye. The researchers concluded that these eyes may require more frequent injections, or more powerful drugs may be needed.
Source: ARVO Presentation 4135: Approach to Previously Vitrectomized Patients with Neovascular Age-Related Macular Degeneration with Reduced Response to Anti-vascular Endothelial Growth Factor Treatment (Mohammad Zubair Y. Arain, et al)
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The media has recently reported a new finding about cholesterol and AMD. We have know for years that cholesterol buildup in the retina can lead to inflammation (i.e. wet AMD), and researchers have been working to find ways to treat it. Statin drugs have been considered, but with little success, and now we hear that restoring the function of our macrophage cells may someday be the way to go.
Macrophages are key immune cells that remove cholesterol and fats from tissues. As they begin to malfunction from age, however, excessive cholesterol builds up. These lipid deposits gradually become more numerous in the retina, destroying the macula and leading to loss of central vision.
Researchers speculate that drugs now being used to prevent artherosclerosis might be effective also in preventing wet macular degeneration. They have identified a protein that macrophages use to do their work, and they discovered how they might be able to improve the level of that protein in the aging macrophages. From this they think the drug might also prevent new blood vessel growth and leakage in AMD patients, since inflammation is a direct result of cholesterol buildup.
This is promising research, but macrophage restoration as a treatment for wet AMD is still a few years away.
Source: Apte RS et al. Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration. Cell Metabolism, vol. 17(4), published online April 2, 2013
ANTI-VEGF THERAPY FOR MYOPIC MD
Myopic macular degeneration is the leading cause of vision impairment from neovascularization in people under 50 years old. Also called pathologic myopia, studies are being conducted to find treatments for the condition other than coagulation of the leaking vessels with a cool laser. This procedure, called photodynamic therapy (PDT), was a standard treatment for wet AMD before the advent of anti-VEGF drug injections in 2006. At least two studies compared PDT with Lucentis during the past year, both finding that. visual function was significantly improved in the subjects receiving Lucentis.
Sources:
ARVO Presentation 1247: Twelve-month efficacy and safety of ranibizumab 0.5 mg(RBZ) versus verteporfin photodynamic therapy(vPDT) in the treatment of visual impairment(VI) due to choroidal neovascularization(CNV) secondary to pathologic myopia(PM) (Francesco Bandello. Ophthalmology, Univ Vita Salute-Scient Inst San Raffaele, Milan, Italy)
ARVO Presentation 1245: Impact of Ranibizumab on Patient-Reported Visual Functioning in Myopic Choroidal Neovascularization: 3- and 6-Month Results Kyoko Ohno-Matsui, et al)
ANTI-VEGF THERAPY RISK FACTORS
Anti-VEGF drug injections are now the standard treatment for wet macular degeneration. The leading drugs are Lucentis, Eylea, and off-label Avastin. There is no doubt about their benefit to thousands of AMD patients, but some risks are also being noticed in follow up studies.
One concern has been the effect of blood thinning medication on of such drugs. That concern, however, has been alleviated in at least one study concluding that there was no significant increase in retinal hemorrhaging between patients with wet AMD taking blood thinners and those who were not
Source: ARVO Presentation 6309: Association of Systemic Anticoagulation and Rate of Intraocular Hemorrhage Following Intravitreal Anti-VEGF Therapy for Age-related Macular Degeneration (Joanna Olson, et al)
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Another concern is that the blood vessel layer of the retina (the choroid) may grow thinner after multiple injections of anti-VEGF drugs. This is a sign of retinal atrophy, which can result in vision loss.
One study found a decrease in the thickness of the choroid after as few as 3 injections. The subjects already had thinner choroids with an average of 12 prior injections. Over the following 8 months, however, there was no statistically significant change with further treatments.(1)
A second study found reduction over time of thickness of the macula, as well. (2) These are only two of several reports on this issue, and not all of them agree, so further study is needed.
Sources:
1. ARVO Presentation: Choroidal Thickness following Anti-Vascular Endothelial Growth Factor Therapy for Neovascular Age-Related Macular Degeneration (Charlotte So, Zac Ravage)
2. ARVO Presentation 6265: Retinal and choroidal thickness changes over time in patients with neovascular age-related macular degeneration treated with anti-VEGF (Thais S. Mendes, et al)
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A disturbing risk factor has arisen since anti-VEGF treatment began. It appears that some patients with wet MD are developing vision loss after successful regression of the blood vessels. The changes in the retina resemble the atrophy seen in advanced dry macular degeneration (geographic atrophy). (1) (2) Researchers have reported that sight cells appear to be injured in up to 20% of patients after prolonged anti-VEGF injections. (3) They recommend that larger studies be undertaken to determine if this could be a result of the drugs or if it is just part of the natural course of the disease.
Sources:
1. ARVO Presentation 6284: Cellular Features of Retinal Pigment Epithelial Atrophy after Regression of Choroidal Neovascularization
(Mina M. Chung)
2. ARVO Presentation 6295: The Role of Anti-VEGF Therapy in the Development and Progression of Geographic Atrophy in Patients with Wet Age-Related Macular Degeneration (Justin Shaw, et al)
3. ARVO Presentation 3658: Geographic atrophy risk factors in participants of the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) (Juan E. Grunwald, et al)
