June 2012




International techniques and technology

Expanding indications for the use of anti-VEGF drugs

by Maxine Lipner Senior EyeWorld Contributing Editor

Anti-VEGF agents provide a good option for conditions such as retinal vein occlusion, which were otherwise very limited

Patients with diabetic retinopathy are among the expanding group that can benefit from anti-VEGF agents Source (all): Amar Agarwal, M.D.

Looking beyond the obvious

Growing applications

Practitioners here and abroad have adopted these neovascular wonder drugs for a host of ocular problems well beyond FDA-approved macular degeneration. "Many people use them for choroidal neovascularization of any etiology, pathological myopia, ocular histoplasmosis, idiopathic choroidal rupture, any inflammatory disease, and android streaks," said Susan B. Bressler, M.D., professor of ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore. "Others may subdivide out neovascular macular degeneration RAP lesions [retinal angiomatous proliferans] or retinal mastomatic lesions." Anti-VEGF (anti-vascular endothelial growth factor) agents are also commonly used in the pediatric realm for retinopathy of prematurity. Some less common uses Dr. Bressler pointed out include the treatment for things such as the rare congenital condition Coats' disease, also known as exudative retinitis, or for choroidal neovascularization in the setting of idiopathic perifoveal telangiectasia. "That's a smattering of entities throughout the world," Dr. Bressler said. In India, at one of the three Agarwal Eye Hospitals, patients with retinal problems such as age-related macular degeneration, retinal vein occlusion, diabetic retinopathy, or macular edema are routinely offered a choice of Avastin or Lucentis (bevacizumab and ranibizumab, Genentech, South San Francisco), according to Amar Agarwal, M.D., director, Dr. Agarwal's Group of Eye Hospitals, Chennai, India. Dr. Agarwal counts himself lucky to have these anti-VEGF agents for varying diseases for which there may be few or no other treatment options. "The advantage with these drugs is we have a good option to treat these conditions that was not there before," Dr. Agarwal said. "In the past, if a retinal vein occlusion came to me I might not have had a good treatment for ittoday I do."

Optimizing against infection

Choosing between the available anti-VEGF agents, Avastin or Lucentis, often comes down to the reality of economics. "Lucentis is a fantastic drug, but the problem is cost; that is a factor especially in a country like India," Dr. Agarwal said. "Here is the reality: If a patient can't afford it, we give him Avastin, which is comparatively much cheaper." Dr. Agarwal tries to keep the patient's budget in mind. "It's not necessary that everyone has to drive a Mercedes, but at the same time he has to reach the destination," he said. "So I give him the advantages, the pros and cons of all the products."

He tells patients that the big advantage of Lucentis is its single dose usage. "When I give Lucentis it is one dosageonce I inject it I throw it out," Dr. Agarwal said. Meanwhile with Avastin he finds that the disadvantage is that since this is supplied in multi-dose format and is kept on the shelf once opened, there is a chance of infection. "One vial is used in 30 patients," Dr. Agarwal said. So a chance of infection exists. To help minimize the risk, Dr. Agarwal has tried a unique strategy at the Agarwal Retinal Center, where he sees patients with a variety of conditions that could benefit from the drug. He schedules all of those who need Avastin for any ocular condition for appointments on the same day. "Let's say we have 30 patients I block on Friday; we open one vial on Friday and by evening we throw it out," Dr. Agarwal said. "The advantage of this method is that infection will not happen." The same cannot be said if he keeps the Avastin vial lingering for a month as patients trickle in. If somewhere along the line a mistake is made and the vial that has been sitting there is contaminated, multiple infections can occur. Serious infections can unfortunately occur in some cases. In Japan, investigators led by Mayumi Inoue, M.D., Yokohama City University Medical Center, Yokohama, Japan, found that Avastin was associated with a higher incidence of endophthalmitis infections. In this July 2011 retrospective study e-published in Ophthalmologica, investigators reported on the incidence of infectious and non-infectious endophthalmitis after intravitreal injection of anti-VEGF agents. Included in this study were 1,209 intravitreal bevacizumab injections, 3,827 ranibizumab injections, and 200 injections of pegaptanib sodium. Of these, investigators found five bevacizumab eyes that developed endophthalmitis. One of the conclusions that investigators reached was that consideration of an appropriate injection protocol should be given.

