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.

Examples of complement-targeted therapies currently under development for AMD includes Phase 2 clinical trials to test compstatin/POT-4, a C3-peptide inhibitor, for intravitreal use in geographic atrophy. A trial of eculizumab, a humanized anti-C5 antibody, has been approved by the FDA to examine its use in geographic atrophy. Another complement component inhibitor, ARC1905, is currently being examined in combination with Lucentis in an open-label phase 1 safety study for the treatment of wet AMD. Many other complement pathway-modulating compounds are currently being considered for and/or under preclinical development for possible use in AMD.

One could imaging 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.

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Patients with choroidal neovascularization (CNV) secondary to pathologic myopia appear to do less well after intravitreal Lucentis (ranibizumab) treatment if they have previously been treated with photodynamic therapy (PDT), according to a new study.

The study included 34 eyes of 32 patients with CNV secondary to pathologic myopia; 13 eyes had previous PDT, and 21 eyes had no previous treatment. The patients were followed for ≥12 months.

Mean best corrected visual acuity (BCVA) improved 8 letters from baseline to 12-month follow-up, and the difference was statistically significant (P < 0.001): 100% of the eyes lost <3 lines of visual acuity, 24% of the eyes improved ≥3 lines. Central retinal thickness decreased significantly from baseline to the 12-month follow-up (P < 0.01).

History of treatment with PDT appeared to affect the success of treatment. Eyes with previous PDT improved a mean 6 letters in 12 months after a mean 4.2 intravitreal injections. Eyes with no previous PDT improved a mean 9 letters in 12 months after a mean 3.2 intravitreal injections. Macular thickness was also higher at 12 months in eyes that underwent previous PDT.

The researchers conclude that one-year results of intravitreal Lucentis for myopic CNV are very promising. Additional prospective studies are necessary to better determine long-term efficacy and safety.

WHAT IT MEANS TO YOU: There is ample evidence that Lucentis is beneficial for myopic CNV. What is interesting about this study is that prior use of PDT may decrease the benefit of Lucentis in patients with myopic CNV. Similar results have been published for patients with AMD. So, while there may be important benefits of PDT, there may be a price to pay in terms of decreased efficacy of subsequent anti-VEGF therapy.

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A series of 5 cases of severe intraocular inflammation that developed after an intravitreal injection of Avastin (bevacizumab) is reported.

In this retrospective case series, 35 patients were treated with an intravitreal injection of Avastin (lot B3003B01) between December 18, 2008 and January 20, 2009.

Five (14.3%) of the 35 cases had severe intraocular inflammation, and the inflammation had some characteristics of toxic anterior segment syndrome (TASS). All had a predominantly anterior chamber reaction, and 4 of the 5 cases were accompanied by hypopyon. All cases were culture negative. The mean BCVA was 0.66 logMAR units before Avastin injection and 0.44 logMAR units at the final visit. These differences were not significant.

In this series of 5 cases the cause of the inflammation was not determined. It may be due to a toxic reaction to the drug, the vehicle, or a contaminant. It could also be an immune-mediated response to Avastin, some breakdown product of Avastin that occurred during the storage, or both.

F. Hoffmann-La Roche recently reported 25 Canadian cases of endophthalmitis, some of whom were diagnosed as TASS, after an intravitreal injection of a specific lot of Avastin. La Roche reported that all test parameters were well within limits established for the authorized use of Avastin. Thus, there is a possibility that the Avastin contained some toxic substance(s) that induced the intraocular inflammation, although it had no significant effect when given systemically.

Taking these observations together, the investigators suggest that the cause of the sterile endophthalmitis associated with Avastin is the result of some toxic byproduct whose concentration may not be high enough when Avastin is given systemically. Degeneration during storage may increase its toxicity, and the eyes sensitized by repeated intravitreal Avastin may respond to the increased antigenicity.

WHAT IT MEANS TO YOU: Severe inflammation following intravitreal Avastin injection continues to be reported. It is unclear what triggers these attacks, but they resolve fully with proper treatment, without any apparent long-term effects. Patients are able to safely resume Avastin therapy after an attack. These episodes have not been reported following Lucentis use. Further study may help elucidate the precise cause of this complication of off-label Avastin use.

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Two related studies published last month demonstrate the superiority of Avastin over PDT for neovascular AMD.

The first study reported that combination therapy of intravitreal Avastin-plus-PDT is more effective than PDT alone. The second study found that intravitreal Avastin alone as effective as combination therapy of Avastin-plus-PDT.