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According to two reports during the period, scarring of the retina is another concern associated with anti-VEGF treatment, no matter which drug or dosage schedule is used. The risk factors for scarring, which can permanently impair vision, may lead to development of treatments that decrease scarring caused by the damaging vessels.
Sources:
1. ARVO Presentation 3661: Risk Factors for Scarring in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) (Ebenezer Daniel, et al)
2. ARVO Presentation 3659: Sustained Severe Visual Acuity Loss in the Comparison of AMD Treatments Trials (CATT) (Gui-Shuang Ying, et al)
COMBINATION DRUG THERAPY
Three drugs have been recently studied that hold promise as combination therapies for treatment of wet MD.
A new drug called Fovista completed phase 2 clinical trials this past year. Used in combination with an anti-VEGF drug, it blocks pericyte cells that hinder the effectiveness of the drugs. The makers of Fovista reported a 62% higher relative visual benefit when it was used in combination with Lucentis.
Source: www.businesswire.com/news/home/20120613005333/en/Ophthotech’s-Anti-PDGF-Combination-Agent-FovistaTM-Demonstrated-Superior
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Another combination therapy is anti-VEGF injection along with photodynamic therapy (PDT), a low voltage laser applied to an injected drug (verteporfin) that coagulates existing blood vessels. Some patients were found to require no further treatment after this combination treatment, which inspired researchers to test it further. Five reports were found concluding that combining anti-VEGF injections with PDT treatment did result in longger-term closure and control of neovascularization. If proven successful in further research, this procedure could reduce the number of injections required for treatment of wet AMD. (1) (2) (3) (4) Similar good results were reported after this combination was applied to patients affected by a kind of sub-group of wet AMD called polypoidal choroidal vasculopathy (PCV) (5)
Sources:
1. ARVO Presentation 4509: Long-Term and Lasting Outcomes of Combination Treatment for Age-Related Macular Degeneration with Photodynamic Therapy and Intravitreal Injection of Anti-Vascular Endothelial Growth Factor (Colleen M. McLellan, et al)
2. ARVO Presentation 3790: AURORE STUDY: a french multicenter retrospective study in wet AMD patients treated with Verteporfin PDT plus Ranibizumab in routine clinical practice (Franck Rumen1, et al)
3. ARVO Presentation 3791: INTRAVITREAL ANTI-VEGF FOLLOWED BY PHOTODYNAMIC THERAPY VERSUS ANTI-VEGF MONOTHERAPY FOR RETINAL ANGIOMATOUS PROLIFERATION (Pietro Monaco1, et al)
4. ARVO Presentation 3792: Long-term Results of Combination Therapy with Half-time Reduced Fluence Photodynamic Therapy and Intravitreal Ranibizumab for Retinal Angiomatous Proliferation (Hirotaka Yokouchi, et al)
5. ARVO Presentation 3789: Photodynamic therapy, anti-vascular endothelial growth factor therapy, and combination therapy for polypoidal choroidal vasculopathy (Hae Min Kang, et al) _______________________________
Finally, treatment with a non-steroidal anti-inflammatory eye drop called Ketorolac has also been found to increase the effectiveness of Lucentis in treatment of wet AMD.
Source: ARVO Presentation 4175: Prospective randomized controlled trial of combination ranibizumab and ketorolac for wet age-related macular degeneration (Andrea Russo, et al)
ANTI-VEGF DRUG RESISTANCE (tachyphylaxis)
Since the advent of anti-VEGF drug treatment in 2006, thousands of people have been able to retain their eyesight. One recent study showed that with strict monthly follow-up and prompt retreatment with Lucentis as needed, good vision can be achieved and maintained for a period as long as four years, with the need for retreatment seeming to decrease significantly after the first 12 months. (1)
2. This kind of response has been a lifesaver for many, but doctors are finding that more than 10% of patients do not respond completely to the treatment. Resistance to the drugs is suspected to account for many of these. In other words, some people may be developing an immunity to the very drug that is intended to help them. Researchers, for example, evaluated the characteristics of eyes with visual acuity loss at a two-year follow-up in patients with wet AMD who were initially treated with Lucentis. The number of patients losing visual acuity increased, especially after 12 months. (2)
3. Realizing that drug resistance might become a serious roadblock to effective treatment for wet MD, researchers are trying to develop ways to identify at-risk patients and to devise alternative methods for helping them. (3)
Sources:
1. ARVO Presentation 3826: Four year results of visual outcome in Neovascular Age Related Macular Degeneration (AMD) treated with Ranibizumab (Anchal Kailey, et al)
2. ARVO Presentation 3795: Visual acuity loss at a two-year follow-up in patients with exudative age-related macular degeneration treated with ranibizumab and as needed retreatment basis (Takeya Kohno, et al)
3. ARVO Presentation 3170: Detection of anti-ranibizumab antibodies among exudative AMD patients (Nicolas Leveziel, et al)
Regeneron, the company that developed the newest anti-VEGF drug, Eylea, has received the most attention as a potential solution. Five studies found that patients who have developed resistance over time to Lucentis and off-label Avastin, are responding well when switched to Eylea. Those studies are listed here:
ARVO Presentation 6270: Aflibercept (Eylea) Effect on Macula Thickness and Visual Acuity in Exudative AMD Patients Recalcitrant to Ranibizumab and Bevacizumab (Vincent Hau, et al)
ARVO Presentation 4176: Aflibercept Rescue of Bevacizumab- or Ranibizumab-Resistant Choroidal Neovascularization in Age-Related Macular Degeneration (Cheryl A. Arcinue, et al)
ARVO Presentation 3833: Short-term Effectiveness of Intravitreal Aflibercept for Persistent Exudative Age-Related Macular Degeneration (Andrew A. Chang1, et al)
