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.

Antiangiogenic Drugs Are Stopping Neovascularization in Wet Macular Degeneration

(Updated 3/12/22)

A substance in the body called Vascular Endothelial Growth Factor (VEGF) is responsible for the growth of new blood vessels. It promotes this growth by stimulating the endothelial cells, which form the walls of the vessels and transport nutrients and oxygen to the tissues. Evidence shows that when the retinal pigment epithelial (RPE) cells begin to wither from lack of nutrition (a condition called “ischemia”), the VEGF goes into action to create new vessels. This process is called “neovascularization,” and it acts as a restorative function in other parts of the body. In the retina, however, the vessels do not form properly, and leaking results. This leakage causes scarring in the macula and eventual loss of central vision.

Antiangiogenic drugs prevent the VEGF from binding with the receptors on the surface of the endothelial cells. In most cases, the drugs are injected into the vitreous of the eyeball, then pass into the subretinal space, where the vessels proliferate. Neovascularization is then blocked, preventing bleeding into the retina.

New research is looking for less invasive and burdensome introduction of the drugs by way of topical eye drops, implanted timed release capsules, and implanted ports of delivery. The most recent breakthrough is FDA approval of Susvimo. This procedure continuously delivers a form of ranibizumab (Lucentis), offering an alternative to anti-VEGF eye injections. The tiny implant is surgically inserted into the eye during a one-time outpatient procedure and refilled every six months. More about Susvimo.
____________________
Here is information on current anti-angiogenic drugs being studied or already being used in the clinics:

In clinic use:
Macugen (pegaptanib sodium) [approved 2004]
Lucentis (ranibizumab) [approved 2006]
EYLEA (aflibercept) [approved 2011]
Avastin (bevacizumab) [available off-label since 2007]
Brolucizumab (RTH-258) [approved 2019]
Byooviz (ranibizumab-nuna) [approved 2021]
Faricimab (Vabysmo) [approved 2022]

Under study:
Abicipar
AKST4290 (oral)
AR-13503
EYP-1901
GB-102
IBI302
ICON-1
KSI-301
OPT-302
PAN-90806
RBM-007
RGX-314
X-82 (oral)


Macugen (pegaptanib sodium)
Macugen, made by OSI EyeTech Pharmaceuticals, was the first antiangiogenic drug to gain FDA approval. Pegaptanib is a chemically synthesized strand of genetic material that bonds with VEGF cells to block replication. A large trial of Macugen on 1,196 patients at 117 centers around the world was completed in 2003. In November of that year, data presented to the American Academy of Ophthalmology (AAO) showed that Macugen stabilized or improved vision in 33% of the patients in the trials, while the same results occurred in 23% of a control group not given Macugen. As many as 71% of the patients given Macugen lost less than three lines of vision during the year, compared with 55% in the control group. The drug is injected directly into the eye every six weeks, or about nine times a year.
Working in conjunction with Pfizer Ophthalmics, Macugen gained FDA approval on December 17, 2004, and was ready for public use beginning in 2005.

Lucentis
Genentech, Inc. announced on May 23, 2005 that a Phase III clinical study of the investigational drug Lucentis (ranibizumab) met its primary efficacy endpoint of maintaining vision in patients with wet AMD. Approximately 95 percent of patients maintained or improved vision (defined as a loss of less than 15 letters in visual acuity) at one year when treated with Lucentis injections compared to approximately 62 percent of those treated in the control arm. Vision improvement was an unexpected result that had not been seen at a significant level in other antiangiogenic drug trials. Lucentis is approved for use in the European Union, Switzerland, India, Canada and the United States. A regulatory decision in Australia is expected before the end of 2007.
On January 14, 2006, one-year data from the second pivotal Phase III study of Lucentis were presented at the Macula 2006 meeting in New York. Data showed that, for the second time in a large, Phase III study, Lucentis improved vision in patients with wet AMD.
On November 13, 2006, several new findings were presented at the 2006 AAO meeting:
Elias Reichel, M.D. reported that in the MARINA trials, there was improvement at all visual acuity levels, but there was not a big difference if the patient’s baseline vision was either low or excellent. This “floor-to-ceiling” effect is not unusual with this kind of study, but it is useful information for patient communicating with patients about expectations.
Nancy Holekamp, M.D., discussed key anatomic endpoints in the MARINA trials, in particular, the total lesion area over time (no growth of the lesion area was noted in the treated patients), the mean area of leakage (the amount of decrease was statistically significant) and the mean foveal retinal thickness (treated eyes showed a significant thinning of the retina). The bottom line is that all anatomic outcomes from the trial favored Lucentis, and the treatment is so effective over a long period of time without any signs of toxicity, there is no indication that anything in lieu of Lucentis should be used to treat wet AMD.
Peter Kaiser, M.D., reported on subgroup analysis of Genentech’s PIER study. The primary endpoint was met, showing a difference of 16 letters visual acuity between the treated group and the sham group. Further, the dosing regimen was effective, but the visual acuity benefit was not as robust when injections went from monthly to quarterly. The persistence of monthly injections may depend upon who has dry lesions and who has wet lesions at the 5th month. The dry lesion group did better than the wet lesion group with quarterly dosing. This data is pointing toward better prediction of dosage outcomes for individual patients.
On February 15, 2007, Dr. Kaiser reported two-year results of the Phase 3 ANCHOR trial comparing Lucentis with photodynamic therapy (PDT) for wet AMD. The study showed that Lucentis helps maintain vision, with few adverse effects, significantly better than PDT. 89.9% of patient randomised to Lucentis in a head-to-head comparison with Visudyne for photodynamic therapy (PDT) lost fewer than 15 letters on a visual acuity chart at 24 months compared to 65.7% of those treated with PDT. 78% of the Lucentis-treated group maintained their baseline visual acuity or gained letters, compared to only 29% of the PDT group. Overall, patients randomised to Lucentis had a 20.5 letter benefit at 24 months (+10.7 EDTRS letters) compared to those treated with PDT (-9.8 letters). This was similar to visual acuity seen at 12 months (+11.3 letters with Lucentis vs -9.6 letters with PDT).
On February 23, 2008, the final results from Cohort 1 of the Phase IIIb SAILOR study of Lucentis in patients with wet AMD were presented on February 23, 2008 at the Bascom Palmer Eye Institute’s Angiogenesis meeting by Dr. David Boyer (Retina-Vitreous Associates Medical Group, Los Angeles). The final, one-year data support the long-term safety and efficacy profile of Lucentis.
The study, titled “Ranibizumab (Lucentis) Safety in Previously Treated and Newly Diagnosed Patients with Neovascular Age-related Macular Degeneration (AMD): The SAILOR Study,” was designed to evaluate the safety of two different doses of Lucentis (0.5 mg, the FDA-approved dose, and 0.3 mg) administered once a month for three months and thereafter as needed based on re-treatment criteria.
For more detail in all of these areas of study, see www.lucentis.com.

