SAILOR Points to Good Safety Profile for Ranibizumab
One-year data on the phase 3b SAILOR (Safety Assessment of Intravitreal Lucentis for AMD) trial showed the drug was safe and was not associated with higher rate of stroke, according to principal investigator David S. Boyer, MD, speaking at Bascom Palmer Eye Institute's Angiogenesis, Exudation, and Degeneration 2008 meeting in Key Biscayne, FL.

The study included approximately 4,300 patients with all subtypes of new or recurrent active subfoveal wet age-related macular degeneration (AMD) who were treated with 0.3-mg or 0.5-mg doses of intravitreal ranibizumab (Lucentis, Genentech). Results were based on information gathered from cohort 1, which included 2,378 patients.

One-year results demonstrated that although the US Food and Drug Administration (FDA) approved dose of Lucentis (0.5 mg) trended toward a higher incidence of stroke (1.2% vs. 0.7% in the 0.3 mg dose group) the results were not statistically significant (P=.21).

The stroke rate in the general US population (65 years of age or older) is 1.4%, according to Anne E. Fung, MD, who presented at the same meeting on the rates of arterial thromboembolic events in Medicare patients.

"I think that we over-analyzed the 6-month data; perhaps it was blown a bit out of proportion in comparison to all of the other studies out there at the time," Dr. Boyer said in a telephone interview with Retina Today. "Genentech reported the 6-month data, as it should have. But I think that [the results of SAILOR] are one of the reasons you wait for a year to get the complete data. We now see that there was no probable statistical significance—the numbers just caught up by the end of the trial. If we examined the data for a longer period of time, those numbers for the two dosing groups might even come closer in line to each other."

As SAILOR was a 1-year study, there are no further plans to continue the trial, Genentech spokeswoman Krysta Pellegrino told Retina Today. Results for the second SAILOR cohort (approximately 1,900 patients), however, will be available sometime later this year.

One-year SAILOR efficacy data for cohort 1 also suggested that treating patients with Lucentis on an as-needed basis may be less effective than monthly dosing, Dr. Boyer said. In general, patients in both dose groups received the required three initial injections, plus an additional 1.6 injections for a total 4.6 injections over 12 months.

"Mandatory exams were held at 3, 6, 9, and 12 months, and that certainly was not adequate follow-up. I strongly suggest that doctors follow up in between, as well."

Patients in the 0.5-mg treatment-na•ve group showed a 7-letter improvement after 3 consecutive months of treatment and a mean of 2.3 letters after 1 year. More than 19.3% in this dosing group also gained 15 or more letters. This is compared with the 0.3 mg treatment na•ve group; they measured a 5.8 letter gain after 3 months, and a 0.5 letter gain after 1 year.

NIH Launches Lucentis, Avastin Comparison Trials
The National Eye Institute (NEI) of the National Institute of Health (NIH) announced the start of a multicenter clinical trial to compare the relative safety and effectiveness of ranibizumab and bevacizumab (Avastin, Genentech).

"This clinical trial will evaluate whether the treatment burden for patients can be reduced without compromising effectiveness," said Paul A. Sieving, MD, PhD, director of the NEI.

The Lucentis—Avastin Trial (CATT) will monitor the outcomes of 1,200 patients who will be treated with either:

• Injection of either bevacizumab or ranibizumab on a fixed schedule of once every 4 weeks for 1 year, with the patient randomly assigned to either an injection of ranibizumab every 4 weeks, or on a variable schedule depending on their response to treatment, in the second year; or
• The injection of either bevacizumab or ranibizumab on a variable schedule.

The clinical trial will be conducted at 47 clinical centers across the country. For a list of centers, eligibility recruitments, and other information, go to: www.nei.nih.gov/CATT.

New Complex Retina Detachment Code Error Corrected
According to an American Society of Cataract and Refractive Surgeons member communication, Centers for Medicaid and Medicare Services has issued an emergency notice to correct an error in the relative value units of the new complex retina detachment code.