ARVO Presentation 3834: Visual And Anatomical Outcomes Following Intravitreal Aflibercept In Eyes With Recalcitrant Neovascular Age Related Macular Degeneration (Dilraj S. Grewal, et al)
ARVO Presentation 3828: Comparison of the Relative Efficacy of Aflibercept in the Treatment of Neovascular Age Related Macular Degeneration in Patients Previously Treated with Alternative Vascular Endothelial Growth Factor Inhibitors (Khushboo K. Agrawal, et al)
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On the other hand, a large comprehensive study found that development of antibodies in patients undergoing Lucentis treatment for up to two years had no significant impact on their response to the drug.
Source: ARVO Presentation 3793: Analysis of 24 month data from the HARBOR study indicates that anti-therapeutic antibodies status had no significant impact on the treatment response to ranibizumab (Gary Sternberg, et al)
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And another study concluded that there was no visual benefit seen by changing to Eylea in patients who were unresponsive to Lucentis and/or off-label Avastin
Source: ARVO Presentation 3801: Comparison of outcomes after switching treatment from intravitreal bevacizumab or ranibizumab to aflibercept in neovascular age-related macular degeneration (Frank X. Venzara1, et al)
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As a side note, a single study found that switching stabilized patients to Eylea may lead to a temporary loss of visual acuity in some, with most of them recovering and improving after further treatment. This event, the researchers concluded, may or may not be different for those patients who have become resistant to the first drug.
Source: ARVO Presentation 3796: Short-term vision changes after switch to aflibercept therapy for age-related macular degeneration previously treated with other antiVEGF agents (Irene A. Barbazetto, et al)
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Another attempt at solving the drug resistance problem has been to switch to either of the other anti-VEGF drugs. The results suggested that doing so may provide short-term benefits. (1)
Researchers have even suggested that alternating drugs, specifically Lucentis and Avastin, bi-weekly might be an answer. Their study showed this regimen to show significant improvement in so-called recalcitrant patients. (2)
Sources:
1. ARVO Presentation 3823: Effect of anti-VEGF medication change on central macular thickness and visual acuity in patients with neovascular age-related macular degeneration (John P. Campbell, et al)
2. ARVO Presentation 3811: The Efficacy Of Biweekly Alternating Intravitreal Bevacizumab And Ranibizumab In Recalcitrant Choroidal Neovascularization Secondary To Age-Related Macular Degeneration (Radha Ram, et al)
ENDOPHTHALMITIS
Eye infection (endophthalmitis) from the injection protocol has also been a concern since the advent of anti-VEGF drug treatment. Recent research, however, has found that the incidence has been low, and that post-injection antibiotic drops do not appear to significantly reduce the risk of developing infection. If infection does occur, it can be easily treated with topical steroids, and in most cases, the condition will not result in vision loss. Patients should be cautioned to be vigilant about any evidence of infection for 24 hours after an injection, and to report any such evidence to their physician.
Sources:
ARVO Presentation 1118: Meta-Analysis of Infectious Endophthalmitis After Intravitreal Injection of Anti-Vascular Endothelial Growth Factor Agents (John Fileta, et al)
ARVO Presentation 1114: Incidence of Endophthalmitis after Anti-VEGF Injections and use of Anti-Microbials in the Comparison of AMD Treatments Trials (CATT) (Colin A. McCannel1, et al)
ARVO Presentation 1113: The role of antibiotic prophylaxis to prevent post-injection endophthalmitis (Philip P. Storey, et al)
ARVO Presentation 1104: The Incidence of Noninfectious Intraocular Inflammation after Intravitreal Aflibercept Injection (Kunjal K. Modi, et al)
STEM CELL THERAPY
One exciting potential therapy for macular degeneration and myopic degeneration is stem cell therapy. This involves transplanting stem cell-derived retinal tissue to replace dysfunctional tissue and maintain photoreceptor function. In trials so far, the procedure has been shown to be safe, and there has even been some success in restoring vision.
In July, Advanced Cell Technology, Inc. (ACT) treated the tenth and final patient in their Phase 1/2 clinical trial at Moorfields Eye Hospital in London. The outpatient transplant surgery was performed successfully without any complications, and the patient was reported to be recovering uneventfully. The company said that improvements in visual acuity initially reported had persisted for a year, and preliminary results indicated that the research is on the right track.
In February of this year, ACT that they had gained approval from the FDA to begin safety trials to evaluate the safety and tolerability of embryonic stem cell replacement in people with severe myopia. This refers specifically to degenerative myopia (aka “myopic
macular degeneration”), offering hope for people who have lost vision to this condition.
Sources:
ACT press release: http://www.advancedcell.com/news-and-media/press-releases/advanced-cell-technology-to-host-conference-call-to-discuss-2013-first-quarter-results-and-provide-a-corporate-update-on-thursday-may-9th/index.asp
_______________________________
Scientists are continuing to search for sources of stem cells that replicate the power of embryonic cells without confronting the ethical issues that have arisen. Two new sources have shown potential this past year, to include the skin of the patients themselves and human breast tissue.
Sources:
“Stem cell trial to treat eye disease” by Simeon Bennett (San Francisco Chronicle, October 9, 2012)