EYLEA (aflibercept injection, formerly VEGF Trap-Eye)
In August 2008, Regeneron Pharmaceuticals, Inc. and Bayer HealthCare AG announced that patients with wet AMD receiving EYLEA (aflibercept injection) 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. There were no drug-related serious adverse events, and treatment was generally well-tolerated.
For all dose cohorts combined, there was a 5.3 mean letter gain in visual acuity at the end of 52 weeks. The mean decrease in retinal thickness was 130 microns versus baseline. During weeks 12 to 52, patients from all dose groups combined received, on average, only two additional injections. This supported Regeneron’s expectation that, with EYLEA treatment, patients’ visual acuity would improve over time without the need for monthly intravitreal injections.
A phase 3 study, VIEW 1, began enrolling patients in late 2007. The VIEW 1 study compared EYLEA and Lucentis. A phase 2 study in diabetic macular edema (DME) was also completed. EYLEA injected into the eye every two months was found to be as effective as monthly doses of Lucentis, and monthly monitoring of patients receiving EYLEA was not necessary.
On June 17, 2011, the Food and Drug Administration advisory panel voted unanimously to recommend EYLEA as a treatment for wet AMD. The advisers also said the injected drug could be given once every two months. This was an improvement upon the typical 4-6 week dosings of both Lucentis and Avastin.
Finally, on November 18, 2011, Regeneron announced that the FDA had approved EYLEA for treatment of patients with wet AMD. Recommended dose is 2 mg every four weeks for the first 12 weeks, followed by 2 mg every eight weeks. EYLEA offers less frequent injections than either Lucentis (4 weeks) or Avastin (6 weeks), and there are no monitoring requirements.
Since September 2012, Eylea has also gained approval in the U.S., Europe, and Japan for use in treating wet AMD, diabetic macular edema, and neovascular myopic degeneration. For more information, see www.regeneron.com.

Avastin (bevacizumab)
Avastin (bevacizumab), has been shown in preliminary off-label studies to stop blood vessel growth and leakage in the retinas of patients with macular degeneration. Testing began in March 2005 at the Bascom Palmer Eye Institute in Miami under the leadership of Dr. Philip Rosenfeld. In July 2005, Dr. Peter Campochiaro followed with subjects at the Johns Hopkins Medical Center in Baltimore. Potential side effects, according to Rosenfeld, are increased risk of stroke or heart attack in patients taking chemotherapy, and elevation of blood pressure. Systemic infusions of Avastin, he said would be needed every few months.
On February 15, 2007, Elias Reichel, M.D. reported to Hawaiian Eye/Retina 2007 that Avastin has shown good results in a small retrospective case series for treatment of neovascularization from myopic degeneration. 15 eyes studied showed a mean improvement in acuity of 3 lines, central foveal thickness decreased an average of 93 micrometers and no complications.
In May 2011, first year results of the Comparison of AMD Treatments Trial (CATT) were announced. The report focused on the relative safety and efficacy of Lucentis and Avastin. After one year, the two compounds have been found to be extremely similar in their improvement of mean visual acuity and the occurrence of adverse events. Five related trials were also undertaken in the UK and Europe.
At the end of the 2-year comparison study, The National Institutes of Health reported that both drugs improved 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. For more information, see www.nih.gov/news/health/apr2012/nei-30a.htm

Faricimab (Vabysmo)
A global Phase III program for faricimab in wet AMD began in 2019. The efficacy of faricimab administered at 12- and 16-week intervals was evaluated against ranibizumab every 4 weeks. At week 24, researchers reported in May 2020 that 65% of faricimab-treated patients were disease activity-free. By January 2021, further research had shown that people receiving faricimab injections at fixed intervals of up to every 16 weeks achieved visual acuity outcomes as effective as those receiving Regeneron’s aflibercept (Eylea) injections every eight weeks. More information.

PAN-90806
PAN-90806 is a topical eye drop for the treatment of neovascular AMD, diabetic retinopathy, and potentially diabetic macular edema (DME). It is being developed by Panoptica and began a phase 1 clinical trials in early 2014, a 2-month open-label study of approximately 30 patients at 15 to 20 sites in the U.S. The study was completed in May 2016. More information.

OPT-302
OPT-302 is soluble receptor developed by Opthea Pty Ltd. It is a derivative of VGX-300 which has been optimised for local ocular administration. OPT-302 potently and specifically blocks VEGF-C and VEGF-D from binding and activating VEGFR-2 and VEGFR-3.
On August 6, 2019, Opthea announced positive Phase 2b results demonstrating that OPT-302 combination therapy showed improvements across multiple secondary endpoints at 24 weeks. Compared to Lucentis monotherapy, OPT-302 (2.0 mg) combination treatment showed improvements that included a higher proportion of patients with stable vision (defined as ≤ 15 letter loss from baseline), and those gaining ≥10 and ≥15 letters of visual acuity. On March 15, 2021, Opthea announced that, based upon the positive Phase 2 results, the first patient has now been enrolled in the Phase 3 trial. More information

ICON-1
The EMERGE study examined the hypothesis that a protein called Tissue Factor (TF), when out of control, initiates inflammation and angiogenesis, resulting in wet AMD. ICON-1 is thought to block the protein and reverse the progression of the disease, both alone and in combination with Lucentis.
Phase 2a results showed that ICON-1 was well tolerated and that in combination with anti-VEGF therapy treated both the symptoms and the underlying process driving inflammation and CNV. The combination effectively reduced CNV lesion size, increased the durability of effect and improved removal of pathologic fluid from the retina. Based on these positive results, the company initiated a Phase 2b study of ICON-1 in combination with anti-VEGF treatment in 2018. More information

RGX-314
Regenxbio’s RGX-314 differs from current therapeutics in that it includes a gene vector (NAV AAV8) which encodes an antibody fragment designed to neutralize VEGF (vascular endothelial growth factor) activity. This modifies the pathway for formation of new leaky blood vessels which lead to retinal fluid accumulation and vision loss.
In August 2019, Regenxbio reported positive phase 1/2a results in patients with wet age-related macular degeneration, and that the drug is continuing to be well tolerated across five dose cohorts.
Investigation of RGX-314 with a phase IIb trial (AAVIATE) is proceeding, with dosing of the first patient using suprachoroidal delivery. As of December 31, 2020, suprachoroidal delivery of RGX-314 was reported to be generally well-tolerated, with no evidence of inflammation.

