rx persepective
Ranibizumab Gives Hope to Patients With AMD
By Carl D. Regillo, M.D.

Neovascular AMD remains the leading cause of severe vision loss in the United States among the elderly population. No prevention exists, and the number of patients diagnosed with AMD is expected to grow as the baby boomers age.

The ophthalmic community needs effective therapies to address AMD, but until now, we have not had a treatment that allowed for clinically meaningful rates of vision improvement or true stabilization. While FDA-approved treatments, such as photodynamic therapy (PDT) with verteporfin (Visudyne, QLT/Novartis) and pegaptanib sodium (Macugen, OSI/Pfizer), have been available as ways to control and minimize vision loss in most patients with wet AMD, no therapy has provided significant gains in improving vision for patients who suffer from the disease.

That is now changing. In June, the FDA approved ranibizumab (Lucentis, Genentech) for neovascular AMD. The phase 3 clinical trials for ranibizumab demonstrated vision outcomes that were far superior to the phase 3 trials for either pegaptanib sodium or PDT with verteporfin. It is, quite simply, a more effective treatment than what we have had available to us.

In brief, ranibizumab is an anti-vascular endothelial growth factor (VEGF) therapy administered via intravitreal injection. It consists of an antigen-binding fragment (Fab) anti-VEGF molecule. Specifically, it is a humanized, affinity-matured antibody fragment that binds all the isoforms of the VEGF-A family of molecules, which inhibits all VEGF isoforms. That ranibizumab inhibits all VEGF isoforms differentiates it from pegaptanib sodium, which blocks only VEGF₁₆₅, and is most likely the reason why it is more effective.

In clinical trials for other AMD therapies, the primary endpoint was loss of three or fewer lines of visual acuity at 12 months, and in general these therapies were successful about 70% of the time.1,2 Ranibizumab, however, achieved a 90% success rate to the same endpoint. The ability to decrease moderate vision loss in clinical trials was far superior.3

In addition, these pivotal phase 2 ranibizumab trials showed significant vision improvement (three or more lines) in 30% to 40% of patients.3 This was not previously seen with any single AMD treatment, and this is what has generated the excitement — the ability to have better stabilizing power and reasonably good rates of vision improvement. Furthermore, the phase 3 clinical trials showed for the first time that patients experienced mean visual acuity improvements, unlike other available treatments that showed an average loss of vision over 12 months (mean one to two lines) and not just decreased vision loss. This was found across all lesion subtytpes (subfoveal and choroidovascular).3,4

Frequency of injections is an issue that continues to evolve with ranibizumab. The results of the PIER trial were somewhat disappointing in that quarterly dosing of ranibizumab failed to achieve a mean improvement of visual acuity or produce visual gains of three or more lines. Following three monthly injections, patients returned to baseline over the long term.5 However, the PrONTO trial showed that after initial monthly injections, individualized regimens based on optical coherence tomography results may allow for visual results that compare more favorably compare with the phase 3 ranibizumab monthly dosing trials.6

The safety profile for ranibizumab is good. It is well tolerated, shows no systemic adverse effects and is associated with low rates of adverse ocular reactions.

Unanswered Questions

It has been well publicized that many physicians have had favorable experiences with the off-label use of intravitreal bevacizumab (Avastin, Genentech). It seems to be more effective than pegaptanib sodium in its ability to control the exudation seen in AMD and in many cases may improve vision to some degree. However, no long-term, prospective data have been collected for intravitreal bevacizumab in the treatment of wet AMD. Therefore, we do not really know its true degree of efficacy, nor do we know how safe it is. Many clinicians in the ophthalmic community are interested in putting bevacizumab to the test, but clinical trials have not yet begun enrolling, so the answers to these questions are, potentially, years away.

The main difference between ranibizumab and bevacizumab is the size of the molecule. Ranibizumab is much smaller and the theory is that because of this, it may penetrate the retina and access the subretinal space better than bevacizumab after an intravitreal injection. Additionally, its plasma half-life is shorter, allowing it to break down and clear from systemic circulation faster than bevacizumab, suggesting it may be safer.

Again, these questions will be answered once a clinical trial is complete. For now, ranibizumab represents a great leap forward in the field of retina. We can now offer our patients with AMD a treatment that not only controls their disease but potentially can reverse to some degree the vision loss that has resulted.

Carl D. Regillo, M.D., is the director of the Wills Clinical Retina Research Unit. He is also professor of ophthalmology at Thomas Jefferson University School of Medicine in Philadelphia. He can be reached at (215) 233-4300. Dr. Regillo has received research grants from Genentech, Eyetech, Novartis and Acuity.

References

1. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR, VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.

2. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report.. Arch Ophthalmol. 1999;117:1329-1345.

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

4. Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: Phase III clinical trial results. Ophthalmol Clin North Am. 2006;19:361-372.

5. Brown D. Lucentis: PIER data. Paper presented at: Annual Retinal Physician Symposium; May 31-June 3, 2006; Atlantis Paradise Island, Bahamas.

6. Rosenfeld PJ, Fung AE, Lalwani GA, Michels S, Venkatraman AS, Puliafito CA. Visual acuity outcomes following a variable-dosing regimen for ranibizumab (Lucentis [TM]) in neovascular AMD: the PrONTO Study. Program and abstracts of the Association for Research in Vision and Ophthalmology; April 30-May 4, 2006; Fort Lauderdale, Florida. Abstract 2958.