TREATING AMD

Looking to the HORIZON of AMD Therapy

Recently released clinical data continues to demonstrate the long-term safety and efficacy of ranibizumab.

By the Editors of New Ophthalmologist

► Anti-VEGF therapy is one of the hottest topics in ophthalmology today. In this class, no agent has received more attention than ranibizumab (Lucentis, Genentech). While nonclinical considerations, such as cost, continue to spark debate, the clinical utility of this drug is clear. New research provides even more support for the long-term safety and efficacy of ranibizumab in the treatment of neovascular (wet) age-related macular degeneration (AMD).

Halting Vision Loss

AMD is a leading cause of irreversible blindness among patients over age 50. The neovascular form of the disease is characterized by the growth of abnormal blood vessels beneath the macula. Because this is the central area of the retina and the region responsible for high-resolution vision, degeneration of the macula produces severe vision loss.

There are two patterns of the disease, classic and occult. This classification is based on the appearance of lesions during fluorescein angiography. Patients with a predominance of classic lesions generally suffer more rapid and more severe vision loss than those with primarily occult lesions.

It's unclear what changes in the aging eye account for the onset of new blood vessel growth. However, the cytokine vascular endothelial growth factor A (VEGF-A) is known to promote neovascularization. Anti-VEGF agents exert their effect by targeting and neutralizing this promoter. This accounts for their antiangiogenic effect.

When ranibizumab was introduced in 2006, it dramatically changed the landscape of AMD therapy. For years, the primary option was photodynamic therapy (PDT) with verteporfin (Visudyne, Novartis). Another anti-VEGF agent, pegaptanib sodium (Macugen, OSI/Eyetech Pharmaceuticals) showed some promise. But while verteporfin and pegaptanib can slow the progression of vision loss, they rarely improve visual acuity.

Potential to Improve Vision

In contrast, several large-scale clinical studies — often carrying nautical monikers such as ANCHOR and MARINA — demonstrated the efficacy of ranibizumab for both reducing vision loss and improving visual acuity. These long-term studies found that therapy with ranibizumab was effective for at least 2 years.

ANCHOR

The ANCHOR trial¹ demonstrated the long-term clinical utility of ranibizumab in patients with predominantly classic AMD. The study, which enrolled approximately 400 patients, compared standard (0.5 mg) or low-dose (0.3 mg) ranibizumab administered monthly against PDT with verteporfin. In terms of vision loss, 96% of patients in the standard-dose group and 94% of those in the low-dose group lost fewer than 15 letters, compared to 64% in the PDT group. Looking at this from the converse perspective of visual gain, 40% of patients in the standard-dose group and 35% of those in the low-dose group experienced improvement in visual acuity of 15 or more letters, compared to 5% in the control group. Overall, visual acuity increased by an average of 11 and 8 letters in the standard and low-dose ranibizumab groups, respectively, and decreased by 9 letters in the PDT group. All of these differences were statistically significant.

MARINA

The MARINA trial² demonstrated similar results for ranibizumab, but in this trial, patients with occult or minimally classic AMD were evaluated. This approximately 700-patient trial compared the same doses and administration of ranibizumab as in ANCHOR, but in this less aggressive form of the disease, the control arm received sham injection. In terms of vision loss, approximately 95% of patients treated with ranibizumab lost fewer than 15 letters whether treated with 0.3 mg or 0.5 mg. In the control group, 62% of patients lost fewer than 15 letters. Visual acuity improved by 15 or more letters in one-third of patients treated with standard-dose ranibizumab and one-quarter of those treated with the low-dose regimen. In the control group, only 5% showed similar improvement. The net difference in visual change between treatment and control (gain of approximately 7 letters with active therapy regardless of dose compared to loss of 10 letters with sham injection) was 17 letters, comparable to that seen in MARINA.

Evaluating Adverse Events

In both ANCHOR and MARINA, the rate of serious ocular adverse events, most notably endophthalmitis and serious uveitis, was low, on the order of 1% to 2% over the 2-year treatment period. In general, the rate of nonocular adverse events also was low. Furthermore, the rate didn't differ between the ranibizumab groups and control arms, and most events were medical problems commonly seen in an elderly population.

However, both studies showed an increase in nonocular hemorrhage in the ranibizumab-treated patients compared to control. In addition, ANCHOR, but not MARINA, found a higher rate of arterial thromboembolic events in the higher-dose ranibizumab group. However, the clinical significance of these trends was unclear and the trials' authors advised the need for additional studies.

Ongoing Research Support

Data from follow-on research continue to support the long-term safety and efficacy of ranibizumab. Earlier this year, final results from Cohort 1 of the SAILOR study³ were presented at the Bascom Palmer Institute's annual Angiogenesis Meeting. Cohort 1 is the controlled phase of the study, which randomized patients to the same 0.3 mg or 0.5 mg doses employed in the pivotal efficacy studies. Cohort 2 was a follow-on, open phase undertaken to continue access to, and monitoring of safety with, ranibizumab before the drug's commercial introduction.

Reviewing the SAILOR Trial

SAILOR is the largest randomized clinical trial ever conducted in wet AMD, with about 4,300 patients. (Cohort 1 included nearly 2,400 patients.) It's a 1-year study designed to evaluate the safety of ranibizumab administered once a month for 3 months, and thereafter as needed based on re-treatment criteria. Large studies like SAILOR are important because they may be able to provide important safety information that smaller studies aren't powered to detect.

