THE LATEST PUBLISHED RESEARCH

Benefits of Ranibizumab Sustained Through Second Year of MARINA Trial
Two-year results from MARINA, one of the Phase III clinical trials that led to the Food and Drug Administration’s approval of ranibizumab (Lucentis) for the treatment of neovascular age-related macular degeneration (AMD), have been published in the New England Journal of Medicine. The prevention of vision loss and improvement in mean visual acuity achieved at year one of the study were maintained through year two.

Source: Genentech

At 24 months, 80 percent to 90 percent of the patients originally enrolled remained in each treatment group (0.3 mg, 0.5 mg, sham). The average benefit associated with ranibizumab over sham injection was approximately 20 letters in the two dose groups. The percentage of patients who lost fewer than 15 letters of visual acuity was 92 percent in the 0.3-mg group, 90 percent in the 0.5-mg group, and 52.9 percent in the sham group (p<0.001 for each comparison). Approximately one-quarter of patients treated with 0.3 mg of ranibizumab and one-third of patients treated with 0.5 mg of ranibizumab gained at least 15 letters in visual acuity compared with 5 percent or less of those in the sham-injection group (p<0.001 for each comparison). Mean change in visual acuity from baseline was +6.6 letters in the 0.5-mg group, +5.4 letters in the 0.3-mg group, and -14.9 letters in the sham group. The visual-acuity benefit associated with ranibizumab was independent of baseline lesion size or type or baseline visual acuity.

During the 24 months, presumed endophthalmitis was identified in five patients (1 percent) and serious uveitis was identified in six patients (1.3 percent) treated with ranibizumab. The rate of arterial thromboembolic events was 3.8 percent in the sham group, 4.6 percent in the 0.3-mg group, and 4.6 percent in the 0.5-mg group.

MARINA was a Phase III, randomized, multicenter, double-masked, sham-controlled study of 716 patients with minimally classic or occult neovascular AMD. Patients were randomized 1:1:1 to receive intravitreal ranibizumab injections (0.3 mg or 0.5 mg) or a sham injection once a month for two years. The primary endpoint was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months.

Source: Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355:1419-1431.

One-Year Results from ANCHOR Trial Published
After year one of the ANCHOR trial, two different doses of intravitreal ranibizumab were found to be superior to photodynamic therapy (PDT) with verteporfin (Visudyne) for the treatment of predominantly classic neovascular AMD. On average, ranibizumab treatment improved visual acuity at one year and was associated with low rates of adverse events.

Source: Genentech

More than 90 percent of patients in each group were receiving treatment at 12 months. The percentage of patients who lost fewer than 15 letters of visual acuity was 94.3 percent in the 0.3-mg ranibizumab group, 96.4 percent in the 0.5-mg ranibizumab group, and 64.3 percent in the verteporfin group (p<0.001 for each comparison). Visual acuity improved by at least 15 letters in 35.7 percent of the 0.3-mg group, 40.3 percent of the 0.5-mg group, and 5.6 percent of the verteporfin group (p<0.001 for each comparison). Mean change in visual acuity from baseline was +8.5 letters in the 0.3-mg group, +11.3 letters in the 0.5-mg group, and -9.5 letters in the verteporfin group (p<0.001 for each comparison).

In the 0.5-mg group, presumed endophthalmitis occurred in two patients (1.4 percent) and serious uveitis occurred in one patient (0.7 percent). Overall, arterial thromboembolic events occurred in three patients (2.2 percent) in the 0.3-mg group, six patients (4.3 percent) in the 0.5-mg group, and three patients (2.1 percent) in the verteporfin group. The authors pointed out that the study was not designed to evaluate small differences in the rates of rare adverse events among treatment groups; therefore, the clinical significance of those particular results is unclear and requires further attention.

ANCHOR is a Phase III, two-year, randomized, multicenter, double-masked, active-treatment controlled study comparing 0.3-mg and 0.5-mg doses of ranibizumab to verteporfin PDT in 423 patients with predominantly classic neovascular AMD. Patients are randomized 1:1:1 to receive intravitreal ranibizumab (0.3 mg or 0.5 mg) once a month or PDT every three months. The primary endpoint was the proportion of patients losing fewer than 15 letters of visual acuity from baseline at 12 months.

Sources: Brown DM, Kaiser PK, Michels M, et al., for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355:1432-1444.

