In a first phase I/II study (FVF 2128), 53 patients were treated with repeated injections of 0.3 or 0.5 mg ranibizumab intravitreally. After 6 months, vision had improved by 3 lines in 45% of patients in the 0.5 mg group and was stable in 97.5% of treated eyes (Heier 2004).
Seven hundred and sixteen patients with minimally classic or purely occult CNV and evidence of presumed recent disease progression were included in the Minimally classic/occult trial of the anti-VEGF antibody ramibizumab in the treatment of neovascular age-related macular degeneration (MARINA) trial, a randomized, multicentre, sham-controlled phase III trial. Patients received monthly injections of 0.3 or 0.5 mg of ranibizumab or sham treatment continuously over 24 months (Miller 2005).
At 12 month follow-up, 95% of ranibizumab-treated eyes compared to 62% of sham-treated eyes lost < 15 letters in VA (Rosenfeld et al. 2006). Visual improvement by ≥ 15 letters was found in 34% of eyes treated with a dose of 0.5 mg. At 24 months, 90% of eyes in the 0.5 mg group had continued to maintain stable vision without loss of > 15 letters compared to 53% in the control group (Rosenfeld et al. 2006) (Table 1).
A mean improvement of 7 letters was documented at 24 month follow-up. The prognosis in terms of vision maintenance as well as gain was independent of initial VA, lesion size or lesion composition. Thirty-three per cent of eyes in the 0.5 mg dose group improved by ≥ 15 letters; 42% of these patients ended up with a VA of 20/40 or better (Table 2). In both dose groups, ranibizumab prevented CNV growth and decreased the mean area of leakage angiographically. Typically, the functional and anatomical effect was seen rapidly within the first 3 months of intervention and was maintained throughout the entire follow-up of 24 months (Rosenfeld et al. 2006). Intraocular inflammation or presumed endophthalmitis was seen in 1.3% of eyes at 0.5 mg; lens damage and a retinal tear were documented in 0.4%. The 2 year cumulative number of deaths was 2.5% in the sham group and the 0.5 mg group and 2.1% in the 0.3 mg group. No significantly increased rate of systemic adverse events was found despite 2 years of continuous ranibizumab injections in 4 week intervals. In addition, ranibizumab-treated patients reported significant improvements in quality-of-life testing (NEI-VFQ-25) for near vision, distance vision and vision-specific dependency (Chang et al. 2006).
The Anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularization in age-related macular degeneration (ANCHOR) study comprised 423 patients with predominantly classic subfoveal CNV because of AMD in a prospective, randomized phase III trial design (Brown et al. 2006). Monthly injections of ranibizumab at 0.3 or 0.5 mg were compared to standard PDT, which was indicated at 3 month intervals, if leakage was seen angiographically. Ninety per cent of all eyes treated with ranibizumab at 0.5 mg lost less than 15 letters compared to 66% of eyes maintaining vision with PDT treatment alone at 24 months. Forty-one per cent of eyes in the higher dose group improved by ≥ 15 letters and 12% improved by ≥ 30 letters, compared to 6% of PDT-treated eyes (Table 2). In addition, these ranibizumab-treated patients demonstrated a mean improvement of 11 letters at 24 months and 38% had a final outcome of 20/40 or better. Initial VA or lesion size had no impact on vision prognosis. The rate of presumed endophthalmitis or uveitis was 0.7%. Death occurred at the same low rate (1.4–2.2%) in each of the different ranibizumab/PDT arms. In the 0.5 mg dose group, 4.3% of subjects experienced systemic arteriothromboembolic events. The frequency of myocardial infarctions was slightly higher in patients treated with 0.5 mg of ranibizumab than in the other two arms, although this difference was not statistically significant (Brown et al. 2006).
