Pearl

Bevacizumab is being used off-label in ophthalmology, and several uncontrolled studies have shown a safety and efficacy profile similar to ranibizumab for the treatment of wet AMD.

Ranibizumab

Drug Overview

Ranibizumab is a humanized antigen-binding fragment (Fab) derived from the same murine monoclonal antibody as bevacizumab. As with bevacizumab, ranibizumab binds VEGF-A at the same location and inhibits all isoforms of VEGF-A as well as the bioactive proteolytic breakdown products of VEGF-A. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with VEGFR1 and VEGFR2 on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation [102]. Compared with the original Fab from the Fab on the humanized monoclonal antibody, ranibizumab contains six amino acid substitutions; five variable domain substitutions, and one constant domain substitution at the C-terminus of the heavy chain. Ranibizumab is a smaller molecule than bevacizumab with a molecular weight of only 48 kD. Like full-length monoclonal antibodies, the Fab molecules have been shown to easily penetrate the retina [57]. When compared with bevacizumab, there were no apparent differences in the retinal penetration and the ocular safety of ranibizumab in rabbit eyes [103]. Ranibizumab (10 mg/ mL) is available in 0.3-mL vials and approved by the FDA for monthly intravitreal injections using a volume (dose) of 0.05 mL (0.5 mg) in patients with neovascular AMD.

Published Trials

Level I evidence supporting the use of ranibizumab for the treatment of neovascular AMD includes the published Phase III trials known as the MARINA (Minimally Classic/Occult Trial of

the Anti-VEGF Antibody Ranibizumab in the treatment of Neovascular AMD) [104] and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic CNV in AMD) [105, 106] trials as well as additional quality-of-life and subgroup analyses [107–111]. In addition, the Phase IIIb trials, including the PIER (A Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovasularization with or without Classic CNV SecondarytoAge-RelatedMacularDegeneration) [112], and SAILOR (Safety and Tolerability of Ranibizumab in Naive and Previously Treated Subjects With CNV Secondary to AMD) [113] trials. Smaller open-label prospective trials such as the PrONTO (Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intraocular Lucentis) study provided additional important dosing information [114, 115].

The pivotal phase III MARINA [104] and ANCHOR [105] trials established ranibizumab as the first FDA-approved drug that prevents vision loss and improves vision in the majority of patients with all subtypes of neovascular AMD. At 12 and 24 months in the MARINA trial, 90–95% of patients treated with 0.3 or 0.5 mg ranibizumab lost fewer than 15 letters of visual acuity compared with 53–64% of control patients; also at 12 and 24 months, 25–34% of ranibi- zumab-treated patients gained at least 15 letters of visual acuity compared with 4–5% of control patients [104]. The ANCHOR trial, which compared ranibizumab with PDT, had similar findings at 12 and 24 months: 90–96% of the ranibizumab-treated versus 64–66% of the PDTtreated patients lost fewer than 15 letters of visual acuity, whereas 34–41% of the ranibizumab group versus 6% of the PDT group gained more than 15 letters [105].

Analyses of fluorescein angiographic data from both the MARINA and ANCHOR studies also revealed statistically significant decreases in area of CNV, leakage from CNV, area of serous sensory retinal detachment (SSRD), and formation of disciform scar/subretinal fibrosis at both 12 and 24 months after ranibizumab

treatment [105, 116]. A retrospective analysis of OCT/fluorescein angiography outcomes prospectively collected in a subset of 46 patients from the MARINA study showed a statistically significant decrease at 12 months in mean foveal center point thickness of the ranibizumab-treated group compared with the sham-treated group [116].

Clinical studies such as the PIER Study, the SAILOR Study, and the PrONTO Study have investigated alternative, less-frequent ranibizumab dosing strategies in an attempt to lower rates of injections while achieving the same visual acuity outcomes. The two-year phase I/II open label PrONTO trial evaluated an OCTguided, variable dosing regimen of monthly intravitreal ranibizumab (0.5 mg) for three months followed by intravitreal ranibizumab as needed based on OCT-defined retreatment criteria in 40 patients with all subtypes of neovascular AMD [114] (Examples of different OCT-guided treatment approaches can be seen in Figs. 6.2 and 6.3). At the first year, 95% (38/40) of treated patients had lost less than 15 letters of visual acuity; 35% (14/40) of treated patients had gained at least 15 letters of visual acuity, and the mean increase in visual acuity was 9.3 letters. The mean number of injections for the first year was 5.6 (range 3–13); the most common reason for reinjection was a loss of at least five letters of visual acuity in association with presence of macular fluid. The earliest signs of recurrent fluid in the macula following cessation of treatment were detectable using OCT (Fig. 6.3) [117]. At 12 months after treatment, the mean central retinal thickness (CRT) as measured by OCT decreased by 178 microns (P <0.001). At 24 months, the results were virtually identical with a mean visual acuity change of 11.1 letters, a mean CRT/OCT decrease of 215 microns, and a mean number of injections of 10 (range 3–25) over two years [114]. The PrONTO trial showed that for future clinical trials and clinical practice, it might be possible to use qualitative OCT to determine the basis for retreatment.

