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Retina Research Breakthroughs: When Physicians, Government, and Industry Work Together, Patients Win

Thursday, October 16, 2014

New drugs are saving vision for millions with retinal disease

Retina specialist Jeffrey Heier, MD, will never forget the sculptor who came to him years ago with wet macular degeneration. As a researcher, Dr. Heier was able to give him an experimental new drug—but only for one eye. Macular degeneration stopped in that eye.

However, the sculptor’s other eye also developed wet macular degeneration, but wasn’t eligible for treatment because his other eye was already enrolled in a scientific research study or clinical trial. Fourteen years later, his treated eye has near-normal vision, allowing the sculptor to continue his career and his art. The untreated eye went legally blind within 6 months.

That drug, Lucentis (ranibizumab), is now widely available. Lucentis and its sister drugs Avastin (bevacizumab) and Eylea (aflibercept), has helped stop blindness in millions of people. Lucentis and Avastin are made by Genentech, Inc; Eylea is made by Regeneron Pharmaceuticals, Inc.

Researchers like Dr. Heier, director of vitreoretinal services at Ophthalmic Consultants of Boston, have made stunning progress in treating wet age-related macular degeneration (AMD) in recent years. “I've had the opportunity to help hundreds, if not thousands, of patients who, in the old days, would have just been devastated,” Dr. Heier says.

The advances came about through a collaboration of industry, government, university researchers, and retina specialists in private practice.

Basic research, often funded by government grants and carried out by university scientists, has slowed in light of funding cutbacks. Fortunately, close collaboration between clinicians and pharmaceutical biotech companies has led to remarkable advances in the management of many, if not most, common retinal diseases. “That collaboration was absolutely critical,” Dr. Heier says. “Without it, we wouldn’t even be remotely close to where we are today.”

“I've had the opportunity to help hundreds, if not thousands, of patients who, in the old days, would have just been devastated,” Dr. Heier says.

The advances of the past 15 years have taken place so quickly, it’s easy to forget how little the field of retina was progressing before that.
  

Shining a light on retinal disease

Wet AMD afflicts some 1.5 million Americans and is the leading cause of blindness in Western countries. It occurs when abnormal blood vessels grow and leak fluid near the macula, a key part of the retina that absorbs light in the back of the eye and sends signals the brain interprets as images.

As recently as the 1990s, doctors could do very little to help most patients with wet AMD or diabetic retinopathy, another disease in which blood vessels proliferate and leak into the retina. At best, they could shine an intense light into the patient’s eye to destroy or seal off the abnormal blood vessels.

This technique, known as photocoagulation, could slow the progress of the disease, but it often caused damage to healthy blood vessels, sometimes harming the patient’s eyesight. The abnormal blood vessels often grew back or started leaking again, requiring more treatments.

So researchers at several universities began studying a concept borrowed from cancer treatments: find a chemical that sticks only to the abnormal blood vessels, but not to healthy ones. Then activate the chemical with light so it destroys the vessels it touches.

“Visudyne was a breakthrough,” recalls David Boyer, MD.

One of these researchers, Julia Levy, PhD, at Canada’s University of British Columbia, had already started QLT, Inc, a company to develop this approach, photodynamic therapy, for cancer.

When her mother was afflicted with macular degeneration, Dr. Levy and her colleagues began developing a similar treatment for AMD in collaboration with doctors and researchers at other universities. The result of this research, QLT’s Visudyne (verteporfin) was approved by the US Food and Drug Administration (FDA) in 2000.

Visudyne works much better than photocoagulation because it can selectively destroy or seal more of the abnormal blood vessels with less risk. This drug quickly became the standard treatment for wet AMD. Still, abnormal vessels continued to grow in the eyes of the patients treated this way, requiring additional treatments—and photodynamic therapy couldn’t restore any vision already lost, and in most cases, eyes treated with Visudyne continued to lose vision. Plus, sometimes Visudyne causes immediate swelling that leads to acute vision loss.

They were zeroing in on a protein that the body uses to signal cells to create new blood vessels: vascular endothelial growth factor (VEGF).

“Visudyne was a breakthrough,” recalls David Boyer, MD, a clinical professor at the University of Southern California School of Medicine who practices in the Retina-Vitreous Associates Medical Group in Los Angeles. “But it was a very small breakthrough.”

By the time Visudyne came on the market, researchers were already working on another approach derived from cancer research. They were zeroing in on a protein that the body uses to signal cells to create new blood vessels: vascular endothelial growth factor (VEGF).

VEGF plays a vital role when new blood vessels are needed—for example, after an injury or when broken bones heal. But tumors also need a blood supply. So they, too, use VEGF to grow their own blood vessels. And the VEGF protein plays a key role in the growth of abnormal blood vessels in wet AMD and diabetic retinopathy.


