January/February 2007 News
CLINICAL NEWS

Genes, Lifestyle Increase Risk of AMD
Age-related macular degeneration (AMD) risk may increase with genetic predisposition and exposure to other risk factors, including obesity and smoking, according to a report published in Archives of Ophthalmology.

Debra A. Schaumberg, ScD, OD, MPH, and colleagues at the Brigham and Women’s Hospital in Boston, studied 457 men and women with AMD to 1,071 controls who were the same age and sex as the cases, but who did not have AMD. The participants, aged 30 to 55 years, were examined when they enrolled in the study and completed a follow-up questionnaire every 2 years. The average age of AMD diagnosis was 68.7 years.

The study showed that participants with one or two copies of a variation of the complement factor H gene (CFH) were 1.98 ([Confidence Interval 95%], 1.64 to 2.40) and 3.92 ([CI 95%], 2.69 to 5.76) times more likely to develop AMD, respectively. In addition, participants with one or two copies of another gene mutation—LOC387715—were 2.38 and 5.66 times more likely to develop AMD ([CI 95%], 1.64 to 2.40 and 2.69 to 5.76, respectively). In addition, they were 22.47 times more likely to develop AMD if they smoked. Sixty-three percent of the 457 AMD cases were attributable to these two variants. Patients with both risk alleles had a 50-fold increased risk of AMD ([CI 95%], 10.8 to 237).

Cigarette smoking and obesity multiplied the risks associated with these variants, authors wrote. Genetic risk factors were not affected by regular aspirin use, fruit intake, fatty acid ratios, or alcohol consumption.

Because genetic mutations are so common, some people have questioned the utility of widespread screening for AMD risk, the authors wrote. “The existence of interactions with modifiable lifestyle factors may provide further impetus for screening individuals who are at potentially greater risk [for AMD]. Knowledge of the substantial risk of AMD among individuals homozygous for either or both of these major AMD-associated variants might help motivate these individuals to stop smoking, lose weight, modify other risk factors, and have regular eye examinations.”

Costs Associated With Caring for AMD Examined
Approximately 8 million people in the United States, aged ≥55 years, have monocular or binocular intermediate AMD or advanced monocular AMD. Jordana Schimer, MA, and colleagues, recently published a study on the impact of visual impairment on use of caregiving by individuals with AMD. The study appeared in Retina.

Researchers found that the mean annual caregiver cost was $5,038, with a range of approximately $225 for participants with the best visual acuity (20/32 or better), to more than $47,086 for individuals with 20/250 or worse vision. On average, patients with AMD received care for 4.7 days per week, and 3.7 hours per day. The spouse or other family members provided most assistance; only 27% of respondents received paid assistance, researchers wrote.

A survey evaluating the use of support, services and caregiving was developed by the authors in conjunction with the Macular Degeneration Partnership to evaluate the use of paid and unpaid caregiving for individuals with AMD, and to explore the impact of visual impairment on caregiving use. A total of 803 AMD patients responded to the survey. The sample was >55% male, with a mean age of 72.9 years. More than 60% of the respondents were married, approximately 70% lived with family, and less than 20% were working. Most respondents were diagnosed with AMD ≥3 years previously, with an increase in severity since the time of diagnosis.

“As the prevalence of AMD increases, it will become more important to consider the societal impact of this condition,” researchers wrote, “Our findings complement results of existing studies on the direct costs associated with AMD and provide support for interventions that preserve vision, thus delaying the need for caregiving.”

Researchers Analyze Photic Retinopathy in Diabetic Patients
A study published in Retina, examines the prevalence of photic retinopathy (PR) after cataract surgery in 2,573 patients, between January 2001 and December 2003. Researchers established a diagnosis rate of 16 (0.62%) for PR. Diabetes was evident in seven (43%) of these cases.