Pilot Study Evaluates Ranibizumab in Patients with DME
Six-month results of a single-center, open-label, dose-escalating pilot study of ranibizumab for the treatment of clinically significant diabetic macular edema (DME) indicated that the treatment has the potential to stabilize or improve visual acuity and reduce retinal thickness.

Ten eyes of 10 patients with DME affecting the center of the macula and best-corrected visual acuity (BCVA) in the study eye between 20/63 and 20/400 were involved in the study. Five eyes received a 0.3-mg intravitreal injection of ranibizumab on day zero and at month one and month two. Five eyes received a 0.5-mg injection at the same timepoints.

At three months, patients in the 0.3-mg group gained a mean of 12 letters in BCVA from baseline, and patients in the 0.5-mg group gained 7.8 letters. At six months, patients in the 0.3-mg group gained a mean of 8.8 letters in BCVA from baseline, and patients in the 0.5-mg group gained 0.8 letters.

At three months, mean decrease in retinal thickness [optical coherence tomography (OCT)] from baseline was 45.3 µm in the 0.3-mg group and 197.8 µm in the 0.5-mg group. At six months, mean decrease in retinal thickness from baseline was 74 µm in the 0.3-mg group and 223.4 µm in the 0.5-mg group.

No systemic adverse events occurred. Five cases of mild to moderate intraocular inflammation occurred. All were manageable and none led to withdrawal from the study. Patients are being observed until month 24.

Source: Chun DW, Heier JS, Topping TM, et al. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 2006;113:1706-1712.

Study Tests Three Different Doses of Bevacizumab for AMD
Mean BCVA improved throughout a 12-week study of three doses of intravitreal bevacizumab (Avastin) for the management of subfoveal choroidal neovascularization (CNV) associated with AMD. Investigators also observed a dose-related effect. In the prospective, nonrandomized, open-label study, 45 patients received a single injection of either 1.0, 1.5, or 2.0 mg of bevacizumab.

Mean BCVA improved from baseline at week one (p=0.001), week six (p<0.001), and week 12 (p=0.001). At week 12, the lesion area stabilized or decreased in 34 of 43 (79.1 percent) patients, and the CNV area stabilized or decreased in 32 of 43 patients (74.4 percent). The 1.0-mg dose resulted in a 0.3-line improvement in BCVA, the 1.5-mg dose resulted in a 0.6-line improvement, and the 2.0-mg dose resulted in a 1.0-line improvement (p=0.02).

Macular architecture did not deteriorate in 36 of 43 (83.7 percent) patients. The single injection was well-tolerated, producing only minor and transient conjunctival hyperemia and subconjunctival hemorrhage at the injection site.

Source: Costa RA, Jorge R, Calucci D, et al. Intravitreal bevacizumab for neovascularization caused by AMD (IBeNA Study): results of a phase 1 dose-escalation study. Invest Ophthalmol Vis Sci 2006;47:4569-4578.

Bevacizumab Causes Regression of Neovascularization Associated with PDR
An interventional, retrospective case series involving 45 eyes of 32 patients showed that intravitreal injection of bevacizumab can lead to rapid regression of iris and retinal neovascularization secondary to proliferative diabetic retinopathy at least in the short term. Most of the eyes in the study, 87 percent, had previously undergone panretinal photocoagulation for active retinal or iris neovascularization. Patients who had uncontrolled hypertension or a recent myocardial infarction or cerebral vascular accident were not included. During the study, eyes were injected with bevacizumab at doses between 6.2 µg and 1.25 mg. Follow-up was between one and 14 weeks (mean five weeks).

Biologic effects were observed after all doses, sometimes in 24 hours. At least partial reduction in leakage was seen on fluorescein angiography (FA) in all eyes except one in which vitreous hemorrhage prevented pre-treatment FA. Leakage from disc neovascularization completely resolved in 19 of 26 (73 percent) eyes. Leakage from iris neovascularization completely resolved in nine of 11 (82 percent) eyes. Investigators noted resolution of leakage in all neovascular areas elsewhere in the eye in 20 of 34 (59 percent) eyes. Also after injection, clinical exam and fundus photography frequently showed involution of neovascularization and a decrease in caliber or visible absence of perfused vessels.

No uveitis, endophthalmitis, ocular toxicity, obvious systemic event or significant blood pressure elevation occurred during the study. In one case, leakage recurred in two weeks, but in other cases it did not recur after 11 or more weeks. In two cases, a subtle decrease in leakage of retinal or iris neovascularization in the fellow eye was noted, raising the possibility that therapeutic systemic levels were achieved after intravitreal injection.

Source: Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695-1705.