As the debate rages over whether Lucentis or Avastin is the drug of choice for treating wet AMD, several papers appeared in the literature last month that adds fuel to the fire. The new research makes choosing between these two drugs more difficult than ever.

First, a retrospective chart review appearing in the British Journal of Ophthalmology compared patients receiving Lucentis or Avastin for exudative AMD. It finds that both drugs are equally effective in decreasing macular thickness and volume, but than Avastin lasts longer. Good, right? Well, not so fast.

In a paper appearing in Graefes Archive of Clinical and Experimental Ophthalmology, researchers find that Avastin, but not Lucentis, accumulates within retinal pigment epithelial (RPE) cells. The study, which examined pig eyes, concluded that there are substantial differences in the pharmacokinetics of these two drugs.

In yet another study published last month, this time in Investigative Ophthalmology and Vision Science, researchers report that higher doses of Avastin, but not Macugen, were associated with greater apoptosis (cell death) of photoreceptors. The study was conducted on rabbit eyes, but the investigators suggested that their findings "may be of some importance for patients with AMD, diabetic retinopathy, or macular edema in which anti-VEGF therapy may last many months."

So, looking at these three studies, what are we to conclude? The fact that we may need to inject less frequently with Avastin is an important advantage, but the knowledge that this could be because it is more heavily absorbed into the tissue and potentially causing greater long-term toxic effects may be an important disadvantage. So, at present, neither drug is clearly superior to the other.

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Using a synthetic form of complement factor H, called CR2-fH, researchers were able to inhibit development of CNV in a mouse model of AMD.

Studies on the pathogenesis of AMD indicate that inflammation is a fundamental component of the disease process and that the alternative pathway (AP) of complement plays a critical role in driving the inflammatory response. Genetic evidence has identified variations in the complement inhibitory protein factor H as a major risk factor for AMD. Factor H is an inhibitor of the AP in humans and rodents.

This study investigated the therapeutic use of a novel recombinant form of factor H, called CR2-fH, in mouse CNV. They found that intravenously administered CR2-fH reduced CNV size, preserved retina function, and abrogated the injury-associated expression of C3 and VEGF mRNA. In therapeutically relevant paradigms involving delayed treatment after injury, CR2-fH remained effective in reducing CNV.

This study demonstrates the importance of the alternative pathway in a clinically relevant therapeutic paradigm using CR2-fH, a novel complement inhibitor specific for the alternative pathway. Of therapeutic relevance, CR2-fH slowed CNV progression when administered days after laser injury during periods of rapid CNV growth. These findings may open new avenues for the development of treatment strategies for wet AMD.

WHAT IT MEANS TO YOU: It is well established that variations in complement factor H genotype is a major risk factor for AMD, and that weak inhibition of the alternative pathway by defective factor H protein underlies this association. Researchers applied this knowledge toward the development of a new treatment for AMD. A fortified, synthetic factor H protein administered intravenously to mice was able to successfully inhibit growth of CNV. We look forward to the development of new treatments based upon this pioneering research.

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A student team in the Virginia Tech College of Engineering is providing the blind with an opportunity many never thought possible: The opportunity to drive.

A retrofitted four-wheel dirt buggy developed at Virginia Tech uses laser range finders, an instant voice command interface and a host of other innovative, cutting-edge technology to guide blind drivers as they steer, brake, and accelerate. Although in the early testing stage, the National Federation of the Blind considers the vehicle a major breakthrough.

"It was great!" said Wes Majerus, of Baltimore, the first blind person to drive the buggy on a closed course at the Virginia Tech campus this summer. Majerus called his drive a liberating experience.

In 2004, the Jernigan Institute challenged university research teams to develop a vehicle that would one day allow the blind to drive. Virginia Tech was the only university in the nation to accept the nonprofit's challenge, said Dennis Hong of Virginia Tech. The National Federation of the Blind provided a $3,000 grant to launch the project.

"I thought it would be a very rewarding project, helping the blind," said Hong, the current faculty adviser on the project. "We are not only excited about the vehicle itself, but more than that, we are excited about the potential of the many spin-off technologies from this project that can be used for helping the blind in so many ways."

Even once the technology is perfected, laws now barring the blind from driving and public perception must be changed, Mark Riccobono, executive director of the Jernigan Institute, said. "This is the piece that we know will be the most difficult," said Riccobono.

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The risk of recurrence following photodynamic therapy (PDT) is greater in patients with both polypoidal choroidal vasculopathy (PCV) lesions and AMD than in patients with AMD alone, according to a new study from Japan.

