Anti-VEGF at a Crossroads

A half-century of progress and controversy in treating retinal disease.

By Jerry Helzner, Senior Editor

One drug is a pioneering, first-in-class therapy that broke new ground in many areas, had a brief moment in the sun and was then largely eclipsed by a more efficacious drug. Another was intended to treat cancer intravenously but was adapted for use in the eye by a brilliant ophthalmologist/scientist. A third drug became the standard of care for the treatment of the wet form of macular degeneration and has recorded billions in sales over the past five years. A fourth may be “the next big thing” in the battle against wet AMD and other retinal diseases.

Their names are Macugen, Avastin, Lucentis and Eylea (formerly VEGF Trap-Eye) and they are known to every ophthalmologist. Delivered by intravitreal injection, they target the vascular endothelial growth factor (VEGF) that causes the vision-robbing proliferation of abnormal blood vessels in the macula that are the hallmark of wet AMD. They are also now being used successfully to treat other retinal diseases and even such non-retinal conditions as neovascular glaucoma.

Though the evolution of anti-VEGF therapy is surely a success story, it is also a source of ongoing controversy. Will one drug emerge as the therapy of choice? Will cheaper Avastin overcome the safety concerns that recently tarnished its reputation? Will a sustained-release format be a game-changer? Will a combination therapy be found that improves results? Here, we will examine milestones in anti-VEGF therapy and the key controversies that have led us to today's crossroads.

The Draftee's Discovery

The saga of anti-VEGF therapies begins with Dr. Judah Folkman. Dr. Folkman (1933-2008) can best be described as a medical prodigy — a combination of towering intelligence, unceasing curiosity and dogged persistence. Even as a freshman at Ohio State University, he was thinking like an accomplished surgeon, designing medical devices and publishing a paper in a prestigious surgical journal. With no challenges left at the undergraduate level, he entered Harvard Medical School at age 19 and soon got involved in such projects as developing the first implantable pacemaker.

However, at age 26, in the midst of his surgical residency at Massachusetts General Hospital, young Dr. Folkman was drafted into military service. In 1960, he was serving in the Navy and performing research on potential blood substitutes for emergency use at the Navy's national medical research center in Bethesda, Md. There, he noticed that tumor cells did not grow when fed by blood substitutes, but did grow when implanted into mice.

He came to the conclusion that tumor growth could be dependent on having a blood supply. And if so, he theorized that malignant tumors could be successfully treated by starving them of their blood supply. This burst of insight, recognizing the danger of unwanted blood supply and angiogenesis in tumor growth, became the foundation of Dr. Folkman's future research and led to the creation of the now-famous Folkman Laboratory at Children's Hospital in Boston, the pediatric arm of the Harvard Medical School.

The Compelling Lecture

Continuing his research on tumor growth and angiogenesis, Dr. Folkman and colleagues published a seminal paper on the topic in 1971 in the prestigious New England Journal of Medicine. However, a skeptical medical community was not impressed with these revolutionary concepts and the ensuing years saw Dr. Folkman fighting a somewhat lonely battle, with even the National Cancer Institute turning down his application for a research grant.

One person who found Dr. Folkman's theories totally credible was a young ophthalmologist named Anthony (Tony) Adamis, MD, who attended a Folkman lecture on angiogenesis in Boston in the late 1980s.

“Dr. Folkman was a compelling speaker,” says Dr. Adamis, who today is vice president and global head of ophthalmology for Genenetch and recognized as a primary contributor to the overall development of anti-VEGF therapies over the past 20 years. “I saw the connection between tumor angiogenesis and the unwanted growth of blood vessels in the eye that characterized certain retinal diseases. Dr. Folkman had already made that connection. He was very interested in the eye and used the eye as a model to prove his theories about angiogenesis. He showed that tumor cells wouldn't grow in the eye until they were fed by blood vessels. He also had ophthalmologists working in his lab.”

Dr. Adamis says he “lobbied” Dr. Folkman for a position in the lab and was hired after Dr. Folkman warned that the young ophthalmologist would have to totally immerse himself in the mysteries of angiogenesis.

“Once I was working in the Folkman lab, I was allowed to devote all of my efforts to the role of VEGF and its link to retinal disease,” says Dr. Adamis. At the lab, he worked with Joan Miller, MD, David Shima, PhD, and other vision researchers to attempt to develop therapies that could combat the effects of angiogenesis in the eye.

