Anti-VEGF agents have sparked swift, dramatic changes in wet AMD treatment

In this installment of our anniversary series discussing the top 10 ophthalmic innovations of the past 25 years, experts discuss pan-VEGF blockers.

The advent of vascular endothelial growth factor inhibitors ushered in a renaissance in the treatment of age-related macular degeneration.

In contrast to a number of laser and drug therapies that dominated wet AMD treatment until late 2004, newer anti-VEGF agents have been shown to improve vision and not just mitigate vision loss.

While some research has shown there might be a small degree of increased cardiovascular risk involved in the new modalities, a large clinical trial is getting under way to assess those risks. Furthermore, combination treatments involving anti-VEGFs, laser and other biochemical agents are also emerging.

In telephone interviews, OSN Retina/Vitreous Section Members Peter K. Kaiser, MD, and Carl D. Regillo, MD, and retinal specialists Mark S. Hughes, MD, and Philip J. Rosenfeld, MD, PhD, discussed the benefits and risks of anti-VEGF agents and looked at the potential of combined therapies. William L. Rich III, MD, FACS, American Academy of Ophthalmology medical director of health policy, commented on a major clinical trial set to begin this fall.

“For a really long time, we really did not have a way to effectively control wet macular degeneration to a satisfactory degree,” Dr. Regillo said. “Up until the year 2000, we had nothing but destructive laser photocoagulation, too destructive to use for the vast majority of wet macular degeneration cases.”

Photodynamic therapy with Visudyne (verteporfin, Novartis) became the standard treatment for wet AMD in 2000. Just a few years later, the advent of anti-VEGF agents drove a paradigm shift in AMD treatment and dramatically improved patient outcomes.

“It’s really a revolution in evolution,” Dr. Hughes said. “We had limited treatments 8 years ago for macular degeneration, so 90%+ of patients were really not treatable. PDT with verteporfin was the first pharmacotherapy to change the natural history of the disease.”

Anti-VEGF agents

In December 2004, the U.S. Food and Drug Administration approved Macugen (pegaptanib sodium, Eyetech/Pfizer), the first anti-VEGF therapy for macular disease.

“It was actually the first anti-VEGF therapeutic in medicine,” Dr. Regillo said. “It allowed us to treat more patients with wet macular degeneration. Like PDT, pegaptanib decreased the growth and leakiness of CNV, and minimized the amount of damage and scarring. But it, too, did not really improve the vision in the vast majority of patients.”

The approval of pegaptanib was a major leap forward as the first non-laser therapy at that time, Dr. Hughes said.

“Obviously an approach using pure pharmacotherapy without laser was a major change,” he said. “Intravitreal drug therapy was a major step forward, far better than natural history, and allowed us to treat all subtypes of choroidal neovascularization with less visual loss.”

Pegaptanib selectively blocks the isoform VEGF-165, rather than all VEGF isoforms in the retina.

Carl D. Regillo

“The VEGF-165 isoform is an important one,” Dr. Regillo said. “It is certainly one that has to be targeted, but now we realize inhibiting all of them or most of them results in better anatomical and visual outcomes. It’s obvious now in retrospect that the more VEGF inhibition the better, at least in the short term.”

During the summer of 2005, pegaptanib had been on the market only about 6 months when Dr. Rosenfeld reported positive outcomes from intravitreal injection of Avastin (bevacizumab, Genentech). The FDA had approved bevacizumab for the treatment of colon cancer in February 2004. In light of the positive ocular results from this systemically indicated drug, ophthalmologists began using bevacizumab off-label for wet AMD.

“That really changed the world for Macugen,” Dr. Regillo said. “They had very limited time on the market and were really unable to compete because pan-VEGF blockade was clearly superior to selective VEGF blockade.”

Bevacizumab and its molecular cousin, Lucentis (ranibizumab, Genentech), are pan-VEGF blockers, which effectively halt, not just reduce, neovascularization growth and leakage, Dr. Regillo said.

“We were starting to get visual acuity improvement,” he said. “The majority of patients were actually improving to some degree, not just having a reduction in vision loss. That was a big step forward.”

Bevacizumab’s popularity continued to expand while ranibizumab underwent clinical trials to secure FDA approval.

“It looked at the time, anecdotally, that Avastin was producing a similar anatomical and vision improvement effect that Lucentis was showing in clinical trials,” Dr. Regillo said. “People around the world were using Avastin for wet AMD and having results that looked better than Macugen and, therefore, became very comfortable with it and started to use it as a primary or first-line agent.”

