Experts discuss role of anti-VEGF options in future of wet AMD treatment

The three leading drugs to treat wet AMD work by blocking vascular endothelial growth factor. Experts discuss some of the differences.

In the pharmaceutical treatment of wet macular degeneration, blocking vascular endothelial growth factor-A is the state-of-the-art. The three most popular options for physicians to treat wet AMD pharmacologically are all anti-VEGF agents. Experts in the field spoke with Ocular Surgery News about the similarities, differences, pluses and minuses of the current options and looked ahead to what is on the horizon.

Anthony P. Adamis

“Shortly after VEGF was discovered, a series of experiments were done in my lab and in other labs around the world that showed that VEGF seemed to play a critical role in the growth of abnormal blood vessels in the eye,” Anthony P. Adamis, MD, told to OSN. “It became a compelling target for treating patients with diseases like AMD and diabetic retinopathy.”

Now, a decade later, there are three main drugs that take this approach to the treatment of choroidal neovascularization in AMD: Macugen (pegaptanib sodium, OSI/Pfizer), Lucentis (ranibizumab, Genentech/Novartis) and the off-label use of the cancer drug Avastin (bevacizumab, Genentech).

The latest development in the field is that the National Eye Institute has announced it will fund a new multicenter clinical trial to compare two of these drugs. According to a statement on the NEI Web site, “the new comparative study will assess the relative safety and effectiveness of Avastin and Lucentis.”

Macugen

The first anti-VEGF therapy approved for treatment of a disease of the macula was Macugen, a selective anti-VEGF that blocks the isoform VEGF-165, rather than all the VEGF in the retina. The drug is an aptamer or RNA molecule.

“As we studied VEGF further, … we realized that it does more than just make abnormal blood vessels grow,” explained Dr. Adamis, the chief scientific officer of OSI/Pfizer, which manufacturers Macugen. “It was learned that some VEGF is required for normal function and other types of VEGF seem to play a more important role in disease.”

The strategy of Dr. Adamis and his colleagues in developing Macugen was to block the isoform VEGF 165, which had “a significant effect” on the rate of vision loss and disease progression, Dr. Adamis explained.

“At that time, it was certainly a revolution in treatment: the first purely pharmaceutical approach for age-related macular degeneration,” Mark S. Hughes, MD, told OSN. “The results were certainly far better than the natural history of the disease. Although as monotherapy, Macugen primarily reduced the rate of vision loss in exudative AMD.”

The drug did not, however, generally improve visual acuity, other experts observed. Although it was revolutionary in concept, said Abdhish R. Bhavsar, MD, it produced results similar to photodynamic therapy (PDT), which was at the time the only pharmaceutical approach available to treat CNV in AMD.

“The treatment really was similar as a monotherapy to what we experienced with PDT as a monotherapy,” Dr. Bhavsar said.

With the introduction of off-label use of Avastin last year, followed by the U.S. Food and Drug Administration’s approval of Lucentis this year, some physicians have begun using these treatments, which block all known forms of VEGF-A, experts said.

“The other treatments – photodynamic therapy with verteporfin, and Macugen – are being used less frequently in our practice. The argument in favor of Macugen over Lucentis is safety, but the phase 3 trials of Lucentis showed Lucentis to be safe,” Philip J. Rosenfeld, MD, PhD, told OSN.

Avastin

Dr. Rosenfeld was the first to report the use of intravitreal injection of bevacizumab, or Avastin, to treat wet AMD. Since the publication of his case reports in 2005, many retinal specialists have adopted this method, although it is an off-label use of Avastin, which is FDA-approved for the systemic treatment of colon cancer and lung cancers. (These case reports appeared in Ophthalmic Surgical Lasers and Imaging a SLACK Incorporated publication.)

Philip J. Rosenfeld

“In a very rapid uptake, retina specialists began treating AMD with intravitreal Avastin,” Dr. Bhavsar said. “That uptake seemed to be exponential, to where within 1 year later, that treatment, in spite of no clinical trials to support treatment of exudative AMD with Avastin, has become without question the standard of care for management of exudative AMD.”