Retina specialists grew concerned after noticing the typo, which created "a decreased rank order anomaly with other retina codes, and a significant decrease for complex retinal detachment repair," according to the communication.

Older Whites More Likely to Have Signs of Future Eye Disease Than Blacks
White individuals 65 years or older are more likely than black individuals to have characteristics that indicate they will develop more advanced forms of AMD, according to a report in Archives of Ophthalmology.

Susan B. Bressler, MD, of the Johns Hopkins University School of Medicine, Baltimore, and colleagues analyzed the eyes of 2,520 individuals (average age 73.5 years) of whom 1,854 were white and 666 were black. Photo-graphs of each eye were taken and assessed for several characteristics of AMD, including drusen and abnormal blood vessel growth.

Larger drusen, connected drusen, those covering a larger area and those closer to the center of the eye were more likely to be found in whites. Whites were also more likely to already have advanced AMD (1.7% whites vs 1.1% of blacks) and geographic atrophy, another form of AMD (1.8% of whites vs 0.3% of blacks).

"Such data strongly suggest that white individuals are more likely to progress to advanced vision-disabling AMD (certainly to geographic atrophy) than black individuals," the authors conclude. The data also suggest that black individuals may have a mechanism for protection against AMD and other eye abnormalities. "The absence of racial differences in these early lesions in the pericentral area suggests that further research is warranted on factors that protect black individuals from lesions in the central zone or promote central lesions in white individuals."

Fluorescent Cells Give Early Warning for Eye Disease
Researchers at the University of Michigan have shown that a new metabolic imaging instrument can accurately detect eye disease at a very early stage.

In a study published in the Archives of Ophthalmology, researchers used the instrument to measure the degree to which a subtle visual condition affected six women. Victor M. Elner, MD, PhD, and colleagues studied women who had recently been diagnosed with pseudotumor cerebri, a condition that mimics a brain tumor and often causes increased pressure on the optic nerve that can lead to vision loss.

Because each woman's disease was in an early stage, the researchers could evaluate how accurately the flavoprotein autofluorescence (FA) instrument would detect vision loss as compared with visual acuity, visual field, and pupillary light response. In each case the imaging instrument provided results that were equal to and often superior to the standard tests.

"Metabolic stress occurs at disease onset and causes altered flavoprotein redox activity that increases FA. Using a new method to measure ocular FA, we studied women with subtle visual dysfunction due to pseudotumor cerebri," the authors wrote. "Each FA value was greater in the more affected eye of each woman with pseudotumor cerebri, permitting identification of that eye in each case."

Flavoprotein autofluorescence values averaged 60% greater in more affected eyes of women with pseudotumor cerebri, but not between control eyes. These results demonstrate the clinical utility of FA and may permit early detection and monitoring of retinal and optic nerve diseases, the authors said.

Researchers Query FDA on Updating Drug Approval Requirements
Scientists and the FDA are discussing how new technologies in ophthalmology, which make it possible to collect better data about experimental treatments, might affect requirements for FDA clinical trials, according to a news release from the Association of Research in Vision and Ophthalmology (ARVO).

Researchers from the NEI, major US universities, and research centers met in a roundtable discussion with FDA representatives to discuss endpoints and clinical trial strategies for evaluating new treatments for AMD, diabetic retinopathy, and other retinal disorders.

The FDA currently recommends that clinical study sponsors compare changes in visual function (measured by visual acuity) as the primary endpoint in assessing the effect of a new treatment compound. According to the release, many scientists feel that the FDA parameters may not be sensitive enough for studying diseases that progress slowly, or for study the effect of new antivascular endothelial growth factor (anti-VEGF) agents commonly used for treating AMD. They wondered if new technologies (eg, OCT) could more efficiently detect a treatment's effectiveness, and hasten the translation of clinical trials into better treatments.

The FDA representatives said they already set "the bar high" for new drug approvals. The agency, however, might consider "a lower bar and different endpoints for clinical trials, provided the degree of risk to the patient is correspondingly smaller and the trial sponsor is able to justify the clinical relevance of the new endpoints," the release said.