“New Type of Pluripotent Cell Discovered In Adult Breast Tissue” by Elizabeth Fernandez (published online March 04, 2013 at www.ucsf.edu/news/2013/03/13610/new-type-pluripotent-cell-discovered-adult-breast-tissue)
GENETICS
Researchers from the Miller School of Medicine have collaborated with an international team to locate more genes associated with AMD. So far, they have identified new locations near seven different genes. For a list of previously discovered genes associated with AMD, see Genetics Home Reference on the web site of the National Institutes of Health (NIH). More information about specific gene discoveries may also be found online in the MD Support Library.
Source: “Seven New Loci Associated with Age-Related Macular Degeneration,” (published online, in Nature Genetics, March 3, 2013)
_______________________________
Genetics is a fascinating science that can help identify pathologies of inherited diseases like AMD. By identifying the altered genes and replacing them, we could theoretically cure every condition. But it’s not as simple as it sounds, and the technology is not yet in place. And that’s why the American Academy of Ophthalmology (AAO) recommends that eye physicians and surgeons avoid genetic testing at this time for complex eye disorders until treatment or surveillance strategies can be shown to be of benefit.
Reporting to the AAO members at their annual meeting in 2012, Dr. Edwin Stone said current genetic tests for AMD are flawed and cannot reliably help predict clinical outcomes. Until such time as genetic testing becomes more reliable, he said, “combining a patient’s family history of eye disease with a standard eye exam will remain the best way to determine his or her risk for AMD.”
Source: Edwin Stone, MD. AAO presentation (Chicago, July 2012)
TECHNOLOGY
Hundreds of low vision devices are now on the market, with the quality of imaging and audio improving at enormous speed. The biggest news this past year, was approval in the United States of a retinal prosthesis that is allowing people with severe vision loss to see again. In September, the FDA Ophthalmic Devices Advisory Panel recommended market approval for Second Sight’s Argus II Retinal Prosthesis System.
The system converts video images captured by a miniature camera, housed in the patient’s glasses, into a series of small electrical pulses. These pulses are transmitted wirelessly to an array of microchips to stimulate the retina’s remaining cells resulting in perceptions of patterns of light in the brain. The resulting image is a simple pixelation of light and dark, but it is providing basic sight to patients who have had no light perception at all.
The Argus II received CE Mark approval in Europe last year, and on February 14 of this year, the FDA unanimously approved it for people who have lost significant vision from retinitis pigmentosa. As the technology advances, the system may someday be useful also for people with degenerative diseases of the macula.
Source: http://2-sight.eu/en/home-en
DIET & NUTRITION
Curcumin is found in the popular Indian spice turmeric. Scientists have learned from a study of rodents that curcumin can suppress neovascularization. Curcumin supplementation, therefore, and by extension, tumeric, is now being considered as a potential therapy for wet AMD.
Source: ARVO Presentation 1242: Suppression of experimental choroidal neovascularization by curcumin in mice (Ping Xie, et al)
_______________________________
A study published July 29, 2012 in American Journal of Epidemiology has concluded that drinking more than 20 g of alcohol per day was associated with an approximate 20% increase in the odds of early AMD when compared with those who reported no alcohol intake at baseline. A typical glass of wine contains about 15 g. The positive association, drawn by researchers at the Centre for Eye Research Australia, was apparent for wine, beer, and spirits.
This is interesting in light of previous research showing red wine to be beneficial to the retina for its antioxidant properties. It is not, however, the alcohol content that provides this benefit, so, as substantiated by these new findings, one glass per day should be the limit.
Source; aje.oxfordjournals.org/content/176/4/289.abstract
DAILY LIVING
Researchers identified why, in addition to central field loss, adults with AMD have trouble recognizing and identifying people’s faces. They believe that it could largely be due to abnormal eye movement patterns and fixations associated with the condition.
The study found that AMD patients made more frequent eye movements compared to those with healthy vision. They believe it could have a lot to do with the way the brain coordinates eye movement. And that gives hope that eye movement control training and training of allocation of attention could improve face perception and eye scanning behavior in individuals with AMD.
Source: Optometry and Vision Science (January 2012)
PREVALENCE OF AMD
A new Northwestern Medicine study shows that senior citizens are reporting fewer visual impairment problems than their counterparts from a generation ago. The researchers said that “improved techniques for cataract surgery and a reduction in the prevalence of macular degeneration may be the driving forces behind this change”.
From 1984 until 2010, the decrease in visual impairment in those 65 and older was highly statistically significant, while there was little change in visual impairments in adults under the age of 65. The study showed that in 1984, 23 percent of elderly adults had difficulty reading or seeing newspaper print because of poor eyesight. By 2010, there was an age-adjusted 58 percent decrease in this kind of visual impairment, with only 9.7 percent of elderly reporting the problem.
The researchers also reported a substantial decline in eyesight problems that limited elderly Americans from taking part in daily activities, such as bathing, dressing or getting around inside or outside of the home. They credited three likely reasons for the decline:

