BMJ  2007;334:269-270 (10 February), doi:10.1136/bmj.39100.460671.BE

Editorials

New treatments for neovascular acute macular degeneration

Drugs that inhibit vascular endothelial growth factor show real promise

The term macular degeneration covers a spectrum of chronic and acute changes in the macular retina of both eyes and occurs in people aged 50 and above. One of the acute degenerative changes, choroidal neovascularisation, comprises an ingrowth of permeable and fragile new vessels from the choroid into the epithelial and subretinal spaces of the pigment layer,¹ stimulated by pathological secretion of vascular endothelial growth factor (VEGF). In the United Kingdom choroidal neovascularisation causes severe visual impairment or blindness in around 3.5% of people aged 75 or more.²

Discovery of the role of vascular endothelial growth factor led to hypotheses that blocking or neutralising this factor might yield a treatment for choroidal neovascularisation.³ Clinicians had low expectations of success, however, because other new types of treatments had shown limited or no benefit. Moreover, the biological agents that induce blockade of the factor have many unwanted side effects. Given systemically, these drugs increase the risk of serious thromboembolic events. Given as intraocular injections they risk infection, haemorrhage, and undesirable ocular immune responses.

Despite these concerns, the absence of other effective treatments led to the vascular endothelial growth factor inhibition study in ocular neovascularisation (VISION), which provided proof of concept that intraocular inhibition of the growth factor for up to two years was feasible and safe.⁴ At 12 months' follow-up, 78% of the eyes treated with repeated intravitreal injections of pegaptanib sodium (a selective antagonist of the VEGF₁₆₅ isoform of the growth factor) had visual acuity within three lines of that at baseline using Snellen charts, compared with 55% of the eyes in the control group, which had sham injections.

Two international multicentre controlled clinical trials (MARINA and ANCHOR) of ranibizumab for treatment of choroidal neovascularisation have now reported positive visual outcomes.^{5 6} Ranibizumab is a monoclonal antibody against vascular endothelial growth factor, which inhibits all its isoforms. At 12 months' follow-up, more than 90% of eyes randomised to ranibizumab had visual acuity that remained within three lines of presenting acuity, whereas a significantly greater proportion of those randomised to placebo⁵ or photodynamic therapy⁶ experienced loss of acuity of three or more lines. Furthermore, around a third of eyes in the ranibizumab group had a visual acuity of Snellen 6/12 or better, an outcome that would have been thought unattainable a short while ago.

How does inhibition of vascular endothelial growth factor work? The impressive improvements in visual acuity seen in the ranibizumab trials are thought provoking. When used in oncology, inhibition of vascular endothelial growth factor leads to normalisation of the leaky, tortuous, and dilated vasculature of the tumour.⁷ In choroidal neovascularisation the same action presumably restores the vasculature. Different isoforms of the growth factor probably contribute to leakiness, abnormal morphology, and fragility of the neovascular complex. Thus, ranibizumab has better outcomes than pegaptanib sodium, which inhibits VEGF₁₆₅ alone.

How long should inhibition of the growth factor continue? The VISION trials showed that two years of continuous treatment was better than one year.⁴ The PIER study, in which the dosing interval for ranibizumab was increased to every three months after three initial monthly injections, yielded less satisfactory outcomes at 12 months than the MARINA and ANCHOR trials in which monthly treatments were continued for two years.⁸ Furthermore, the PrONTO study, a small case series of patients in which ranibizumab was given without fixed dosing intervals but treatment was tailored to morphological parameters, resulted in 12 month visual outcomes similar to those of the major trials.⁸

What are the potential dangers of these treatments? Vascular endothelial growth factor is a survival factor for neuronal cells and a fundamental requisite for the maintenance of fenestration of the choriocapillaris, which is necessary for normal physiological functioning of the choroid itself, retinal pigment epithelium, and outer retina. Potentially, chronic inhibition of this growth factor could lead to atrophy of these tissues.⁹ However, the severity of vision loss in untreated choroidal neovascularisation has to be put into perspective. The impairment in quality of life and ability to carry out normal everyday activities in patients with bilateral neovascular acute macular degeneration is equivalent to that seen in cancer and severe myocardial disease.¹⁰ Low dropout rates in the vascular endothelial growth factor inhibition trials suggest that patients accept the potential long term risks associated with such treatment so that they can maintain vision in the short term.