‘Perfect storm of events’

Dr. Rosenfeld recalled the events surrounding the rise of bevacizumab and ranibizumab.

Imaging technology, namely optical coherence tomography, played a key role in assessing the effectiveness of ranibizumab in clinical trials, Dr. Rosenfeld said.

“It’s all a very intertwined story between Lucentis, OCT and Avastin,” he said. “I call it a perfect storm of events.”

Dr. Rosenfeld and colleagues used a prototype OCT platform during phase 1 and phase 2 clinical trials of ranibizumab between 2000 and 2002. OCT demonstrated fluid disappearing from the macula almost immediately, he said.

“Never before had we seen such a dramatic, rapid response to all the treatments for wet macular degeneration,” he said. “The OCT response was associated with improvement in vision. … We immediately realized that OCT was going to be a valuable tool in monitoring the effects of the anti-VEGF therapy.”

OCT imaging dispelled uncertainty about the effectiveness of ranibizumab, Dr. Rosenfeld said. What remained to be seen was whether the effect could be sustained over the long term.

“There was no doubt in our minds,” he said. “After we saw the OCT data and the subsequent angiographic data, there was no doubt in our minds that we were seeing a highly effective drug. The question was, could we keep it up with multiple injections over 2 years and sustain the improvement?”

After bevacizumab was approved and made available for clinical use in cancer patients, Dr. Rosenfeld and colleagues obtained institutional review board approval to administer the agent at a cancer dose to patients with wet AMD. They recruited an initial group of 18 patients who received two or three infusions of bevacizumab.

“The results were dramatic,” Dr. Rosenfeld said. “Following the systemic Avastin infusion, we saw the exact same OCT response that we saw with Lucentis.”

However, many ophthalmologists were reluctant to administer systemic bevacizumab because of a possible increase in cardiovascular risks. Dr. Rosenfeld and colleagues considered two options: using a lower systemic dose or injecting the agent into the eye, he said. The preferred path became clear when it was noted that bevacizumab was sold at an optimal concentration for injection into the eye and at a lower cost than ranibizumab.

While bevacizumab costs around $15 or less per injection, ranibizumab can cost as much as $2,000 per injection.

“This is where all the pieces fell into place because, fortuitously, commercial Avastin was packaged at such a concentration that we could inject the same volume as Lucentis into the eye and it was the same amount of drug as Lucentis,” Dr. Rosenfeld said. “We knew that Avastin was effective systemically. We also knew from looking at the literature that Avastin and Lucentis were essentially the same molecule, except Avastin was larger.”

Head-to-head trial

The FDA approved ranibizumab for wet AMD in June 2006. Since then, the debate over whether bevacizumab or ranibizumab will become the dominant choice for AMD therapy has grown more intense.

Combination treatments: Next level of efficacy Combination treatments involving anti-VEGF agents could hold the key to even more effective ways to combat AMD, according to Peter K. Kaiser, MD. Peter K. Kaiser “Currently, when you look at combination therapy, we really are talking about either PDT with Avastin, PDT with Lucentis or PDT with Macugen,” he said. “It would make no sense to combine Lucentis with Avastin or Lucentis with Macugen because they’re similar drugs, essentially. Right now, when we talk about combination treatment, we’re talking about PDT with something else because they’re hitting the neovascularization at two different sites.” Agents such as Tyrosine kinase inhibitors may work in tandem with bevacizumab and ranibizumab, Dr. Kaiser said. He also pointed to the phase 3 COBALT trial. Bevasiranib (Opko Health) is an RNA interfering agent designed to deactivate the genes that propagate VEGF. The COBALT trial is designed to compare bevasiranib instilled every 8 to 12 weeks with ranibizumab given every 4 weeks, according to an Opko news release. The trial includes more than 330 wet AMD patients. “We have a drug that works on RNA interference, that blocks the production of VEGF itself, so you could use that in combination with Lucentis,” Dr. Kaiser said. The DENALI study will examine a combination of ranibizumab and PDT, Carl D. Regillo, MD, said. Furthermore, two triple therapy trials, TAPER and RADICAL, have been designed for patients with wet AMD. The triple therapies are composed of ranibizumab, PDT and dexamethasone. Dr. Regillo and Jason Slakter, MD, were instrumental in designing the protocol for the TAPER study, which recently got under way. “TAPER is more like a rescue therapy,” he said. “It’s for patients not responding fully to just Lucentis, so triple therapy is introduced as a way to get more effective control of the condition.” In Europe, the PROTECT study focused on same-day PDT combined with ranibizumab. The combined treatment reduced central retinal thickness up to 9 months, decreased mean greatest lesion dimension and stabilized leakage up to 9 months. The data from the study were presented at the European Society of Ophthalmology meeting.