VEGF Neutralization May Damage Brain Vessels
New research from the Schepens Eye Research Institute in Boston may help explain why bevacizumab causes potentially fatal brain inflammation in certain patients. After mimicking the drug's activity in mice, scientists found that it damaged the cell lining in the brain that holds cerebral spinal fluid after it is produced, according to the study published in the Journal of Experimental Medicine.

"This finding is significant because it may ultimately modify the way we use systemic drugs that block blood vessel growth, and it also suggests that VEGF plays a more extensive role in the body then we previously thought," said Patricia A. D'Amore, PhD, and lead investigator for the study.

Dr. D'Amore and colleagues found that VEGF normally protects the specialized cells that create a seal between the brain and ventricle and thus prevent fluid from leaking into the brain. When VEGF was blocked in mice, these cells were damaged and the animals developed brain lesions. The authors suspect that bevacizumabs' side effects in humans may be caused by a similar phenomenon. These symptoms, however, only occur in a small amount of patients.

Genetic Discovery in Development of Retinoblastoma
Researchers from St. Jude Children's Research Hospital in Memphis believe that a gene called N-myc coordinates the growth of the retina and other eye structures to ensure that the retina has the proper thickness necessary to convert light from the lens into nerve impulses that the brain transforms into images. The study, reported in Genes and Development, represents the first example of the Myc gene in retinal development, according to the authors.

"Genes in the Myc family carry out vital roles during prenatal development by regulating the proliferation, size, differentiation, and survival of cells. Myc genes are also protooncogenes. Malfunctioning N-myc genes are often associated with pediatric neural cancers (eg, neuroblastoma, medulloblastoma, and retinoblastoma)," the authors said.

In the study, researchers discovered the N-myc is not involved in regulating cell survival or neuronal differentiation in the developing retina. The gene, however, is crucial for the proper proliferation of retinal cells. In mice with inactivated N-myc, the volume of the retina was significantly smaller than in mice with the normally functioning gene.

The team found no evidence of an increase in progenitor cell deaths between normal and N-myc deficient retinas. They then concluded that the smaller retinas likely resulted from an N-myc–related proliferation defect in the progenitor retinal cells.

"N-myc's activity occurs early in the cascade of reactions that control development of the retina in other eye components. Therefore, when something deactivates the gene, the result is both a reduction in retinal progenitor cell proliferation and a reduction in the signaling cues that coordinate the growth of the eye and retina," researchers hypothesized.

European Clinical Trial For Argus II Retinal Implant, Announced
Second Sight Medical Products Inc. (Slymar, CA) has completed enrollment of the first phase of a US FDA-approved clinical study of the Argus II Retinal Prosthesis System. The company also announced that enrollment at key European sites is underway as studies continue in Mexico.

The Argus II is the second generation of an electronic retinal implant designed for the treatment of blindness due to retinitis pigmentosa (RP). The Argus II implant consists of an array of 60 electrodes that are attached to the retina. These electrodes conduct information acquired from an external camera to the retina to provide a rudimentary form of sight to implanted subjects.

The development of this technology was largely supported by the NEI, the NIH, and the Department of Energy's Office of Science Artificial Retina Project, which is helping to advance the implant's design and construction.

Ten subjects were recruited for the phase 1 trial at four leading ophthalmic centers throughout the United States. This 3-year investigational device exemption trial is the only long-term study of a retinal prosthesis currently being conducted anywhere in the world.

"The pioneering efforts of the individuals that participate in this clinical trial will lead to advances for the many people in the world afflicted with blindness," said Mark Humayun, MD, PhD, Professor of Ophthalmology, Biomedical Engineering, and Cellular and Neurobiology at the Doheny Eye Institute, Keck School of Medicine of University of Southern California. Dr. Humayun was the first physician to perform an Argus II implantation procedure in the United States.

