Features

Author: Michael Lavin

As controversy builds about access to new treatments for choroidal neovascularisation AMD, ophthalmologist Michael Lavin recounts his experiences with Lucentis and its cheaper 'parent' drug Avastin. He calls for clinical trials comparing Avastin and Lucentis but is impressed by the safety record and cost effectiveness of Avastin

In 2005 a quiet revolution occurred in ophthalmology. For the first time in the history of ophthalmology we now have treatments (intravitreal ranibizumab/Lucentis intravitreal or systemic bevacizumab/Avastin) which stabilise or improve vision in the great majority of patients with neovascular age-related macular degeneration (AMD). These treatments do not necessarily represent a permanent cure, and may need to be repeated from time to time, but their effects on vision are dramatic and maintained.

AMD is the leading cause of visual loss in patients over 65 years, and about 90 per cent of this visual loss is a result of the development of growing or leaking blood vessels (neovascular membranes, often referred to as 'wet' AMD), as a complication of AMD. Patients with severe visual loss from AMD suffer a serious handicap in quality of life, comparable to that of a catastrophic stroke.¹

Until 2005, patients with neovascular membranes were offered laser treatment (in about 5 per cent), or photodynamic therapy (PDT) with verteporfin dye injection and laser treatment (in about 20 per cent), while the remainder were left untreated, usually suffering severe and permanent visual loss. PDT is characterised by a loss of vision from baseline over the course of treatment, requiring an average of 5.5 treatments over two years, with a drug cost of £850 per treatment. ^2,3,4

Monthly intravitreal ranibizumab/Lucentis injection achieves significantly better outcomes.^5,6 Ranibizumab is derived from the parent molecule of bevacizumab/Avastin, both being humanised mouse monoclonal antibodies directed against all isoforms of vasoactive endothelial growth factor (VEGF). VEGF has a central position in regulating CNV. Ranibizumab/Lucentis-treated eyes show rapid regression of CNV, with an average improvement of 8.5 letters (compared to a loss of 9.5 letters for standard PDT treatment), and 30 per cent to 39 per cent of ranibizumab-treated eyes achieve driving-level vision (compared to only 3 per cent of PDT-treated eyes).^5,6

Clearly, ranibizumab/Lucentis treatment is far superior to PDT in terms of visual outcomes, and has the added advantage that it can be used to treat all neovascular AMD, unlike PDT. In non-randomised studies, intravitreal bevacizumab/Avastin injection shows similar risk and visual outcomes to ranibizumab, but with less frequent dosing, and substantially lower cost.^7-10 Cost can be a major barrier to treatment access.

Macugen/pegaptanib was the first anti-VEGF treatment introduced and is now a licensed product. Macugen/pegaptanib is superior to PDT in that it is effective in all types of neovascular AMD. However, Macugen treatment is associated with a loss of vision over the course of treatment (broadly similar to PDT results), while both Lucentis and Avastin treatments are associated with an average improvement in vision. Current data do not support the use of Macugen in most patients, but do favour either Avastin or Lucentis.

Case study

Mr E C presented in October 2005 with a history of previous right neovascular AMD treated with three PDT treatments, and recent left visual loss.

Vision was hand movements right eye, and 6/24 left eye, having been 6/9 in the left some months previously. The left eye had subretinal haemorrhage and subretinal fluid from a neovascular membrane complicating AMD. Treatment options were discussed, and intravitreal bevacizumab/Avastin was given. One week after treatment, vision had improved to 6/9 in the left eye with complete resolution of subretinal fluid. A single further intravitreal bevacizumab injection was given in May, and the patient maintains good vision, continuing to drive.

The optical coherence tomography scans (Figure 1) show the very marked therapeutic effect of intravitreal bevacizumab on one of Professor P Rosenfeld's patients. These show marked improvement in vision, reduction in retinal thickening, and resolution of pathologic changes.

Lucentis v Avastin

The series of Lucentis trials have shown, for the first time, that we now have effective treatments which prevent severe visual loss, and actually improve vision, in most patients with neovascular AMD.