Upcoming clinical trial

A much-anticipated head-to-head clinical trial, scheduled to begin in early 2008, is expected to shed more light on this controversy.

The Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) is sponsored by the National Institutes of Health and the National Eye Institute. The set of randomized clinical trials will be conducted at more than 40 sites throughout the United States.

The CATT will include about 1,200 patients randomly assigned to four treatment arms: monthly dosing of ranibizumab; monthly dosing of bevacizumab; three injections of ranibizumab with subsequent injections as needed; and three injections of bevacizumab with subsequent injections as needed.

“What we’re trying to find out is the efficiency and safety and maybe use less intense dosing than what’s currently out there,” Dr. Rich said. “This is a unique trial in that it actually is comparing two drugs to look at their effectiveness and safety. Normal trials in this country, like FDA trials, look at safety and efficacy, but when a new drug or device is introduced, they compare it to placebo. They’re not comparing it to other things that are on the market.”

The study will follow patients for 2 years and take a total of 4 years to complete. Patient enrollment is scheduled to begin later this year, and 1-year follow-up data are expected to be released in 2009.

Dr. Kaiser praised the trial as an effort to evaluate the safety and efficacy of ranibizumab and bevacizumab.

“It’s a very good study because from a public health standpoint, and especially a public policy standpoint, it’s a question that we need to answer,” Dr. Kaiser said. “I think that Lucentis is slightly better than Avastin. It has a faster onset of action and a more complete decrease in retinal thickness.”

However, he said he does not anticipate that the trial will show a great difference in efficacy between the two drugs.

Dr. Kaiser said he is interested to see if there is a difference in the safety between the two drugs.

“Give the considerably longer systemic half-life of Avastin, the difference in systemic safety will be another important finding from the CATT,” he said. According to Dr. Kaiser, the final question that will be answered by the study is the best way to deliver the drugs, as both as-needed and monthly dosing are being tested.

Clinical outcomes will be key, Dr. Hughes said.

“If the end result for visual acuity and OCT measurements are similar between the two, then you have established credibility for the clinical use of Avastin, an off-label drug, in age-related macular degeneration,” he said. “If, at the end of the day, you say that, biologically, they behave in a similar fashion with similar endpoints, then I think that you have lent a lot of credibility to its use. The CATT is critical in order to document the benefits of Avastin in terms of efficacy; however, the CATT is not powered to answer the question of systemic safety or increased cardiovascular risk with the use of Avastin as compared to Lucentis.”

Dr. Rich noted that the results will affect clinicians around the globe.

For more information:

• Mark S. Hughes, MD, can be reached at Ophthalmic Consultants of Boston, 50 Staniford St., Suite 600, Boston, MA 02114; 617-314-2715. Dr. Hughes has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned. He is on the speakers bureau and has received research funds from QLT, Novartis and OSI/Eyetech.
• Peter K. Kaiser, MD, can be reached at the Cole Eye Institute, Division of Ophthalmology, A31, 9500 Euclid Ave., Cleveland, OH 44195; 216-444-6702. Dr. Kaiser serves on the scientific advisory boards for Genentech, Alcon, Novartis, QLT, Bausch & Lomb, Occulogix and Allergan. The Cole Eye Institute, his employer, has received research grant support for his work from Alcon, Allergan, OSI/Eyetech, Genentech, Novartis, QLT and Sirna Therapeutics.
• Carl D. Regillo, MD, can be reached at Retina Service, Wills Eye Institute, 840 Walnut St., Suite 1020, Philadelphia, PA 19107; 856-755-1278. Dr. Regillo has been a consultant for Genentech, Eyetech, Novartis and QLT. The Retina Service of Wills Eye has received research grant support from Genentech, Eyetech, Novartis, Regeneron, Alcon and QLT.
• William L. Rich III, MD, FACS, can be reached at American Academy of Ophthalmology, Government Affairs Division, 1101 Vermont Ave. NW, Suite 700, Washington, DC 20005; 202-737-6662.
• Philip J. Rosenfeld, MD, PhD, can be reached at Bascom Palmer Eye Institute, University of Miami School of Medicine, 900 NW 17th St., Miami, FL 33163; 305-326-6148. Dr. Rosenfeld has received clinical research grants from Genentech and sits on its study advisory board.

• Matt Hasson is an OSN Staff Writer who covers all aspects of ophthalmology. He focuses on regulatory, legislative and practice management topics.