PCV is characterized by an abnormal network of polyp-like blood vessels within the choroid. It has been proposed that PCV may be a variant of neovascular AMD. AMD and PCV may coexist in the same eye. Photodynamic therapy with verteporfin has been reported to be an effective and safe treatment for PCV.

Sixty-three eyes of 63 consecutive patients with AMD or AMD plus PCV who underwent PDT were included in this study. Change in mean visual acuity and recurrence of active lesion during the follow-up period up to 2 years were assessed.

The visual acuity after PDT in AMD-only patients was maintained for 2 years after the treatment. Patients with both AMD and PCV had stable vision for 1 year but not thereafter. The risk of recurrence in patients with PVC lesions increased 82% every 3 months after 12 months.

The investigators conclude that patients with both AMD and PCV are at risk of late recurrence and massive hemorrhage 1 year after PDT.

WHAT IT MEANS TO YOU: There is a growing recognition of the significance of PCV in the long-term prognosis of patients with AMD. PCV is less responsive to anti-VEGF therapy than typical choroidal neovascularization (CNV). Some doctors are now routinely performing indocyanine green angiography in addition to fluorescein angiography on all exudative AMD patients in an effort to detect PCV early in the course of treatment. PDT seems to be the treatment of choice for this condition; however, this study shows that the long-term prognosis for PCV remains guarded.

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A study on rabbits finds that intravitreal injection of Avastin (bevacizumab) and Macugen (pegaptanib sodium) caused a significant increase in apoptotic activity (cell death) in photoreceptor cells. Avastin, but not Macugen, demonstrated greater apoptotic activity at higher doses.

Different doses of Avastin and Macugen were injected intravitreally in rabbits. The eyes were then enucleated and the retinas examined. The customary clinical dose of both drugs caused a significant increase in apoptosis in comparison to saline injection (control). In addition, repeated injections of the same dose of Avastin triggered more apoptosis than a single dose. Similar dose-related adverse effects were not found for Macugen.

Studies have found that VEGF not only induces angiogenesis, but also works as a survival factor, protecting cells from apoptosis. Withdrawal of VEGF leads to apoptosis in vitro and in vivo. A neuroprotective effect of VEGF may explain the observed increase in apoptosis following VEGF inhibition.

These findings may be of importance to patients with AMD in which anti-VEGF therapy may last many months. Further studies are needed to test these results and clarify the long-term toxic effect of anti-VEGF treatments on retinal neuronal cells.

WHAT IT MEANS TO YOU: This study reminds us that VEGF has important physiologic functions, and that blockade with anti-VEGF drugs may have potentially deleterious effects. This study would suggest that Macugen has less pro-apoptotic potential than Avastin; however, this study was funded by Pfizer (manufacturer of Macugen). Nonetheless, it is important that patients receive the least amount of drug necessary to keep the macula dry.

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A prospective survey of patients undergoing Lucentis (ranibizumab) intravitreal injection finds that the procedure was less painful than patients had anticipated.

Despite the therapeutic benefits of Lucentis, repeated injections are required as often as every 4 weeks. This study investigated the pain, anxiety, and discomfort that patients undergoing Lucentis therapy experience.

One hundred consecutive patients receiving the intravitreal Lucentis were recruited into this prospective survey. A questionnaire that covered the levels of discomfort, anxiety, and fear was administered to all of the patients 1 hour before the intravitreal injection procedure. A postoperative questionnaire was administered by telephone 2 weeks later.

During the intravitreal injection procedure, 62 patients (62%) did not experience any discomfort and 38 patients (38%) felt mild discomfort. Fifty-one patients (51%) reported that intravitreal injection was less uncomfortable than anticipated, 34 patients (34%) felt the same discomfort as expected, and 16 patients (16%) experienced more discomfort than expected. Overall, 93 patients (93%) were neither anxious nor fearful after the first injection.

The investigators conclude that intravitreal injection was less painful than anticipated and that patients are less fearful and anxious after their first injection.

WHAT IT MEANS TO YOU: When discussing anti-VEGF therapy with treatment naive patients, it is not unusual to have patients recoil at the notion of having a medication injected directly into the eye. Although it is rare to have a patient not consent to the procedure, they may do so reluctantly, and with considerable anxiety. This study provides some valuable data that provides an empirical basis for telling patients that "it's not as bad as you think".

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A team of researchers has shown that human beings can develop echolocation, the system of acoustic signals used by dolphins and bats to explore their surroundings.

"In certain circumstances, we humans could rival bats in our echolocation", said researcher Juan Antonio Martinez.