At 1 year, the rates of ocular and nonocular adverse events, serious and overall, were generally low, consistent with the findings of the MARINA and ANCHOR studies. Furthermore, there was no significant difference in adverse events between the standard and low-dose groups. While earlier analysis had suggested an excess of strokes with the standard dose, this was unsupported by the final, 1-year data. There was a trend toward a higher incidence of stroke in the 0.5-mg dose group — 1.2 percent vs. 0.7 percent in the low-dose arm — but it wasn't statistically significant. Equally important, the rate of stroke was well within the range expected for older patients overall. For example, the incidence of stroke in Americans age 65 or older is 1.4%.

Examining New 3-Year Data

The newest safety data for ranibizumab were presented in September at the annual meeting of the Retina Society. Researchers presented the first findings from the HORIZON study.⁴ HORIZON evaluated the standard 0.5-mg dose of ranibizumab administered on an as-needed basis to patients with all types of wet AMD. It's a 1-year, open-label, extension trial that was open to patients who completed the ANCHOR, MARINA or FOCUS⁵ trials. The last was a smaller-scale 2-year study that compared ranibizumab plus photo-dynamic therapy versus PDT alone.

"At the time HORIZON began, ranibizumab wasn't commercially available. One benefit of the study was that it provided research patients with an opportunity to continue on therapy if they wished to do so," said SriniVas Sadda, MD, associate professor of ophthalmology and the principal investigator for the HORIZON study at the University of Southern California clinical site. "Safety was chosen as the primary endpoint because this is important data to collect over the longer-term. The investigators in the HORIZON study were allowed to treat patients with ranibizumab up to monthly intervals at their discretion, without strictly defined re-treatment criteria. The study wasn't designed to determine if other dosing schemes could have resulted in better outcomes."

HORIZON evaluated 3 cohorts: "Treated initial" were patients who had been randomized to therapy with ranibizumab or ranibizumab plus PDT in one of the three earlier studies and thus had received monthly injections for 2 years (n=600); "treated cross-over" were patients who had been randomized to sham injection or PDT in the earlier trial but were then treated with ranibizumab at some point in the initial or HORIZON trial (n=168); and "untreated" were those who never received ranibizumab during the full 3 years of study participation (n=85).

At the end of 1 year, approximately 60% of patients in the treated initial group and 85% of the treated crossover group had received additional injections of ranibizumab. The two groups didn't differ significantly in terms of the number of injections. On average, these patients received three to four injections over the 12 months of the study.

Repeated intravitreal injections of ranibizumab were well tolerated, with a very low rate of adverse events. There was one serious adverse ocular event, a vitreous hemorrhage. Mild intraocular inflammation occurred in nine patients. There was a reported difference in cataract progression, in the range of 6% to 8% in the treated groups compared to 2.5% among untreated patients, though this was based on an informal rating by the treating physician.

"These findings are completely consistent with the safety profile we saw in the pivotal studies, so now we can be more confident about the longer-term safety of ranibizumab," Dr. Sadda noted. "We saw no new concerns from a systemic safety perspective. The rate of serious ocular events was extremely low. It's true that there was a slightly higher rate of minor events but these weren't really clinically significant."

Chronic Disease Process

Although HORIZON wasn't designed to study the most effective dose, the investigators believe it can provide some insight into what happens over the long-term in eyes treated with anti-VEGF therapy.

"HORIZON is interesting because it gives us an opportunity to look at a wide range of patients and compare the effects of treatment from two distinct points in time, with different approaches to treatment," Dr. Sadda explained. "We can see how vision changed compared to the HORIZON baseline 1 year earlier, as well as from baseline at the point of original enrollment 3 years earlier."

Because the HORIZON population was a combined subset of patients from three other studies, the investigators first established how vision changed in each group in the 2 years from the time of enrollment in the original study to the time of enrollment in HORIZON. In that period, the treated initial group had a 9-letter gain, the treated crossover had an 11-letter loss and the untreated lost 5 letters. At the end of HORIZON 1 year later, the treated initial group still had a gain relative to their vision 3 years earlier but that benefit had narrowed: They had lost 5 letters, leaving them with an improvement of only 4 letters compared to initial baseline. The other two groups each lost another 2 or 3 letters by the end of year 3.

The researchers also looked at change in vision as a function of how many patients gained, lost or remained stable over the course of the study. They found that only 2% to 3% of patients gained 3 or more lines of vision in the third year of treatment, regardless of which group they were in. The number of patients who lost 3 or more lines ranged from 14% in the treated initial group, to 11% in the treated crossover group and 7% in the untreated group, a finding that researchers attributed to the fact that the treated initial group had more vision at baseline to lose. By far, the majority of patients in all cohorts remained unchanged after enrolling in HORIZON.

"We can't say for sure why the patients in the group that was treated initially lost some of the gain in visual acuity," Dr. Sadda noted. "It may be the result of less regular administration of ranibizumab, since these patients were treated on an as-needed basis. It may be due to the fact that some vision loss is inevitable as the disease progresses, even in the face of treatment. Or it may be a combination of these and other factors. The study wasn't designed to answer this question.

"What we can say from these findings is that if you have neovascular AMD, by the end of 2 years, most of what's going to happen to your eye will have happened, and it's unlikely that vision will improve. However, if you've been treated early, additional treatment may preserve some of the vision you've gained or slow down further vision loss."

Chronic Disease Requires Long-term Solution

As Dr. Sadda points out, HORIZON adds to our knowledge about therapy for wet AMD because it's the only study that gives data into the third year of treatment. And he has been struck by the fact that some patients, even those who've already had 2 years of therapy, still require additional treatment with ranibizumab.

"HORIZON underscores that we're dealing with a chronic disease, not one that can necessarily be treated for a short period of time and you're done," Dr. Sadda said. "This is very valuable insight that has already changed the way I counsel patients." nMD