In the first study, after 12 months of follow-up, PDT monotherapy for wet AMD achieved an average BCVA gain of 0.7 letter, compared to a 8.8 letter gain with combination therapy (P = 0.04). Ten eyes (43%) in the PDT- only group and 19 eyes (86%) in the PDT-plus-Avastin group received only one treatment (P = 0.005)

In the second study, BCVA and central foveal thickness (CFT) measured by OCT improved significantly at 12 months, and there was no difference in BCVA or CFT between the Avastin-only and Avastin-plus-PDT groups. The total number of Avastin injections was not reduced when PDT was given.

Taken together, these studies demonstrate that Avastin alone is superior to PDT monotherapy, and has similar efficacy to Avastin-plus-PDT combination therapy. Furthermore, the addition of PDT to Avastin therapy does not appear to decrease the need for retreatment.

WHAT IT MEANS TO YOU: Data from Summit, the large, multicenter, randomized clinical trial program of Lucentis-plus-PDT combination therapy, may help clarify the risks and benefits of adding PDT to an anti-VEGF treatment regimen. Currently, based upon small, retrospective case series such as those presented here, there does not appear to be much benefit. Therefore, for most patients with recent-onset, treatment naive neovascular AMD, the first-line treatment of choice remains anti-VEGF monotherapy.

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Advanced Cell Technology, Inc., a biotechnology company, announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for the company's MA09-hRPE cells for use in the treatment of Stargardt's Macular Dystrophy (SMD).

Orphan drug designation is granted to companies with products aimed at treatment of a rare disease or condition that affects fewer than 200,000 Americans. The National Institutes of Health (NIH) recently proposed broadening the definition of a human embryonic stem cell to include ACT's "single blastomere technology platform" which was used to derive ACT's MA09-hRPE cells.

Stargardt's macular dystrophy is an untreatable form of juvenile macular degeneration leading to blindness in patients much younger than those affected by age-related macular degeneration (AMD).

ACT's treatment for eye disease uses stem cells to re-create the retinal pigment epithelium (RPE). These cells are often the first to die off in SMD and AMD, which in turn leads to loss of vision.

"We are pleased that the FDA has, for the first time, granted orphan drug status for the use of an embryonic stem cell derived therapy in treating an unmet medical need," said Edmund Mickunas, ACT Vice President

WHAT IT MEANS TO YOU: This exciting development paves the way for research to proceed in developing a possible treatment for Stargardt's. The Orphan Drug Act provides incentives for companies to develop products for rare diseases, such as Stargardt's. Under the law, companies that develop a drug for a disorder affecting fewer than 200,000 people in the United States may sell it without competition for seven years, and may get tax and other financial incentives.

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Female hormone replacement therapy (HRT) decreases the risk of neovascular AMD, especially in women who are positive for the ARMS2 genetic polymorphism.

It has been reported that hormone replacement therapy decreases the risk of late-stage AMD. It is not clear how female hormones mediate this effect, but various estrogen compounds are potent antioxidants. Estrogens may also exert biological function by regulating the expression of genes.

When comparing all cases (n = 560) with controls (n = 239), significant inverse associations were observed for HRT (odds ratio [OR] = 0.65, P = 0.008) and birth control pills (BCPs, OR = 0.60, P = 0.048). When analyses were stratified by AMD severity (early versus geographic atrophy versus neovascular), the inverse association remained significant (HRT OR = 0.45; BCP OR = 0.55) only when comparing neovascular AMD with the control. The strongest genetic interactions were observed for ARMS2 rs10490923 (P = 0.007) and rs17623531 (P = 0.019).

The researchers state that their findings provide the first evidence suggesting that ARMS2 interacts with HRT to modulate AMD risk and are consistent with previous reports demonstrating a protective relationship between exogenous estrogen use and neovascular AMD.

WHAT IT MEANS TO YOU: It is well established that HRT decreases the risk of neovascular AMD. This study is the first to identify a genetic interaction between HRT and risk of AMD. Women who take female hormones (either HRT or birth control pills) have a decreased risk for wet AMD if they are positive for the ARMS2 polymorphism. Previous studies have found that one's genetic make-up determines the protective effect of the AREDS nutritional supplement, and also the treatment response to anti-VEGF and photodynamic therapy.