More information

Brolucizumab (RTH258)
Novartis announced on October 8, 2019 that the US Food and Drug Administration (FDA) approved BEOVU® (brolucizumab-dbll) injection for the treatment of wet age-related macular degeneration (wet AMD).  BEOVU® carries a recommended dosing schedule of monthly for the first three doses followed by one dose every 8-12 weeks. More information.

Abicipar
Allergan trials have demonstrated that the biological drug Abicipar is equal to Genentech’s Lucentis (ranibizumab), with the added benefit that Abicipar treatments are effective at up to 12-week dosages. This is longer than Lucentis (4 weeks), Avastin (6 weeks), and Eylea (8 weeks), the three currently available drugs for treatment of wAMD. Trials are ongoing. More information

KSI-301
Kodiak trials showed good results for treatment of diabetic macular edema. Twelve weeks after a single dose of KSI-301 saw improvement of almost two lines (9 eye chart letters) and retinal edema of 121 microns. Unfortunately, Phase 3 results showed that, although KSI-301 demonstrated strong durability and was safe and well tolerated, it did not meet the primary efficacy endpoint of showing non-inferior visual acuity gains for subjects dosed on extended regimens compared to aflibercept given every eight weeks. More information.

GB-102
Graybug Vision’s novel investigational depot approach is designed to continuously inhibit activity of all VEGF receptors for the treatment of wet AMD. In Phase 1 trials, GB-102 was well-tolerated with no dose limiting toxicities, drug-related serious adverse events or inflammation. 88% and 68% percent of evaluable patients were maintained only on a single dose of GB-102 at 3- and 6-months, respectively. Patients with wet-AMD require intravitreal injections every 6 to 8 weeks, on average, with the current standard-of-care.

Graybug Vision’s Phase 2b ALTISSIMO study of GB-102, was completed in January 2021. Topline data are expected to be announced in the second quarter of this year, and full results presented in the later part of 2021 at a medical conference.

Graybug announced in April 2022 that it plans to proceed with a Phase 2 clinical trial of an optimized formulation of GB-102 in wet AMD patients following successful demonstration of improved performance in an extensive battery of novel in vitro stress tests. This decision, supported by a significantly more favorable competitive landscape following recent readouts of other long-acting vascular endothelial growth factor (VEGF) inhibitors, is anticipated to result in a six-month data readout available in the third quarter of 2023.

More information

X-82 (Oral)
Under study by Tyrogenex, Inc., this oral medication is intended for use in combination with anti-VEGF injections. The expectation is that the combination therapy will reduce the number of injections required for stabilizing the retina. Phase 2 trials began in 2017. More information.

AKST4290 (Oral)
Alkahest Inc. has reported that AKST4290, an oral medication for treatment of wet AMD, was shown in trials to be safe, effective, and “extremely promising”. Two Phase 2a clinical trials for AKST4290 were recently completed: one in naïve patients and one in refractory wet AMD patients. Results are pending. More information

IBI302
In April 2019, Innovent Biologics announced that it had dosed the first patient in a phase 1 trial of IBI302, the company’s wet AMD treatment candidate. A single intravitreal injection of IBI302, a recombinant fully human bispecific fusion protein targeting VEGF and complement proteins, will be evaluated in 36 patients with wet AMD in the open-label, single-center, dose escalation clinical trial. More information

AR-13503

In August 2019,  Aerie Pharmaceuticals, Inc. (Aerie), began patient dosing in their first human clinical trial of a sustained release implant in patients with wet macular degeneration or diabetic macular edema. The polymer implant provides controlled release of AR-13503, an injectable drug that inhibits blood vessel growth in the retina, while potentially reducing the treatment burden associated with more frequent intravitreal injection. More information

RBM-007
RBM-007 is a novel oligonucleotide-based aptamer with potent anti-FGF2 (fibroblast growth factor 2) activity. A Phase 2 Study assessing the safety, efficacy and durability of RBM-007 is underway. More information

Byooviz (ranibizumab-nuna)
The first biosimilar to ranibizumab injection for wet AMD. Also approved to treat macular edema and myopic choroidal neovascularization. More information.

EYP-1901
A potential twice-yearly sustained delivery intravitreal anti-VEGF treatment for wet age-related macular degeneration (wAMD). More information

