Bevacizumab versus ranibizumab: either way, patients win

Intravitreal medical therapy for age-related macular degeneration (AMD) is dominated by the two anti-vascular endothelial growth factor (VEGF) drugs, ranibizumab and bevacizumab (Lucentis and Avastin, respectively, Genentech). They both appear very similar in their ability to increase visual acuity and stabilize vision in patients with AMD. Cost currently seems to be affecting physicians' choices between the two, but the results of two comparison studies may settle the question of which drug is more efficacious, according to Philip J. Rosenfeld, MD, PhD, who spoke at the American Academy of Ophthalmology annual meeting.

"The advances of the last 12 years have been dramatic in our ability to treat neovascular AMD. Up to about 6 years ago, we could only slow the vision loss, but now in the age of 'Luvastin' we actually started to see vision improve starting in 2001," he said. Dr. Rosenfeld is professor of ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine.

Along with this improvement in vision has been a dramatic increase in the number of intravitreal injections performed as well as in the use of optical coherence tomography (OCT) to document and study those changes in the retinal anatomy. "This has been a dramatic paradigm shift in our ability to care for patients and it has created significant stresses on the delivery of patient care," he noted.

OCT imaging shows where the reversible fluid has accumulated in the macula. "One OCT B-scan through the macula of a patient with wet AMD can show fluid under the retina, in the retina, and under the pigment epithelium," he demonstrated. Dr. Rosenfeld likes to describe OCT as the "VEGF-ometer" that shows where the VEGF-dependent fluid is being secreted.

Ranibizumab, bevacizumab, and the VEGF trap, the last of which is currently in phase 3 trials, are the available agents that can target the extracellular VEGF in the eye.

"The biggest differences between ranibizumab and bevacizumab are in their sizes and affinity. Both are derived from the same mouse monoclonal antibody and they have been humanized. The antibody-binding fragment ranibizumab was genetically affinity-matured so that its binding affinity is from 5- to 20-fold higher compared with the bevacizumab affinity for VEGF. Bevacizumab is the larger molecule, but it is also substantially cheaper ($5.50 per mg for bevacizumab versus $4,000 per mg for ranibizumab)," he noted.

The 1-year results of the ANCHOR and the 2-year MARINA studies provided the basis for the FDA approval of ranibizumab to treat wet AMD. The importance of the minimally classic and occult AMD data from the MARINA study was that for the first time there was an increase in average visual acuity during the first 3 months of treatment that was sustained over 24 months. This difference achieved in the treatment versus the sham treatment groups amounted to 20 to 21 letters of vision, depending on the dose of the drug.

The 2-year results from the ANCHOR study in which ranibizumab was compared with verteporfin photodynamic therapy (Visudyne, Novartis Ophthalmics) showed that there was an 18- to 20-letter difference in vision using ranibizumab, depending on the dose of the drug.

The PRONTO study was carried out at the Bascom Palmer Eye Institute to look at alternative dosing regimens for ranibizumab with the goal of avoiding monthly intravitreal injections for 2 years or longer. Initially, the patients received injections at baseline, and months 1 and 2; any subsequent injections were based on need (i.e., changes in central retinal thickness) as determined by OCT.

"On average the patients in the PRONTO study received 10 intravitreal injections over the 2 years of the study, with most patients getting three to nine injections. Of the 40 patients, only two patients required injections almost on a monthly basis," Dr. Rosenfeld reported.

When the investigators compared the results from the ANCHOR, MARINA, and PRONTO studies, the results were similar for the ranibizumab dose of 0.5 mg.

Dr. Rosenfeld presented the case of the first patient in the United States who he injected with bevacizumab at the Bascom Palmer Eye Institute. The patient, who had a large classic lesion with diffuse leakage on angiography, was given ranibizumab as salvage therapy following no response to photodynamic therapy, pegaptanib (Macugen, OSI/ EyeTech), and intravitreal triamcinolone acetonide. Four months after only one injection of ranibizumab, the retina was dry; however, there was a recurrence of the leakage along the margin of the original lesion. Within 1 week of a second injection to the retina, the lesion was once again dry. After a follow-up of more than 2 years and after only two injections, Dr. Rosenfeld emphasized, the retina remains dry and the patient continues to see well.

"This widespread acceptance of bevacizumab as a low-cost alternative to ranibizumab has been a global effort and everyone deserves credit. We now perceive bevacizumab therapy as safe and effective and its global use is fueled by its availability and the fact that it is inexpensive," Dr. Rosenfeld said.

At this time, it is not known definitively if either ranibizumab or bevacizumab is superior or whether they are equivalent. Three comparison studies, one in the United States, one in the United Kingdom, and one in Germany, are underway, and in about 2 years the results should indicate how effective they are in these head-to-head studies.

"We finally have a treatment that has the potential to improve or stabilize vision in the vast majority of patients with neovascular AMD. Our goal is to get the macula dry and keep it dry. Another goal is to decrease the injection burden without sacrificing visual acuity. The debate at this and other meetings is how to decide between ranibizumab and bevacizumab and how to decide between the different treatment regimens to keep the macula dry," Dr. Rosenfeld concluded.

"With the growing body of evidence, the current standard of care now includes both therapies and the cost factor seems to be winning out when ophthalmologists are faced with the choice of drug."