It is very encouraging that a widely available and licensed drug (bevacizumab/Avastin) appears to be equally effective, with no demonstrable differences in outcomes, and can be safely sub-divided to provide single doses at a very low cost. There is a clear need for trials to compare Lucentis and Avastin.

Questions of risk, licensing and safety arise. There is a very small risk (about 1 in 800 injections) that any intravitreal injection could introduce infection, or cause retinal detachment, with possible blindness. It is important to consider any treatment strategy which reduces injection frequency, in order to reduce risk. While the original Lucentis trials required monthly Lucentis injections, the Pronto study appears to show that similar results may be seen in the first year, with reduced frequency dosing. Also, Avastin injections appear to be effective after one injection in about 50 per cent of patients, the remainder needing two to five injections in the first year.¹⁰ At the present time, there is no evidence of any direct toxic effect from either Avastin or Lucentis injections into the eye.

Licensing does not prevent serious problems: the recent case of VIOXX is an example (this pain-killing tablet was withdrawn after it was found that it increased the risk of heart disease, and that known facts on this side effect had not previously been made available). Patients want treatments that are effective and acceptably safe in the context of the disease being treated. It is commonplace, in the practice of medicine, to use unlicensed or off-label treatments.

Safety is an important issue, but the data is more robust for bevacizumab/Avastin than for ranibizumab/Lucentis.^{2-9 11-16} Bevacizumab is licensed (for colorectal cancer) for systemic injection at doses up to 400 times higher than those used for intravitreal injection^17,18 there is no data on systemic administration of ranibizumab. Experience with both drugs is considerable, and does not warrant the label 'experimental', although there is still a need for more data. Vascular complications are documented in patients receiving high dose systemic bevacizumab, but low dose (less than 2.5mg) intravitreal bevacizumab and ranibizumab have a risk which is similar to untreated age-matched controls with AMD.19

The costs of drugs can limit patient access to treatment, but equally the real costs of laboratory research and development (as opposed to marketing) should be rewarded. The attractions of bevaci-zumab/Avastin are both reduced dose frequency, and also cost. Ranibizumab/Lucentis currently costs £1,050 (+VAT) for a 0.6mg dose although bevacizumab/Avastin costs £247.50 for a 100mg vial, this can be subdivided to produce 20 or more doses, so that the drug cost per dose becomes very low.

The potential advantage of bevacizumab is not just cost, but a significant reduction in risk, due to reduced dose frequency. If Thomas' figures are borne out for longer periods, 100 patients would require 500 injections over two years, for a total of 7.5mg total intraocular bevacizumab dose per patient on average (range 3mg to 12mg). Since we have robust data on intravenous delivery of total doses estimated to be 25 500mg (assuming an average US adult weight), excessive risk aversion (in the context of blinding eye disease) with ocular doses as low as 7.5mg (0.029 per cent of the maximum systemic dose administered in FDA data) is inappropriate. It is not yet clear whether reduced dose strategies will deliver similar visual results for Lucentis and Avastin.

Conclusion

At the present time, neither Lucentis nor Avastin treatment is routinely offered by the NHS. The problem is that while individual ophthalmologists may wish to offer this treatment, and while their patients may wish for this treatment when facing inevitable visual loss, health care managers and purchasers do not fund access to these treatments. They continue to fund access to PDT, although it is substantially less effective than either Lucentis or Avastin. NHS purchasers also fund a wide range of other treatments (varicose vein, hernia, warts, an eyelid cyst, or a watery eye) which are of much lower healthcare benefit or utility than sight-saving treatment for neovascular macular disease with Avastin or Lucentis.

We know that in the relatively short-term, intravitreal bevacizumab is safe in doses less than 0.5 per cent of those for which it is licensed for systemic administration. Further data is required for both drugs, but this argument should not be used as an excuse to prevent delivery of effective care.

REFERENCES:

1 Brown G C, Brown M M,Sharma S, Stein J D, Roth Z, Campanella J, Beauchamp GR. The burden of age-related macular degeneration: a value-based medicine analysis. Trans Am Ophthalmol Soc 2005103:173-186.