Summary of Research and Developments in Macular Degeneration, 2010-2011

by Dan Roberts
June 19, 2011
Introduction
Since 2006, I have done my best to condense the high points of the previous year’s macular degeneration research into a single report that is concise and understandable for the layperson. I do so, because I understand first hand how important it is to be aware of everything being done on our behalf by the scientific community. Fear of the unknown is often the worst part of this disease. Information, therefore, is an effective weapon that we should all have access to.
Developments in the field of low vision treatment are occurring at an exponential rate. So fast that vision restoration and cures could conceivably become realities in some of our lifetimes. Through the years, we have seen impressive achievements in the areas of surgery, nutrition, and pharmacology. This past year, pharmacology has taken the lead, so most of this summary will discuss the drugs that are now under development and in clinical trials.
PHARMACOLOGY
Results From the Comparison of AMD Treatments Trial (CATT)
The most interesting development this past year was the findings from the Comparison of AMD Treatments Trial (CATT), sponsored by the National Eye Institute. This trial was designed to study the relative safety and efficacy of Genentech’s Lucentis, the approved treatment for wet AMD, and off-label Avastin, a similar, but less expensive drug originally developed by the same company for treatment of colon cancer. At the end of the first year of the two-year trial, the two compounds have been found to be extremely similar in their improvement of mean visual acuity and in the occurrence of adverse events.
These are top line results, with more detail to come later. Meanwhile, the subjects will continue under observation as the trial proceeds through its second year. Five related trials are also underway in the UK and Europe, all of which deserve watching for potential new findings.
In addition to the general findings, the results also revealed surprisingly little difference in the efficacy of scheduled injections and the efficacy of injections delivered on an as-needed basis for both drugs.
The general consensus of opinion among doctors using Avastin is that they will continue using the drug off-label. At the same time, they will ensure that patients are fully aware of adverse events (SAE) that have been determined at this time to be neither significant nor insignificant to the end results. No discussions have yet been held with the Centers for Medicare and Medicaid Services (CMS) regarding changes in policy for reimbursement for Avastin as a treatment for wet AMD.
Another report will be published following conclusion of the trials next year. Meanwhile, it is important that patients discuss their treatment with their doctors for a full understand of the current findings.
Fenretinide
ReVision Therapeutics’ Phase 2 trials have been completed with a surprising outcome. In addition to expected positive results, researchers have found that the drug fenretinide, taken orally once a day, also reduces by 2.2-fold the rate of conversion to neovascularization (hemorrhaging) in patients with geographic atrophy (end stage dry AMD). This means that fenretinide, in addition to slowing the progression of dry AMD, could also become a pre-treatment for wet AMD, a condition that is responsible for 85-90% of AMD related vision loss.
As a result of these findings, the scientists hope to move forward to a larger phase 3 clinical trial to evaluate this therapeutic effect in a larger patient population.
Lucentis “Super Dose”
Genentech’s HARBOR trial has revealed that a higher dose of Lucentis (ranibizumab) for treatment of wet AMD has been found to be more effective in fifty “incomplete responders” over 24 months. “Incomplete responders” are individuals who have shown no appreciable response to the normal treatment. Intravitreal injection with 2.0 mg, however, rather than the current 0.5 mg, led to a significant decrease in retinal thickness (swelling) after the first 3 months, plus a 4-letter gain after 8 weeks. This improvement was maintained up to one year with no serious adverse events.
AL-8309
Alcon Pharmaceuticals Company is developing a topical drug, AL-8309, which, when given one to two times daily has been shown to block the inflammatory response in rodent retinas exposed to blue light. Since inflammation is thought to be a contributor to development of AMD, and since AL-8309 inhibits the complement system that initiates inflammation, the drug is showing promise as a potentially effective treatment for dry AMD.
VEGF Trap-Eye
Regeneron Pharmaceuticals, Inc. and Bayer Health Care, have entered phase 3 trials comparing the anti-angiogenic drug, VEGF Trap-Eye, with Lucentis for treatment of wet AMD, central retinal vein occlusion (CRVO), and diabetic macular edema (DME). The drug is expected to improve patients’ visual acuity over time without the need for monthly intravitreal injections.
In the Phase 3 GALILEO study, patients with CRVO received six monthly injections of either VEGF Trap-Eye at a dose of 2mg or sham injections. At the primary endpoint patients gained 15 letters of vision from baseline. At a secondary endpoint they gained, on average, 18 letters of vision. These early findings showed that VEGF Trap-Eye has the potential to provide patients and physicians a new treatment option for central retinal vein occlusion.
Regeneron is now seeking marketing approval for treatment of CRVO in the United States. Bayer HealthCare is planning to submit regulatory applications in Europe in 2012.
Lucentis
The current treatment protocol is recognized by the company as a burden on patients. Researchers are, therefore, working on ways to improve the delivery method. One possibility is reduction of frequency of injections.
Practitioners are finding that not all patients are responding as expected with Lucentis. About 10% of patients have actually lost 2-3 lines of acuity after treatment. To address this issue, the new DAWN study will identify ahead of time, by means of a blood test, how well a patient will respond to the drug. Treatment could then be adjusted for best benefit. Genentech scientists are also looking at potential genetic causes for those patients who are not responsive to Lucentis.
As a side note, Novartis Pharmaceuticals Corporation is initiating a 5-year patient management study (LUMINOUS) to gain further understanding of long-term effectiveness of Lucentis, treatment patterns, long term safety, and health-related quality of life issues. The study was launched in 34 countries in March 2011.
NT-501
Another drug, NT-501, developed by Neurotech, is a treatment designed to protect, and in some cases rescue, dying photoreceptors in the retina in order to preserve vision. This treatment relies on a growth factor produced by the human body called neurotrophic factor (CNTF). Human cells engineered to produce CNTF are implanted in the eye in a tiny specially designed capsule which protects these cells from the patient’s immune system and continually releases a small amount of the growth factor. Neurotech has announced that this so-called encapsulated cell technology (ECT) has completed Phase 3 trials with good results.
There have been no serious ill effects associated with the treatment or with having the capsule implanted. NT-501 is also being tested as a treatment for other retinal degenerative disorders including retinitis pigmentosa.
New Treatment Possible for Dry AMD
A new study published in the February 2011 journal Nature reports that dysfunction of an enzyme called DICER1 may be a cause of geographic atrophy (dry AMD). Researchers at the University of Kentucky found that levels of the enzyme are higher in healthy retinas than in eyes affected by AMD. They demonstrated that low DICER1 levels lead to buildup of a toxic genetic material called alu, This, in turn, causes geographic atrophy (dry AMD).
Two treatments may potentially halt the progression of the disease: one which boosts levels of the enzyme, and the other which breaks down the toxic Alu RNA. To test the hypothesis, the University of Kentucky is planning to start human trials by the end of 2011.
SURGERY