Altug Cetinkaya, MD, and colleagues, found that all 16 PR patients had undergone surgery with retrobulbar anesthesia. No lesions were described with patients who received topical anesthesia. The mean surgery duration from insertion of the lid speculum to its removal was 29.9 ±9.9 minutes (range, 18 to 45 minutes) for the seven PR patients with diabetes and 38.2 ±5.3 minutes (range 30 to 45 minutes) for the nine PR patients without diabetes. All operations were performed using the same coaxial illuminated microscope (OPMI VSIU 200 Bright Flex; Zeiss, Oberhocken, Germany).

“In line with previous studies, the observations for our seven cases suggest that there may be a relationship between diabetes and PR,” authors wrote. “On the other hand, PR is not observed in all diabetic patients. Furthermore, in our case series, the occurrence of this injury did not seem to be related to diabetic retinopathy signs, because only two of our seven patients had signs of diabetic retinopathy before cataract surgery.”

In addition, researchers found that for patients who underwent cataract surgery with retrobulbar anesthesia, the frequency of PR was still higher in the diabetes group than in the group without diabetes (7/298 vs 9/1277, respectively.)

“Our seven cases are of interest because they show that systemic vascular disease with impact on the ocular circulation may render patients more prone to phototoxic insult, especially in long-standing cases,” the authors concluded. “We recommend that cataract surgery on diabetic patients be completed as quickly as possible and that special precautions be taken intraoperatively to prevent light-induced retinopathy in all cataract operations.”

CCK-8 May Prove Therapeutic Against Diabetic Cataracts
New research from China shows that cholecystokinin octapeptide-8 (CCK-8) might be a useful therapeutic agent against diabetic cataracts. Authors of the report published in the Chinese Medical Journal, wrote, “Cataracts are considered to be formed because of an abnormal glucose metabolic pathway or oxidative stress. We explored the damaging role of ONOO—an antagonist of CCK-8—in diabetic cataractal rats lenses.”

Researchers believe an antagonizing mechanism in CCK-8 may be related to direct antagonism of ONOO, as well as its inhibition of the production of nitric oxide, which therefore decreases the formation of ONOO.

L.N. Hao and colleagues at Hebei Medical University said in the journal, “A diabetic cataractal animal model was established by peritoneal injection of streptozotocin (STZ). Thirty-six normal rats were taken as a control group; 72 were give STZ (45 mg/kg) and then divided into STZ group and CCK-8 group (peritoneal injection CCK-8).”

Data showed the STZ group developed lens opacity by 20 days that reached a high level by 60 days after STZ injection. CCK-8 group rats delayed the cataract formation … and showed a weak expression of neurotrophin and down regulation of inducible nitric oxide synthase mRNA.

AMD Associated With Hip Fractures
According to a recent study published in the American Journal of Ophthalmology, patients with atrophic AMD had an 11% greater risk of hip fractures than patients with exudative AMD or no AMD.

In a 5% random sample of 1,013,748 Medicare beneficiaries in 1995, researchers found 8,596 cases of exudative AMD and 26,942 cases of atrophic AMD. An adjusted analysis showed the risk of hip fractures was similar in cases with exudative AMD (odds ratio [OR], 1.03; [confidence index {CI} 95%], 0.95 to 1.12) compared with cases with no AMD. But the ration was significantly higher in cases with atrophic AMD (OR, 1.11; [CI 95%] 1.0 to 1.16).

In the non-AMD group, the cumulative incidence of hip fractures over the 4-year follow-up period was 4.9%. For cases with exudative AMD and atrophic AMD, it was 7.7% and 8.1%, respectively.

“Given the devastating consequences of hip fractures—a major cause of morbidity and death in elderly patients—any reduction in the frequency of hip fractures would have substantial public health impact,” the authors wrote. “Because our findings are based on Medicare claims data, future studies on the risk of hip fractures in patients with AMD are needed to further investigate this finding.”

Adults With Diabetes Fear Blindness More Than Death
Adults in the United States with diabetes fear vision loss or blindness more than they fear dying prematurely, according to results from the US portion of a seven-country survey, presented at the International Diabetes Federation 19th World Diabetes Congress, in Cape Town, South Africa.