2 Clinical effectiveness and cost utility of photodynamic therapy for wet age-related macular degeneration National Institute for Clinical Excellence, April 2002 http://www.nice.org.uk/page.aspx?o=30223.

3 Bressler N M. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularisation in age-related macular degeneration with verteporfin: two-year results of two randomised clinical trials-TAP report two. Arch Ophthalmol., 2001119:198-207.

4 British National Formulary, BMA Publishing, London, September 2005, 51st edition, p 545.

5 Genentech press release New York, 14 January 2006. http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=9307

6 Genentech press release, New York, 28 February 2005 http://www.gene.com/.

7 Spaide R F, Laud K, Fine H F, Klancnik Jr J M, Meyerle C B, Yannuzzi L A, Sorenson J, Slakter J, Fisher Y L, Cooney M J. Intravitreal Bevacizumab treatment of choroidal neovas-cularization secondary to age-related macular degeneration. Retina 200626:383-390.

8 Rich R M, Rosenfeld P J, Puliafito C A, Dubovy S R, Davis J L, Flynn H W Jr, Gonzalez S, Feuer W J, Lin R C, Lalwani G A, Nguyen J K, Kumar G. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina. 200626:495-511.

9 Fung A E, Rosenfeld P J, Reichel E. The international intravitreal bevacizumab safety survey: Using the internet to assess drug safety worldwide. Br J Ophthalmol. 2006 Jul 19: [Epub ahead of print]

10 Personal communication, Edgar L. Thomas, M D. Retina-Vitreous Associates, Beverly Hills, CA, US July 31, 2006. Data presented at European Vitreous Society meeting, Cannes, September 2006.

11 Bakri S J, Cameron J D, McCannel C A, Pulido J S, Marler R J. Absence of histologic retinal toxicity of intravitreal bevacizumab in a rabbit model. Am J Ophthalmol. 2006142(1):162-4.

12 Luthra S, Narayanan R, Marques L E, Chwa M, Kim D W, Dong J, Seigel G M, Neekhra A, Gramajo A L, Brown D J, Kenney M C, Kuppermann B D. Evaluation of in vitro effects of bevacizumab (Avastin) on retinal pigment epithelial, neurosensory retinal, and microvascular endothelial cells. Retina. 2006 May-Jun 26(5):512-8.

13 Spitzer M S, Wallenfels-Thilo B, Sierra A, Yoeruek E, Peters S, Henke-Fahle S, Bartz-Schmidt K U, Szurman P. Antiproliferative and cytotoxic properties of bevacizumab (avastin) on different ocular cells. Br J Ophthalmol. 2006 May 24 [Epub ahead of print].

14 Maturi R K, Bleau L A, Wilson D L. Electrophysiologic findings after intravitreal bevacizumab (Avastin) treatment. Retina. 2006 Mar 26(3):270-4.

15 Shahar J, Avery R L, Heilweil G, Barak A, Zemel E, Lewis G P, Johnson P T, Fisher S K, Perlman I, Loewenstein A. Electrophysiologic and retinal penetration studies following in-travitreal injection of bevacizumab (Avastin). Retina. 2006 Mar26(3):262-9.

16 Manzano R P, Peyman G A, Khan P, Kivilcim M. Testing intravitreal toxicity of bevacizumab (Avastin). Retina. 2006 Mar26(3):257-61.

17 http://www.fda.gov/cder/foi/label/2006/125156lbl.pdf

18 http://www.gene.com/gene/products/information/tgr/lucentis/insert.jsp#clinical_studies

19 Hawkins B, Werther W. Cardiovascular and cerebrovascular events in patients with neovas-cular age-related macular degeneration. Program and abstracts of the Association for Research in Vision and Ophthalmology April 30-May 4, 2006 Fort Lauderdale, Florida. Significant interest group 251.

◆ Please note that these views are those of the author at the present time, and do not necessarily reflect the views of any employer or NHS trust.

◆ Michael Lavin is a consultant ophthalmologist based in Manchester

Providing exclusive eye care news, information and educational needs every week, including a FREE CET programme. Subscribe to Optician Print Edition.