GENETECH INC. ANNOUNCED LAST MONTH THAT ITS study of the investigational drug Lucentis (ranibizumab) met its primary efficacy endpoint of maintaining vision in patients with wet age-related macular degeneration when used in combination with verteporfin (Visudyne) photodynamic therapy.

Approximately 90 percent of patients maintained or improved vision (defined as a loss of less than 15 letters in visual acuity) when treated with the combination of Lucentis and PDT compared to approximately 68 percent of those treated in the control arm of PDT alone (P=0.0003) in a single-masked Phase I/II clinical. Patients treated with Lucentis plus PDT at 12 months had, on average, a significant improvement in visual acuity compared to visual acuity at study entry, a secondary endpoint, while the PDT-alone group demonstrated a decrease in mean visual acuity from baseline to 12 months. One-year data from the trial will be presented at this month's Annual Meeting of the American Society of Retina Specialists, in Montreal.

A preliminary analysis of the data showed there was an increased risk of the serious ocular adverse event uveitis in patients treated with Lucentis in combination with PDT compared to patients treated with PDT alone. An amendment to the study protocol was made after data safety monitoring identified this imbalance. After uveitis, endophthalmitis was the second most common ocular serious adverse event occurring in patients treated with Lucentis. Among non-ocular serious adverse events, the frequency of cerebral vascular events was slightly higher in those treated with Lucentis, while the frequency of myocardial infarctions was slightly higher in the PDT-alone arm. In neither case was the difference between groups statistically significant.

Lucentis is a humanized therapeutic antibody fragment developed at Genentech and designed to bind and inhibit VEGF-A, a protein that plays a critical role in angiogenesis (the formation of new blood vessels). Lucentis is designed to block new blood vessel growth and leakiness, which lead to wet AMD disease progression and vision loss.

The FOCUS (RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety) trial is a Phase I/II randomized, single-masked study evaluating the safety, tolerability and efficacy of Lucentis in combination with PDT in 162 patients with predominantly classic subfoveal wet AMD. In this study, patients were randomized 2:1 to receive PDT followed by either 0.5 mg injections of Lucentis or sham injections for 23 months. To perform a sham injection, the treating physician prepares and anesthetizes the patient's eye but does not perform an injection. The FOCUS study was conducted at 25 sites in the United States.

Lucentis is being developed by Genentech and the Novartis Ophthalmics Business Unit. Genentech retains commercial rights for Lucentis in North America (United States, Canada and Mexico). Novartis has exclusive commercialization rights for the rest of the world.

Genentech and Novartis Pharma AG recently announced top-line positive results from the Phase III MARINA (Minimally classic/occult trial of the anti-VEGF antibody RhuFab V2 in the treatment of neovascular AMD) study, a randomized, multicenter, double-masked, sham-injection controlled study evaluating the safety and efficacy of two different doses of Lucentis in 716 patients with minimally classic or occult subfoveal wet AMD. A preliminary analysis of the MARINA data showed that adverse events were similar to those seen in earlier trials of Lucentis. Common side effects occurring in the Lucentis arms more frequently than in the control group were mild to moderate and included conjunctival hemorrhage, eye pain and vitreous floaters. Serious ocular adverse events occurring more frequently in Lucentis-treated patients were rare (<1 percent) and included uveitis and endophthalmitis. There appeared to be no imbalance in serious non-ocular adverse events in the MARINA study.

Vision Advocates Target Washington
For the second year, members of the House Vision Caucus, Prevent Blindness America and the Advanced Medical Technology Association joined in Washington, D.C., for a Capitol Hill educational program aimed at increasing patient access to new technologies to detect age-related vision disorders. This year"s program expanded to include the four most common eye diseases that affect Americans over 40: cataract, diabetic retinopathy, glaucoma and age-related macular degeneration.

Kerry Solomon, MD, addressed Washington lawmakers on the impact of age-related eye diseases.

     "Age-related eye diseases are taking sight from older Americans in growing numbers, yet much of the vision loss associated with age can be prevented through early detection and treatment," said Dan Garrett, of Prevent Blindness America.
      The exhibition provides congressional leaders an opportunity to witness the potential of current technology to improve diagnosis and treatment of age-related eye diseases.

Diabetic Retinopathy Occurs in Pre-Diabetes

DIABETIC RETINOPATHY HAS BEEN FOUND IN NEARLY 8 percent of pre-diabetic participants in the Diabetes Prevention Program (DPP), according to a report presented at the American Diabetes Association's 65th Annual Scientific Sessions. Diabetic retinopathy was also seen in 12 percent of participants with type 2 diabetes who developed diabetes during the DPP. No other long-term study has evaluated retinopathy in a population so carefully examined for the presence or development of type 2 diabetes.

"These findings reinforce the recommendation that patients with newly diagnosed type 2 diabetes should be screened for retinopathy," said Emily Chew, MD, of the National Eye Institute, which funded the study. "We advise good control of blood glucose, blood pressure and cholesterol as well as regular eye exams," she added.

"Previous studies have not accurately defined when type 2 diabetes begins, so our understanding of the onset of diabetic eye disease has been limited," said Richard Hamman, MD, DrPH, vice chair of the DPP. "Now we know that diabetic retinopathy does occur in pre-diabetes. We're also seeing it early in the course of diabetes, within an average of three years after diagnosis. This adds to our understanding of the development of retinopathy and suggests that changes in the eye may be starting earlier and at lower glucose levels than we previously thought."

Pre-diabetes is a condition in which blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes. The condition is sometimes called "impaired fasting glucose" or "impaired glucose tolerance," depending on the test used to diagnose it. People with pre-diabetes have an increased risk of developing type 2 diabetes, heart disease and stroke.

"Certain retinopathy lesions are considered indicative of the presence of diabetes because they are the first retinal changes to develop in this disease," said Dr. Hamman. "Although the retinopathy seen in the DPP participants was at a very early stage and did not affect vision, eye changes typical for diabetes were found in 8 percent of our study population before they developed diabetes. These observations may lead diabetes experts to reconsider the diagnostic thresholds used to define diabetes, which are based on levels of blood glucose associated with the development of eye, nerve and kidney complications of diabetes."

DPP study chair David Nathan, MD, of Massachusetts General Hospital, pointed out that the retinopathy results are based on a random sample of only 12 percent of DPP participants, all of whom had impaired glucose tolerance, a form of pre-diabetes, when the study began. "These initial findings confirm what other studies have suggested. The complications of diabetes may begin before diabetes is diagnosed, at least by the current-day standards," he explained. "Ideally, an expanded study of the remaining 88 percent of DPP Outcome Study participants might enable us to define more appropriate diagnostic thresholds."

The Diabetes Prevention Program was a major clinical trial in 3,234 people with impaired glucose tolerance. The study's main results were announced in 2001 and reported in 2002 in the New England Journal of Medicine.

Three hundred two, or about 12 percent, of the DPP Outcome Study participants who had not developed diabetes during the study, and 588 of 876 participants who had developed diabetes, were selected to participate in the retinopathy study. To detect diabetic retinopathy, an evaluation of the fundus was performed with a special camera that provides a detailed look at the retina.

Participants with pre-diabetes and retinopathy typically had a small number of microaneurysms in the eye characteristic of early, mild retinopathy that is not yet linked to vision loss. Those who had developed diabetes in the previous one to five years had slightly more severe retinopathy. Higher average blood glucose levels and higher blood pressure were associated with the risk of developing retinopathy in the new-onset diabetic patients, similar to previous findings in people with longstanding diabetes who develop retinopathy.