Pivotal AMD Treatment Studies Update
Pivotal AMD Treatment Studies Update
As was the case at the 2011 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), so too at the 2012 meeting was therapy of the exudative ("wet") form of age-related macular degeneration (AMD) one of the major areas of interest. Intravitreal therapy with new anti-vascular endothelial growth factor (anti-VEGF) agents, as well as longer-term follow-up of some older anti-VEGF agents, was highlighted.
Bhisitkul and associates reported on 7-year outcomes in a prospective multicenter cohort study of patients with exudative AMD treated with ranibizumab intravitreal injections, assessing long-term visual outcomes from the ANCHOR/MARINA trials.
Fourteen clinical trial sites in the United States recruited 65 patients originally treated in the ANCHOR and MARINA trials (enrolled between March 2003 and September 2004) and who received further ranibizumab treatment in the HORIZON extension study. Patients were reevaluated with ETDRS vision charts, complete ophthalmologic examination, and retinal imaging (ie, fundus photographs, fluorescein angiography, spectral domain, optical coherence tomography, and fundus autofluorescence), with analysis by the Doheny Image Reading Center (Los Angeles). More than one third (37%) of original study eyes had ETDRS visual acuity of 20/70 or better 7-8 years after initiation of ranibizumab treatment. The mean visual acuity in study eyes was 20/125.
Within the cohort, subgroups showed favorable outcomes, with good vision (≥ 20/40) in 23% of eyes and durable choroidal neovascularization quiescence in 35%. Another group showed poor outcomes, with 37% of eyes having vision of 20/200 or worse. Ongoing exudative disease activity, defined as evidence of choroidal neovascularization leakage or hemorrhage at study visit or within the previous 6 months, was found in 54% of study eyes, and 23% required ongoing treatment. Evaluation of the nonstudy fellow eyes showed that 51% of patients had bilateral exudative AMD, and 20% of fellow eyes were also receiving current or recent AMD treatments. Six percent of patients were legally blind (visual acuity of 20/200 or worse) in both eyes.
The investigators concluded that most patients treated in these cohorts required ongoing intravitreal ranibizumab therapy, and even with that, obtaining or maintaining good vision was unlikely.
Suner and associates reported on similar issues in the HARBOR study, with 1-year efficacy and safety results of treatment with 2.0 mg vs 0.5 mg ranibizumab in patients with subfoveal choroidal neovascularization secondary to AMD.
Patients aged 50 years or older with subfoveal wet AMD (n = 1097) were randomly assigned to receive 2.0 mg or 0.5 mg ranibizumab intravitreal injections dosed monthly or on an as-needed basis after 3 loading doses. Primary endpoint analyses were performed at 12 months, using the last-observation-carried-forward technique to impute for missing data. Table 1 shows the mean change from baseline in best corrected visual acuity (BCVA), mean number of ranibizumab injections, proportion of patients who lost fewer than 15 letters from baseline, and mean change in central foveal thickness in the 4 treatment groups.
Table 1. Month 12 Findings From HARBOR Study
BCVA = best corrected visual acuity; PRN = as needed
The investigators concluded that the 1-year results of the HARBOR study demonstrated excellent and clinically meaningful improvement in visual acuity and anatomic outcomes across all 4 treatment groups. The higher dose was not superior to the lower dose, and the as-needed treatment groups did not meet the prespecified noninferiority criteria (margin of 4 letters) to ranibizumab 0.5 mg monthly; this suggests that monthly injections, rather than injecting and observing with subsequent as-needed therapy, may be the superior treatment.
Heier and colleagues presented the results of a comparison study of monthly intravitreal aflibercept vs ranibizumab injections in the care of patients with wet AMD, including a treatment group that received the former drug every 8 weeks. Table 2 shows the proportions of patients who maintained visual acuity, BCVA gains, and average number of injections at week 96 and average number of injections during the follow-up period after week 52 in the 4 study groups.