MacuSight Announces Positive Preliminary Results From Phase 1 AMD Study
MacuSight, Inc. (Union City, CA), announced positive preliminary data from a phase 1 study of its lead product candidate in patients with wet AMD. Similar to its phase 1 study in patients with diabetic macular edema (DME), preliminary results from this prospective study of 30 patients demonstrated that MacuSight's proprietary formulation of sirolimus (rapamycin) was safe and well-tolerated in all doses tested with two different routes of administration.

In addition, improvements in visual acuity consistent with anatomical retinal changes were observed following a single administration of sirolimus. Pravin U. Dugel, MD, presented these findings at the Angiogenesis 2008 conference.

Dr. Dugel is a member of MacuSight's scientific advisory board, managing partner of Retinal Consultants of Arizona, clinical instructor of vitreoretinal diseases and surgery at University of Arizona, and a member of the Retina Today editorial board.

As part of the design of this randomized, open-label study, investigators evaluated the safety, tolerability and biological activity of sirolimus when delivered by either a subconjunctival or intravitreal injection. The trial showed no evidence of increased intraocular pressure, inflammatory response to treatment, or indication of progression of cataracts. Furthermore, the study provided an initial assessment of sirolimus' biological activity in AMD with patients demonstrating improvements in visual acuity despite extended duration of disease prior to entering the study. Additionally, patients experienced anatomical improvements as demonstrated by a reduction in retinal thickness. These preliminary findings demonstrated that sirolimus administered via subconjunctival injections was as effective, if not more so, than sirolimus administered via intravitreal injections.

"We are pleased to see the trial's positive safety and tolerability measures combined with promising indications of efficacy marked by consistent and rapid improvements in visual acuity and retinal thickness following a single injection of sirolimus," Dr. Dugel said. "Furthermore, the fact that patients in the subconjunctival injection arms exhibited efficacy measures equal to, and in some cases greater than, those in the intravitreal injection arms indicates that this product also has the potential to offer physicians and patients significant safety and ease of administration advantages."

Genentech Announces Changes to Lucentis Access Program
Beginning this month, Genentech will implement enhancements to patient and provider support programs for ranibizumab injection (Lucentis).

New enhancements include:

• Phone confirmation that a patient who is uninsured or denied coverage, is or may be eligible to free drug within 48 hours in most cases.
• Conditional enrollment for eligible patients with inconclusive insurance coverage who otherwise qualify medically and financially, faxed to the physician's office.
• Increased support to independent nonprofit copay organizations, with a focus on groups with fast and efficient processes in place (ie, the Chronic Disease Fund).
• Expanded eligibility criteria for all of Genentech's products' access programs, to include patients who meet the approved medical criteria and have an annual adjusted gross income of up to $100,000 vs the previous amount of $75,000, as well as patients who have reached their maximum lifetime insurance limits.

Physicians can contact Lucentis Access Solutions and the Genentech Access to Care Foundation at +1 866 724 9394, or www.LucentisAccessSolutions.com

Sirion Acquires Ophthalmic Product License
Sirion Therapeutics (Tampa, FL) has entered into an exclusive licensing agreement with Bridge Pharma (San Francisco) for the worldwide rights to develop and market topical ophthalmic formulations containing Bridge Pharma's proprietary antiinflammatory agent norketotifen.

Under the terms of this licensing agreement, Sirion will have the rights to manufacture, sell, and distribute norketotifen for ocular use either alone or in combination with other drugs.

Company Awarded for Research in OCT Technology
Bioptigen, Inc., (Triangle Park, NC) has been awarded the Frost & Sullivan 2007 North American Excellence in Research Award for its work in ophthalmic optical coherence tomography (OCT).

"Bioptigen and our collaborators in academia and industry recognize the importance of our spectral domain (SD) OCT implementation to preclinical research and development as well as to the clinical diagnosis of disease at its very earliest stages, " commented Eric Buckland, Co-founder and Chief Executive Officer of Bioptigen, Inc. "This recognition is validation of our vision for the current and future potential of SDOCT. Our emphasis looking forward is to extend the capabilities of our systems for functional imaging, and to search for new biomarkers of disease processes that will be uniquely accessible through the power of SDOCT," added Joseph Izatt, Bioptigen' s co-founder and Chief Technology Officer, and Professor of Biomedical Engineering and Ophthalmology at Duke University.