In the study, the team analyses the physical properties of various sounds, and proposes the most effective of these for use in echolocation. "The almost ideal sound is the palate click, a click made by placing the tip of the tongue on the palate, just behind the teeth, and moving it quickly backwards, although it is often done downwards, which is wrong", Martinez explains.

In order to learn how to emit, receive and interpret sounds, the scientists are developing a method that uses a series of protocols. This first step is for the individual to know how to make and identify his or her own sounds (they are different for each person), and later to know how to use them to distinguish between objects according to their geometrical properties.

Some blind people had previously taught themselves how to use echolocation by trial and error. The best-known of these are Daniel Kish and Ben Underwood. However, no special physical skills are required in order to develop this skill.

"Two hours per day for a couple of weeks are enough to distinguish whether you have an object in front of you, and within another two weeks you can tell the difference between trees and a pavement", said Martinez.

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In the EUREYE study, a positive association between diabetes mellitus and neovascular AMD was found. Participants aged 65 years and over in this cross-sectional population-based study underwent an eye examination including digital retinal photography. Data on diabetes history and potential confounders were available in 2117 control subjects without AMD, 2182 with early AMD, 49 with GA and 101 with neovascular AMD. Of all participants, 13.1% reported a history of diabetes. After adjusting for potential confounders, subjects with neovascular AMD compared with controls had increased odds for diabetes (odds ratio 1.81). Subjects with early AMD or GA had no increased odds for diabetes compared with those without AMD. The finding of an association between diabetes and AMD is not consistent with prior studies, including a meta-analysis of 3 large prospective population-based studies, that have failed to find any association between diabetes and AMD. This study was published in the British Journal of Ophthalmology.

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OXiGENE has initiated a phase 2 study of its vascular-disrupting agent Zybrestat (fosbretabulin) for treating patients with PCV, the company announced in a press release. In patients with PCV, dense clusters of polyp-like vascular structures, or polypoids, can be observed on the choroid with ICG angiography. Studies suggest that these polypoids may exist in up to one-third of wet AMD patients. To date, there are no approved therapies for PCV, and anti-VEGF and photodynamic therapies have shown limited utility. The Company believes that because Zybrestat is a vascular disrupting agent, it could target these polypoids more effectively than agents currently being used, and may have meaningful therapeutic advantages. The Company expects to announce data from the Phase 2 trial in the first half of 2010. "Assuming data from [this study] are supportive, we anticipate being in a position to initiate a phase 1 trial with topical-route Zybrestat with a rationally determined dose and schedule in 2010," John Kollins, chief executive officer for OXiGENE, said in the release.

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A retrospective review of records at a vitreoretinal clinic finds that anaphylaxis following intravenous fluorescein angiography (IVFA) developed in 4 of 1400 (0.3%) patients undergoing the procedure. Anaphylaxis is a sudden, severe, potentially fatal allergic reaction. Consecutive vitreoretinal patients who underwent IVFA between 1998 and 2005 at 1 satellite vitreoretinal clinic of Duke University Eye Center were included in this retrospective analysis. Anaphylaxis developed in 4 of 1400 (0.3%) patients within minutes after they had received intravenous fluorescein. This was the first exposure to IVFA for these 4 patients. In each case, the reaction was recognized promptly and treated with injectable epinephrine by the physician, and symptoms resolved quickly. In the literature, reports of 21 cases of anaphylaxis and 7 deaths have been published in the past 55 years. The frequency of death from IVFA has been estimated to be 1 in 222,000. In summary, although uncommon, anaphylaxis as a reaction to intravenous fluorescein does occur. As this is potentially life-threatening, prompt diagnosis and treatment are crucial. This study was published in the Canadian Journal of Ophthalmology.

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A new study finds that Lucentis improves vision and decreases uveitis-associated cystoid macular edema (CME) in patients that have failed to respond to standard corticosteroid therapy. Uveitis is an inflammatory condition that affects the uvea. Cystoid macular edema (CME) is the most common cause of visual impairment in uveitis patients. While corticosteroid injections may reduce CME and improve vision, the effect is often variable. In this case series, 7 consecutive patients with controlled uveitis and refractory CME who had failed corticosteroid treatment were studied. Intravitreal Lucentis injections were given monthly for 3 months, followed by reinjection as needed. At 3 months, the mean increase in acuity for the 6 patients who completed follow-up was 13 letters, and the mean decrease in CRT was 357 um. Both VA and CRT improved significantly between baseline and 3 months. The researchers conclude that intravitreal Lucentis led to an increase in VA and regression of uveitis-associated CME in patients refractory to or intolerant of standard corticosteroid therapy. This study was published in the American Journal of Ophthalmology.