Dr. Bhavsar explained that Avastin is a full-length antibody designed to block all isoforms of the VEGF-A gene. Targeting VEGF-A has proved to be more effective than other treatments for wet AMD, he said.

“It was apparent to most retina specialists, even in early use of Avastin, that this treatment was better than most other treatments that we’d had before,” Dr. Bhavsar said.

Typically, treatment has been performed approximately every 6 weeks, Dr. Bhavsar said, but some physicians are beginning to time the treatments on an individualized basis.

Dr. Hughes agreed that since its introduction, and despite the lack of data from prospective, controlled clinical trials, intravitreal Avastin rapidly became the leading treatment for wet AMD before the approval of Lucentis.

“The use of Avastin took off like wildfire, and, probably over the last year, significantly more patients have been treated with intravitreal Avastin than have been with intravitreal Lucentis,” he said. “It reflected our desperation for a better treatment for our patients.”

Lucentis

The adoption of the oncology drug Avastin by ophthalmologists for treatment of AMD was based upon the assumption that it would act much like ranibizumab, or Lucentis, which was not yet FDA-approved in 2005 but had shown promise in clinical trials, Dr. Bhavsar explained.

Lucentis is a humanized antibody fragment designed to specifically target the retina and subretinal space and engineered for intraocular use.Avastin is a full-length antibody. Both were derived from the same mouse antibody and both bind and inhibit VEGF-A, according to Genentech.

“The percentage of patients that had substantial visual acuity improvement [with ranibizumab] typically ranged from 25% up to 40%,” Dr. Bhavsar said. “That result was one that we had never seen before as retina specialists in the treatment of wet AMD.”

Dr. Rosenfeld added, “Lucentis is the first proven therapy that can, for the average patient, improve visual acuity.” Still, he noted, 25% of patients will not see visual improvement, and it is important to inform patients that Lucentis is not a “cure.”

“Unfortunately, the mass media use terms like ‘restore vision’ and ‘cure AMD’ when announcing Lucentis, and it’s our job to manage expectations appropriately,” he said.

Individualized dosing

The FDA-approved labeling of Lucentis states that the drug can be given monthly or “treatment may be reduced to one injection every 3 months after the first four injections if monthly injections are not feasible.”

Dawn Kalmar, in Genentech’s corporate relations department, said the company anticipates that “the average patient will receive between five and seven injections of Lucentis per year.”

Dr. Rosenfeld said he favors an individualized approach to treatment with both Avastin and Lucentis, based on optical coherence tomography of the patient’s retina.

“When we started using Avastin a year ago, we adopted a treatment paradigm using an OCT-guided variable dosing regimen with our Avastin population. Our experience with variable dosing is based on our use of Lucentis in the extension studies from the phase 1 and 2 studies and in a Genentech-sponsored study at the Bascom Palmer Eye Institute called the PrONTO (Prospective OCT imaging of patients with neovascular AMD treated with intra-ocular Lucentis) study,” Dr. Rosenfeld told OSN.

“We’ve been impressed by our ability to improve vision and maintain this improved vision by treating as needed based on the detection of macular fluid by OCT. Some patients need few injections over a year, and other patients have to be reinjected every 6 to 8 weeks.”

In the PrONTO study, 40 patients received three Lucentis injections on the monthly schedule and were then observed and treated only when fluid was seen on OCT.

When it was time for the first clinically determined injection at month 3, injections were required in only three of the 40 patients, Dr. Rosenfeld said. At the end of 1 year, seven of the 40 patients had not required another injection, he said, and another eight needed one additional injection. Overall, 37.5% of patients needed only one injection or no additional injections.

The 1-year results of the PrONTO study suggest that monthly injections of Lucentis may be unnecessary if the physician monitors patients’ eyes carefully, he said.