Disease Leads to Vision Loss More Frequently in Blacks
Black people are more likely to lose vision as a result of idiopathic intracranial hypertension, according to a study published in Neurology.

The racial difference does not appear to be based on differences in diagnosis, treatment, or access to care, said study author Beau Bruce, MD, of Emory University School of Medicine in Atlanta. Although the cause is not known, the disease affects black people more aggressively, and includes symptoms such as headache, ringing in the ears, bluriness and double vision. It is most common in young obese women.

Researchers reviewed the medical records of all patients at Emory University with intracranial hypertension over a 17-year period. Of 450 patients, 197 were black, 246 were white, five were Hispanic, and two were Asian.

Black patients were 3.5 times more likely to have severe vision loss in at least one eye, and nearly five times as likely to become legally blind than the non-black patients.

Dr. Bruce noted that the blacks in the study had other risk factors, such as higher body mass index and higher frequency of low blood iron as well as higher pressures around the brain, compared with the non-black participants. These factors could partially account for the increased risk in vision loss, he said.

Stem Cells May Regenerate Injured and Diseased Retinas
Scientists at the Schepens Eye Research Institute have discovered what chemical in the eye triggers the dormant capacity of certain nonneuronal cells to transform into progenitor cells, a stem-like cell that can generate new retinal cells, according to a study published in Investigative Ophthalmology and Visual Science.

Scientists have long assumed that Müller cells were responsible for keeping retinal tissue protected and clear of debris. In recent years, however, researchers have reported that these cells sometimes exhibit progenitor cell behavior and reenter the cell cycle by dividing and differentiating into other type of cells. Progenitor cells are similar to stem cells but are more mature and more limited into the number of cells they can become, according to a news release from Schepens.

In the study, Dong Geng Chen, MD, PhD, and colleagues from Schepens observed that when the naturally occurring chemicals—known as glutamate and aminoadipate—were injected into the eye, the Müller cells began to divide and proliferate. Researchers added each chemical separately to cultures of pure Müller cells and injected each into the space below the retina in healthy mice. When aminoadipate was added, the newly minted retinal cells migrated to where they might be needed in the retina and turned in desirable cell types. Specifically, researchers showed that by injecting the chemical below the retina, the cells give rise to new photoreceptors which are damaged by RP or AMD.

The next step, according to the release, is to test this process in animals that have been bred to mimic the aforementioned diseases.

"We believe that a drug created from the chemical aminoadipate or a similar compound has potential for healing damaged retinas," Dr. Chen said.

Blood Vessel Protein Discovered as Potential Treatment for DR
Age-related macular degeneratio and diabetic retinopathy (DR) have been treated in mice, using a drug that activates a protein found in blood vessel cells, researchers at the University of Utah School of Medicine and several other institutions announced in a new study in Nature Medicine.

Damage from both diseases was reduced when the protein, Robo4, was activated in mice models that simular AMD and DR.

"Many diseases are caused by injury or inflammation destabilizing blood vessels and causing them to leak fluid into adjacent tissues as well," said Dean Y. Li, MD, PhD, and lead author on the study. "The Robo4 pathway counteracts this by stabilizing blood vessels."

Companies Change Agreement on Collaboration for DME Treatment
Alimera Sciences (Atlanta) and pSivida Ltd. (Boston) have amended a license and collaboration agreement relating to Medidur FA, the investigational treatment for diabetic macular edema, and other Medidur products, according to a joint company news release.

Alimera is also increasing its equity in the future profits of Medidur FA from 50 to 80% in exchange for consideration of up to approximately $78 million to pSivida.

Consideration to pSivida includes an up-front payment of $12 million, and a $25 million milestone payment upon FDA approval of Medidur FA. Other payments of up to approximately $21 million will be made, according to the release.

— Compiled by Leah D. Farr, News and Industry Editor