Human Retinal Cells Developed From Non-embryonic Stem Cells
On March 24, 2011, Georgetown University Medical Center reported in the journal “Stem Cells” that their researchers have, for the first time, produced retinal cells from human induced pluripotent stem (hiPS) cells, rather than embryonic stem cells. hiPS cells are derived from the patient’s own body, thus bypassing the moral issue of using human embryos.
This is an important step in the research, but several viability and safety issues still need attention before hiPS cells can be introduced into humans.
Microplasmin for vitreal adhesion
A single intravitreal injection of a new drug called microplasmin has been shown in Thrombogenics’ Phase 3 trials to relieve adhesion of the vitreous (the gel that fills the inside of the eye) to the inside of the retina. This reduces risk of damage from the tugging of the vitreous on the retina, which can lead to such conditions as diabetic vitreous hemorrhage and macular hole. It accomplishes this by inducing a gentle post vitreous detachment (PVD), and that can help eliminate the need for surgery to remove the vitreous from the eye.
Implantable Miniature Telescope Approved
VisionCare Ophthalmic Technologies, Inc. announced on July 6 that the FDA approved the company’s Implantable Miniature Telescope to improve vision in patients with end-stage AMD.
The telescope implant is designed to improve visual acuity. The magnification provided by the implant reduces the impact of the blind spot caused by end-stage AMD.
VisionCare will conduct a post-approval study to monitor patient outcomes under commercial conditions. A second smaller study will follow clinical trial patients for an additional two years.
VisionCare is submitting an application to the Centers of Medicare and Medicaid Services for a new code to establish Medicare beneficiary access to this implantation procedure. For more information about the telescope implant and related treatment program, see www.centrasight.com.
Radiation Therapy Continues To Show Promise
In October, NeoVista made public the company’s one-year results from the preliminary study MERITAGE-I. The study was designed to examine their radiation procedure (epimacular brachytherapy) for patients undergoing chronic therapy with anti-VEGF agents for wet AMD. Study results showed that a single radiation treatment stabilized visual acuity in 79% of this patient population, while decreasing the number of anti-VEGF injections required. Most importantly, 47% of patients enrolled in the study experienced some improvement in their visual acuity, while 10% of patients gained 15 or more letters of visual acuity at 12 months.
The study results also pointed to a favorable trend with respect to a reduced number of anti-VEGF injections following delivery of radiation versus the period of time leading up to the intervention. In addition, 25% of patients remained injection-free at 12 months following the procedure.
NUTRITION
AREDS2
The National Eye Institute’s second Age-Related Eye Disease Study (AREDS2) is continuing. The original AREDS formula was approved in 1998. This time, subjects are being given a slightly altered formula containing the original vitamin dosages minus beta-carotene, a lower dosage of zinc, and addition of lutein, zeaxanthin and omega-3. The purpose is to see if the revised formula will help even more to slow the progression of AMD to the advanced stages. The new study began in June 2008, and results are expected in the year 2013. Meanwhile, many nutriceutical companies have gone ahead and updated their products to reflect the more current research. It is advisable to discuss with all of your professional care providers any additions or changes in your diet or supplementation.
TECHNOLOGY
iPad2
The most common complaint about low vision technology is the high price of assistive devices. With government assistance available only to veterans, many people simply cannot afford to purchase the products that can make their lives so much easier. With this year’s introduction of Apple’s new iPad 2, however, that has almost become a non-issue.
For less than half the cost of most electronic magnifiers, visually impaired people can now own virtually every low vision gadget all wrapped up in a device no larger than a thin book. The iPad2 can read to you in 21 languages, magnify images and text, tell you what color your shirt is, guide you across town, magnify the face of your grandchild, call a friend, shop online, manage your finances, identify currency, help you type a letter, read Braille, tell the date and time, and so much more. And it can all be done using tactile buttons or touch screen controls. Apple also offers a year of personal training on the iPad2 for $99.
This has set the standard, and we can now expect more advances at even lower prices to come our way. And if that doesn’t brighten your day, read on:
Driving Blind
The National Federation of the Blind announced on January 29, 2011 that, for the first time, a blind individual has driven a street vehicle in public without the assistance of a sighted person.
The car was equipped with laser range-finding sensors that conveyed information to a computer inside the vehicle, allowing it to create and constantly update a three-dimensional map of the road environment. The computer sent directions to vibrating gloves on the driver’s hands, indicating which way to steer, and to a vibrating strip on which he was seated, indicating when to speed up, slow down, or stop.
Also this past year, Google revealed it’s own version of what they call an autonomous vehicle. The company has been working in secret on vehicles that can drive themselves.
According to the New York Times, seven Google test cars have driven 1,000 miles without human intervention and more than 140,000 miles with only occasional human control. One even drove itself down Lombard Street in San Francisco, one of the steepest and curviest streets in the nation. The only accident, engineers said, was when one Google car was rear-ended while stopped at a traffic light.
They say this technology may be available to the public in eight years. If that happens, one of the thorniest problems of low vision, transportation, will no longer be an issue.
AMD Numbers Continue to Fall
“The number of Americans with macular degeneration fell 30 percent in about two decades,” according to a study published in the January issue of the Archives of Ophthalmology, “reducing the threat from the leading cause of [visual impairment] among the elderly.”
The study authors explained that “Reductions in smoking and blood pressure, key risks for the condition, and increased use of antioxidant vitamins that keep the disease at bay may account for the decline”. The study also revealed that the rate of advanced AMD among all the participants was 0.8 percent, and that AMD affects approximately 6.5% of adults ages 40 and over, compared with the previous estimate of 9.4%.
Data was obtained from 7,081 people, aged 40 and older, who took part in the 2005 to 2008 National Health and Nutrition Examination Survey.
Other research has been confirming this trend. In 2007, a study found 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. 2,968 participants with early AMD and 3,588 participants with late stage AMD were examined at 5-year intervals between 1988 and 2005 as part of the Beaver Dam Eye Study.
Then, in 2010, a study reported to the Association for Research in Vision and Ophthalmology showed a 68% lower incidence of macular degeneration in the Baby Boom population. That research suggested that improvements in environment, behaviors, and other such modifiable factors may have contributed to the results. The “birth cohort” effect remained even after adjusting for AMD risk factors such as obesity, heavy drinking, and sunlight exposure.
The results of this research further emphasize the importance of environmental and lifestyle factors to retinal health.
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This wraps up my summary for this year. I hope you will share this information with your family, friends, and doctors. You are in a position to help others understand, and by doing so, you will be serving a valuable purpose. Thank you for your help!