Forty-one percent of US adults with diabetes cited vision loss, (eg, significant problems not correctable with glasses or contacts, or blindness) as what they feared the most. Only 16% of respondents cited premature death as their greatest fear.

Commissioned by the Lions Club International and Eli Lilly and Company (Indianapolis), the survey interviewed 250 US adults with diabetes on their experiences and understanding of diabetes complications.

Diabetes is the leading cause of blindness in working-age adults in the United States. Many survey participants who have not yet experienced vision loss reported being worried about losing the ability to conduct certain daily life activities, (ie, driving, 65%; reading, 61%; and continuing hobbies and interests, 43%). In addition, the study found that 69% of adults with diabetes were aware that vision loss or blindness were potential complications. Sixty percent recognized kidney disease as a complication, while only 49% recognized stroke as a complication of diabetes.

Earlier Treatment Improves Outcome in Retinopathy of Prematurity
In children with retinopathy of prematurity (ROP) researchers found earlier treatment improved retinal structure at age 2 years. According to a report published in the British Journal of Ophthalmology, of 339 children with ROP, unfavorable structural outcomes were reduced from 15.4% in conventially managed eyes to 9.1% in earlier treated eyes (P=.002) at age 2 years. Unfavorable structural outcomes included (1) a posterior retinal fold involving macula, (2) a retinal detachment involving the macula, or (3) retrolental tissue obscuring the view of the posterior pole.

Ophthalmic side effects, excluding retinal structure, from the ROP or its treatment were similar in the earlier treated eyes and the conventionally managed eyes. Long-term follow-up is planned to determine structural and functional outcomes at age 6 years.

The study, which examined infants with bilateral high-risk ROP, found that the benefit of earlier treatment endured to age 2 years, and was not counterbalanced by any known side effect caused by earlier intervention, authors wrote. Structural outcomes also remained stable from age 9 months to 2 years, but were much more notable for eyes in higher risk categories than for eyes in lower-risk categories.

Laser Treatment Ineffective for Early AMD
An extensive National Institutes of Health-supported study found that low-intensity laser treatment, thought to be possibly beneficial in slowing or preventing the loss of vision from AMD, is ineffective—both in preventing complications and vision loss. This is the major conclusion of the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT), a research study of more than 1,000 people, published in Ophthalmology.

The study was designed to assess the safety and effectiveness of laser treatment in preventing vision loss among people with large drusen in both eyes. The study examined a total of 1,052 participants aged ≥50 years, who had >10 large drusen and a visual acuity of ≥20/40. One eye of each participant was treated and the other eye was observed throughout the 5-year trial. At the end of 5 years, 20.5% of the treated eyes and 20.5% of the untreated eyes had lost three or more lines of visual acuity. Likewise, 20% of both the treated and untreated eyes progressed to advanced AMD.

“At present, the only established way to decrease the risk of vision loss in people with early AMD is to take daily supplements of vitamins and minerals [vitamins C and E, beta-carotene, zinc, and copper], “ said National Eye Institute Director Paul Sieving, MD, PhD.

Vision Problems Among Most Costly
Major vision problems among Americans aged ≥40 years, result in estimated economic costs of $35.4 billion annually, according to a report published in the Archives of Ophthalmology.

The study performed by David Rein, and colleagues from RTI International, in Research Triangle Park, NC, examined the cost of eye disease (ie, visual impairment, blindness, refractive error, AMD, cataracts, diabetic retinopathy, and glaucoma) in 2004. Three components were measured: including (1) direct medical costs, (2) other direct costs, and (3) productivity losses. Information was obtained from private insurance and Medicare claims data to estimate costs, as well as multiple published sources.

The authors found that major adult visual disorders equaled an annual total financial burden of $35.4 billion; ($16.2 billion in direct medical costs, $11.1 billion in other direct costs, and $8 billion in productivity losses) and the annual governmental budgetary impact was $13.7 billion.

