Ranibizumab otherwise known as Lucentis is a humanized IgG1 kappa recombinant monoclonal antibody fragment that recognizes and binds extra-cellular VEGF with high affinity. Ranibizumab has the ability to bind and inactivate all isoforms of VEGF-A including the soluble VEGF fragments (110, 121, and 165) and the tissue-bound isoforms 189 and 206. Theoretically, ranibizumab, due to its small molecular size, is able to penetrate the retina and reach the subretinal space and inhibit VEGF. Its half life is two to four days which results in a rapid systemic clearance and improved safety.
A large randomized, multicenter, sham controlled phase III study, (MARINA study) enrolled 716 subjects with minimally classic and occult lesions with evidence of recent disease progression. Subjects were randomized to two treatment groups and one sham group. The treatment groups received a mean of 22 injections (monthly interval) of ranibizumab (0.3 or 0.5 mg) through 24 months. Another prospective randomized phase III trial, (ANCHOR), enrolled 423 subjects with predominantly classic subfoveal lesions. This study included a monthly injection of either 0.3 or 0.5mg of ranibizumab versus the vPDT treated group. The PIER study included 184 subjects with all types of macular exudative lesions and evaluated the efficacy and safety of ranibizumab, which was administered monthly for three doses, followed by a fixed regimen of re-treatments in three month intervals.
The results of the MARINA and ANCHOR studies showed that 95% to 96% of the subjects treated with ranibizumab (0.5 mg) maintained stable vision within 3 lines (compared to 62-64% of sham or PDT group treated eyes) at one year. Thirty-four percent to 40% of the treated eyes improved by ≥ 3 lines of vision (compared to 6% in the vPDT group and 4 % in the sham group). In the PIER study, only 13% of the treated subjects experienced an improvement in vision, which highlights the importance of an individualized re-treatment regimen on a monthly basis. On average, subjects treated with Lucentis in the MARINA study experienced an improvement from baseline of 6.6 letters at two years compared to a loss of 14.9 letters in the sham group. In the ANCHOR study, subjects treated with ranibizumab, on average, experienced an 11.3 letter gain from baseline at one year compared to a loss of 9.5 letters in the vPDT group. Up to 40% of subjects treated with ranibizumab achieved vision of 20/40 or better.
Patient age, initial visual acuity, lesion composition or size did correlate with the functional results (visual acuity stabilization or improvement The Optical Coherence Tomography Imaging Patients with Neovascular age related macular degeneration Treated with Intra-Ocular Lucentis (PrONTO) study, evaluated an OCT-guided, variable-dosing regimen with intravitreal ranibizumab for the treatment of subjects with neovascular age-related macular degeneration. This was a prospective open-label study which evaluated whether OCT criteria at monthly intervals could be used to guide retreatment with ranibizumab. Patients were enrolled within the study regardless of lesion type or previous treatment. Patients received intravitreal 0.5-mg ranibizumab injections at 0, 1, and 2 months. For the remainder of the study, strict criteria were established to determine whether the patient received additional intravitreal ranibizumab. The criteria used were: 1) decrease in acuity of 5 letters and any fluid by OCT, 2) increase in central macular thickness of 100 microns even if visual acuity did not, 3) new hemorrhage, 4) new classic CNV by fluorescein angiography, and 5) persistent fluid from CNV after last treatment. Forty patients were enrolled in the study and received a total of 222 injections over the 12 months of follow-up. On average, patients gained 9.3 letters at 12 months with 95% of patients stable or improved. Only 37.5% of patients needed 3 or 3 + 1 dose of intravitreal ranibizumab to quiesce the choroidal neovascular membrane. The mean time to first retreatment was 4.3 months.
Preliminary results from the PrONTO study suggest that fewer injections will most likely result in visual acuity improvements similar to the results from the phase III trials and suggest that less frequent treatment with ranibizumab is possible by using a variable dosing regimen with OCT. However, the Pronto study does not bring the same level evidence that MARINA or ANCHOR brought due to its small sample size (40 patients and limited follow-up and treatment recommendations warrant further investigations and should be practiced with caution.
Systemic safety was excellent and the death rate did not differ between the groups. The frequency of systemic thromboembolic events (myocardial infarcts), however, was slightly higher (not statistically significant) in subjects treated with 0.5mg of ranibizumab as compared to the other treatment groups. A phase IIIb SAILOR (Safety Assessment of Intravitreal Lucentis for Age-Related Macular Degeneration) study and the HORIZON trial which is a long-term extension study that follow-up subjects who participated in the MARINA and ANCHOR trial for five years are underway to evaluate the safety of ranibizumab. The ranibizumab at a dose of 0.5 mg was approved by the FDA in June 2006 and by the EMEA in January 2007 for the treatment of all lesion types in exudative age related macular degeneration. An individual monthly evaluation allowing treatment on demand when leakage or activity of the neovascular lesion is detected is recommended.