The Adamis/Guyer Connection

While working in the Folkman lab, Dr. Adamis reconnected with David Guyer, MD, who today is a partner in the venture capital firm SV Life Sciences and chairman of the drug development company Ophthotech. The two had been fellows together at Massachusetts Eye and Ear Infirmary but Dr. Guyer had moved into the academic world, eventually becoming chair of the department of ophthalmology at New York University.

Dr. Anthony Adamis's career spans the evolution of anti-VEGF.

“I had a major interest in clinical trials,” says Dr. Guyer. “We saw some potential in the first angiogenic inhibitor, interferon-alpha. It had weak antiangiogenic activity but it had proven successful in treating pediatric hemangiomas.”

Drs. Guyer and Adamis believed that interferon-alpha had potential as a treatment for wet AMD. Together, they designed and conducted a large, worldwide, phase 3 trial for Roche, targeting reduction or elimination of the proliferating blood vessels that characterize the neovascular AMD.

“That trial failed,” says Dr. Guyer. “It was disappointing, but many of us believed that this was just the beginning of the effort to find effective treatments for wet AMD.”

In the years following the failed trial for Roche, a number of companies contacted Drs. Guyer and Adamis to consult about potential therapies for wet AMD. By this time — the mid 1990s — VEGF had already been discovered by a Genentech researcher, Napoleone Ferrara, PhD, and VEGF had been identified as the key target in halting tumor angiogenesis. Dr. Ferrara's discovery, coupled with Genentech's work on the antiangiogenic cancer drug Avastin, gave Genenetch a strong start on its own program to develop an antiangiogenic therapy for wet AMD.

Finding a Drug to Develop

One of the companies that was working on a possible wet AMD drug was NexStar. The company had brought in Drs. Guyer and Adamis as consultants and the two ophthalmologists saw potential in the drug, pegaptanib sodium, a pegylated anti-VEGF aptamer that had proved promising in preclinical testing. However, NexStar was in the process of being bought out by Gilead Sciences and Gilead had little interest in developing ophthalmic drugs.

“One of our biggest problems was finding a company to work with,” recalls Dr. Guyer. “The big drug companies looked at retinal disease and ophthalmology in general as a small market. The decision-makers in these companies were not ophthalmologists.”

With no major drug company willing to back them, Drs. Guyer and Adamis got together with Samir Patel, MD, a brilliant retina specialist who gave up a secure and prestigious position at the University of Chicago to work with the anti-VEGF pioneers in an effort he strongly believed in.

The three doctors joined with two former Genentech executives, Marty Glick and John McLaughlin. The goal was to start a company that could successfully develop a drug for wet AMD.

It was this group that founded Eyetech, the company that eventually developed the first FDA-approved anti-angiogenic drug for wet AMD — Macugen.

“Tony, Samir and I had the ability to develop the drug and design the clinical trials,” says Dr. Guyer. “Marty and John had the knowledge on the business side, obtaining venture capital and attracting potential partners.”

On April 5, 2000, newly formed and New York City-based Eyetech struck a deal with Gilead Sciences, acquiring a worldwide license for pegaptanib sodium, then in early clinical trials, for an upfront payment of $7 million, milestone payments of up to $25 million and Eyetech stock options.

The Race for Approval

As the 21st century began, Eyetech and Genenetch were beginning what Dr. Adamis calls “a friendly competition” to develop the first effective antiangiogenic drug to treat wet AMD. “We knew that Genentech was working on a parallel course so we moved as quickly as we could to navigate the clinical trials and the FDA approval process,” he says.

Drs. Guyer (left) and Patel were key co-founders of Eyetech.

On the fringe of this burgeoning competition was a Tarrytown, NY, company called Regeneron. Formed in 1988 to develop drugs for nervous system disorders, Regeneron eventually switched focus as it came to view antiangiogenic agents as potential therapies for both cancer and retinal diseases. Regeneron initially partnered with Aventis on an elegant intravenous treatment for wet AMD called VEGF Trap-Eye. The “elegance” was in Trap-Eye's mechanism of action, which employed a decoy receptor that attracted and “trapped” the VEGF before harmlessly flushing it out of the eye.