  • Improved techniques and outcomes for cataract surgery
  • Less smoking, resulting in a drop in the prevalence of macular degeneration
  • Treatments for diabetic eye diseases are more readily available and improved, despite the fact that the prevalence of diabetes has increased

Future studies should identify which treatment strategies help prevent vision in older adults and then make those treatments available to as many people as possible.
Source: http://medicalxpress.com/news/2012-06-debilitating-eyesight-problems-decline-older.html#jCp
CONCLUSION
This concludes my summary for this year. I hope it will leave you with confidence in our future and the future of those who are following us. Please pass this information along to them. And if you don’t remember the details of the overwhelming amount of research being done (and who could?), just tell them things are getting better at an ever-quickening pace, thanks to the unceasing dedication of researchers and developers around the world..
Our hope lies with them and in the doctors who make the therapies and treatments available to us. We thank them for that, and I thank you for listening.

Summary of Research and Developments in Macular Degeneration: 2008-2009

by Dan Roberts
June 11, 2009
Laser Rejuvenates the Retina

According to a study announced at the Euretina Congress in May 2008, a laser treatment that “cleans up” Bruch’s membrane may slow down the progression to AMD.
Bruch’s membrane is the tissue that separates the photoreceptor cells (our sight cells) from the nourishing blood vessel layer of the retina. It is through Bruch’s
membrane that the nourishment passes. As we age, however, the membrane can become clogged with debris, inhibiting the process and leading to cell malnutrition. Research at St. Thomas’s Hospital in London has resulted in development of a
therapeutic approach to the problem. The Retinal Rejuvenation Therapy (2RT, Ellex) uses a special green nanosecond pulse laser for “reconditioning” Bruch’s membrane and photo-regeneration. Improvement in visual function has been noted in
humans during preliminary studies. Now, under the guidance of
John Marshall, Ph.D., researchers are setting up a trial to treat the yet-unaffected second eyes of patients who have already lost vision in one eye due to neovascular problems.
The ultimate goal, said Dr. Marshall, is to treat patients in their 40s to keep their eyes young and prevent age-related degenerations of the retina. The treatment is noninvasive and seems to have no adverse effects on the photoreceptors or other parts of the eye.
Good Visual Outcome Following Cataract Surgery

A new study (Nature, Aug 2008) has found good visual outcome following cataract surgery in patients aged 90 and older. The study compared visual outcome of patients with macular degeneration, glaucoma and various other ocular conditions.
Overall visual acuity improvement was 68%, whereas unchanged and worsening rates were 16% each. Results showed that AMD patients showed less improvement than patients with glaucoma or with no visual problems.
The researchers concluded that approximately 70% of very elderly patients can achieve visual acuity improvement following cataract surgery, which rises to 82% in those without accompanying problems. Although patients with AMD show less improvement, 62.5% can still enjoy improvement in visual acuity.
Cataract Surgery Appears Safe

More recent studies, however, are disputing that finding, starting with a report in 2005 that patients who had cataract surgery did not have a higher risk of progressing to more advanced forms of macular degeneration when compared to those who did not have cataract surgery.
This was supported by research published in the February 2009 issue of the Journal of Ophthalmology. Led by Emily Chew, MD (also involved in the 2005 study), the team reported that, after reviewing 11 years of patient follow-up data from the large Age-Related Eye Disease Study (AREDS), “The frequency of neovascular age-related macular degeneration, geographic atrophy, and central geographic atrophy did not differ between patients who had cataract surgery and those who did not. . . [This] may provide some reassurance to patients with age-related macular degeneration who are considering cataract surgery.”
A large comprehensive cohort study reported by J.J. Wang to the 2009 ARVO meeting also confirmed previous studies in finding no significant increased incidence of AMD in eyes having undergone cataract surgery. Dr. Wang stressed, however, that here may be an increase in combination with other AMD risk factors.
New Drug May Reduce Number of Injections for Wet AMD
Regeneron Pharmaceuticals, Inc. and Bayer HealthCare AG Have announced that patients with wet AMD receiving VEGF Trap-Eye in a Phase 2 extension study on an “as needed” dosing schedule continued to show highly significant improvements in retinal thickness and vision gain at 52 weeks. During weeks 12 to 52, patients from all dose groups combined received, on average, only two additional injections. This supports Regeneron’s expectation that, with VEGF-Trap-Eye treatment, patients’ visual acuity will improve over time without the need for monthly intravitreal injections.
Zinthionein in Trials for Treatment of Dry AMD

Zinc has been shown to be an effective antioxidant, which is beneficial to the retina. In July 2008, researchers at Pipex Pharmaceuticals announced success with a complex that evidently results in a more potent antioxidant than zinc alone. This “zincmonocysteine” molecule was developed by combining L-cysteine and zinc in a ratio of 1:1.
Under the commercial name Zinthionein, it was then administered as a 25 mg oral capsule twice a day to 80 test subjects for a period of six months. According to the
phase 2 study results (David Newsome, primary investigator), these patients demonstrated a highly statistically significant improvement in visual acuity, contrast sensitivity and photorecovery time. Continued success in the trials could lead to a new and effective therapy for dry AMD.
More info: www.adeonapharma.com
New Dry AMD Gene Found

As reported in the Aug. 28 online edition of the New England Journal of Medicine, researchers have found a genetic link associated with dry AMD. That’s the good news. The bad news is that siRNA drug therapy may increase the risk for dry AMD in patients who have that genetic variant.
The research team found that the protein TLR3 helps fend off certain viral infections. However, it also increases the risk for dry AMD in subjects taking an experimental anti-VEGF drug called “small interference ribonucleic acid” (siRNA),
which activates TLR3. In fending off viral infections, TLR3 also attacks infected retinal cells, resulting in “a 60 percent spike in retinal cell death among mice and humans
genetically susceptible to developing dry AMD.”
Patients currently involved in the siRNA study (labeled Cand5) sponsored by Acuity Pharmaceuticals should contact their doctors for more information.
“Low Luminance Deficit” May Predict More Severe Vision Loss

It appears that, of people with advanced dry AMD (geographic atrophy) who have a corrected visual acuity of 20/50 or better, those who test more poorly in dim light may progress sooner to more severe vision loss.
A research team under the direction of MD Support advisor Janet Sunness, M.D. (Hoover Services for Low Vision and Blindness, Greater Baltimore Medical Center), found that visual dysfunction under low light can predict subsequent visual acuity loss in late-stage AMD patients.
Of subjects with a visual acuity of 20/50 or more, those who had the worst “low luminance deficit” at the beginning of the study showed a significantly greater loss of visual acuity at two years. 40% of this group showed a loss of three or more lines on the acuity test chart. Identification of this risk factor may provide an important means of predicting the rate of vision loss in patients with advanced dry AMD.
Brain Reorganizes to Adjust for Loss of Vision

