Retina specialists have a new therapy in their armoury: on January 24th 2007, the European Commission approved ranibizumab (Lucentis, Novartis) for the treatment of patients with wet age-related macular degeneration (AMD).
The reason that this approval is so significant is that, although other treatments have been able to slow visual deterioration, none before Lucentis have been actually able to help improve vision.
As a recombinant humanized IgG1 kappa isotype therapeutic antibody fragment, Lucentis is specifically developed for intraocular use. Given by intravitreal injection, the drug binds to and inhibits VEGF-A.
The European Commission approval was based on efficacy and safety data collected in an extensive clinical trial programme, including two pivotal Phase III studies: MARINA (Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab In the treatment of Neovascular AMD) and ANCHOR (Anti-VEGF antibody for the treatment of predominantly classic CHORoidal neovascularization).
MARINA randomly assigned 716 patients to three groups to receive monthly treatment with ranibizumab 0.3 mg, 0.5 mg or sham injection. ANCHOR compared the same two doses plus sham verteporfin (Visudyne, Novartis) photodynamic therapy (PDT) against sham intravitreal injections plus verteporfin PDT in 423 patients.
At 12 months from baseline in both trials, nearly all patients (approximately 95%) treated with 0.5 mg ranibizumab achieved the primary efficacy endpoint of maintaining vision (<15 letter loss) compared with less than two-thirds of patients in the control groups. Perhaps most strikingly, however, 34% of patients in MARINA and 40% of patients in ANCHOR achieved a clinically significant improvement in vision (at least 15 letters). Such an improvement occurred in only 5-6% of controls.
The prescribing information for Lucentis recommends that it is given by intravitreal injection once a month for three months, followed by a maintenance period in which patients are monitored monthly. It is advised that if a patient loses more than five letters of visual acuity (VA), Lucentis should be re-administered. This advice follows the results of the PIER study (a Phase IIIb, multicentre, 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 secondary to age-related macular degeneration). The trial enrolled 184 patients who were randomly assigned to ranibizumab 0.3 mg, 0.5 mg or sham injections. All patients received a series of three monthly injections, then the treatment frequency was decreased to once every three months. Patients treated with 0.5 mg had a mean gain of 4.3 letters in VA after their first three monthly injections but an average of 0.2 letter loss at month twelve compared with baseline. In the sham group there was an average 16.3 letter loss at one year.
Is it as safe as they say it is?
Intravitreal ranibizumab has also been associated with a very favourable safety profile. Adverse events occurring with an incidence that was at least 6% higher than in the control arm included conjunctival haemorrhage, eye pain, vitreous floaters, increased IOP and intraocular inflammation. Serious adverse events related to the injection procedure include endophthalmitis, retinal detachment and traumatic cataract. Each occurred in less than 0.1% of injections.