In the design of the PrONTO trial, “We could inject with Lucentis if fluid started to re-accumulate in the macula,” Dr. Rosenfeld explained. “Some patients went 2 to 6 months without needing another Lucentis injection. From the phase 1/2 studies, I have patients who have gone over 3 years now without needing another Lucentis injection.”

Dr. Rosenfeld’s conclusion is that each patient is unique in his or her treatment needs.

“We tailored PDT to meet our patients’ needs, and now we’re going to tailor Lucentis and Avastin the same way. If there’s evidence of leakage, then treatment should be applied.

“I thought that was a practical paradigm that prevented unnecessary treatment and made physicians feel like physicians again,” Dr. Rosenfeld said. “We’re using a logical clinical approach to decide if a patient really needs a needle stuck in their eye.”

He said he is aggressive in treating patients with Avastin or Lucentis when there is evidence of fluid in the macula, especially when it is in the patient’s better eye. He is less aggressive when it is the patient’s worse eye and the vision loss has been long-standing or an obvious scar is present.

“As long as I see any fluid in the macula using OCT imaging, there’s a chance for some vision improvement. Where there’s fluid there’s hope,” Dr. Rosenfeld said.

Safety discussion

There has been some discussion of the safety of the VEGF-A blocking drugs. Dr. Hughes expressed the concern that intravitreal Lucentis may have the same cardiovascular and stroke side effects that systemic, intravenous Avastin has shown in rare instances in cancer patients. Although in the ANCHOR and MARINA trials the incidence of cardiovascular events was not statistically significant between the control and treatment groups, there was still a safety signal. He said the clinical studies have not been large enough to take that into consideration.

“Not only do I worry might there be an increased risk of heart attack or stroke, but if someone has had a heart attack or stroke, will the use of a pan-VEGF blocking agent in any way impair or impede their healing?” he asked in speculation. “There are forms of VEGF that are considered protective in terms of neural tissue after a stroke, so if we block that, will we have a different result?”

Dr. Bhavsar said that, although this may be a theoretical concern, Lucentis still has the most safety and efficacy data of all the anti-VEGF drugs for AMD, along with the most level 1 data to support its use over the use of Avastin and Macugen.

“I think Lucentis is the best studied of the VEGF-A inhibitors,” Dr. Adamis acknowledged. “I would say that it is, from an efficacy standpoint, really right now a breakthrough of sorts.”

Another concern that Drs. Hughes and Adamis expressed about both Avastin and Lucentis was that their methods of blocking all known VEGF-A isoforms could potentially damage the retina in the long term. There is some suggestion of progressive thinning of normal perifoveal retina on OCT after prolonged Lucentis therapy in some patients.

“What is the effect of blocking VEGF on normal tissues?” Dr. Adamis asked. “As literally thousands of patients get treated, I think more data will speak to whether blocking all VEGF or blocking just a subset of it is preferable.”

The data cited by Drs. Hughes and Adamis were based on animal models, which other physicians interviewed by OSN felt were not applicable.

“There’s no data to support the contention that Macugen is safer than Lucentis. In fact, the Lucentis studies included patients regardless of a history of thromboembolic events, while the Macugen studies excluded such patients,” Dr. Rosenfeld said. “Even with these patients included in the Lucentis studies, when we compare the two studies, the overall death rate and thromboembolic rates were higher in the Macugen studies than in the Lucentis studies. There’s just no evidence over 2 years to support that contention.”

NEI will fund multicenter study comparing Lucentis, Avastin The National Eye Institute of the National Institutes of Health will fund a new multicenter clinical trial to compare two drugs currently used to treat advanced age-related macular degeneration, according to a statement on the NEI Web site. The two drugs are Lucentis (ranibizumab, Genentech/Novartis) and Avastin (bevacizumab, Genentech). According to the NEI statement, the new comparative study will assess the relative safety and effectiveness of Avastin and Lucentis. The drugs have never been directly compared in a multicenter trial. Philip J. Rosenfeld, MD, PhD, of Miami’s Bascom Palmer Eye Institute, told Ocular Surgery News, “The recently announced NIH trial comparing Lucentis and Avastin will include both monthly dosing arms and p.r.n. [ie, as needed] dosing arms, so we’ll find out in a large prospective study whether p.r.n. dosing is as good as monthly dosing.” No other information on the study was available as this article went to print.