The breakthrough: Anti-VEGF therapy

In 1989, Genentech molecular biologist Napoleone Ferrara, MD, first identified VEGF and began working on compounds that could bind to VEGF and stop it from signaling cells to produce blood vessels.

Trials showed that patients who had pegaptanib injected into their eyes were less likely to lose vision than patients who had injections of a fake or “sham” drug known as a placebo.

After years of work, he developed such a compound—bevacizumab—and, with the help of many doctors, showed it could treat certain types of cancer. The FDA approved the drug under the name Avastin in 2004 for treating colorectal cancer. But Genentech did studies suggesting that Avastin wouldn’t work in wet AMD.

Meanwhile, scientists at Eyetech Pharmaceuticals, Inc. and Pfizer, Inc. began developing pegaptanib, a drug that binds to VEGF165, the form of VEGF most involved in creating abnormal blood vessels.
  

Trials showed that patients who had pegaptanib injected into their eyes were less likely to lose vision than patients who had injections of a fake or “sham” drug known as a placebo. In 2004, the same year it approved Avastin for cancer, the FDA authorized the sale of pegaptanib under the name Macugen as the first anti-VEGF therapy for macular degeneration.

Macugen was a significant advancement, says Dr. Boyer. The benefits were similar to photodynamic therapy. Macugen works on some types of abnormal blood vessels that photodynamic therapy could not treat, and it slowed down vision loss. A few patients even had improved vision.

But Macugen didn’t enjoy the limelight for very long. Macugen entered the market in January 2005, and by May of that year, Philip Rosenfeld, MD, PhD, a professor of ophthalmology at Bascom Palmer Eye Institute at the University of Miami’s Miller School of Medicine, had shown that systemic Avastin could reverse the leakage in wet AMD. Dr. Rosenfeld reported in July 2005 that intravitreal Avastin was better than Macugen in stopping disease progression.

Macugen can stop vision loss in about 65% of patients, with perhaps 6% experiencing some improvement. Lucentis stops vision loss in about 95% of patients and significantly improves vision for about 40%.

Avastin use spread globally and got a head start on Lucentis, which was FDA approved in June 2006. Genentech’s drug Lucentis was derived from the same genetic sequence as Avastin, and just like Avastin, it blocked VEGF and all other types of VEGF. Lucentis and Avastin were more effective than Macugen.

Macugen can stop vision loss in about 65% of patients, with perhaps 6% experiencing some improvement. Lucentis stops vision loss in about 95% of patients and significantly improves vision for about 40%.

“Patients diagnosed with wet macular degeneration before 2006 inevitably went blind in their first eye,” says David Brown, MD, whose Greater Houston Retina Research Center has recruited many of the patients for clinical trials of these drugs. “And when the second eye became involved, they lost the ability to drive and even to recognize the faces of their loved ones. Now these patients routinely maintain driving vision, continue working, and enjoy their senior years.”

Dr. Brown directly credits pharmaceutical researchers such as Dr. Ferrara for the advance. “Napoleone should win the Nobel Prize,” he remarks.

But the story doesn't end there.
  

Saving money and vision

Dr. Rosenfeld had directed some key clinical trials of Lucentis, and he couldn’t help questioning Genentech’s concerns about side effects with Avastin.

“It became abundantly clear because of the literature that Genentech had published that Avastin should do the same thing as Lucentis,” he says. “Genentech deserves accolades because they treat their scientists like academics and they encourage them to publish.”

So Dr. Rosenfeld organized his own trial of Avastin and proved it was just as effective as Lucentis in treating wet AMD.

Studies have confirmed that Avastin does not appear to cause more serious side effects than Lucentis, and Avastin offers one big advantage. Genentech priced the drug for use in relatively large quantities for use in cancer treatment. Because only small amounts are needed for the eye injections used to treat macular degeneration, Avastin costs only $50 per injection. By comparison, Lucentis costs $1950 per injection.

Physicians are still debating which drug is better. And because the FDA has not yet approved Avastin for use in treating retina diseases, physicians have to use it off-label—an accepted  practice in which a drug is used by a doctor for a condition that is not specifically listed on the label. But Medicare pays for this use. And most retina specialists are very grateful to have multiple effective medications for a disease that defied treatment for so long. “It certainly has made my job a lot more pleasurable than it was before,” says Dr. Boyer.

In 2011, he and his retina colleagues got yet another anti-VEGF drug to add to their toolbox when the FDA approved Regeneron’s Eylea. This new drug’s price of $1850 per dose isn’t as good a bargain as Avastin, but some studies show patients need about half as many doses of Eylea as they need when treated with Lucentis.

OCT imaging measures results

While inventors of these drugs have justifiably received accolades for the many patients they have helped, the advances could not have happened as quickly without another significant development, says Dr. Rosenfeld. “None of this would have happened as quickly without OCT.”