Mouse Study Links Low Blood Sugar to Vision Loss
Chronic low blood sugar leads to vision loss, according to a State University of New York (SUNY) Upstate Medical University study. The study showed that metabolic stress from moderate hyperglycemia led to loss of retinal function in mice, loss of visual acuity and eventual death of retinal cells.

The study, reported in the Proceedings of National Academy of Sciences, is the first to demonstrate a metabolic-stress induced loss of vision in animals. “Linkage between low blood glucose and loss of vision in mice may highlight the importance for glycemic control in diabetes and retinal diseases related to metabolic stress as macular degeneration,” noted study author Robert Barlow, PhD, SUNY Upstate professor of ophthalmology.

To assess the effect of chronic low blood glucose on vision, researchers used mice bred to be hypoglycemic. They found that chronic hypoglycemic in these mice led to decreased retinal function, retinal cell death, and loss of visual acuity by 10 months of age, whereas mice with normal glucose levels retained visual acuity past 16 months. Restoring blood glucose to normal levels through the diet delayed vision loss in the mutant mice by several months.

The study’s finding may be of special importance to people with diabetes, who are susceptible to recurrent hypoglycemia because of intensive insulin treatment. “These actions of recurrent and chronic hyperglycemia, which our research addressed, may further underscore the importance of glycemic control by [diabetic patients],” Dr. Barlow said in a news release.

Cell Transplants Restore Sight in Blind Mice
Scientists have overcome a major hurdle in central nervous system repair to restore vision in blind mice according to a report published in Nature. The research, funded by the Medical Research Council, could have a significant impact on stem cell therapy, particularly for patients with untreatable eye diseases.

The mice had photoreceptor loss, which occurs in many human eye diseases (eg, AMD and diabetic retinopathy.) Researchers from the University College London (UCL) Institute of Ophthalmology and UCL institute for Child Health, and Robert MacLaren, DPhil, FRCS, FRCOphth, from Moorfields Eye Hospital, restored some vision to blind mice by transplanting stem cells into retina cells committed to becoming photoreceptors. In previous attempts, researchers had used undifferentiated stem cells at the earliest developmental stages. This time, however, cells were transplanted at a later developmental stage.

In order to achieve equivalent results in humans, there is a possibility of using embryonic stem cells, but it is thought this might not be necessary. “Recent research has shown that a population of cells can be found on the margin of the adult retina which have stem cell-like properties; in other words they are capable of self-renewal. These could be harvested through minor surgery and grown in the lab to become photoreceptor precursors before being reimplanted on the retina.

“This research is the first to show that photoreceptor transplantation is feasible. We are now confident that this is the avenue to pursue to uncover ways of restoring vision to thousands who have lost their sight. We will be pursuing the idea of using the stem cell-like retinal cells, particularly as these could be harvested from the affected patient, thus avoiding rejection,” said Dr. MacLaren in news release.

INDUSTRY AND BUSINESS NEWS

Lucentis Receives EU Approval
Ranibizumab (Lucentis; Genentech, San Francisco) received European Union (EU) approval as a new treatment for patients with wet AMD.

The European Commission decision comes just 11 months after submission and applies to all 27 member states as well as Iceland and Norway. Novartis (Basel, Switzerland) will launch ranibizumab in European countries throughout 2007 and 2008. In addition to the EU, Lucentis is already approved for use in patients with wet AMD in Switzerland, India and the United States. Novartis expects regulatory decisions in Australia and Canada during the first half of 2007.

Until now, available therapies have only been able to slow decline in vision. Ranibizumab has shown in clinical trials to improve vision and vision-related quality of life in a significant number of people suffering from neovascular AMD.

“The positive European Commission decision for Lucentis is a major breakthrough for the wet AMD community and gives hope to many of us,” said MacDonald Curran, chairman of AMD Alliance International, a non-profit alliance of organizations dedicated to the prevention and treatment of macular degeneration. “We now look forward to regulatory authorities in the EU member states continuing to recognize the value of Lucentis by reimbursing it as quickly as possible, to avoid unnecessary blindness.”