However, Aventis dropped the partnership after merging with Sanofi and re-evaluating the combined Sanofi-Aventis pipeline, leaving Regeneron to develop VEGF Trap-Eye on its own. The company lost more precious time by changing the method of administration from intravenous to intravitreal injection as a way to avoid possible systemic side effects.

Fortunately, Regeneron had a very stable and talented scientific team to redirect the development of VEGF Trap-Eye, headed by a former academic superstar, George Yancopolous, MD, and supported by company co-founder Leonard Schliefer and chairman of the board P. Roy Vagelos, MD, the former chairman and CEO of Merck and a force in drug development. Regeneron was able to resume its clinical trials for VEGF Trap-Eye in 2005 with a highly successful six-week phase 1 study that drew plaudits from such highly respected retina specialists as Boston's Jeffrey Heier, MD, and Peter Campochiaro, MD, of the Wilmer Eye Institute at Johns Hopkins.

Dr. Napoleone Ferrara of Genentech, discoverer of VEGF.

As Genentech moved steadily forward on its wet AMD drug, soon to be known as Lucentis, Eyetech was attracting positive attention from venture capital investors. SV Life Sciences was the lead in an initial $35 million financing. A second round of financing raised $108 million. Just before the phase 3 trial of the Eyetech drug, now known as Macugen, pharmaceutical giant Pfizer committed a total of $750 million to Eyetech, obtaining a 50/50 split of future US profits.

With expert navigation of the clinical trial process, Macugen received FDA approval a week before Christmas in 2004, achieving the company founders' goal of being the first antiangiogenic drug for the treatment of wet AMD.

The Bittersweet Macugen Experience

Drs. Guyer, Adamis and Patel are all proud of the contribution that Macugen made to the advancement of anti-VEGF treatments for retinal disease. This is despite the fact that Macugen's success in the marketplace was short-lived and very soon eclipsed by the remarkable success of Genentech's Lucentis. The advantage of Lucentis over Macugen was that it could actually reverse the visual deficits caused by wet AMD in many patients when maintenance injections were given periodically.

“You have to remember that previous treatments for wet AMD were mainly surgical, and some of them were barbaric,” says Dr. Guyer. “Macugen introduced the era of medical treatment for wet AMD.

Macugen stopped progression of the disease, which is in itself a major accomplishment and the primary goal in the development of the drug. Of course, Dr. Guyer wishes that Macugen's initial success had lasted longer, but he believes the drug's place is secure in the pantheon of eyecare milestones.

“With Eyetech and Macugen,” Dr. Guyer says, “we can take satisfaction that we developed the concept of intravitreal injection for a chronic disease; we were first with an induction/maintenance injection timetable; we pioneered in obtaining reimbursement; we were a launching pad for seven future CEOs of eyecare companies, and we demonstrated that venture capital could make a commitment to ophthalmic initiatives and succeed. Overall, we changed the paradigm in a number of ways.”

Adds Dr. Patel, “Macugen did represent an important step in not only advancing the treatment of wet AMD, but also in the validation of anti-VEGF as a key to treatment and in creating a great interest by venture capitalists in funding capital-intensive companies that develop drugs for retinal diseases. So in those respects, Macugen has been very important.”

Strange Turns and Controversy

Macugen's dominance of the wet AMD marketplace lasted only about 18 months, or until the FDA approved Lucentis for wet AMD in June 2006. However, during that time Eyetech was sold to OSI Pharmaceuticals for a total of about $900 million in a transaction that immediately raised eyebrows both in the ophthalmic community and on Wall Street.

The deal was done at a time when the highly promising data on Genentech's Lucentis was readily available to all. One-year results from the phase 3 MARINA trial of Lucentis for wet AMD were spectacularly positive and released in July 2005, yet OSI announced the purchase of Eyetech one month later. It was no stretch of the imagination to foresee that Lucentis was going to marginalize the use of Macugen as a wet AMD therapy. The OSI stock price dropped sharply on the day the deal was announced.

OSI worked hard to position Macugen as a “safer” alternative to Lucentis, citing fears of increased cardiovascular incidents with the Genentech drug. Though the argument may have had some validity, elderly patients preferred improved vision to slightly higher risk factors.