A new study from Georgia Tech shows that when patients with macular degeneration focus on using another part of their retina to compensate for their loss of central vision, their brain seems to compensate by reorganizing its neural
connections. The study appears in the December edition of the journal Restorative Neurology and Neuroscience.
Eric Schumacher, assistant professor in Georgia Tech’s School of Psychology, said, “Our results show that the patient’s behavior may be critical to get the brain to reorganize in response to disease. It’s not enough to lose input to a brain region for that region to reorganize; the change in the patient’s behavior also matters.”
In this case, that change of behavior comes when patients with AMD make up for this loss by focusing with other parts of their visual field.
Schumacher and his research team found that when patients visually stimulated the preferred retinal locations, they increased brain activity in the same parts of the visual cortex that are normally activated when healthy patients focused on objects in their central visual field. They concluded that the brain had reorganized itself.
While there is evidence with other tasks that suggests that the brain can reorganize itself, this is the first study to directly show that this reorganization in patients with retinal disease is related to patient behavior. The research group is currently studying how long this reorganization takes
and whether it can be fostered through low-vision training in eccentric viewing.
The Latest on AREDS

Emily Chew, M.D., reported to the ARVO meeting that genotypes determine the extent of protection offered by the AREDS formula. In the ARED study, people with genotype TT showed the greatest protective effect, while those with genotype CC
showed the greatest risk of progression to advanced geographic atrophy.
Dr. Chew said that patients can probably discontinue the AREDS supplements once the advanced wet stage is reached. Patients with non-central geographic atrophy (dry MD) and no choroidal neovascularization (vessel growth and leakage) should continue.
Finally, Dr. Chew on the new AREDS2 study. This is a followup to the original “Age-Related Eye Disease Study” completed in 1998. That study resulted in most doctors recommending the AREDS formula to patients in the intermediate stage of
AMD, in order to slow progression to the advanced stage. The formula contains vitamin C, 500 mg; vitamin E, 400 IU; beta carotene, 15 mg; and zinc, 80 mg. The new formula now being tested is slightly altered, with less zinc, no beta-carotene, and the addition of lutein, zeaxanthin and omega-3 fatty acids DHA and EPA. The purpose is to see if the new formula will be even more effective. The AREDS2 cohort has been fully recruited, and first results are expected in 5 years.
PDT Still a Viable Treatment in Some Cases

Several years ago, photodynamic therapy (PDT) was the most effective treatment for wet AMD, but it has been mostly replaced by the new antiangiogenic drugs. This treatment involved injection of the light-activated drug Verteporfin (Visudyne) into a vein, followed by targeting the leaking blood vessel with a low power laser. This destroyed the vessel and stopped the leakage, but it also caused some residual
damage to surrounding cells after repeated procedures. Still, PDT is used in some cases where the vessel’s location is not close to the center of the macula and quick action is necessary.
Now, a new less damaging and more effective approach called “Targeted” Photodynamic Therapy (TPT) is being studied. According to Dr. R.A. Adelman in a report to the ARVO meeting, a protein called Factor VII is conjugated with Verteporfin.
Intravitreal injection of the compound in a rat model with choroidal neovascularization showed efficacy at 1/10th the usual dose of Verteporfin and 3x better visual function
after lasering. This proved to be more effective and safer for surrounding cells than standard PDT at a significantly lower dose.
The Latest on Lucentis

Lucentis, developed by Genentech Pharmaceuticals, is one of two FDA approved drugs used in treatment of wet AMD. The other is Macugen, which has been shown to be less effective. Avastin is also being used off-label with reported success, but it has
yet to be shown to be safe and efficacious in large studies.
Three followup studies of Lucentis, called HORIZON, EXCITE and SUSTAIN, were reported on at the ARVO meeting by Drs. M. Singer, C. Simader and F.G. Holz.
The HORIZON study, which ended in Sep 2008, followed Genentech’s Marina, Anchor and Focus trials, all of which were followup studies of Lucentis. The results showed that the rate of ocular and nonocular adverse events was low, repeated
injections were well tolerated after 4 years, and delay in initial treatment resulted in a higher loss of vision.
The EXCITE study compared quarterly treatment with monthly treatment using Lucentis. Best corrected visual acuity and retinal morphology were found to be better with a monthly regimen of injections.
The SUSTAIN study analyzed safety of monthly dosages of 0.3 and 0.5 mg. Lucentis was found to be safe and effective, no matter what the amount of dosage or the interval of time between treatments.
Since monthly treatment on an as-needed basis at 0.5 mg has been found to be most effective, more refined testing (eg. higher resolution OCT) will be needed in order to better judge if and when patients need to be retreated.
Bilateral Injections Appear Safe

Dr. KariAnne Galler reported to the ARVO meeting that there is no particular increase in risk for patients with bilateral macular degeneration treated with bilateral injections
of anti-VEGF drugs. Also, there is a strong patient preference for the ease and convenience of having bilateral rather than unilateral injections.
Obama Lifts Limits on Stem Cell Research

President Obama has lifted the Bush administration’s limits on human embryonic stem cell research. Mr. Obama announced the decision on March 9, saying he hoped Congress would follow with bipartisan legislation that would ease the existing restrictions even more.
The president acknowledged that studying stem cells extracted from human embryos is deeply divisive, but he said the majority of Americans “have come to a consensus that we should pursue this research; that the potential it offers is great,
and with proper guidelines and strict oversight the perils can be avoided.”
First Human Embryonic Stem Cell Study Approved By FDA

