DRUG MECHANISM

Alternative splicing of the VEGF-A gene results in four main VEGF-A isoforms, of 121, 165, 189, and 206 amino acids. Several minor splice variants have also been described.1 The most abundant isoform is VEGF-A165; this and the longer isoforms are bound to the extracellular matrix but may be released into a soluble form by plasmin cleavage, generating VEGF-A110.

Ranibizumab binds to the VEGF receptor-binding domain that is common to all isoforms and proteolytic cleavage products of VEGF-A. Ranibizumab binding to VEGF-A inhibits VEGF-A binding to its receptor on the surface of endothelial cells. Consequently, the signaling cascade which results in endothelial cell proliferation, vascular leakage, and angiogenesis is not initiated.

DRUG USE IN RETINAL DISEASES

VEGF-A levels are increased in many ocular neovascular diseases. Intraocular levels of VEGF have been shown to be significantly greater in patients with neovascular disease and VEGF has been implicated as playing a major role in active intraocular neovascularization.13

In addition to AMD, elevated VEGF levels have been identified in the aqueous humor of diabetic patients with macular edema,14 in patients with iris neovascularization,13 and in patients with central retinal vein occlusion (CRVO).15 In patients with diabetic macular edema, VEGF is implicated in the breakdown of the blood– retinal barrier, leading to a vascular permeability imbalance.16 VEGF has been shown to stimulate neovascularization of the anterior and posterior segment of the eye, and capillary leakage, leading to macular edema associated with CRVO.15 Furthermore, in an animal model, VEGF is sufficient to induce iris neovascularization in a nonhuman primate.17

In light of the integral part played by VEGF in retinal neo­ vascular­ disease, there is a strong scientific rationale to support the investigation of treatment of these disorders with ranibizumab. Such treatment would aim to reduce hyperpermeability and inhibit neovascularization.

EFFICACY

EFFICACY IN AMD

Ranibizumab was the first therapeutic agent to demonstrate an improvement in VA and patient-reported outcomes for patients with neovascular AMD. Data from two pivotal 2-year, randomized, controlled phase II trials, ANCHOR (n = 423)18 and MARINA (n = 716),7 led to the licensing of ranibizumab for AMD treatment (Table 1). The ANCHOR trial compared monthly injections of two ranibizumab doses (0.3 and 0.5 mg) with verteporfin photodynamic therapy (PDT), while the MARINA trial compared monthly doses of ranibizumab (0.3 and 0.5 mg) with monthly sham injections. In the two trials, 90% of patients receiving ranibizumab 0.5 mg experienced stabilization of VA (loss of <15 letters from baseline) at 24 months, and 33–41% of patients gained VA (experienced improvements of 15 letters from baseline). At 24 months, the mean increase in VA from baseline with ranibizumab 0.5 mg was 10.7 and 6.6 letters in ANCHOR and MARINA, respectively. These outcomes were significantly better (P < 0.001) than those achieved by the control groups. In both trials, a biphasic treatment effect was observed, with the majority of the visual gain achieved in the first 3 months of treatment (the ‘oading phase) followed by stabilization of the gain (the maintenance phase).

Patient-reported outcomes were also assessed in the ANCHOR and MARINA trials, using the National Eye Institute Visual Function Questionnaire, to measure the influence of the ranibizumab-mediated

Initial nonresponders

Initial responders – not maintained

Initial responders – maintained

Figure 33.1  Subgroup analysis of visual acuity gain in PIER.

improvements in VA on quality of life. The data demonstrated that patients treated with ranibizumab were more likely to report improvements in near activities, distance activities, and vision-specific dependency which were maintained over the 2-year duration of the trial.19,20 These data demonstrate that the clinical improvements seen with ranibizumab treatment translate into meaningful benefits for the patient.

The observed biphasic treatment effect raised the possibility that, after the initial 3-month loading phase, maintenance of the VA gain may be achieved with less frequent treatments. A third phase III trial, PIER (n = 184),21,22 evaluated ranibizumab administered monthly for 3 months, followed by quarterly injections, and compared this with sham treatment. Under this administration schedule, ranibizumab did provide a significant VA benefit; a significantly greater number of patients achieved VA stabilization at 24 months compared with patients receiving sham treatment. However, subgroup analysis revealed that VA gains observed during the first 3 months of treatment were only maintained in 40% of patients over the duration of the trial, and for the remaining 60% quarterly dosing was not suitable (Figure 33.1).

Subsequent to the PIER trial, further investigation of a flexible dosing approach was carried out. The phase IIIb EXCITE trial (n = 353) directly compared a maintenance phase of quarterly injections against the monthly regimen. Consistent with previous observations, an initial gain was made in the first 3 months, after which patients receiving monthly injections continued to gain VA, whilst those receiving quarterly injections showed a decrease from their month 3 VA levels.23

The SUSTAIN trial (n = 531) is a 12-month, open-label, nonrandomized trial in which patients received three consecutive monthly loading doses of ranibizumab, followed by a maintenance phase of monthly visits and treatment guided by either VA (>5-letter decrease from the highest VA score at any previous visit) or OCT measurements (>100 m increase in central retinal thickness (CRT) from the thinnest measurement at any previous visit). The results of an interim analysis of 69 patients show that, at 12 months, the initial VA gain is maintained with a mean VA gain of 6.7 letters and an average of 2.3 injections during the maintenance phase. This suggests that good efficacy outcomes can be achieved with a lower than monthly average number of treatments.24

Trials of ranibizumab in different patient populations have also been undertaken or are planned (Table 2). The EXTEND-I trial (n = 88) in Japanese patients has reported results consistent with previous phase III trials of ranibizumab and demonstrated that ranibizumab is safe and effective in the Japanese population.25

Diseases Retinal in Mechanisms and Drugs • 4 section