Eventually, OSI gave up on Macugen, took its loss, and sold the drug and related intellectual property to a group of former Eyetech employees who have actually been able to increase Macugen sales by finding several smaller niches (e.g., patients with a history of cardiovascular incidents, maintenance therapy) where the drug fits comfortably.

Though OSI's ill-timed purchase of Eyetech created controversy, a bigger bombshell was yet to come. Noting the molecular similarity between Lucentis and Genentech's intravenous cancer drug Avastin, the brilliant and highly respected Bascom Palmer retina specialist Philip Rosenfeld, MD, PhD, took the bold step of breaking Avastin into small, individual doses and injecting it into a few wet AMD patients. What he found was that the Avastin produced effectiveness in reducing the symptoms of wet AMD on a par with Lucentis.

For the close-knit retina community, Dr. Rosenfeld's “find” was a revelation. Soon, despite cautions from Genentech that Avastin was not designed for use in the eye, many retina specialists around the country were using inexpensive, off-label Avastin well before pricey Lucentis hit the market. The drug was broken into small, individual doses by compounding pharmacies.

VEGF Trap Moves Into Contention

While the Lucentis/Macugen/Avastin scenario was playing out, Regeneron quietly got its act together, found an international partner for VEGF Trap-Eye in the form of Bayer, and conducted a series of highly impressive clinical trials that culminated in 2010 with the stunning phase 3 VIEW trials that were cleverly designed and produced excellent results.

In effect, the VIEW trials, which earned the drug priority review status, showed that a 2 mg dose of VEGF Trap-Eye (now known as Eylea) intravitreally injected every two months could equal the efficacy of 0.5 mg of Lucentis given monthly for wet AMD.

A fairer comparison of the efficacy of Eylea vs. Lucentis may be found in Genentech's HARBOR trial, using a 2 mg dose of Lucentis monthly and in another arm of the trial 2 mg PRN. Twelve-month results of the 1,098-patient fourarm study, released at the recent AAO meeting in October, indicated that the 2 mg dose of Lucentis, given monthly or PRN, is slightly less effective in improving vision than the approved 0.5 mg dose given monthly. Though not a head-to-head trial between Lucentis and Eylea, the data from the 2 mg dose of each drug is at least interesting in terms of efficacy.

The results of the Eylea VIEW trial, with a safety profile similar to Lucentis, led an FDA advisory committee to vote 10-0 earlier this year to recommend the approval of Eylea for the treatment of wet AMD. Just as Genenetch has expanded the approved indications for Lucentis, Regeneron and Bayer are also currently conducting clinical trials for Eylea in DME and retinal vein occlusion.

Though FDA approval of Eylea for wet AMD was initially expected in August based on a priority review timetable, the mountain of paperwork accompanying the application has caused a delay in the approval process. Eylea approval is now anticipated later this month.

CATT and the Compounders

With a national debate raging over the relative effectiveness, safety and cost of Lucentis and Avastin, the National Institutes of Health stepped in to fund a large-scale head-to-head comparison of the two therapies. After delays and negotiations, the trial kicked off in January of 2008 under the direction of Cleveland Clinic retina specialist Daniel Martin, MD, and the Emory University Eye Center in Atlanta.

Genentech did not participate in the CATT study.

One-year results of CATT, encompassing 1,185 patients at 43 clinical sites, were released in the spring of this year. The bottom line finding was that the two drugs demonstrated essentially equivalent efficacy, though the safety profile marginally favored Lucentis. Two-year results, which should clear up some issues that arose with the one-year data, are eagerly awaited.

Just as the initial CATT trial data was signaling an increased role for Avastin in the treatment of retinal disease, two incidents involving tainted Avastin processed by compounding pharmacies raised doubts anew about the safety of the drug. A total of 16 serious infections, four at a Tennessee VA facility and 12 in South Florida, were reported in August.

The fallout from these incidents was dramatic, with the VA banning use of Avastin for retinal diseases until further study of compounding pharmacy processes could be conducted.

Regeneron's management team has been together for many years. L-R: Drs. Roy Vagelos, Leonard Schliefer and George Yancopolous.

Dr. Rosenfeld defended the continued use of Avastin in the eye, noting that in millions of injections, these were the first incidents involving tainted Avastin.

“It took six years for something like this to happen,” he told the New York Times, noting that there have been more than two million injections of Avastin into eyes in the United States alone since the practice began in 2005. He said careless procedures at compounding pharmacies were the most likely cause of the two incidents.