Summary of Research and Developments in Macular Degeneration: 2009-2010

by Dan Roberts
June 10, 2010
Introduction
If I were to describe the past twelve months in a word, it would be “progress.” No spectacular breakthroughs have occurred during that time to make big news in the AMD world, but a lot of persistent work has been reaping promising results. moving us ever closer to effective treatments. Even the cure we hope for is now being thought of more in terms of “sooner” than “later.”
This summary is a brief overview of the news that has been of interest to us during the period of June 2009 through May 2010. More details about the reports from the 2009 Meeting of the American Academy of Ophthalmology (AAO) may be found on this site. Other reports in this summary are annotated with sources for further reference.
I’ll begin by mentioning two studies in the area of nutrition, since nutraceuticals are currently our most immediate hope for slowing the progression of vision loss from AMD.
NUTRACEUTICAL
1. Omega-3 Lowers AMD Risk
For the past couple of years, we have been made aware of the benefits of Omega-3 fatty acids in our diet, and nutritionists have been recommending several servings of fish each week or supplementation with fish oil. To further confirm these benefits, 671 subjects in the 2009 ALIENOR Study were given eye examinations seven years after plasma fatty acid measurement. As hoped, lower risk of geographic atrophy (advanced dry AMD) was associated with higher plasma levels of total omega-3 fatty acids, in accordance with previous studies of dietary intake.
Ref: AAO 2009 Paper: “Plasma Omega 3 Fatty Acids and Risk for Age-Related Maculopathy: The ALIENOR Study” (Presenting Author: Jean-Francois Korobelnik MD)
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2. Saffron Improves Vision
Another interesting finding was reported in March 2010, when clinical trials in Italy and Australia showed that the spice, saffron, can improve vision in people with AMD.
Subjects experienced up to 2 lines of improvement in their vision while taking saffron pills, but the effect quickly disappeared when the dose was discontinued. This indicates that it may improve the vision function of surviving cells but it does not reverse the damage that is already present.
If you intend to add saffron to your diet, be sure you are actually purchasing saffron, not safflower, which is sold as saffron by some unscrupulous dealers.
Ref: www.mdsupport.org/library/saffron.html
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SURGICAL
Seven surgical procedures headed the news during these past 12 months.
1. FDA Considering Approval of IMT
The investigational implantable miniature telescope (IMT), discussed here last year, is designed to be a solution for moderate to profound vision loss due to advanced, end-stage forms of AMD that have no current surgical or medical treatment options.
If you remember, the telescope prosthetic device, which is smaller than a pea, is implanted in one eye during an outpatient surgical procedure. In the implanted eye, the device renders enlarged central vision images over a wide area of the retina to improve central vision, while the non-operated eye provides peripheral vision for mobility and orientation. On March 27, 2009, the FDA Ophthalmic Devices Advisory Panel unanimously recommended that the FDA approve, with conditions, the premarket application of the IMT for End-Stage AMD. The device has received CE Mark approval in Europe, but we are still waiting for approval in the US at this time. No explanation has yet been given for the delay.
Ref: AAO 2009 Session: “Implantable Miniaturized Telescope” (Presenter: Mark R. Wilkins, MD)
Ref: www.mdsupport.org/library/imt.html
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2. LMI Approved in Europe
In 2007, Optolight Vision Technology announced success from implantation of the LMI, which is a second generation of the implantable miniature telescope. They reported that the LMI may be an effective solution for optical rehabilitation of patients with ARMD or other macular pathology by increasing the central image on the retina while preserving peripheral vision. This preservation of the peripheral field is the main difference between the LMI and the IMT, allowing it to be implanted in both eyes.
On June 17, 2009, OptoLight Vision Technology announced that it received CE mark approval in Europe, which allowed OptoLight to immediately begin marketing the implant in Europe and other markets outside of the United States.
Ref: www.mdsupport.org/library/lmi.html
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3. Skin Cells Changed Into Retina Tissue
In August 2009, scientists at the University of Wisconsin-Madison reported that they had reprogrammed skin cells and turned them into different kinds of retinal cells. The work added to a growing weight of evidence that stem cells made by reprogramming have similar, if not the same, abilities as the more controversial embryonic stem cells.
Scientists may now be able to take a skin biopsy from someone with a vision ailment, create retinal cells, and observe how the disease unfolds and how the cells die over time. They hope to also use reprogramming as a way to generate damaged or diseased cells on which pharmaceutical companies can test their drugs and to find ways to correct genetic defects.
Farthest off, but most exciting to many researchers, is the possibility of using reprogramming to produce healthy cells that can replace those that have died.
Ref: “Skin Cells Changed Into Retina Tissue,” by Mark Johnson (Journal Sentinel Online.
August 24, 2009)
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4. UCI Researchers Create Retina
As recently as the end of May 2010, University of California Irvine scientists have created an eight-layer animal retina from human embryonic stem cells. This is the first three dimensional tissue structure to be made from stem cells, and it could be a big step toward retina replacement in eyes affected by macular degeneration. It is an advancement over creation of single cell layers, since the multi-layered human retina might then be replaced in its entirety in one procedure.
The researchers are testing the early-stage retinas in animal models, in hopes that success will lead to human clinical trials.
Ref: today.uci.edu
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5. Brachytherapy May Improve Vision
Epimacular brachytherapy involves radiation treatment delivered by a small plaque sewn to the sclera (the white covering of the eyeball). In November 2009, NeoVista, Inc. announced results from a study designed to examine the company’s brachytherapy procedure when used in patients undergoing anti-VEGF drug injections for wet AMD.
Preliminary study results suggest that a single procedure of epimacular brachytherapy can further improve visual acuity in a majority of this patient population while decreasing the number of injections required. Most importantly, they researchers reported, 63% of patients enrolled in the study experienced improvement in their visual acuity, while 50% of patients gained 5 or more letters of visual acuity at 6 months.
Ref: www.neovistainc.com/meritage.html
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6. New Radiation Treatment Under Study
Another radiation therapy system entering trials this past year was the Oraya IRay system. This delivers a robotically controlled dose of low-energy X-ray radiation to the retina.
Oraya Therapeutics, Inc. began enrolling patients at seven European sites to demonstrate the safety and effectiveness of radiation therapy for the treatment of wet AMD. According to the company, the radiation dosages close inflammation mediated capillaries and further stop the inflammatory process that leads to wet AMD. In this study, the procedure is used in conjunction with anti-VEGF injections.”
Ref: www.orayainc.com/clinicaltrials.asp
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7. Tinted IOLs May Slow AMD