What are the economic consequences for the National Health Service? A technology appraisal of pegaptanib and ranibizumab by the National Institute of Health and Clinical Excellence is due by the end of this year. The estimated annual incidence of choroidal neovascularisation is between 25 000 and 30 000 cases.¹¹ With pegaptanib sodium the annual drug bill alone can be expected to exceed £0.5bn (0.75bn; $1.0bn). Substitution with ranibizumab will increase the overall cost because of the need for more frequent administration and higher unit cost (although a definitive UK price has not yet been set). Substitution with bevacizumab, the cheaper parent molecule of ranibizumab, will cost a more manageable £2m. Visual outcomes are reported to be equivalent to that of ranibizumab, but the data come from multiple case series.¹² Bevacizumab is licensed solely for treatment of colorectal cancer, does not carry a label for acute macular degeneration, and is not licensed for intraocular delivery. Retrospective case series are no substitute for outcomes measured prospectively; therefore, a controlled clinical trial of bevacizumab versus ranibizumab should be a priority for health services already struggling to meet the demands of ever ageing populations.

¹ The Queen's University of Belfast, Belfast BT12 6BA, Northern Ireland, ² Doheny Retina Institute of the Doheny Eye Institute, University of Southern California Keck School of Medicine

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Competing interests: UC has been on scientific advisory boards of Novartis, Pfizer, Genaera, Jerini, and Eyetech, all of whom have proprietary interest in agents that inhibit vascular endothelial growth factor. She was a member of the VISION Trials Study Group. She has received financial assistance from some of the above for speaking engagements at conferences. JIL has been on scientific advisory boards of Novartis, Pfizer, EyeTech, Genentech, and Allergan. She was a member of the VISION, MARINA, and ANCHOR clinical trials study groups.

Provenance and peer review: Not commissioned, peer reviewed. Pfizer, the company marketing the vascular endothelial growth factor inhibitor Macugen (pegaptanib sodium), asked UC to write an editorial on the drug. She had been an investigator in trials of that agent which showed some benefit on acute macular degeneration. However, until better evidence was available she was highly sceptical about such invasive and potentially harmful treatments. She declined the offer to write an editorial funded by the Pfizer, but the suggestion gave her the idea of writing about the wider topic of vascular endothelial growth factor inhibition in acute macular degeneration.

References

1. Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv Ophthalmol 1988:32:375-88.
2. Owen CE, Fletcher AE, Donoghue M, Rudnicka AR. How big is the burden of visual loss from age-related macular degeneration in the United Kingdom? Br J Ophthalmol 2003;87:312-7.[Abstract/Free Full Text]
3. Krzystolik MG, Afshari MA, Adamis AP, Gaudreault J, Gragoudas ES, Michaud NA, et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol 2002;120:338-46.[Abstract/Free Full Text]
4. Gragoudas ES, Adamis AP, Cunningham ET, 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;351:2805-16.[Abstract/Free Full Text]
5. Rosenfeld P, Brown DM, Heier J, Boyer D, Kaiser PK, Cheung CY, et al; Marina Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-31.[Abstract/Free Full Text]
6. Brown DM, Kaiser PK, Michels M, Soubrane G, Kim RY, Sy JP, et al; Anchor Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-44.[Abstract/Free Full Text]
7. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:58-62[Abstract/Free Full Text]
8. Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab phase 3 clinical trials. Ophthalmol Clin North Am 2006;19:361-72.[Medline]
9. Storkebaum E, Lambrechts D, Carmeliet P. VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 2004;26:943-54.[CrossRef][ISI][Medline]
10. Brown GC, Sharma S, Brown MM, Kistler J. Utility values and age-related macular degeneration. Arch Ophthalmol 2000;118:47-51.
11. National Institute for Health and Clinical Excellence. Macular degeneration (age related)—photodynamic therapy. Technology appraisal 68, London: NICE, 2003. www.nice.org.uk/page.aspx?o=ta068.
12. Rich RM, Rosenfeld PJ, Puliafito CA, Dubovy SR, Davis JL, Flynn HW Jr, et al. Short-term safety and efficacy of intravitreal bevacizumab (avastin) for neovascular age-related macular degeneration. Retina 2006;26:495-511.[CrossRef][Medline]

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