Maintenance therapy

Eyetech and Pfizer have begun enrollment in the LEVEL study, in which patients will be treated initially with Lucentis and then maintained on injections of Macugen every 6 weeks.

“If you look at how (Lucentis) works, all the visual improvement that one sees is within the first 3 months of treatment,” Dr. Adamis said. “Could you treat with Lucentis for 3 months and then maintain those gains with Macugen, which seems to have potentially a safer profile?”

Dr. Hughes said he previously tried this strategy with Avastin induction followed by Macugen maintenance in a small prospective case series of 20 treatment naïve patients and saw “a very favorable response.”

Of those 20 patients, nine gained more than three lines of vision and no one lost more than three. He said 95% gained at least one line and the mean gain was 2.4 Snellen lines over 1 year.

“My concept was to hit the lesion hard with a pan-VEGF blockage agent and … then to maintain them on a specific VEGF blocker, specific for VEGF-165, because I feel that the other isoforms of VEGF may have an important role in terms of maintenance of neural health,” he said.

Dr. Hughes speculated that physicians may see an increase in neuronal thinning in eyes treated with anti-VEGF-A therapy over long periods of time.

Ms. Kalmar, of Genentech, noted that the terms “nonselective” and “pan-VEGF blocker” are not accurately applied to Lucentis. “Lucentis binds and inhibits all known forms of VEGF-A, not VEGF-B, VEGF-C, PDGF, etc.,” she said in an e-mail to OSN.

Drs. Bhavsar and Rosenfeld both said there is no reason to be concerned at this time about negative effects of Avastin or Lucentis. Dr. Rosenfeld said he had also had anecdotal experience with Macugen maintenance when Avastin was not covered by Medicare and was “not impressed.”

“Selective vs. nonselective inhibition of VEGF inside the adult eye – my gut feeling is that it’s not clinically relevant,” Dr. Bhavsar said. He explained that he would be more concerned if treating developing eyes because VEGFs play a more physiologic role during development.

Dr. Rosenfeld said he determines the best course of patient treatment based upon safety, efficacy and cost. Depending upon the situation, one may outweigh the others, he said.

“Let’s compare Lucentis and Macugen using those three variables,” he said. “First, safety. Macugen is safe and Lucentis is safe. There’s no difference in terms of safety. Let’s look at efficacy. Lucentis beats Macugen in efficacy hands-down. And when we talk about cost, most of the time we’re talking about patients who have Medicare coverage, secondary insurance or HMO.”

He concluded, “In comparing Lucentis and Macugen, I see no role for Macugen right now.” Avastin, which is less costly for patients to pay for out of pocket, is an option if cost is an issue, he said.

Drs. Adamis and Hughes noted that although there is data to support Lucentis, physicians should be aware of possible complications with all anti-VEGF treatments.

“As physicians, we need to be cognizant of all the things that VEGF does,” Dr. Adamis said. “We’re using these very powerful drugs now in patients and need to keep an eye open for potential side effects, not just with Lucentis, but with Macugen as well.”

He continued, “Experience with other drugs has shown that you really don’t understand what a drug does until it’s approved and out in the population for a long period of time. … It’s an ongoing process collecting data and seeing how safe these drugs are.”

Dr. Rosenfeld agreed. “For example, we were not aware of the anaphylactoid reactions caused by Macugen until the drug was approved,” he said. “These adverse reactions were identified during post-marketing surveillance. Similarly, we might find problems with Lucentis and Avastin.”