Table 2. Week 96 Findings From VIEW 1 and VIEW 2 Studies
BCVA = best corrected visual acuity
In the 25% of patients who required the most intense therapy (greatest number of injections), 2 mg aflibercept given monthly and every 8 weeks required an average of 1.5 and 1.4 fewer injections, respectively, than did monthly ranibizumab (6.5 and 6.6 vs 8.0 injections, respectively). The incidence of ocular and systemic adverse events was balanced across treatment groups.
The investigators concluded that the visual improvements achieved at week 52 were maintained through week 96 with intravitreal aflibercept and ranibizumab. The original group that received 2 mg aflibercept every 8 weeks achieved efficacy results that were similar to those of ranibizumab, but with an average of 5.3 fewer injections over the 96-week period.
AMD continues to be a major cause of vision loss among elderly persons, and the promise of effective therapy for the nonexudative ("dry") form of the disease is as yet a promise unfulfilled. Treatment of the far less prevalent wet form of the disease continues to evolve with newer agents, but intravitreal injections of all such agents are required. Varying protocols in timing of and duration between injections continue to evolve, but it seems very clear that such therapy is a major advance in the care of patients with this form of macular degeneration.
AMD: A Continuing Area of Interest
As was the case at the 2011 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), so too at the 2012 meeting was therapy of the exudative ("wet") form of age-related macular degeneration (AMD) one of the major areas of interest. Intravitreal therapy with new anti-vascular endothelial growth factor (anti-VEGF) agents, as well as longer-term follow-up of some older anti-VEGF agents, was highlighted.
ANCHOR/MARINA: Good Vision Unlikely
Bhisitkul and associates reported on 7-year outcomes in a prospective multicenter cohort study of patients with exudative AMD treated with ranibizumab intravitreal injections, assessing long-term visual outcomes from the ANCHOR/MARINA trials.
Fourteen clinical trial sites in the United States recruited 65 patients originally treated in the ANCHOR and MARINA trials (enrolled between March 2003 and September 2004) and who received further ranibizumab treatment in the HORIZON extension study. Patients were reevaluated with ETDRS vision charts, complete ophthalmologic examination, and retinal imaging (ie, fundus photographs, fluorescein angiography, spectral domain, optical coherence tomography, and fundus autofluorescence), with analysis by the Doheny Image Reading Center (Los Angeles). More than one third (37%) of original study eyes had ETDRS visual acuity of 20/70 or better 7-8 years after initiation of ranibizumab treatment. The mean visual acuity in study eyes was 20/125.
Within the cohort, subgroups showed favorable outcomes, with good vision (≥ 20/40) in 23% of eyes and durable choroidal neovascularization quiescence in 35%. Another group showed poor outcomes, with 37% of eyes having vision of 20/200 or worse. Ongoing exudative disease activity, defined as evidence of choroidal neovascularization leakage or hemorrhage at study visit or within the previous 6 months, was found in 54% of study eyes, and 23% required ongoing treatment. Evaluation of the nonstudy fellow eyes showed that 51% of patients had bilateral exudative AMD, and 20% of fellow eyes were also receiving current or recent AMD treatments. Six percent of patients were legally blind (visual acuity of 20/200 or worse) in both eyes.
The investigators concluded that most patients treated in these cohorts required ongoing intravitreal ranibizumab therapy, and even with that, obtaining or maintaining good vision was unlikely.
HARBOR: Promising 1-Year Results
Suner and associates reported on similar issues in the HARBOR study, with 1-year efficacy and safety results of treatment with 2.0 mg vs 0.5 mg ranibizumab in patients with subfoveal choroidal neovascularization secondary to AMD.