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Systemic infusion of Avastin may be offered to some patients with wet AMD who refuse or cannot receive intravitreal injections, according to a study published in the British Journal of Ophthalmology. Systemic Avastin may be especially advantageous for patients with bilateral neovascularization. A total of 8 patients were enrolled in the randomized, placebo-controlled, double-masked study; 4 patients received systemic Avastin and 4 received sodium chloride (placebo). Lesion size was reduced by 0.5 mm in patients in the Avastin group, and macular thickness was reduced by 103.6 um after 24 weeks of follow-up. Overall, visual acuity remained stable in seven eyes and decreased in one. The researchers conclude that systemic Avastin could be offered to patients with exudative AMD in both eyes and/or patients who refuse intravitreal injections if blood pressure is normal and there is no history of thrombosis. These findings are consistent with an earlier report that found intravenous Avastin to be safe and effective in treating patients with neovascular AMD.

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A new study involving mice finds that a diet with high levels of omega-3 fatty acids results in slower lesion progression, with improvement in some lesions. A diet high in omega-3 fatty acids has been found to protect against a variety of diseases including atherosclerosis and Alzheimer's disease. This study evaluated the effect of a diet that is high in omega-3 polyunsaturated (n-3) fatty acids on the retinas of mice that develops AMD-like retinal lesions. AMD-developing mice that ingested a high n-3 fatty acid diet showed a slower progression of retinal lesions compared with the low n-3 fatty acids group. Some mice also had lesion reversion. The authors suggest that "a diet enriched in EPA and DHA can ameliorate the progression of retinal lesions in their mouse model of AMD." The researchers conclude that these findings are in line with human studies of AMD risk reduction by long-chain n-3 fatty acids. The study was published in the American Journal of Pathology.

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A study finds that persons undergoing anti-VEGF therapy for wet AMD were more likely to be hyperopic (far-sighted) than persons undergoing cataract surgery at the same institution. The study included 379 patients who underwent anti-VEGF therapy for exudative AMD, and 191 patients without exudative AMD who underwent cataract surgery. The AMD group compared with the cataract group showed a significantly shorter axial length (23.31 mm vs 24.20 mm) and was significantly more hyperopic (0.65 D vs -1.71 D). After the exclusion of pseudophakic AMD patients and matching by age and gender, the difference of refractive error and axial length between both groups remained statistically significant. The investigators conclude that short axial length was associated with AMD. This is consistent with other research that has frequently identified hyperopia as a risk factor for AMD and myopia are relatively protective. It is unclear why hyperopia is a risk factor for AMD. The study was published online July 10 by the journal Eye.

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ThromboGenics announces that microplasmin, which is in Phase III trials for the treatment of vitreomacular adhesion, is progressing according to schedule. Focal vitreomacular adhesion is a condition in which the vitreous gel has an abnormally strong adhesion to the retina. These adhesions can cause vessel and retinal distortion which results in deterioration in the patient's vision. Vitreomacular adhesion is also potentially associated with a much poorer prognosis in certain eye conditions, including AMD. Both of the Phase III studies are will evaluate 125 ug of microplasmin versus placebo in the intravitreal treatment of patients with focal vitreomacular adhesion. The trials will enroll a total of approximately 320 patients each across approximately 40 centers in the North America and Europe. The primary endpoint of the trials is the non-surgical resolution of focal vitreomacular adhesion within one month. It is estimated that the studies will be completed by the end of 2010.

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An editorial in the Indian Journal of Ophthalmology explores the legal and ethical implications of off-label Avastin use for the treatment of AMD. The editorial finds that the legal arguments against off-label Avastin are weak. The author was unable to find anyone with legal or regulatory authority in India to suggest that intravitreal use of Avastin was in any way in violation of legal standards. The editorial then countered the arguments set forth by Roche, the manufacturer of both Avastin and Lucentis, that intravitreal injection of Avastin was potentially less safe and effective than Lucentis. The author found little evidence in support of these claims, with one possible exception - the risk of contamination of the drug during making up of smaller samples for intravitreal use. The author believes that this risk can be minimized by recruiting a compounding pharmacy to prepare the drug. Finally, the editorial addresses the ethical implications of off-label Avastin use. He decides that there are no ethical dilemmas here unless new evidence emerges to suggest that Avastin is less safe or effective than Lucentis.

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