ANCHOR STUDY

Final Trial Results Confirm Consistency, Superiority of Anti-VEGF Therapy

Two-year outcomes from the ANCHOR study of ranibizumab vs. PDT will be published soon.

As you peruse peer-reviewed journals between now and the beginning of next year, you'll see detailed results from the second, and final, year of the ANCHOR clinical trial. ANCHOR is the phase 3 study that compared two different doses of ranibizumab (Lucentis, Genentech) to verteporfin (Visudyne, Novartis) photodynamic therapy (PDT) for the treatment of patients with neovascular age-related macular degeneration (AMD).

The study involved 423 patients with predominantly classic, subfoveal lesions who were randomized to receive either PDT as needed every 3 months (and sham injections), monthly 0.3-mg injections of ranibizumab (and sham PDT) or monthly 0.5-mg injections of ranibizumab (and sham PDT).

A total of 343 patients completed the study (83.6% of the 0.3-mg group, 82.9% of the 0.5-mg group and 76.9% of the PDT group). The FDA based its 2006 approval of ranibizumab on 1-year data from ANCHOR, as well as the results from another pivotal phase 3 trial, MARINA.

The 2-year ANCHOR results confirm the safety and effectiveness of ranibizumab therapy, according to members of the ANCHOR Study Group. "The 2-year data demonstrate remarkable consistency in duration of effect for ranibizumab," says Jeffrey Heier, M.D., Ophthalmic Consultants of Boston. "Vision gains seen at 1 year essentially were maintained for the entire study. There was very little vision drop-off from year 1 to year 2." (See "ANCHOR Trial: Years 1 and 2".)

Visual Acuity Outcomes

Furthermore, according to Peter K. Kaiser, M.D., of the Cleveland Clinic's Cole Eye Institute, "the statistically significant vision benefit of ranibizumab over PDT for predominantly classic, subfoveal lesions was maintained from month 12 to month 24."

After 2 years of treatment, 90% of patients who were treated with 0.3-mg doses of ranibizumab lost fewer than 15 letters of visual acuity from baseline, which was the study's primary endpoint. The perecentages of patients who lost fewer than 15 letters in the 0.5-mg dose and PDT groups were 89.9% and 65.7%, respectively. Other key endpoints evaluated at 2 years were mean change in visual acuity and percentage of patients gaining 15 or more letters of visual acuity from baseline. On average, patients in the 0.3-mg ranibizumab group gained 8.1 letters; patients in the 0.5-mg ranibizumab group gained 10.7 letters; and patients in the PDT group lost 9.8 letters. "This was a difference of 20.5 letters between the PDT group and the 0.5-mg ranibizumab group," Dr. Kaiser says.

Also, 34.3% of the patients in the 0.3-mg ranibizumab group gained 15 or more letters of visual acuity, and 41% of the patients in the 0.5-mg ranibizumab group gained at least 15 letters of visual acuity compared with 6.3% of the PDT group.

Safety Update

Dr. Heier describes the ANCHOR 2-year safety results as reassuring. "It was encouraging that the systemic safety findings of the first year didn't increase in the second year," he says. "In other words, at the end of year 1, although not statistically significant, there were more arteriothrombolic events (ATEs) in the 0.5-mg ranibizumab group than in the other two treatment groups. But after 2 years, there was essentially no difference. The differences between groups, as far as systemic safety issues, shrunk rather than grew."

Dr. Kaiser says the ATE rates between the PDT group and the 0.5-mg ranibizumab group were essentially the same, "and there didn't appear to be any signal of an increased rate associated with ranibizumab." Dr. Kaiser also explains that the rate of ocular adverse events was no different in the second year of the study than it was in the first year. He added that the injection itself seems to be relatively safe. "Over the course of the entire study, 5 patients had endophthalmitis," he said. "That translates to a rate that can be expected with an intravitreal injection."

Additional Data Analysis

Data from the ANCHOR trial have been analyzed in other ways, too. For example, subgroups based on age, gender and lesion size at baseline were evaluated to check for differences in outcomes compared with the patient groups as a whole.

"The long and short of it is ranibizumab performed significantly better than PDT across all subgroups that were analyzed," Dr. Kaiser says. "Also, greater vision gains at 12 months were associated with better vision, smaller lesions and younger age at baseline."

Mean visual acuity by month also was analyzed. "Basically, these data show that visual acuity improves rather rapidly with ranibizumab treatment and stays constant over 24 months," Dr. Kaiser says. "Vision improves and then stabilizes." According to Dr. Heier, "In general, the visual acuity benefit of ranibizumab was evident after the first few months of treatment — after the first month in many cases — and then vision stabilized. However, in some instances, patients who didn't experience that early benefit did respond later in their course of treatment."

A crossover analysis from the ANCHOR trial also is under way. In January 2006, approximately 50 study patients were offered the choice of continuing with their original treatment assignment or crossing over into a ranibizumab treatment group. Most of them elected to receive ranibizumab. Dr. Kaiser says this is a complicated analysis because patients switched groups at different times in their course of treatment. "It will be interesting to see how these patients do on ranibizumab compared with how they did on PDT," he said.

So far, according to Dr. Heier, the crossover analysis is showing that the patients who switched to ranibizumab are unlikely to lose vision, and safety hasn't been an issue. "The patients who'd been in the study the longest experienced the biggest changes in vision, but those results weren't really consistent," Dr. Heier says. "We haven't been able to draw conclusions about percentages of gains, etc., because these patients had multiple PDTs. We know that, over time, this causes a stable scar. Therefore, the patients already may have been stabilized by the time they crossed over without the potential for visual gain that treatment-naive patients experienced when first treated with ranibizumab."

Questions Remain

"The 2-year ANCHOR results confirm that in ranibizumab, we have an AMD treatment that can consistently stabilize vision and, in fact, improve vision by 3 lines or more in roughly one-third of patients," Dr. Heier says. However, he and Dr. Kaiser agree that more randomized clinical trials are needed to determine the most effective and least burdensome way to use ranibizumab outside of clinical trials. "The bottom line is that we still don't know if we have to treat monthly or whether it's safe and effective to use an as-needed treatment regimen like that used in the PrONTO study," Dr. Kaiser points out. "PrONTO achieved good results, but it's important to remember that it's a 40-patient case series from a single center. There are randomized studies currently looking at prn ranibizumab dosing vs. monthly dosing to see if the results can be replicated. But until we see those results, we simply don't know what the best dosing scheme is." nMD