Patients aged 50 years or older with subfoveal wet AMD (n = 1097) were randomly assigned to receive 2.0 mg or 0.5 mg ranibizumab intravitreal injections dosed monthly or on an as-needed basis after 3 loading doses. Primary endpoint analyses were performed at 12 months, using the last-observation-carried-forward technique to impute for missing data. Table 1 shows the mean change from baseline in best corrected visual acuity (BCVA), mean number of ranibizumab injections, proportion of patients who lost fewer than 15 letters from baseline, and mean change in central foveal thickness in the 4 treatment groups.
Table 1. Month 12 Findings From HARBOR Study
| Treatment Group | 0.5 mg monthly |
2.0 mg monthly |
0.5 mg PRN |
2.0 mg PRN |
|---|---|---|---|---|
| Mean change in BCVA (number of letters) | +10.1 | +9.2 | +8.2 | +8.6 |
| Mean ranibizumab injections (n) | 11.3 | 11.2 | 7.7 | 6.9 |
| Patients who lost < 15 letters (%) | 97.8 | 93.4 | 94.5 | 94.9 |
| Central foveal thickness (μm) | -172.0 | -163.3 | -161.2 | -172.4 |
BCVA = best corrected visual acuity; PRN = as needed
The investigators concluded that the 1-year results of the HARBOR study demonstrated excellent and clinically meaningful improvement in visual acuity and anatomic outcomes across all 4 treatment groups. The higher dose was not superior to the lower dose, and the as-needed treatment groups did not meet the prespecified noninferiority criteria (margin of 4 letters) to ranibizumab 0.5 mg monthly; this suggests that monthly injections, rather than injecting and observing with subsequent as-needed therapy, may be the superior treatment.
VIEW 1 and VIEW 2: Sustained Improvements
Heier and colleagues presented the results of a comparison study of monthly intravitreal aflibercept vs ranibizumab injections in the care of patients with wet AMD, including a treatment group that received the former drug every 8 weeks. Table 2 shows the proportions of patients who maintained visual acuity, BCVA gains, and average number of injections at week 96 and average number of injections during the follow-up period after week 52 in the 4 study groups.
Table 2. Week 96 Findings From VIEW 1 and VIEW 2 Studies
| Treatment Group | Ranibizumab 2 mg monthly | Aflibercept 2 mg monthly | Aflibercept 0.5 mg monthly | Aflibercept 2 mg every 8 weeks |
|---|---|---|---|---|
| Patients maintaining visual acuity (%) | 92 | 92 | 91 | 92 |
| BCVA gain (number of letters) | 7.9 | 7.6 | 6.6 | 7.6 |
| Mean injections over 2 years (n) | 16.5 | 16.0 | 16.2 | 11.2 |
| Mean injections during follow-up (n) | 4.7 | 4.1 | 4.6 | 4.2 |
| Patients requiring ≥ 6 injections during follow-up after week 52 (%) | 26.5 | 14.0 | -- | 15.9 |
BCVA = best corrected visual acuity
In the 25% of patients who required the most intense therapy (greatest number of injections), 2 mg aflibercept given monthly and every 8 weeks required an average of 1.5 and 1.4 fewer injections, respectively, than did monthly ranibizumab (6.5 and 6.6 vs 8.0 injections, respectively). The incidence of ocular and systemic adverse events was balanced across treatment groups.
The investigators concluded that the visual improvements achieved at week 52 were maintained through week 96 with intravitreal aflibercept and ranibizumab. The original group that received 2 mg aflibercept every 8 weeks achieved efficacy results that were similar to those of ranibizumab, but with an average of 5.3 fewer injections over the 96-week period.
A Major Advance for Wet AMD
AMD continues to be a major cause of vision loss among elderly persons, and the promise of effective therapy for the nonexudative ("dry") form of the disease is as yet a promise unfulfilled. Treatment of the far less prevalent wet form of the disease continues to evolve with newer agents, but intravitreal injections of all such agents are required. Varying protocols in timing of and duration between injections continue to evolve, but it seems very clear that such therapy is a major advance in the care of patients with this form of macular degeneration.
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