OCT imaging allows retina specialists to diagnose macular degeneration and to measure precisely whether the retina is getting thicker because fluid is building up, or thinner because of a loss of tissue.

That’s optical coherence tomography, a technique for making images of tissues inside the eye. Although OCT technology was first described in 1991, it didn’t become commercially available until 1996. By 2002, OCT imaging devices were becoming so valuable that every retina specialist had to have one—despite the $50,000 price tag.

OCT imaging allows retina specialists to diagnose macular degeneration and to measure precisely whether the retina is getting thicker because fluid is building up, or thinner because of a loss of tissue, explains Jay Duker, MD. Dr. Duker is chairman of ophthalmology at Tufts University in Boston and has worked with many of the OCT device companies. “We can measure the effects of our drugs immediately, and these drugs do work very fast,” he says.

That kind of immediate feedback has helped researchers develop drugs more quickly. OCT imaging also helps doctors calibrate exactly how often to treat their patients, saving unnecessary discomfort, expense, and side effects.

Already retina specialists like Dr. Duker are using OCT imaging to speed the progress of a development they hope will be the next leap forward: treatments for dry macular degeneration. Although not usually as damaging as wet macular degeneration, dry AMD afflicts about 10 times as many people.
  

Only 1 in 6 drugs in phase 1 trials eventually gains FDA approval

Looking back, the advances in retina disease diagnosis and treatment sound almost inevitable. But many other drugs that once looked promising in early stages of research eventually proved ineffective or dangerous. And finding out which ones work is expensive. The kind of large clinical trial needed to show whether a drug is safe and effective can cost $1 million or more. Often only private companies are willing to foot the bill. “The government can’t fund everything,” says Dr. Rosenfeld.

The kind of large clinical trial needed to show whether a drug is safe and effective can cost $1 million or more.

Having participated in key anti-VEGF trials, Pravin Dugel, MD, of Retinal Consultants of Arizona, agrees. The treatments have saved far more in medical expenses than they cost, he says, because they have prevented blindness in so many people.

“The research money has come mainly from industry,” Dr. Dugel explains. “To continue this kind of progress, physicians have to continue to work with industry in a collaborative and transparent manner.”
  

Why physicians get involved in research

Dr. Rosenfeld argues that doctors can’t just wait on the sidelines while drug companies search for cures. As the people with the most direct experience in treating diseases, physicians provide crucial advice about how the trials should be done, he says.

For example, in one trial Genentech proposed giving some patients Lucentis and other patients a sham drug, known as a placebo, then measuring changes in the vision of each group. Rallying his fellow retina specialists, Dr. Rosenfeld persuaded the company to give the patients who weren’t getting Lucentis photodynamic therapy instead. That way, their eyes would not be left to deteriorate without treatment.

“All of this has to be done as a collaborative effort between industry and clinicians or it will never succeed,” he says. “They need our expertise. We help them design the clinical trials, keep them ethical, and bring the trials to our patients.”

Rosenfeld: “If you’re working with industry and you run a well-run clinical trial, and it’s published in peer-reviewed medical journals, everyone wins. Industry wins, clinicians win, and the public wins.”

The same is true of OCT imaging, says Dr. Duker. Initial discoveries came from university researchers such as James Fujimoto, PhD, at the Massachusetts Institute of Technology, Dr. Duker recalls. “But there is a limitation to how much a scientific lab can develop an instrument like this. The collaboration between industry, research labs, and clinicians is crucially important.”

Dr. Duker frequently works with medical device companies like Carl Zeiss Meditec AG, trying out their devices in his practice and offering suggestions for improvements.

“They’ve streamlined the device to make it user-friendly, so it’s easy for the patient to have the test done and easy for the operator to perform the test,” he says. “They then add software improvements. For example, if we say it would be important to measure a certain layer of the retina, they develop software to do it.”

Because doctors get so involved in the studies, research money often flows through their clinics. This funding can appear significant in public disclosure documents such as those required by the Physician Financial Transparency Reports (the US government’s Open Payments Program, or Physician Payments Sunshine Act). But these disclosure documents show only the income supporting the research, not the doctors’ research expenses.

“There are all kinds of costs for conducting clinical research—designing the trial, submitting paperwork and required reports to the FDA, recruiting patients, getting adequate informed consent, submitting to the institutional review board, seeing the patients, presenting at meetings,” Dr. Brown explains. “Physicians, not drug company sponsors, are doing this work.”

And physicians have safeguards against conflicts of interest, says Dr. Rosenfeld. In particular, these measures require researchers to disclose financial relationships. “I think our profession does a pretty good job of keeping people from abusing the relationship,” he says. “If you’re working with industry and you run a well-run clinical trial, and it’s published in peer-reviewed medical journals, everyone wins. Industry wins, clinicians win, and the public wins.”

But the biggest winners of all are the patients whose vision can now be saved.

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