The PIER study, a phase IIIb trial, included 182 patients with all lesion types and evaluated the efficacy and safety of ranibizumab administered monthly for three doses followed by dosing every 3 months. While patients in the sham group lost a mean of 16 letters during 12 months of follow-up, patients with either dose of ranibizumab remained stable at baseline VA. Ninety per cent in the 0.5 dose group lost < 15 letters compared to 49% in the sham group; 13% versus 10% gained ≥ 15 letters (Schmidt-Erfurth & PIER Study Group 2006). The fact that the control group performed considerably worse than in the previous trials suggests that this was a different patient population. However, while the mean change in vision after three initial monthly ranibizumab injections was only slightly lower than the VA benefit achieved by the MARINA and ANCHOR trials, the overall VA in PIER returned to baseline from month 3 to month 12 after switching to quarterly dosing. This reduction in treatment benefit appears to highlight the need for a flexible regimen to maintain optimal results. A subgroup analysis revealed that 40% of PIER study patients were permanent gainers and maintained their initial benefit during long-term follow-up despite a reduction from monthly to quarterly reinjections. However, for the remaining 60% a reduced retreatment regimen was not appropriate and recurrent leakage activity and further vision loss occurred. Angiographic and optical coherence tomography (OCT) analysis revealed that a large proportion of patients experienced recurrent leakage and increased retinal thickness followed by VA loss (Mieler & PIER Study Group 2006). Obviously, an individualized retreatment regimen is required whereby retreatment is performed when recurrence is documented.
Safety was excellent: there were no incidences of endophthalmitis, traumatic lens or retinal injury and no arteriothrombolic systemic events in the PIER trial (Schmidt-Erfurth & PIER Study Group 2006).
In a phase IIIb, single-masked, multicenter, randomized study to evaluate the safety and tolerability of ranibizumab in naïve and previously treated subjects with CNV secondary to age-related macular degeneration (AMD) (SAILOR) trial, arteriothrombolic events occurred more frequently with the higher dose of 0.5 mg of ranibizumab compared to the lower dose of 0.3 mg with a treatment frequency of four treatments during 9 months and retreatments performed at the investigator's discretion.
Lucentis has been approved by the FDA for all lesion types in neovascular AMD in the USA since July 2006. An approval by the EMEA for countries in the European Union was granted in January 2007.
The approved dose is 0.5 mg of ranibizumab.
The treatment regimen found to obtain optimal results in vision outcome was injections given monthly. A fixed regimen of quarterly injections was inferior to the monthly schedule. The overall rate of vision improvement was substantially lower under the quarterly PIER regimen compared to the monthly MARINA and ANCHOR regimen. Subgroup analysis identified a proportion of patients with an initial and maintained vision gain compared to a proportion of patients losing the initial visual benefit with the fixed quarterly regimen. Therefore, an individualized retreatment indication is recommended, with a continuous diagnostic follow-up allowing treatment on demand when leakage activity and/or lesion growth recurs. The optimal treatment regimen offers patient management that is practical in terms of follow-up and retreatment rates and offers maximal systemic and ocular safety; affordable costs have yet to be determined. Appropriate studies (a randomized, double-masked, active-controlled, multicenter study comparing the efficacy and safety of ranibizumab (0.3 mg and 0.5 mg) administered as two dosing regimens in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (EXCITE) trial, and a phase IIIb, open-label, multi-center 12 month study to evaluate the safety, tolerability and efficacy of ranibizumab (0.3 mg) in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (SUSTAIN) trial) are underway. Diagnostic tools such as optical coherence tomography may offer useful parameters for retreatment decisions. Maintenance of vision can be expected in 90–95% and improvement by at least 3 lines was found in 30–40% of treated patients. All angiographic lesion types appear to respond favourably to the treatment. Frequent injections of ranibizumab are tolerated well for as long as 2 years. Ocular and systemic safety is extremely high. Risks and precautions to be taken in relation to the treatment procedure are identical to the experience with other antiangiogenic agents such as pegabtanib.
Recommendations are based on the ANCHOR, MARINA and PIER study data (evidence level I).