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A series of patients that developed sustained elevation of intraocular pressure (IOP) after intravitreal anti-VEGF injection for the treatment of neovascular AMD is presented.

Elevation of IOP is a risk factor for glaucoma. If the IOP is elevated, but glaucoma is not present, the patient is said to have ocular hypertension (OHT). IOP reflects a balance between the rate that fluid flows into the eye and the rate that it exits the eye. If inflow increases or outflow decreases, then IOP will go up. Intravitreal injection of drugs, such as Lucentis or Avastin, increases the amount of fluid within the eye, and hence will increase IOP. Normally, as the excess fluid gradually exits the eye over a period of time, the IOP returns to normal. However, there is a growing number of cases of patients undergoing Lucentis and Avastin therapy that develop elevation of IOP that does not return to normal. The frequency of this complication of unknown, nor is the reason for the sustained elevation of IOP.

In this retrospective case series, 4 out of 116 patients with AMD (3.45%) developed sustained elevated IOP after multiple intravitreal injections of Avastin and/or Lucentis. None of the patients had a previous diagnosis or family history of glaucoma/OHT. The range of IOP increase was 17-21 mmHg (mean, 18.75 mmHg). Mean number of pan-anti-VEGF injections prior to OHT was 13.3 (range, 3-19).

The investigators conclude that persistent OHT may occur after intravitreal anti-VEGF injection in patients with no previous diagnosis of glaucoma or OHT. OHT may persist across several visits and patients may require IOP-lowering therapy. Sustained elevation in IOP usually occurs after multiple injections. A disrupted posterior capsule might predispose patients to the development of OHT.

WHAT IT MEANS TO YOU: It appears that anti-VEGF drugs may, in some persons, lead to sustained elevation of IOP and possible glaucoma. It is not clear why this occurs, nor have any risk factors for this adverse effect, such as family history of glaucoma, been identified. Nor is it clear whether the IOP elevation is permanent, or whether IOP may return to normal after cessation of anti-VEGF injections. Glaucoma medications can lower IOP after it has been elevated by anti-VEGF drug use.

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The rate of intravitreal injections in Ontario grew 8-fold between 2000 and 2008, according to a new study. Using a population-based retrospective design, researchers studied monthly fee claims for intravitreal injections submitted to the Ontario Health Insurance Plan between January 1, 2000, and March 30, 2008, and linked procedures to the physicians who performed them. Following regulatory approval of Avastin in 2005, off-label use of this drug for the treatment of retinal disease became increasingly common. The rate of intravitreal injections in Ontario rapidly grew 8-fold. Moreover, in 2007, more than 50% of intravitreal injections in Ontario were performed by 3% of ophthalmologists. These physicians administered 162 injections per month in September 2005 and 1,436 injections per month in November 2007. The researchers state that because intravitreal injections require direct physician administration and the bulk of injection procedures are performed by a small number of ophthalmologists, there is the potential to adversely affect services for other vision-threatening conditions. The study appears in the March 2010 edition of Archives of Ophthalmology.

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The natural history of eyes containing drusenoid pigment epithelial detachment (DPED) is characterized by a high rate of progression to both central geographic atrophy (CGA) and neovascular AMD (NV-AMD), according to a new report from the AREDS study group. A DPED is defined as a fairly well circumscribed, shallow elevation of the RPE formed by a confluence of soft drusen, often located in the central macula. Of 282 eyes with DPED but without advanced AMD at baseline, 17% of eyes progressed to NV-AMD by 3 years follow-up and 23% by 5 years follow-up. The rate of progression that was significantly higher than that found in a comparison group of eyes lacking a DPED. This study indicates that eyes with DPED are at high risk for progression to both CGA and NV-AMD and for clinically important decreases in visual acuity. Drusenoid pigment epithelial detachments appear to progress through a life cycle involving the later development of hypopigmentation and calcified drusen, and, for eyes not progressing to NV-AMD, the final development of CGA or hypopigmentation. The study appears in the March 2010 edition of the journal Ophthalmology.