Geron, a biotech company, has announced that the federal government will allow the world’s first test in people of a therapy derived from human embryonic stem cells. Until now, federal financing for research on embryonic stem cells has been restricted, because creation of the cells entails the destruction of human embryos.
The intended reversal of this policy by the newly-elected administration may or may not have influenced this recent decision.
Geron will enroll paralyzed patients who can be treated within 2 weeks of their injury. The subjects will then be evaluated for at least one year, after which the company hopes to increase the dose and expand the number of participants.
This release of government funding is expected to set a precedent for more stem cell research in the low vision field. For more information about the research to this point, see “The First Seven Years: An Overview of Stem Cell Transplantation Research for Treatment of Retinal Disease” on this site.
Stem Cell Therapy Presents Challenges

A special interest group discussed the challenges of bringing stem cell therapy to the patients. The topics were addressed by P.J. Coffey (Institute of Ophthalmology, University College, London), H. Klassen (Univ. of California, Irvine), and M. Friedlander (Scripps Research Institute).
The topics of discussion were:

  • Ways of getting the cells to the site of action, either by surgical insertion or injection into the vitreous fluid.
  • The safety of the procedure
  • The length of time it will take for the procedure to have an effect
  • The question of whether the body will reject the implants
  • Sources of stem cells

To summarize:
Dr. Coffey stated that the goal of The London Project at Moorfields Hospital is to reconstruct the macula by repopulating the retinal pigment epithelium (RPE) to nourish the photoreceptors. This has been accomplished successfully by macular translocation and RPE transplantation. The problem, however, is that these procedures take several hours and at least two separate visits to the clinic. The solution, said Dr. Coffey, is to implant (by injection) a permanent artificial membrane of human embryonic cells. This has been shown to stop pig photoreceptors from dying, and there has been no immunological response (i.e. rejection) so far.
Dr. Klassen discussed culture and transplantation of retinal progenitor cells (RPC), which he says is a key developmental stage in the pathway to replicating rod photoreceptors, even for Müller and ciliary cells. RPCs have been obtained from
animals and encouraged (by adding a growth factor) to differentiate into photoreceptors. They have been well-tolerated in the treated retinas. He added that human RPCs have been successfully used in China to repair the optic nerve.
Dr. Friedlander discussed adult stem cell based therapies. Sources for such cells are the cornea, bone marrow, peripheral blood, spinal cord blood, skin, hair and dormant stem cells. He introduced a new strategy involving rebuilding retinal vessels instead of inhibiting neovascularization. He described how this “vasculotrophic rescue” can be done with bone marrow derived stem cells.
FDA Panel Recommends Approval of IMT

On March 27, 2009, the FDA’s ophthalmic device panel recommended approval of Vision Care Ophthalmic Technology’s implantable miniature telescope (IMT) for patients with advanced stage AMD. After 5 years of trials and a prior unsuccessful submission to the panel, the IMT has now met all requirements for safety and efficacy.
The FDA usually follows the recommendations of an advisory panel, but is not required to do so. The panel recommended approval of the device with conditions including post-approval surveillance and labeling suggestions. The panel decision
was reached by a vote of 8 to 0.
Allen W. Hill, CEO of VisionCare, said “We are pleased with the panel’s recommendation for approval and will work closely with FDA to address the approval conditions. We look forward to providing the ophthalmic community a new treatment option to improve vision and quality of life for patients with untreatable, end-stage agerelated macular degeneration.”
I spoke to the panel shortly before the vote. I told them that, until now, nothing has offered long-term vision restoration for people in the advanced stage of the disease.
That stage has traditionally been one of transition to nonvisual skills such as cane use and Braille. With the IMT, it may be possible for some of us to put that off indefinitely, and that gives us one more cannon to fire.
For more information on the research, visit VisionCare’s website at www.visioncareinc.net or call (408) 872-0526.
Seeing With Your Tongue

One of the most interesting developments reported at Vision 2008 in Montreal was new device called BrainPort, which (according to the abstract) enables perception of visual information using the tongue and camera imaging system as a paired substitute for the eye.
Visual information is collected from a head mounted image sensor and translated into electrical patterns displayed on the surface of the tongue. The system has tested favorably on subjects with no vision, and it is now being adapted to assist individuals with macular degeneration and related diseases.
The long term goal is to develop a fully portable, unobtrusive
device that will track with the userís gaze point, capture information centered in the area of vision loss, and display the information on the tongue. This device will “fill in”
the area of vision loss, will be compatible with other vision-assisting devices, will not be surgically invasive, and will be easily customizable and upgradeable. Developers are hoping to have the BrainPort commercially available within 2
years. Here is where you can read more about it:
vision.wicab.com/technology
DIET & NUTRITION
Statins May Hasten Onset of Wet AMD

What effect do cholesterol-lowering drugs have on the retina? A pilot study in 2006 found “that treatment with simvastatin increased blood-flow velocity in the retinal arteries and veins and decreased intraocular pressure. (Nagaoka T et al. Arch Ophthalmol 2006; 124:665-670.)
This study supports the thinking that increased blood flow is generally beneficial to the retina. Recent research, however, has shown that taking statins to lower cholesterol levels might hasten the onset of wet AMD in people who are already
affected by the dry form. The abstract for this study may be read on the Web at www.tinyurl.com/5ksj6a.
Considering the proven beneficial effects of drugs like simvastatin for people with circulatory problems and high cholesterol, it would be wise to keep this information in mind, but it would not be wise to stop taking them altogether without professional consultation. Until researchers have sorted out the facts, a patient’s decision should be based upon individual circumstances and discussed with professional care providers.
Vitamin C May Lower Statin Levels