A 2009 study showed that implantation of a blue light-filtering intraocular lens (IOL) at the time of cataract surgery increases macular pigment in the retina. This increase may provide protection against the development and/or progression of AMD.
Macular pigment is thought to protect against AMD by absorbing blue light before it reaches the photoreceptors in the retina. The retina is exposed to as much as six times the amount of blue light in a person having the lowest level of macular pigment when compared to a person with the highest level. This gives rise to the belief that blocking blue light with replacement IOLs and other types of protective lenses may help slow down the disease process.
Ref: Macular Pigment Research Group: www.mprg.ie
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PHARMACEUTICAL
The pharmaceutical industry leads the way this year, with nine newsworthy headlines.
1. Fenretinide Granted Fast-Track Status
Fenretinide (ST-602), a drug that has been used to treat certain cancers, rheumatoid arthritis, acne, and psoriasis, has been found to also slow the production and accumulation of a toxin called A2E that leads to buildup of lipofuscin (waste deposits) in the retina, resulting in vision loss in people with dry AMD. If the drug proves effective with dry AMD patients, it may then also be used off-label for treatment of Stargardt’s disease, a juvenile form of macular degeneration.
The trials, which began in 2006, were granted fast-track designation in April 2009, based upon strong results from phase 2.
Ref: ARVO 2009 Paper: “Fenretinide for the Treatment of Geographic Atrophy in Patients with AMD: One-Year Interim Analysis” (Presenting Author: Roger Vogel MD)
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2. Lucentis Still the Gold Standard
Incidence of ocular and non-ocular safety events continues to be low and consistent with prior Lucentis trials. For 600 patients who received Lucentis in prior trials, the most common ocular adverse events over 2 years have been worsening macular degeneration (35%), retinal hemorrhage (25%), and conjunctival hemorrhage (25%). Lucentis is still showing excellent results, and it is still considered the gold standard for treatment of wet AMD.
Ref: AAO 2009 Paper: “Safety Outcomes Over 2 Years in the HORIZON Extension Trial of Ranibizumab (Lucentis) in Neovascular AMD” (Presenting Author: Matthew S Benz MD)
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3. POT-4 Found Safe and Effective
POT-4 is a synthetic peptide that has been found to inhibit a genetic process that can lead to local inflammation, tissue damage (as in dry AMD) and the resulting blood vessel growth in wet AMD. Inflammation is thought to be the cause of AMD in as many as 50% of cases, so a good deal of research is being done in this area.
It was reported in 2009 that phase 1 studies found POT-4 to be well tolerated, safe, and effective in improving macular edema.
Ref: AAO 2009 Paper: “Phase 1 Results of the Complement C3 Inhibitor POT-4 in AMD” (Presenting Author: Philip J Rosenfeld MD PhD)
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4. VEGF Trap-Eye Completes Phase 2
AAO 2009 Poster: “VEGF Trap-Eye Vision-Specific Quality of Life Through 52 Weeks in Patients With Neovascular AMD in CLEAR-IT 2: A Phase 2 Clinical Trial” (Presenting Author: Allen C Ho MD)
VEGF Trap-Eye is a molecule which has been shown to block choroidal neovascularization (blood vessel growth) in eyes with wet AMD. Two studies were reported in 2009 to have been successful in both improvement of the affected retina and improvement in patients’ quality of life.
AAO 2009 Poster: “OCT and Fluorescein Angiography Outcomes Through 1 Year for a Phase 2 Study of Intravitreal VEGF Trap-Eye in Neovascular AMD” (Presenting Author: Peter K Kaiser MD)
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5. Oral Drug For Dry AMD Enters Phase 2
Following the success of the Phase I clinical trial, Acucela Inc. has begun recruiting participants with dry AMD for a Phase II study of the oral drug ACU-4429 for dry AMD. Known as the ENVISION Clarity Trial, Acucela is planning to enroll at least 56 participants at multiple sites throughout the U.S. Participants will receive either the drug or a placebo.
Ref: www.medicalnewstoday.com/articles/149919.php
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6. Alzheimer’s Disease Treatment May Benefit AMD Patients
Copaxone (glatiramer acetate) injections are given in Alzheimer’s disease to decrease destructive beta-amyloid deposits. These deposits are similar to the proteins seen in
drusen found in dry AMD, so researchers are trying copaxone for treatment of dry AMD. In week 12 of a small preliminary study, 4 eyes (3 patients) treated with copaxone showed a total reduction of drusen area from baseline of 66%. Two eyes receiving sham injection had essentially no significant change in drusen area.
Ref: www.medscape.com/viewarticle/564015_2
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7. MC-1101 Eye Drop For Wet AMD Proves Safe
MC-1101 is an eye drop which affects the blood flow in the choroid, hopefully stopping the progression of AMD. So far, a small Phase 1 study by MacuCLEAR, Inc. has established the safety of seven dosages over three days, and plans for further trials are underway.
Ref: www.macuclear.com
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8. Aspirin May Aggravate AMD
We have been told that aspirin might help to inhibit the inflammation process, thereby slowing the progression of AMD. But here is frustrating news of a study just completed that suggests aspirin might actually be somehow associated with progression of the disease. 4691 patients 65 years and older were asked about their use of aspirin and about other possible risk factors for aging macula disorders. The results showed that odds ratios for all grades of early aging macula disorder rose with increasing aspirin intake frequency for subjects who reported daily use. The researchers, therefore, concluded that frequent aspirin use seems to be harmful for aging macula disorder in older populations.
Study leader Dr. Paulus de Jong said, however, that patients with cardiovascular disease should not stop taking aspirin. “But if they are taking it as a pain killer, there are other medications they can use.”
Of course, more study is needed before definite conclusions can be drawn, and other studies have shown no correlation, even beneficial correlations, between aspirin and macula disorders. But moderate intake of aspirin might be something we need to consider until more is known.
Ref: Association for Research in Vision and Ophthalmology (AAO) 2010 Annual Meeting: Abstract 1620. Presented May 3, 2010.
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9. Studies Show Lucentis and Avastin to be Equal
In February 2010, investigators at Kaiser Permanente Southern California in Pasadena reported that Avastin and Lucentis performed equally. Of 452 patients treated for wet AMD, 22.9 percent of Avastin patients and 25.0 percent of Lucentis patients attained visual acuity better than or equal to 20/40 after a year of treatment. Similar numbers of patients in each
group also showed some degree of vision improvement at 12 months.
The Kaiser Permanente study is one of several comparing the two drugs. The largest, and probably most definitive, study is the National Eye Institute’s ongoing Comparisons of Age-Related Macular Degeneration Treatments Trials (CATT), with results expected next year. Avastin, originally designed as a cancer drug, is administered off-label, but research like the Kaiser study has been showing it to be at least as safe and effective as Lucentis for use in treatment of wet AMD.
We should remember that the comparison trials will not lead to FDA approval of Avastin for treatment of wet AMD. It may or may not confirm what we already know, but the drug will, in either case, remain on off-label status. Since large scale Avastin trials by the parent company, Genentech, are not likely, this will still be considered a safety issue.
Ref: Ophthalmology (Feb 2010)
Ref: www.mdsupport.org/library/catt.html
Drugs Under Study For Wet AMD