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Autologous translocation of retinal pigment epithelium (RPE) and choroid is not effective for the treatment of neovascular AMD after an average follow-up of 11 months. In the present study, 12 eyes which underwent surgery for neovascular AMD were included in the study. The surgical procedure included extraction of the submacular neovascular complex; preparation of a full-thickness graft consisting of RPE, Bruch's membrane and choroid; and translocation of the graft to the macular area. Comparing BCVA preoperatively and at the end of follow-up, BCVA had improved in six eyes, was unchanged in three eyes, and had deteriorated in three eyes. Surgery-associated postoperative complications impairing the functional outcome occurred in five eyes, including rhegmatogenous retinal detachment and proliferative vitreoretinopathy. Revision surgery had to be performed in four eyes (30%). The investigators state that functional results of surgery were rather disappointing. The researchers state that in selected cases of neovascular AMD unresponsive to other treatment options, autologous translocation of RPE and choroid may still be considered. The research is published in the March 2010 edition of Acta Ophthalmologica.

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Acucela Inc. and Otsuka Pharmaceutical Co. have announced that they have received Fast Track designation from the U.S. Food and Drug Administration (FDA) for ACU-4429, an investigational oral treatment for dry AMD. The FDA's Fast Track programs are designed to facilitate the development and expedite the review of new drugs that demonstrate the potential to address unmet medical needs. There are currently no therapies approved to treat dry AMD. ACU-4429 utilizes Acucela's proprietary visual cycle modulation (VCM) technology. Preclinical data indicate that ACU-4429 slows the rod visual cycle, resulting in decreased accumulation of a toxic by-product that is the precursor of lipofuscin. The accumulation of lipofuscin in the retina has been implicated in a number of degenerative retinal diseases, including AMD. ACU-4429 is administered orally as a pill, rather than by injection into the eye. After presenting successful Phase 1 data at several medical conferences in 2009, Acucela and Otsuka Pharmaceutical launched the ENVISION Clarity Trial, a Phase 2 clinical trial of ACU-4429 in patients with dry AMD in January 2010.

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pSivida Corp., reports that new 24-month data from the FAME Phase 3 study for Iluvien (fluocinolone acetonide) therapy of diabetic macular edema (DME) was presented at the Angiogenesis 2010 meeting. Iluvien is an investigational, extended release steroid intravitreal insert that is being developed for the treatment of DME. The FAME (fluocinolone acetonide in diabetic macular edema) study enrolled 956 patients to study Iluvien for treatment of DME. The enrollees were randomized 2:2:1 to receive the high dose Iluvien, low dose Iluvien, or a sham procedure. Among the new efficacy data reported, over 50% of Iluvien low dose patients gained at least 5 letters at 24 months, and over 75% low-dose patients received only a single administration of Iluvien. Over one-third of the one-administration patients gained more than 15 letters at 24 months. Also reported was additional safety data. Patients receiving low dose Iluvien were slightly more likely to develop glaucoma (2.7% Iluvien versus 1.1% of control) and were approximately twice as likely to develop cataract (80% of Iluvien versus 45% of control) and approximately three times more likely to have cataract surgery.

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Intravitreal Avastin (IVB) and intravitreal steroid (triamcinolone acetonide, IVTA) are equally effective in treating patients with macular edema secondary to branch retinal vein occlusion (BRVO). The current study is a retrospective comparative case series of 134 consecutive patients that were treated with either IVTA or IVB for macular edema secondary to BRVO. Visual acuity and central macular thickness improved significantly in both groups 12 months after injection (p < 0.001). Neither visual acuity (p = 0.892) nor macular thickness (p = 0.612) improvements were statistically significantly different in the two treatment groups. The investigators conclude that steroid and Avastin injections were similarly effective in treating macular edema secondary to BRVO. However, the IVTA group showed longer mean improvement duration and less disease recurrence, and required fewer injections than the IVB group. The study appears in Graefe's Archive of Clinical and Experimental Ophthalmology.

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Intravitreal Avastin is effective for myopic CNV, but vision gains are lost after 2 years of follow-up. In this prospective non-randomized, interventional case series, 19 highly myopic eyes from 18 patients with subfoveal and juxtafoveal CNV were treated by three monthly intravitreal injections of Avastin. Eleven eyes were treatment naive and eight eyes had been previously treated by PDT. BCVA averaged 0.54 logMAR at baseline; 0.40 logMAR at 1 year; and 0.47 logMAR at 2 years (p = 0.04 and p = 0.20, respectively). Re-treatment was performed in 4 eyes during the first year and 4 eyes required one re-injection during the second year. The investigators conclude that intravitreal Avastin seems to be effective for subfoveal and juxtafoveal CNV in highly myopic eyes. However, vision gain is no longer significant by the end of the second year. The study appears in Graefe's Archive of Clinical and Experimental Ophthalmology.

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