A UC Berkeley study, led by Gladys Block, PhD, suggests that 1,000 mg of daily supplemental vitamin C can lower concentrations of C-reactive protein (CRP), the marker associated with systemic inflammation. (Free Radical Biology and Medicine, Jan. 1, 2009). It suggests that a daily dose of supplemental vitamin C can lower CRP levels in healthy, non-smoking adults in two months.
Gladys Block and her staff found that for people with elevated CRP levels, the amount of CRP reduction achieved by taking vitamin C in this particular study is comparable to that in many statin studies.
A multinational clinical trial led by researchers at Harvard Medical School (the Jupiter Trial), found that among people who had high levels of CRP at baseline, levels of CRP were 37 percent lower in the subjects who took statins compared to those who took the placebo.
In the UC Berkeley study on vitamin C, participants who started out with CRP levels greater than 2 milligrams per liter had 34 percent lower levels of CRP with vitamin C compared with a placebo after two months.
“This is clearly a line of research worth pursuing,” said Dr. Block. “It has recently been suggested by some researchers that people with elevated CRP should be put on statins as a preventive measure. For people who have elevated CRP but not elevated LDL cholesterol, our data suggest that vitamin C should be investigated as an alternative to statins, or as something to be used to delay the time when statin use
becomes necessary.”
The benefits to the consumer are that Vitamin C is considerably less costly, and it does not carry the risk of serious side-effects associated with statins.
Source: Ellen Troyer, MT, MA (Chief Research Officer, Biosyntrx .com
Excess Weight Contributes to Mortality

by Ellen Troyer, MT MA
Biosyntrx Chief Research Officer
Excess weight is an epidemic in the United States. There is strong scientific agreement that excess weight (BMI over 25) contributes to overall mortality. It also significantly increases the risk of serious degenerative diseases, including cataracts, macular degeneration, glaucoma, and diabetic retinopathy.
The National Center for Health Statistics estimates that 65% of the U.S. population is overweight, with 34% of the population being clinically obese. Scientists have also identified the significantly increased risks associated with excess weight for 20 other diseases or conditions. According to the U.S. Surgeon General report, excess weight and obesity are responsible for 300,000 deaths every year in the U.S.
Vitamins B-6, B-12 and Folic Acid May Protect Against AMD

Ellen Troyer, MT MA
Biosyntrx Chief Research Officer
A recent study suggests that a combination of vitamin B-6, vitamin B-12 and folic acid may protect women against age-related macular degeneration. Epidemiologists at Harvard Medical School and Women’s Hospital in Boston analyzed data collected as part of a large trial originally designed to test the effects of other vitamins on women with heart problems. All subjects were permitted to take multivitamins with B-6, B-12 and folate up to, but not exceeding, recommended
daily allowances (RDAs). Those getting the B-6, B-12 and folate supplements received much larger amounts.
After 7.3 years, researchers found 82 cases of age-related macular degeneration among women taking placebos and only 55 cases in the women receiving the high-potency B vitamin supplements. While an explanation for the apparent protection from macular degeneration remains unknown, it is known that folate, B-6 and B-12 can drive down blood concentrations of homocysteine, a methionine metabolism by-product compound
suspected of damaging blood vessels.
On the surface this study seems to be very positive, but it raises some concerns about the folic acid dosage. Excessive supplemental folic acid can mask or obscure fairly common vitamin B-12 deficiencies in older people. This can result in an increased risk of progressive, unrecognized neurological damage. Dosage of supplemental folic acid over 1 mg per day has also been associated with impaired gastrointestinal absorption of zinc in some cases.
It’s good to remember that more is not always better.
Too Much Red Meat?

Research* has revealed that a diet high in red meat may increase one’s risk of developing AMD, while consumption of chicken may lower the risk.
Researchers followed 6,734 persons aged 58-69 years, from 1990 through 2006. Final data showed that higher red meat intake was positively associated with early AMD. The odds ratio for consumption of red meat 10 or more times a week versus less than 5 times a week was 1.47. Conversely, consumption of chicken 3.5 or more times a week versus less than 1.5 times a week was inversely associated with late AMD. The team concluded that different meats may differently affect AMD risk and may be a target for lifestyle modification.
Inflammation is being identified as the main culprit in the development of AMD, and cholesterol is inflammation’s “partner in crime.” Fatty red meat is a major source of cholesterol, while lean red meat actually produces less than the body does by itself.
High quantities of red meat, therefore, may be an important risk factor, but it appears that we can sidestep the problem by consuming less, and only the leanest cuts.
*Red Meat and Chicken Consumption and Its Association With Age-related Macular Degeneration, Elaine W.-T. Chong, et al (American Journal of Epidemiology, November 25, 2008).
Occurrence of AMD Declining

A new study reports a lower 5-year incidence of early AMD in patients born or examined more recently, compared to similarly aged persons born or examined in an earlier period.
The study included 2,968 participants with early AMD and 3,588 participants with late stage AMD, all of whom were examined at 5-year intervals between 1988 and 2005 as part of the Beaver Dam Eye Study.
The investigators cannot yet explain the results. Improvements in health care and lifestyle over the previous 15 years do not explain the decline, but other factors might. These include other exposures earlier in life (e.g., infectious disease
outbreaks such as the flu pandemic of 1918), dietary restrictions specific to a period (e.g., the Great Depression), or other unmeasured factors.
Personally, I would like to think that greater health conciousness and awareness of the risk factors for AMD have made a positive contribution. We can play a part in maintaining that decline by continuing to educate ourselves and others about how we may fend off this disease, at least until these promising cures we hear about reach our hospitals and clinics.
Thank you for reading this summary. The fact that it has been lengthy is testament to the encouraging work being done in the field, and let’s continue to remain positive about the positive outcomes, whether for our benefit or for the benefit
of those who follow us.