POSITIVE RESULTS FROM THE PHASE III MARINA STUDY OF THE investigational anti-VEGF drug Lucentis (ranibizumab, Genentech) in 716 patients with wet age-related macular degeneration were released last month. In addition to meeting the study's primary efficacy endpoint of maintaining vision in patients with wet AMD, secondary endpoint results show there was a 17-letter difference in mean change in visual acuity from study entry between patients treated with Lucentis (regardless of 0.3 mg or 0.5 mg dose) and those in the control group, as measured by ETDRS. At 12 months, patients treated with Lucentis gained an average of seven letters in visual acuity compared to study entry, while those in the control group lost an average of 10.5 letters. One-year data from the study were presented at last month's meeting of the American Society of Retina Specialists in Montreal.
"These data are very compelling because, for the first time, we have a potential treatment which has been shown to improve vision in a significant number of patients with wet AMD as opposed to just slowing progression of vision loss," said Joan W. Miller, MD, retina specialist at the Massachusetts Eye and Ear Infirmary. who presented the data.
An analysis of the one-year data showed that adverse events were similar to those seen in earlier trials of Lucentis. Common side effects occurring more frequently in the Lucentis arms 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 uncommon (<1 percent) and included uveitis and endophthalmitis. There appeared to be no imbalance in serious non-ocular adverse events.
Lucentis is a humanized therapeutic antibody fragment developed at Genentech and designed to bind and inhibit VEGF-A, a protein that is believed to play a critical role in angiogenesis.
Additional key study findings:
• 95 percent (452/478) of Lucentis-treated patients lost fewer than 15 letters compared to baseline, the primary endpoint of the study, compared with 62 percent (148/238) for the sham injection control group.
• 25 percent (59/238) of patients treated with 0.3 mg of Lucentis and 34 percent (81/240) treated with 0.5 mg of Lucentis improved vision by a gain of 15 letters or more compared to approximately 5 percent (11/238) of patients in the control group.
• Nearly 40 percent (188/478) of Lucentis-treated patients achieved a visual acuity score of 20/40 or better at 12 months compared to 11 percent (26/238) in the control group.
Earlier, Genentech announced it has requested a fast-track designation for the Lucentis development program in wet AMD. If granted by the Food and Drug Administration, this could enable Genentech to begin a rolling Biologics License Application filing by the end of 2005.
MARINA, the Minimally classic/ occult trial of the anti-VEGF antibody ranibizumab (formerly, RhuFab) in the treatment of neovascular AMD, is a Phase-III study of 716 patients in the United States with minimally classic or occult wet AMD who were randomized 2:1 to receive intravitreal Lucentis injections or a control regimen. The control regimen consisted of a sham injection, meaning the treating physician prepares and anesthetizes the patient's eye but does not perform an injection. Patients treated with Lucentis were further randomized to receive either a 0.3 mg or 0.5 mg dose of Lucentis once a month for two years.
Exclusion criteria included prior subfoveal laser treatment, verteporfin photodynamic therapy or experimental treatments for wet AMD. Patients participating in the MARINA study could receive PDT therapy if they converted to predominantly classic disease while on the study or if they had small, active minimally classic or occult lesions and lost 20 letters or more in visual acuity on two consecutive physician evaluations. As a result, 11 percent (25/238) of patients in the control group, 0.4 percent (1/238) of patients in the Lucentis 0.3 mg group and no patients in the 0.5 mg group received PDT in the first year of the study.
Genentech and Novartis Pharma AG are conducting an additional Phase-III study of Lucentis, ANCHOR (anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularization in AMD). This is a randomized, multi-center, double-masked, active treatment-controlled study comparing two different doses of Lucentis to PDT in 423 patients. The trial is ongoing in the United States, Europe and Australia in patients with predominantly classic wet AMD. Results from this study are expected in the fourth quarter of 2005.
Genentech is conducting an additional Phase-IIIb study, PIER, a multicenter, randomized, double-masked, sham injection-controlled study comparing one of two doses of Lucentis to sham injections in 184 patients in the United States with wet AMD. In this trial, Lucentis is administered once per month for the first three doses followed thereafter by doses once every three months for two years. Results from this study are expected in the first quarter of 2006.
Genentech recently began enrollment in the HORIZON Phase III open-label extension study, which allows eligible patients who have completed participation in certain other Lucentis clinical studies to continue to receive the investigational drug.
New Compound May Cut Risk of Diabetic Vision Loss
INITIAL RESULTS OF A PHASE III CLINICAL TRIAL DEMONSTRATED that 32 milligrams per day of the PKC-beta inhibitor ruboxistaurin was well-tolerated and may reduce the risk of moderate vision loss, especially in patients with diabetic macular edema.
The multicenter international study was reported in the July issue of Diabetes. The purpose of the PKC-Diabetic Retinopathy Study (DRS) was to evaluate the safety and effect of ruboxistaurin on retinopathy progression or visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy. In the double-masked, randomized multiple-dose study, 252 patients with type 1 or type 2 diabetes received either ruboxistaurin or a placebo over a period of three to four years. The study measured the effect of three orally administered doses of 8, 16, or 32 mg/day on progression of diabetic retinopathy, moderate visual loss and sustained moderate visual loss. The study was conducted at Boston's Joslin Diabetes Center and medical centers across the United States as well as in Canada, Denmark, the Netherlands and the United Kingdom.
Ruboxistaurin inhibits the activity of protein kinase C. PKC is essential to the normal production of energy in the body, but a specific form of the enzyme—PKC-beta— has been linked to diabetic complications of the eye and other parts of the body. Ruboxistaurin was designed to be selective for the single PKC-beta isoform, which contributes to the inhibitor's excellent safety profile, according to the researchers.
"[Although ruboxistaurin] did not prevent progression to proliferative diabetic retinopathy, it may reduce the risk of moderate vision loss caused by macular edema," said study chairman Lloyd Paul Aiello, MD, PhD, an associate professor of ophthalmology at Harvard Medical School. "If these findings hold true in a currently ongoing larger clinical trial, then [ruboxistaurin} may eventually offer a new treatment option for patients with diabetes, especially in light of the lack of serious side effects reported to date." The PKC-DRS study was funded by Eli Lilly and conducted by the PKC-DRS Study Group.
Fruit, Veg Intake Lowers Women's Cataract Risk
A HIGH INTACK OF FRUIT AND VEGETABLES MAY HAVE A MODEST protective effect on cataract, according to a report in June's American Journal of Clinical Nutrition. Researchers at Boston's Brigham and Women's Hospital, Harvard Medical School, and the Harvard School of Public Health analyzed data on cataract in relation to total fruit and vegetable intake at baseline in 1993 in a prospective cohort of 39,876 female health professionals with the use of a validated, semiquantitative food-frequency questionnaire.
A total of 35,724 of these women were free of a diagnosis of cataract at baseline and were followed for incident cataract and cataract extraction. During an average of 10 years of follow-up, 2,067 cataracts and 1,315 cataract extractions were confirmed. Compared with women in the lowest quintile of fruit and vegetable intake, women with higher intakes had modest 10 to 15-percent reduced risks of cataract (P for trend < 0.05).
Am J Clin Nutrition 2005;81:1417-1422.