Here is a list of drugs currently under study for treatment of wet AMD. Three of them (Macugen, Lucentis and Avastin) have already entered clinical use, but followup studies continue to confirm their safety and efficacy.
Macugen
Lucentis (ranibizumab)
Avastin (bevacizumab)
Verteporfin PDT (in combination)
Tryptophanyl-tRNA synthetase (TrpRS)
AdPEDF
VEGF-TRAP-EYE
AG-013958
JSM6427
TG100801
ATG3
Perceiva
Endostatin
Pazopanib
siRNA
Ref: www.mdsupport.org/library/anti-angio.html
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Drugs Under Study For Dry AMD
Here is a shorter list, but still encouraging, of drugs under study for potential treatment of the dry form of AMD:
ACU-4429
Copaxone
Fenretinide (ST-602)
Iluvian (fluocinolone acetonide)
MC-1101
OT-551
POT-4
Retinylamine
Ref: www.mdsupport.org/library/treatments.html
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So there are at least 23 chances for treatments or cures from the pharmaceutical industry.If I haven’t mentioned them in this summary, it’s because most are still in the trial process, with no significant findings to report as yet. We may not hear very much about this work in the daily news, but rest assudred that the race is on, and no matter who reaches the finish line first, we, the patients–or at least our children and grandchildren–are going to be the eventual winners.
GENETICS
A great deal of research is being carried out in the field of genetics, as this is very likely where the cures for most diseases will be found. Two developments have stood out during the past 12 months.
1. RPE65 Gene Therapy Showing Promise
First, three young adults who received gene therapy for Leber congenital amaurosis (LCA), a blinding eye condition, remained healthy and maintained previous visual gains one year later. One patient also noticed a visual improvement that helped her perform daily tasks.
In this study, researchers injected healthy copies of the RPE65 gene under a healthy area of the retina in an attempt to repair the visual cycle. One year after the procedure, evidence shows that the newly introduced gene is functional and is increasing the light sensitivity of the retina.
This is the first study that reports the one-year safety and effectiveness of successful gene therapy for LCA. It paves the way for similar techniques, which can eventually be applied to other genetic diseases such as AMD.
Ref: www.mdsupport.org/library/breakthrough.html
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2. PEG-POD: A New Gene Delivery Tool
The second bit of news came in January 2010, when researchers reported having developed a new tool for gene therapy which significantly increases gene delivery to cells in the retina compared to other carriers and DNA alone.
A peptide called PEG-POD provides a safe and effective vehicle for transferring DNA into cells without using a virus, currently the most common means of DNA delivery. PEG-POD protects DNA from damage in the bloodstream, allowing for gene therapy treatments that can be administered through an IV and directed to many other parts of the body.
The researchers found that gene expression in specimens injected with PEG-POD was 215 times more effective than two other carriers tested.
Ref: www.mdsupport.org/library/PEG-POD.html
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Envisioning A Cure For AMD (by Rick Trevino, OD)
I would like to quote from an article by Dr. Rick Travino, who is active in our online community and who hosts one of the most informative web sites about vision research and developments. In his commentary, “Envisioning A Cure For AMD,” he wrote:
“One of the most exciting developments in the field of AMD research has been the discovery of a relatively small number of genes that seems to control a large amount of the risk of developing the disease.
“Most of the genes that are known to influence the risk of developing AMD involve various components of the complement cascade. Most prominent among these is complement factor H (CFH); however, variants in genes coding for other components of the complement system have also been discovered and shown to be associated with AMD risk and protection. The complement system is very important in regulating the body’s immune system and directing inflammatory processes. Several lines of evidence suggest that dysregulation of inflammation plays a key role in the development of AMD.
“Now, thanks to these discoveries, we are beginning to see treatments that are specifically tailored to address abnormalities in the complement system. This raises the very real possibility of a truly preventative treatment, or even a cure, for the disease. . . Many . . . complement pathway-modulating compounds are currently being considered for, and/or are under, preclinical development for possible use in AMD.
“One could imagine a day when persons are screened at an early age to determine whether they harbor the genes that will ultimately lead them to develop AMD later in life. Then, based upon their specific genetic make-up, persons could take medications, or perhaps undergo gene therapy, that will prevent AMD from ever occurring. In this scenario, the eradication of AMD is a real possibility.”
Thank you, Dr. Trevino for reinforcing our hope for the future.
Ref: www.myvisiontest.com
GOOD NEWS
Incidence of AMD Declining
And finally, to continue on a positive note, I reported last year that a recent study found 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. That 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.
Now we have more good news along those same lines. A new study reported this year has shown a 68% lower incidence of macular degeneration in the Baby Boom population. The research suggests that improvements in environment, behaviors, and other such modifiable factors may have contributed to the results. The “birth cohort” effect remained even after adjusting for AMD risk factors such as obesity, heavy drinking, and sunlight exposure.
More study is necessary as the younger population continues to age, but the results further emphasize the importance of environmental and lifestyle factors to retinal health.
Source: Karen J. Cruickshanks, MD (University of Wisconsin School of Medicine and Public Health in Madison) and reported at the Association for Research in Vision and
Ophthalmology (AAO) 2010.
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Conclusion
One of the worst aspects of living with macular degeneration is that there is little we can do about our inevitable loss of vision. To alleviate some of the frustration that causes, we want to leave no stone unturned in our daily battle to maintain our healthiest eyesight.
I hope our news updates and annual summaries are serving that purpose by providing you with some comfort in knowing about all the good research being done. With this kind of information in hand, we no longer have to say, “Why didn’t someone tell me?”
Now, please accept the challenge of passing this information along. Educating others is one of the best ways to keep from being victimized by this disease, and your help is greatly appreciated!

Study Shows Lucentis and Avastin to be Equal

by Dan Roberts

February 3, 2010

Investigators at Kaiser Permanente Southern California in Pasadena reported in the February 2010 issue of Ophthalmology that Avastin and Lucentis performed equally in recent testing.
In an indirect comparison of the two drugs, study author Dr. Donald Fong and coauthors reviewed the records of 452 patients treated for wet AMD with Avastin or Lucentis. They found that 22.9 percent of Avastin patients and 25.0 percent of Lucentis patients attained visual acuity better than or equal to 20/40 after a year of treatment. Similar numbers of patients in each group also showed some degree of vision improvement at 12 months.
The Kaiser Permanente study is one of several comparing the two drugs. The largest, and probably most definitive, study is the National Eye Institute’s ongoing Comparisons of Age-Related Macular Degeneration Treatments Trials (CATT), involving 44 centers across the U.S. Results from that research are expected in 2011.