Lucentis Stalls Blood Vessel Growth in Macular Degeneration

MIAMI, Oct. 5 -- Lucentis (ranibizumab) is an effective treatment for neovascular age-related macular degeneration, according to two large randomized controlled trials.

One of the reports found that over two years, on average, patients receiving injections of Lucentis gained more than one line of visual acuity on a standard eye chart, whereas those receiving sham injections lost more than two lines.

The second study found that at one year the average patient receiving Lucentis gained about two lines of visual acuity. By contrast, the average patient receiving photodynamic therapy as a sham treatment lost about two lines on the eye chart.

In both studies, which appeared, in the Oct. 5 issue of the New England Journal of Medicine. the most feared complication, bacterial infection inside the eye, occurred in one of every 2,000 injections.

However, in an editorial in the same NEJM issue, Edwin Stone, M.D., of the Carver Center for Macular Degeneration at the University of Iowa, said that now that these two trials have shown the drug's "miraculous" effects, there is a crucial next step. It is to compare Lucentis, approved for this use in June 2006, with a related drug Avastin (bevacizumab), approved for colon cancer in 2004. Avastin, used off-label for the eye, has been shown to be effective in smaller studies, he said.

The price of Avastin, Dr. Stone pointed out, is less than 10% of Lucentis'. Both drugs, marketed by Genentech, are recombinant, humanized, monoclonal antibodies that inhibit vascular endothelial growth factor (VEGF). Only their molecular weights differ.

In the first NEJM report, two years of intravitreal administration of Lucentis prevented vision loss and improved mean visual acuity in patients with minimally classic or occult choroidal neovascularization secondary to age-related macular degeneration. Rates of serious adverse events were low, said Philip Rosenfeld, M.D., Ph.D., of the Bascom Palmer Eye Institute here and colleagues.

In the phase III study, 716 patients were randomized to either 24 monthly injections of Lucentis (0.3 mg or 0.5 mg) or sham injections. The multicenter two-year, double-blind, sham-controlled study is known as the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA).

At 12 months, 94.5% of the group given 0.3 mg of Lucentis and 94.6% of those given 0.5 mg lost fewer than 15 letters of vision, compared with 62.2% of patients receiving sham injections (P

In conclusion the researchers said, these efficacy outcomes were achieved with a low rate of serious ocular adverse events and with no clear difference from the sham-treated group in the rate of nonocular adverse events.

In the second similar study in the NEJM, researchers presented one-year results from a two-year study titled, Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR).

In the multicenter, double-blind study, the investigators compared monthly injections of two different Lucentis doses (0.3 mg or 0.5 mg) with photodynamic therapy using Visudyne (verteporfin) in the treatment of 423 patients with predominantly classic neovascular age-related macular degeneration.

According to the 12-month results, Lucentis prevented central vision loss and improved visual acuity at one year, with low rates of serious ocular adverse events. Although the study was not designed to test dose efficacy, the results suggest a dose-response effect, said David Brown, M.D., of Vitreoretinal Consultants at Methodist Hospital in Houston, and colleagues.

Patients were randomly assigned in a 1:1:1 ratio to receive monthly intravitreal injections of Lucentis (0.3 mg or 0.5 mg) or sham Visudyne therapy or monthly sham injections plus active Visudyne therapy.

At 12 months, 94.3% of the patients given 0.3 mg of Lucentis and 96.4% of those given 0.5 mg lost fewer than 15 letters of visibility (moderate loss), compared with 64.3% of those in the Visudyne group (P

Nonocular serious adverse events were similar in all three groups: 14.6% (0.3 mg), 20.0% (0.5mg), and 19.6% (Visudyne).

However, nonocular hemorrhage, an adverse event that potentially reflects systemic VEGF inhibition, was higher in the Lucentis groups.

Nevertheless, the investigators reported, there was no increase for Lucentis in the rates of hypertension and proteinuria, other adverse events potentially reflecting systemic VEGF inhibition.

In summary, Dr. Brown and his colleagues said, the first-year results of their ANCHOR study and the two-year results of the MARINA study, considered together, demonstrate that Lucentis was "effective with an acceptable adverse-event profile in the treatment of all angiographic subtypes of choroidal neovascularization associated with age-related macular degeneration."

In his editorial reviewing these two studies, Dr. Stone wrote that age-related macular degeneration is now epidemic in the developed world.

In about 10% of patients, a choroidal neovascular complication develops, and is so devastating that it is responsible for the vast majority of cases of legal blindness attributable to this disease. An effective treatment for choroidal neovascularization has been sought for more than two decades, he said.

Commenting on the results of the two studies, Dr. Stone said that for any physician who has ever intentionally destroyed the fovea of a patient in an attempt to limit the eventual size of the macular scar, the results of the Lucentis studies and results for Avastin (bevacizumab) in several previous studies are exciting.

However, he said, "as with most exciting results, there remain questions that merit further investigations." Many patients might be effectively treated with fewer than the 24 monthly injections given in Dr. Rosenfeld's study, he said, urging researchers to evaluate ideal dosing for anti-VEGF drugs.

Furthermore, Dr. Stone said, a large and growing body of anecdotal experience and at least four clinical trials, though uncontrolled and short term, suggest that Avastin, used off-label, is also an effective treatment for this disease.

Tens of thousand of doses of Avastin were given nationwide, while physicians waited for Lucentis to be approved. The primary difference between the two drugs is their molecular weights (Lucentis is smaller), which might result in differing abilities to reach their site of action, he said.

These results, coupled with the fact that a single dose of Lucentis costs more than ,000 compared with less than per dose for Avastin, suggest that a head-to-head study of the two drugs and a careful evaluation of an induction and follow-up strategy with either drug are probably the next most useful steps in this field, he said.

Lucentis "is an absolutely spectacular drug compared with treatments we had in the past," Dr. Stone said. "But what if it turns out that the stuff is just as good?"

The MARINA study was supported by Genentech and Novartis Pharma. Dr. Rosenfeld reported having received consulting fees from Genentech, Eyetech, Novartis Ophthalmics, Protein Design Labs,Allergan, BioAxone, Tanox, Genaera, Jerini, Quark, and Athenagen; lecture fees from Genentech, Eyetech, and Novartis Ophthalmics; and grant support from Genentech, Eyetech, and Alcon Laboratories

Coauthors received lecture and consulting fees and grant support from a variety of firms including Genentech, Eyetech, Alcon Laboratories, Allergan, Jerini, Oxigene, Allergan,Genzyme, iScience, ISTA, Pfizer, Regeneron, Theragenics, Genaera. VisionCare, Novartis, and QLT. Two of the researchers are employees of Genentech and own Genentech stock

The ANCHOR study was also supported by Genentech and Novartis Pharma. Dr. Brown reported receiving consulting and lecture fees from Genentech, Alcon, Eyetech, Novartis, and Allergan; grant support from Alcon, Acuity Pharmaceuticals, Allergan, Alimera, Eyetech, Pfizer, Novartis, Genentech, Eli Lilly, Oxigene; he also has an equity interest in Pfizer.

Coauthors reported receiving support from Genentech, Alcon, Allergan, and Novartis, Pfizer-(OSI) Eyetech, Thea, Alimera, Oxigene, Novartis, Allergan, Genzyme, iScience, ISTA, Pfizer, Regeneron, Theragenics, VisionCare, and Jerini, and Eli Lilly Theragenics. Three of the investigators are full-time employee of Genentech and have received stock options.