Welcome to the premier issue of AMD Update! 

It is estimated that 15 million people in the United States have age-related macular degeneration (AMD), with more than 1.75 million having advanced disease (defined as neovascular AMD or geographic atrophy); the number with advanced disease is expected to climb to almost 3 million by the year 2020. AMD is the leading cause of blindness in adults over 55 years of age. 

AMD Update is a monthly e-newsletter dedicated to bringing to the ophthalmologist the latest and most useful clinical information and literature reviews on the management of AMD in a quick, easy to review format.  The articles will be written by a variety of authors in order to draw upon a wealth of expertise. 

I am pleased to serve as Editor of AMD Update. I hope that you will find the information timely and applicable to your practice, and that you will look forward to each issue.

Ingrid U. Scott, MD, MPH
Professor of Ophthalmology and Health Evaluation Sciences
Penn State College of Medicine

Lucentis and Avastin: When to Use Which?

By: Robert Avery, MD
California Retina Consultants, Santa Barbara, CA

Few drugs have ever gained market-share, acceptance, and even enthusiastic use as rapidly as intravitreal Avastin has over the past year. This feat is particularly remarkable since its use is strictly “off-label”.  One reason for Avastin’s rapid acceptance is its apparent similarity to Lucentis.  By the time most people heard of intravitreal Avastin, the 1 year Marina results had been presented showing that Lucentis provided a dramatic efficacy improvement over the standard of care, and there was quite a “buzz” about the potential for anti-VEGF therapy.  However, because Lucentis would not be available for at least a year, and patients and doctors did not want to wait for FDA approval if a similar treatment were available, many retina specialists started offering intravitreal Avastin.  Now, over a year later, we have significantly more experience with Avastin, and we also have the FDA approval of Lucentis; hence the dilemma as to which drug to use.

The case for Lucentis is formidable.  Multiple phase III randomized controlled clinical trials evaluating its use in neovascular AMD have shown a striking efficacy benefit over the previous standard of care, with a good safety profile.^1,2  On the other hand, many more patients worldwide have now been treated with Avastin than Lucentis.  There are multiple published series of Avastin for AMD that demonstrate an anatomic and visual effect similar to that seen with Lucentis; however, most of these studies are short term, retrospective, uncontrolled and lack the standardized vision measurements and safety reporting required in FDA trials.^3-9 Theoretically, the significantly longer serum half-life of Avastin compared to Lucentis could increase its risk of systemic complications.  On the other hand, the intravitreal dose of Avastin is several orders of magnitude less than what is used intravenously in cancer patients. Finally, the intravitreal half-life of Avastin may be significantly longer than that of Lucentis and allow for less frequent injections.  In primates, a Genentech study found an intravitreal half-life of 5.6 days for a full-length humanized monoclonal antibody similar to Avastin and 3.2 days for a Fab fragment similar to Lucentis.¹⁰   Many clinicians currently use Avastin every 6 to 8 weeks, while Lucentis is approved for use every 4 weeks.

Another important difference between Avastin and Lucentis is the cost of the drugs.  Medicare in most states covers Avastin, and the reimbursement varies from carrier to carrier. In many states, Medicare allows $57 for one unit of Avastin.  The allowable for Lucentis is $2,067.  To Genentech’s credit, the company has developed a program to facilitate access to Lucentis for those who cannot afford it.

So which agent do we offer to our patients?  Interestingly, in a recent survey of members of the American Society of Retina Specialists, the 389 responders were about equally split between Avastin and Lucentis when choosing a drug for neovascular AMD.¹¹  I offer patients both drugs with a detailed explanation of the potential advantages and disadvantages of each.  For some patients, the proven safety and efficacy of Lucentis overrides the cost concern, and for others, Avastin has worked very well for them for over a year and they see no reason to change.  For indications other than AMD, Lucentis is not typically covered, and Avastin is usually selected.  For patients with a significant, recent thromboembolic history, Avastin is rarely selected because of potential safety and medicolegal issues, and Lucentis is offered cautiously.  Fortunately, the NIH has agreed to sponsor a head to head trial of Avastin and Lucentis to help our patients and physicians decide which drug to use.

References:
 1.  Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, et al.  Ranibizumab for neovascular age-related macular degeneration.  N Engl J Med 2006 Oct 5;355(14):1419-31.
2.  Brown DM, Kaiser PK, Michels M, Soubrane G, et al.  Ranibizumab versus verteporfin for neovascular age-related macular degeneration.  N Engl J Med 2006 Oct 5;355(14):1432-44.
3.  Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.  Ophthalmology 2006 Mar;113(3):363-372.e5.
4. Spaide RF, Laud K, Fine HF, Klancnik JM Jr, Meyerle CB, Yannuzzi LA, Sorenson J, Slakter J, Fisher YL, Cooney MJ.  Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration.  Retina 2006 Apr;26(4):383-90. 
5.  Rich RM, Rosenfeld PJ, Puliafito CA, Dubovy SR, Davis JL, Flynn HW Jr, Gonzalez S, Feuer WJ, Lin RC, Lalwani GA, Nguyen JK, Kumar G. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.
Retina 2006 May-Jun;26(5):495-511.
6.  Ladewig MS, Ziemssen F, Jaissle G, Helb HM, Scholl HP, Eter N, Bartz-Schmidt KU, Holz FG.   Intravitreal bevacizumab for neovascular age-related macular degeneration.  Ophthalmologe 2006 Jun;103(6):463-70.
7.  Bashshur ZF, Bazarbachi A, Schakal A, Haddad ZA, El Haibi CP, Noureddin BN.  Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration.
Am J Ophthalmol 2006 Jul;142(1):1-9.
8.    Costa RA, Jorge R, Calucci D, Cardillo JA, Melo LA Jr, Scott IU.  Intravitreal bevacizumab for choroidal neovascularization caused by AMD (IBeNA Study): results of a phase 1 dose-escalation study.
Invest Ophthalmol Vis Sci 2006 Oct;47(10):4569-78.
9.   Abraham-Marin ML, Cortes-Luna CF, Alvarez-Rivera G, Hernandez-Rojas M, Quiroz-Mercado H, Morales-Canton V.  Intravitreal bevacizumab therapy for neovascular age-related macular degeneration: a pilot study.  Graefes Arch Clin Exp Ophthalmol 2006 Sep 28; [Epub ahead of print]
10.  Mordenti J, Cuthbertson RA, Ferrara N, et al. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol 1999;27:536–544.
11. Preferences and Trends (PAT) Survey.  Presented at the American Society of Retina Specialists. Cannes, Sept 2006.