The labeling of Macugen was changed in April to reflect “rare reports of anaphylaxis/anaphylactoid reactions, including angioedema” associated with the injection procedure. OSI and Pfizer, which co-market the drug, announced at that time that no direct relationship has been established between the anaphylactic reactions and Macugen or the various medications administered as part of the injection process. The FDA required labeling of Lucentis includes a warning concerning the possibility of increased risk of cardiovascular or thromboembolic events. The Avastin labeling has recently been modified to include the possible risk of reversible posterior leukoencephalopathy, a central nervous system disorder.

Future prospects

While physicians continue to work with the current treatments for wet AMD, others are working on the future. Experts interviewed by OSN said the current focus of research is on combination therapies and delivery methods while other drugs are being developed.

“Our focus is going to be on looking at ways to decrease the need for frequent injection in patients that need frequent injection,” Dr. Rosenfeld said. “I’m not alone in predicting that we’ll see some sort of combination strategy in that population of patients who require frequent therapy with Lucentis or Avastin.”

Dr. Bhavsar noted that PDT combined with anti-VEGF therapy is a safe and effective treatment that has spurred thoughts of combining verteporfin PDT with Avastin or Lucentis. In addition, he mentioned that others are looking into triple therapy with verteporfin, ranibizumab and triamcinolone.

Along with combination therapy, Drs. Hughes and Adamis spoke about the development of longer-lasting aptamers to allow less frequent treatment.

“They’re hearty molecules and can be reformulated into extended-release formulations,” Dr. Adamis said. “Formulating an aptamer into an extended-release formulation so you only have to give it a couple times a year will prove to be a significant benefit in the future.”

On the horizon are new medications, such as short-interfering RNA (siRNA), which is designed to block the production of VEGF before it can cause wet AMD, and anti-platelet-derived growth factor (PDGF) medications which block the site where PDGF binds. (See related article.) Dr. Bhavsar also mentioned Regeneron’s VEGF Trap.

Dr. Hughes said the push toward finding a better treatment stems from the fact that there is no “single best treatment” yet.

“If our odds of success were like they are with retinal detachment – over 90% chance of success – I don’t think we’d be having this tremendous effort to find a different combination or a better type of therapy,” Dr. Hughes said.

For more information:

• Anthony P. Adamis, MD, is chief scientific officer of OSI/Pfizer. He can be reached at 3 Times Square, 12th Floor, New York, NY 10036; 212-824-3100; fax: 212-824-3101; e-mail: tony.adamis@eyetech.com. Dr. Adamis is a full-time employee of OSI Pharmaceuticals, maker of Macugen.
• Mark S. Hughes, MD, can be reached at Ophthalmic Consultants of Boston, 50 Staniford St., Suite 600, Boston, MA 02114; 617-367-4800. Dr. Hughes has no direct financial interest in the products discussed in this article, nor is he a paid consultant for any companies mentioned. Dr. Hughes is a member of the Speakers Bureau of Novartis, OSI/Eyetech and Pfizer, and has received research funds from Novartis and OSI/Eyetech.
• Abdhish R. Bhavsar, MD, can be reached at 710 E. 24th St., Suite 304, Minneapolis, MN 55404; 612-871-2292; fax: 612-871-0195; e-mail: bhavs001@umn.edu. Dr. Bhavsar does research for and has received research funds from Genentech, Novartis, Ista and Allergan. He has also served as a consultant to Genentech, Eyetech, Novartis and ISTA.
• Philip J. Rosenfeld, MD, PhD, can be reached at Bascom Palmer Institute, University of Miami School of Medicine, 900 NW 17th St., Miami, FL 33163; 305-326-6148; fax: 305-326-6417; e-mail: prosenfeld@med.miami.edu.

• OSI/Pfizer, maker of Macugen, can be reached at 3 Times Square, 12th Floor, New York, NY 10036; 212-824-3100; fax: 212-824-3101; Web site: www.macugen.com. Genentech, maker of Avastin and Lucentis, can be reached at 1 DNA Way, South San Francisco, CA 94080-4990; Web site: www.gene.com.

• Katrina Altersitz is an OSN Staff Writer who covers all aspects of ophthalmology.