The two-year PIER trial [112] examined the efficacy and safety of 0.3 or 0.5 mg ranibizumab monthly for three months followed by quarterly dosing. The first-year data showed that a

significantly greater proportion of patients receiving ranibizumab lost less than 15 letters of visual acuity (83.3% of patients in the 0.3 mg group and 90.2% of patients in the 0.5 mg group) compared with 49.2% of patients in the sham-treated group (P < 0.0001 for each dose level versus sham). However, there was no significant difference in the proportion of patients who gained at least 15 letters: 11.7 and 13.1% of treated patients (0.3 and 0.5 mg, respectively) compared with 9.5% in the sham group. Although the overall safety profile of ranibizumab in the PIER trial was similar to the first year of the MARINA and ANCHOR trials, the efficacy outcomes of the PIER trial were less beneficial than the MARINA and ANCHOR trials most likely because some patients required more frequent dosing than quarterly dosing to achieve maximal benefit. On the basis of the PrONTO and PIER trials, OCTguided retreatment appears more promising than less-frequent fixed-interval dosing for all patients if the goal is to achieve the same excellent outcomes as monthly dosing while reducing the number of overall injections (Fig. 6.4). Another strategy to decrease the treatment burden is to use the treat-and-extend strategy. In this approach, patients are treated at every monthly visit until there is no longer any fluid in the macula, and then the visit interval is extended by about two weeks and injections are given at every visit. The interval is extended until fluid is detected at a follow-up visit or a fixed interval of every three months is achieved [118, 119].

Pearl

Ranibizumab is the most effective antiVEGF drug approved by the FDA for the treatment of wet AMD. Several studies are exploring different doses and treatment intervals with ranibizumab as well the combination of ranibizumab with other treatment modalities. To date, anti-VEGF therapy alone, given at a dose of 0.5 mg, either given as a monthly injection or given as needed based on OCT surveillance, results in the best visual acuity outcomes.

Fig. 6.2 An 83-year-old man with age-related macular degeneration diagnosed with an occult lesion in the right eye. He received the three ranibizumab injections using a treat and extend strategy without recurrence. Color fundus images with earlyand late-phase fluorescein angiographic images at baseline are shown. Optical coherence

tomography (OCT) response from baseline to one year after the last ranibizumab injections are shown. Horizontal (left) and vertical (right) OCT B-scans through the central macula and visual acuity are shown. The patient had a good anatomical improvement without gain of visual acuity after the intravitreal injections

Safety Data

After two years of follow-up, MARINA and ANCHOR showed that the most common ocular complications were presumed endophthalmitis

(1.3% of eyes in MARINA; 1.4% of eyes in ANCHOR) and uveitis (1.3% of eyes in MARINA; 0.7% of eyes in ANCHOR) [104–106]. A recent review evaluated the safety data from the 3,252

Fig. 6.3 A 78-year-old woman with age-related macular degeneration diagnosed with an occult lesion in the left eye. She received the three ranibizumab injections using a treat and extend strategy with recurrence. Color fundus images with earlyand late-phase of fluorescein angiogram at baseline are shown. Optical coherence tomography (OCT) responses from baseline are shown.

Horizontal (left) and vertical (right) OCT B-scans through the central macula and visual acuity are shown. The patient had a good anatomical and functional response after the second injection. However, the intraretinal fluid recurred just before the third injection. This patient should be followed closely to avoid lost of visual acuity

patients in ANCHOR, MARINA, PIER, and SAILOR (level I evidence), who had received over 28,500 intravitreal ranibizumab injections.

The rate per injection of presumed endophthalmitis (0.05%) and serious intraocular inflammation (0.03%) were low [120].

a MARINA; Monthly regimen: 0.1% PC, 63.0% MC, 36.9% ONC

c PIER; Quaterly maintenance; 18.0% PC, 38.6% MC, 43.0% ONC

b ANCHOR; Monthly regimen; 96.9% PC, 2.8% MC, 0.2% ONC

d EXCITE; Monthly vs quarterly maintenance; 20.7% PC, 40.2% MC, 39.1% ONC

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Fig. 6.4 Mean change from baseline in best-corrected visual acuity by month for ranibizumab trials: (a) MARINA, (b) ANCHOR, (c) PIER, (d) EXCITE, (e)

PrONTO, (f) SUSTAIN (Reprinted from Mitchell et al. [120]. With permission from BMJ Publishing Group Ltd)