The pivotal studies used in the regulatory submissions of ranibizumab and recently published in the New England Journal of Medicine, show that approximately 95% of ranibizumab-treated patients maintained their vision, as defined by a loss of less than 15 letters in visual acuity. More than 68% of ranibizumab-treated patients gained some vision—defined as any increase above baseline visual acuity. To date, this gain in vision has been sustained at 2 years with monthly ranibizumab treatment.

“With Lucentis, we have a new option for wet AMD that offers real hope,” said Francesco Bandello, MD, full professor and Chairman of the Department of Ophthalmology at the University of Udine, Italy. “Lucentis offers patients the possibility that they will not only gain some vision but also independence by restoring the ability to recognize faces and do day-to-day activities.”

Ranibizumab was developed by Genentech, and Novartis Pharma AG (Basel, Switzerland). Genentech has the commercial rights to Lucentis in the US, while Novartis has exclusive rights in the rest of the world.

Compounding Firms Warned Regarding Topical Anesthetic Creams
The Food and Drug Administration (FDA) has sent a warning letter to five firms to stop compounding and distributing standardized versions of topical anesthetic creams. These creams, according to an FDA news release, are marketed for general distribution rather than responding to unique medical needs of individual patients.

The firms that have received warning letters are Triangle Compounding Pharmacy, University Pharmacy, Custom Scripts Pharmacy, Hal’s Compounding Pharmacy, and New England Compounding Center. “Firms that do not resolve violations in FDA warning letters risk enforcement such as injunctions against continuing violations and seizure of illegal products,” the FDA news release states.

In a warning letter FDA sent to Barry J. Cadden, the Director of Pharmacy and owner of the New England Compounding Center, the FDA also noted a violation with regard to the firm’s repackaging of bevacizumab (Avastin; Genentech, San Francisco). The letter states that FDA is in receipt of a complaint alleging that the firm is repackaging the injectable drug into syringes for promotion and sale to health professionals. According to the letter, “Avastin is unpreserved and is packaged and labeled in 4- and 16-mL single-use glass vials. The labeled precautions include ‘disregard any unused portion left in a vial.’ ”

The warning goes on to say that processing and repacking, including repackaging of approved drugs, is beyond the practice of pharmacy and is thus subject to the Federal Food, Drug, and Cosmetic Act (FDCA) which establishes jurisdiction over new drugs, including compounded drugs. In other words, the repackaged dosage being offered by New England Compounding Center is subject to premarket approval requirements.

The firm’s alleged promotional materials offer bevacizumab to ophthalmologists, although as the FDA points out in the letter, the drug has no approved indications in the eye. This is also a violation of the FDCA, according to FDA, as is the fact that the product lacks adequate labeling for its intended use. The letter states that the firm must notify the FDA of receipt of the letter and any corrective action that will be taken.

OCT Makes Cleveland Clinic’s Top Ten List
A panel of physicians and researchers from the Cleveland Clinic in Ohio has named ocular coherence tomography (OCT) one of the top 10 medical innovations expected to improve health care in 2007. The list, which includes therapies for cancer, asthma, and vascular disease, was released during the Cleveland Clinic’s 2006 Medical Innovation Summit.

The FDA approved the Stratus OCT (Carl Zeiss/Meditec, Inc., Dublin, CA) for ophthalmic use in 2003. Since then, ophthalmologists have used this noninvasive imaging technique to diagnose and manage glaucoma, AMD, and diabetic retinopathy.

The introduction of the Visante OCT system (Carl Zeiss,/Meditec) in 2005 expanded the utility of this technology to include high-resolution imaging of the anterior segment.