A month prior to the reports of the infections from tainted Avastin, Dr. Rosenfeld had testified before the Senate Special Committee on Aging as to the history of Avastin as a treatment for wet AMD and the large cost savings generated by using this alternative treatment.

He also criticized incentive programs, including rebates paid by Genentech for volume use of Lucentis and cash-back programs for credit card purchases of Lucentis.

“As a clinician, I don't want CMS telling me which drug to use, and I don't want patients worrying that the decision to inject their eye is being influenced by financial incentives,” asserted Dr. Rosenfeld in his testimony. “By addressing the financial incentives that currently promote the use of the most costly alternative, CMS could level the playing field and allow physicians and patients to focus on efficacy, safety and cost when deciding between drugs.”

Meanwhile, CMS and Congress awaited further developments, recognizing the huge cost savings to Medicare that came with wide use of Avastin but also weighing the safety issues that accompany the role of compounding pharmacies as the weak link in the Avastin sterility chain.

Looking Ahead

Assuming that Eylea is approved by the FDA for wet AMD in the near future with safety and efficacy somewhat comparable to Lucentis, the next event to watch will be how Genentech and Regeneron price their drugs in a head-to-head battle for market share. There have already been reports that Switzerland-based Novartis, which has the international rights to Lucentis, has lowered the price of the drug by 30% in its home country following pressure by the Swiss government. This action may be construed as a precursor of more price cuts to come or simply a “hometown discount.”

It's also certain that the controversy over the use of Avastin will continue, as the federal Department of Health and Human Services has already signaled in a report issued in September that it would like to see greater use of inexpensive Avastin as one way to reduce Medicare outlays. Gaming out various prescribing scenarios, HHS concluded that CMS could have saved $1.1 billion if Avastin had been used exclusively over Lucentis during 2008 and 2009.

However, safety issues, particularly those that arise with the use of compounding pharmacies to process Avastin for individual dosing, remain a huge concern for any federal agency before it would contemplate a change in approved agents that favors Avastin over Lucentis.

Given the burden that frequent intravitreal injections puts on both patients and retina specialists, both Genentech and Regeneron say they are actively exploring sustained-release formats for their respective anti-VEGF drugs. Genentech is partnering with SurModics to develop a sustained-release delivery system. Regeneron has not announced any partnerships for sustained-release delivery of Eylea but has indicated that such a format is under consideration. Any sustained-release format in the works for Lucentis or Eylea would require a clinical trial — and none have been announced as of yet.

Dr. Philip Rosenfeld pioneered the use of Avastin for wet AMD.

Rhode Island-based Neurotech has developed an anti-VEGF implant using its proprietary encapsulated cell technology to deliver a VEGF-fighting agonist on a sustained-release basis. This technology is in clinical trials. The new Eyetech has focused its Macugen-delivery strategy on its “Luer Lok” syringe, which it claims is the safest and most advanced method of performing intravitreal injections.

Finally, PanOptica has secured financing to begin a clinical trial using an anti-VEGF eyedrop to treat wet AMD. The formulation (PAN-90806) has shown promise in pre-clinical tests and was studied in humans for oncology use.

Potential Combination Therapies

At the clinical level, expect increasing use of anti-VEGF drugs in a number of eye diseases, including for such non-retinal areas as glaucoma surgery. A number of combination therapies that involve the use of anti-VEGF are now either in everyday practice or are being investigated. One example is the Ozurdex dexamethasone implant combined with an anti-VEGF drug to treat DME. Currently under investigation by NeoVista is a combined anti-VEGF/radiation treatment regimen that shows promise of reducing the number of injections that a wet AMD patient would require.

And Drs. Guyer and Patel, so instrumental in developing Macugen, are working on novel new investigational treatments for both wet and dry AMD at Ophthotech. Though the Ophthotech drugs are not anti-VEGF, they may prove to be useful in combination with anti-VEGF therapies to improve upon current standards of care.

Though it has only been about seven years since the approval of Macugen, the first anti-VEGF drug for eye disease, progress with this class of drugs has been rapid and remarkable. We should expect nothing less in the next several years. New anti-VEGF agents — and new research illuminating the use of older ones — will continue to pave the road ahead. OM