SPECIAL REPORT
Where Are We with Lucentis?
PETER K. KAISER, MD

The 1-year primary analyses of the pivotal phase 3 trials have been completed, and ranibizumab (Lucentis, Genentech) therapy for wet age-related macular degeneration (AMD) is currently awaiting approval by the Food and Drug Administration. Based upon the results thus far, it appears likely approval will be granted soon (perhaps by the time you read this). This article will review the recent trial data on ranibizumab and provide an overview of what we know about this therapy.

MECHANISM OF ACTION

Ranibizumab is a humanized, antigen-binding fragment (Fab) of a second-generation, recombinant mouse monoclonal antibody directed against vascular endothelial growth factor-A (VEGF-A), one of several forms of VEGF. VEGF-A is produced by several types of cells in the retina, and causes the growth of new vascular endothelium which bleeds and leaks, disrupting vision. Unlike pegaptanib (Macugen, [OSI] Eyetech, Pfizer) that binds only VEGF165, ranibizumab binds active isoforms of
VEGF-A. Ranibizumab has been affinity-matured to offer 140 times greater binding of VEGF-A than the original Fab fragment. Following intraocular injection, ranibizumab binds to and inactivates active forms of VEGF-A, halting neovascularization and vascular leakage that characterize wet AMD. The major phase 3 trials that have been undertaken with ranibizumab are MARINA, ANCHOR, and PIER.

CLINICAL TRIAL DATA

The MARINA trial studied patients with neovascular AMD and subfoveal choroidal neovascularization (CNV) that was minimally classic or occult with no classic component. Subjects received either sham injections, 0.3 mg ranibizumab, or 0.5 mg ranibizumab every month for 24 months. At 24 months, 91% of patients in both ranibizumab groups lost <15 letters compared to baseline, compared to 53% of sham-injected patients. Moreover, 26% of the patients receiving 0.3 mg ranibizumab, and 33% of the 0.5 mg group showed gains of at least 15 letters, compared to 4% of the sham group. At the 24-month follow-up, ranibizumab treatment resulted in a dose-dependent mean gain from baseline of 5.4 and 6.6 ETDRS letters in the 0.3 mg and 0.5 mg groups respectively, compared to a mean loss of 14.9 letters in the sham group. Quality-of-life scores for near visual activities, such as reading newsprint and paying bills, and distance activities, such as watching TV and reading street signs, were also improved compared to baseline and significantly better than sham. Patients also reported having significantly less dependency on others for visual tasks.

The ANCHOR trial studied patients with neovascular AMD and subfoveal CNV that was predominantly classic. Patients were randomized to either monthly ranibizumab injections (0.3 or 0.5 mg) or photodynamic therapy (PDT) with verteporfin for injection (Visudyne, Novartis) every 3 months if leakage was present on fluorescein angiography. Despite the fact that in this trial, ranibizumab was pitted against the standard treatment for predominantly classic CNV, the results were very similar to those of the MARINA trial. For the primary outcome (percent of patients at month 12 who lost <15 letters from baseline), ranibizumab was superior to PDT therapy (94%-96% vs 64%, respectively). The percentage of patients with a gain of at least 15 letters was greater with ranibizumab (36%-40%) than with PDT (6%). The mean change in visual acuity with 0.3 mg ranibizumab was 8.5 letters, and was 11.3 letters with 0.5 mg ranibizumab, compared to a 9.5-letter loss with PDT at 12 months.

As for safety, the incidence of systemic safety problems was comparable for ranibizumab-treated and sham-treated patients in the MARINA trial as well as ranibizumab-treated and PDT-treated patients in the ANCHOR trial. Ocular adverse events were largely mild-to-moderate in both trials, and included conjunctival hemorrhage, vitreous floaters, increased intraocular pressure, and eye pain.

Together, the ANCHOR and MARINA trials establish that ranibizumab alone among current therapies for wet AMD is capable not only of preventing vision loss, but also for the first time, can improve vision for a substantial number of patients. Nonetheless, some questions remain.

Foremost among them is the timing and dosage of ranibizumab necessary for full therapeutic effect. Some of these questions were addressed by the presentation of the 1-year results of the Phase 3b PIER study, which treated patients initially with 3 monthly doses of ranibizumab, followed by mandated quarterly injections for a period of 2 years. On average, patients treated with ranibizumab returned to baseline visual acuity by month 12, while patients in the sham group (receiving sham injections) experienced significant vision loss. At month 12, patients treated with ranibizumab lost -1.6 letters and -0.2 letters (0.3 mg and 0.5 mg) compared to a loss of -16.3 letters in the sham group (P<0.0001). These data suggest that treating patients on a quarterly basis may be less effective than a monthly or individualized dosing regimen. Data from ongoing phase 3b studies and emerging results from other Investigator Sponsored Trials should help us learn more about the optimal dosing regimen for patients.

ADDITIONAL DATA ON DOSING, SAFETY, AND COMBINATION THERAPY

Further treatment regimen and safety data will come from the SAILOR trial, another phase 3b study. SAILOR, which is actively enrolling, will include patients with all AMD lesion subtypes, whether treated previously or not. Patients will receive 3 monthly injections of either 0.3 or 0.5 mg of ranibizumab, followed by quarterly evaluations with criteria-based retreatment.

Another question is the role of combination therapy. The FOCUS trial was a phase 2/3, randomized, single-masked, controlled study of patients with predominantly classic CNV secondary to AMD treated with monthly injections of 0.5 mg ranibizumab or sham injections, combined with verteporfin PDT. At 12 months, 90.5% of ranibizumab-treated patients lost <15 letters of visual acuity compared with 68% of sham-injected patients. In the combination group, less than 1 additional PDT treatment was required. Since these results are similar to ranibizumab monotherapy in the ANCHOR study, the role of combination therapy in reducing the number of treatments required still needs to be explored.

Upon its approval, ranibizumab is likely to become the mainstay therapy for wet AMD. What remains to be seen is exactly how it will be dosed, and the manner in which it will be integrated into the expanded armamentarium of therapeutic options for AMD. RP

Peter K. Kaiser, MD, is director of the Clinical Research Center and Digital OCT Reading Center (DOCTR) of the Cole Eye Institute at the Cleveland Clinic Foundation. Dr. Kaiser is a consultant for Alcon and Genentech. The Cole Eye Institute has received research grant support from Alcon, Allergan, Bausch & Lomb, Eyetech, Genentech, National Eye Institute, Novartis, Regeneron, SIRNA, and QLT. The DOCTR has received research grant support from Acuity, Alcon, Allergan, Eyetech, Genaera, Novartis, Occulogix, and Regeneron. Dr. Kaiser can be e-mailed at pkkaiser@aol.com.