In the September 2006 issue of Cataract & Refractive Surgery Today, a sister publication to Retina Today, John A. Vukich, MD, said “I am very excited about the [Visante OCT] and feel confident that it will become a part of routine office evaluations. [It’s] application for refractive surgery includes defining the corneal flap’s thickness and assessing corneal structure. Beyond that, it will be likely have a role in calculating the size of angle- and sulcus-based phakic implants.”

IND Filed for Antisense Drug
Isis Pharmaceuticals, Inc., (Carlsbad, CA) an Isis licensee called iCo Therapeutics, has filed an Investigational New Drug application with the FDA for iCo-007, for the treatment of eye diseases including AMD and diabetic retinopathy. Designed by Isis, iCo-007 is a second-generation drug that inhibits the production of c-Raf kinase, an enzyme associated with the formation of new and often abnormal or fragile blood vessels in the eye.

C. Frank Bennett, PhD, Isis senior vice president of research, said, “Our antisense drug partnering strategy continues to be successful, enabling us to efficiently expand our pipeline and move more antisense drug candidates into the clinic. The preclinical profile of iCo-007 is further evidence of the broad therapeutic applicability of Isis technology.”

AMD Clinical Study Announces Enrollment
Othera Pharmaceuticals, Inc., (Exton, PA) is enrolling patients in a phase 2 clinical trial of Othera’s topical eye drop OT-551 in patients with geographic atrophy (GA), an advanced form of dry AMD. The study is being conducted at the National Institutes of Health Medical center in Bethesda, MD, and is designed to evaluate OT-551’s potential to reduce the loss in central visual acuity and to slow enlargement of the atrophic area in the macula. OT-551 has high bioavailability in the eye and distributes to the retina after topical dosing.

This phase II study will enroll 10 patients with bilateral GA. Patients will receive three daily doses of OT-551 ophthalmic solution over 2 years. The primary efficacy measure will be change in the BCVA. Secondary measure will include (1) change in area of GA in each eye, as measured by fundus photo grading, (2) progression to advanced neovascular or wet AMD, (3) progression of GA area based on autofluorescence, (4) changes in contrast sensitivity and (5) change in drusen area.

“GA is an unmet medical need that results in severe and irreversible loss of vision,” said Len Parver, MD, medical director of Othera Pharmaceuticals. “An eye drop like OT-551 that could potentially prevent or arrest progression would be a major breakthrough in treating this disease.”

For more information please visit www.othera.com.

Retinitis Pigmentosa Trial Seeks Participants
Second Sight Medical Products, Inc., (Sylmar, CA) received FDA approval for an Investigational Device Exemption (IDE) to conduct a clinical study of the Argus II Retinal Prosthesis System.

The Argus II is the second generation of an electronic retinal implant designed for the treatment of blindness due to retinitis pigmentosa (RP). RP causes the degeneration of photoreceptor cells in the retina, which capture and process light.

The implant consists of an array of electrodes that are attached to the retina and used in conjunction with an external camera and video processing system to provide a rudimentary form of sight to implanted patients. An IDE trial of the first generation implant (ie, Argus 16) is ongoing at the Doheny Eye Institute at the University of Southern California. This device was implanted in six RP patients between 2002 and 2004, and has enabled them to detected when lights are on or off, describe an object’s motion, count items, as well as locate and differentiate basic objects in an environment. The next generation Argus II retinal stimulator is designed with 60 independently controllable electrodes, which should provide patients with higher resolution images.

The study will be conducted in patients who:
• Have a confirmed history of RP with remaining visual acuity of bare light perception or worse in both eyes with functional ganglion cells.
• Have a history of former useful vision.
• Are aged 50 years or older.
• Reside within 2 hours of surface transport from the investigational side.
• Are able to verbally communicate in English.

The study will require each participant to be followed for at least 3 years with visits to the implanting center up to two times per week. Enrollment of subjects in the Argus II trial begins early this year.

Patients with optic nerve disease, glaucoma, diabetic retinopathy, ocular trauma, or a history of retinal detachment are not suitable candidates for this study. For more information or to recommend a patient, please contact
patients@2-sight.com; 818-833-5027.