Latest anti-VEGF

With expanding uses for anti-VEGF also comes the need for innovation. One new anti-VEGF agent available to combat the multitude of retinal conditions that has been found to be successful is Eylea (aflibercept, Regeneron Pharmaceuticals, Tarrytown, N.Y.). "This has been approved in the U.S. for neovascular AMD, but once it is approved and available it can be used in an off-label fashion," Dr. Bressler said. The less frequent dosing schedule makes the drug desirable, she finds. "Dosed eight times over the course of a year and a dosing regimen of monthly for the first 3 months and Q8 weeks for the following 9 months has been shown to be equivalent to Lucentis given every single month for neovascular AMD," she said. Once again, however, economics may play a role in in-roads that Eylea ultimately makes globally. On the upside, Dr. Bressler pointed out that from the perspective of price, Eylea has the edge compared with ucentis."Given that the price of Eylea is $100 per dose and that one could use eight doses over the course of a year compared to 13, you'd be saving money per dose and per ann[um] and allegedly not sacrificing vision or anatomical results," Dr. Bressler said. Dr. Bressler suspects that many practitioners in the U.S. will begin to use Eylea in an off-label fashion for a variety of ocular conditions just as they have with other anti-VEGF agents. Ironically, however, in areas of the world where patients are cash strapped, she doesn't see Eylea as making in-roads. "Where economics is the driving factor, bevacizumab has the market cornered," she said. This stems from its early origins. "Because it was developed for cancer, the price was set for a unit of drug," she said. So, for example, if the drug was priced at $2,000 for a quart and all that ophthalmologists need is a teaspoon, the cost may be a mere $5, something with which there is no competing. "Even if that has to be given every single month, if what's driving decisions is economics, that is still going to be log-units less expensive," Dr. Bressler said.

In contrast, Terence Hurley, spokesperson for Genentech, added, "Even though the monthly wholesale cost of Lucentis in the U.S. for wet AMD is $1,950, the average cost for 1 year of Lucentis treatment in the U.S. depends on the number of injections a patient receives and typically ranges from $9,750-15,600 (for wet AMD, we currently estimate that in the first year of treatment, the average patient receives ~8 injections and then approximately 5 injections in the second year)."

Anti-VEGF offers options

Overall, Dr. Agarwal is impressed by all of the anti-VEGF agents and what they can offer a wide swath of his retinal patients. "From an ophthalmic point of view all of these drugs are fantastic," he said. "They are definitely helping the patients; there is no doubt about it because we have this documented everywhere in the world." He urged practitioners everywhere to begin using these. "The doctor has to move into it because when it affects and helps the patients, it is also going to favor the doctor because he is going to get better results," Dr. Agarwal said. "Anti-VEGF products are a real boon for patients."

Dr. Bressler agrees. Going forward she thinks that the most powerful strategy will be to make these agents more user friendly. "I think that these are wonderful drugs and that what we can accomplish now is enormously different from where we were 10 years ago," she said. "The best means of building upon that is going to be with a longer-acting agent or better ways of delivering it rather than something that is going to be more powerful in terms of vision change or a quicker response."

Editors' note: This article discusses off-label uses of anti-VEGF drugs.

For those with neovascular age-related macular degeneration in the U.S., use of anti-VEGF drugs such as Lucentis and Avastin to stabilize blood vessels and stop the proliferation of new ones is common practice. Likewise for a host of other retinal diseases these anti-VEGF agents are gaining traction, both here and around the globe, according to Dr. Bressler. Mr. Hurley clarified, "Avastin is not manufactured or approved for use in the eye, and thus we do not promote or support its use in the eye. It was developed and is approved for the treatment of patients with certain forms of cancer. Safety findings from large observational studies suggest the risk of systemic serious adverse events may be higher when injecting Avastin into a person's eye compared to Lucentis, which is approved and manufactured for use in the eye. Therefore, uncertainty remains about the safety of Avastin in the eye." He added, "We believe Lucentis is the most appropriate treatment for wet AMD, and physicians should have the ability to prescribe the medicine they think is right for their patients."

Anti-VEGF agents are well-suited to treat many different retinal conditions. "One, they stop blood vessels from growing," Dr. Bressler said. "Two, they seem to stop them from leaking, and both are desirable attributes." Drs. Agarwal and Bressler have no financial interests related to this article. Mr. Hurley has financial interests with Genentech.

Contact information

Agarwal: +91-44-2811-6233, dragarwal@vsnl.com
Bressler: 410-955-5080, sbressler@jhmi.edu
Hurley: 650-225-1000

Expanding indications for the use of anti-VEGF drugs Expanding indications for the use of anti-VEGF drugs
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