Where were you last summer when retina specialists at the University of Miami published two case reports suggesting that bevacizumab (Avastin) had potential in treating wet macular degeneration and macular edema from CRVO? Even if you missed the original reports,1,2 you can’t miss their aftermath: The intravitreal use of Avastin for age-related macular degeneration—an off-label application—has taken off at a blistering pace, rapidly altering the retina landscape.
"It became a global phenomenon within six months," said Philip J. Rosenfeld, MD, PhD, associate professor of ophthalmology at the University of Miami. "But it just goes to show that when patients are losing vision despite receiving approved therapies, there is a tremendous unmet need. And when a potential therapy is introduced that seems rational, based on science and our clinical experience with related drugs, and it’s inexpensive, our profession understands that there is an ethical obligation to at least inform our patients that such a treatment is available, even if all the risks have yet to be identified."
From One Disease to Another
Avastin was the first VEGF-blocking drug to be approved by the FDA. However, it was developed for treating colorectal cancer. How did Dr. Rosenfeld and his colleagues make the leap to using it for AMD?
"We came to this from the background of clinical and research data. There’s a lot of good, logical information and practical, useful data that clearly indicated that this might be useful," he said. For instance, they were seeing good responses to ranibizumab (Lucentis), a fragment of Avastin, in early clinical studies.
On the flip side, they noted that the average patient treated with pegaptanib (Macugen) was still continuing to lose vision. And they couldn’t help but note the cost differential (see "Follow the Money," below).
Intravenous use. Dr. Rosenfeld and his colleagues first evaluated intravenous Avastin in AMD patients. In this study, they found a significant increase in visual acuity within one week. At 12 weeks, the median and mean visual acuity scores increased by eight and 12 letters, respectively, after just two or three doses.1
Although no serious adverse events were identified among the 18 patients, Dr. Rosenfeld was always concerned about the risks posed by the systemic drug and began investigating ways to reduce the drug dosage. Upon reviewing literature from the 1990s that supported the contention that Avastin could not penetrate the retina and would not be successful for treating neovascular AMD, Dr. Rosenfeld discovered that Avastin had never been studied in this manner. (However, an Avastin-like antibody had been injected into a monkey model of neovascular glaucoma with dramatic results.)
Intraocular use. He then calculated that a small amount of Avastin would be roughly equivalent to the dose of Lucentis being evaluated in clinical trials—and it seemed reasonable that this dose of Avastin, 400-fold less than the systemic dose, could be injected into an eye. Dr. Rosenfeld injected a patient who had responded poorly to previous Macugen treatment with 1 milligram of Avastin—and reported improvement in angiographic and OCT outcomes.2
The Nays and Yeas
Any off-label use is bound to raise eyebrows, at least initially. "There’s a spectrum of opinion with something like this," said Dr. Rosenfeld. "It’s controversial. Not everyone is in agreement."
No, not yet. Indeed, some retina specialists are taking a wait-and-see approach, keeping the drug at arm’s length until more data on safety and efficacy are available. For instance, because Avastin was not created to be given intravitreally, there are no published data on retinal toxicity. Moreover, Avastin has been associated with an increased risk of thromboembolic events.
Well, maybe. Others are using Avastin but are doing so selectively. For instance, Dr. Rosenfeld and his colleagues use the drug as salvage therapy, at a dose of 1.25 mg, in patients who continue to lose vision despite treatment with approved therapies. In addition, they don’t use Avastin in patients with a recent history of heart attack or stroke. "If they had a heart attack or stroke in the distant past, that doesn’t prevent usage," he said.
Yes, now. But intravitreal Avastin is moving beyond salvage therapy and is becoming an option as a primary treatment for those with wet AMD, said Sharon Fekrat, MD, associate professor of ophthalmology at Duke. "With any type of wet AMD, I sit down with patients and discuss all of their options. We talk about frequency of treatment, mode of administration and cost. It’s a long conversation. At the end, they typically choose Avastin."
While Dr. Fekrat does exclude patients with recent heart disease, she noted, "When you think about the protocol for colon cancer patients, they’re getting 300 to 400 mg intravenously every two weeks. We’re using 1 mg in the eye. I don’t think toxicity is as much of a concern."
She added, "Any time we use something off-label, and there isn’t a lot of information, we have to make sure that we’re as well-informed as possible, have very candid discussions with our patients and then make the best decision we can. Of course you have to be cautious, but the responses with Avastin are striking."
Results Coming In
Dr. Fekrat began using Avastin at the end of July 2005, and has modeled her administration protocol on that which is being used in Genentech’s SAILOR3 trial. "I treat once a month for three months, then wait. I see [the patient] six weeks later for the first checkup, then six weeks after that for a second checkup."
To date, she hasn’t had to re-treat any patients at the time of the first checkup, but she reported that she is re-treating about half of her patients t the time of the second checkup. "They tend to have a recurrence of CNV lesions somewhere between that first and second checkup." She uses the same dose (1 mg) with re-treatments.
Of course, the optimal protocol—and the full picture of safety and efficacy —won’t be known until results of clinical trials are in.
"Things are moving very quickly," Dr. Rosenfeld noted. "We have presented a protocol to the FDA and are working with them on a prospective clinical trial. Other groups are working on trials as well, including head-to-head comparisons of Avastin and Lucentis."
As for concerns about retinal toxicity, Dr. Rosenfeld said that he and his colleagues set up an Internet safety survey to collect data. "We will be presenting the results at the ARVO [Association for Research in Vision and Ophthalmology] meeting, but so far, it’s fair to say that there are no indications of problems with toxicity."
Follow the Money
You can’t discuss Avastin without discussing money. The drug is cheap, particularly in comparison with Macugen.
A 0.3-mg dose of Macugen is approximately $1,000, or $3,300/mg. In comparison, a 1-mg dose of Avastin runs around $6. And for many patients, out-of-pocket costs tip the balance in choosing therapies. "If cost is an issue, they don’t have to think too long," said Dr. Fekrat.
Because of Avastin’s off-label status for AMD, reimbursement varies significantly by state. "It’s a crazy quilt at the moment," said Dr. Rosenfeld. "Let’s just say that we’ll be talking with Medicare as more studies are published, so that reimbursement issues can be clarified."
Fair is fair. Dr. Fekrat, whose state covers the injection procedure but not the drug, noted a related point: "If a state declines the cost of the injection for Avastin, that means that they shouldn’t pay for injecting triamcinolone [Kenalog] either. That’s off-label as well."
Whatever happens with reimbursement battles, it’s fair to say that Avastin is going to continue to capture the attention of researchers and clinicians. As Dr. Rosenfeld said, "This has taken on a life of its own. It’s not going away. It’s too reasonably priced, and there are too many knowledgeable people—people who understand the progression of neovascular AMD—who are believing what they see with their own eyes when they inject Avastin."
1 Michels, S. et al. Ophthalmology 2005;112(6): 1035–1047.
2 Rosenfeld, P. J. et al. Ophthalmic Surg Lasers Imaging 2005;36:331–335.
3 Safety Assessment of Intravitreal Lucentis for AMD.
Dr. Fekrat has no related financial interests. Dr. Rosenfeld has received support for clinical trials from Genentech, Eyetech/OSI Pharmaceuticals, Novartis and QLT. He sits on scientific advisory boards for Genentech, Novartis, Allergan and BioAxone.