Avastin/Lucentis Update 41: The Story Behind the Invention of Avastin and Lucentis

Several months ago, I received a request from a university student writing a paper about Lucentis and Avastin. She asked about the references I had used in my first writeup on the two drugs. I sent her a copy of the reference and she used several quotes from it in her paper about the story behind the invention of Lucentis and Avastin. I asked her to send me a copy of her paper upon its completion and when I read it, I realized that based on her research and writing, you should also have that opportunity.

I asked her permission to reproduce the paper in my online Journal, and after checking with her instructor and the people she used as sources, permission was granted and, so, here is her paper, submitted to a science writing class in the Genetics Department at the University of Wisconsin - Madison, by Wendy Bedale.

Avastin vs. Lucentis in Wet Age-Related Macular Degeneration

By: Wendy Bedale

In my home I have a beautiful Halloween jack-o-lantern quilt and a cozy fleece blanket crafted by my Aunt Maureen. Each year my Christmas tree is adorned with many hand-painted Christmas ornaments she has given me, including a little sled, all of which she made by hand. For my wedding, I received a dozen decorative hand towels embroidered with hearts, shamrocks, fall leaves. She is generous with her talents and her gifts.

A few Christmases ago Aunt Maureen gave me a resin basket festooned with snowmen. She apologized because it wasn’t handmade.

Around that time I noticed that emails from her were now printed in a giant font. And on occasions when I visited her in Florida, her eyeglasses were very thick.

She was going blind.

This isn’t really a story about Aunt Maureen, however. It is about a miracle drug for macular degeneration, or rather, two miracle drugs: Lucentis and Avastin, one expensive, the other almost dirt cheap. It is about the drug company, Genentech, that developed both drugs, and the difficult and controversial decisions made in developing and marketing these drugs. It is about pioneering doctors who want to help their patients, and patients who take risks for the chance to see again.

Aunt Maureen suffers from age-related wet macular degeneration, or AMD. AMD is the leading cause of vision loss in the elderly, affecting about 1.5% of the population over the age of 40 [1]. In the early stages of AMD, a patient might notice that straight lines look wavy, or that the center part of their vision is blurry and without color. AMD doesn’t involve physical pain, but the loss of vision in otherwise healthy individuals is devastating.

“It really started acting up when I was in my mid-40s,” said Aunt Maureen. “My doctor told me I would be blind by the time I was 60.”

Aunt Maureen has some of the risk factors for AMD: older age, female, of Northern European descent [1,2]. She has lived in Florida for about fifteen years now, and high exposure to sunlight is more common in AMD patients [3]. However, she doesn’t smoke and doesn’t have a history of cardiovascular disease or chronic kidney disease, which are other important risk factors [1]. There is also evidence of a genetic component to AMD [3], although none of Aunt Maureen’s immediate family has had any problems with their vision. AMD is not always predictable, nor is it preventable.

AMD is a disease of the retina. The retina is the part of the eye lining most of its inner surface. Like film in a camera, light strikes the retina and forms an image. The macula is part of the retina, the part that is in the back central region of the eye. It is responsible for the clear, sharp central vision needed to drive, read, embroider or paint [3].

There are two forms of AMD: dry and wet. The dry form is less severe and may not affect vision significantly. Dry AMD may or may not progress to the more severe wet form, which affects about 10% of AMD patients [1]. Aunt Maureen initially had the dry form of the disease, but progressed to the wet form about ten years ago.

Wet AMD is called “wet” because fluids, especially blood, are responsible for the damage to the eye. For unknown reasons, new blood vessels behind the eye start to grow in AMD patients. The new blood vessels grow and grow. Blood and other fluids leak from these blood vessels, damaging the macula. In most cases, the damage is irreversible, like the damage done to a photo album stored in a damp basement. The damaged macula can no longer process images clearly and sharply [1].

However, if the renegade blood vessel growth could be stopped before leakage occurs, additional damage and visual loss might be prevented. Therapies for AMD target these blood vessels. Some, like laser therapies, seek to obliterate the blood vessels, but these approaches have been described as being “like using a blowtorch to stop weeds”, according to retinal specialist Dr. Anne Fung of San Francisco [4].

“Treatment of macular degeneration was very depressing five years ago,” says Dr. Ron Danis, a retinal specialist at the University of Wisconsin-Madison. He cites a patient named Donna, who had a long history of AMD in both eyes. Five years ago she was legally blind, and Danis had run out of therapeutic options for her.

More recently, biotechnology has allowed a more targeted approach to treating AMD. Newer drugs for wet AMD block specific molecules that trigger growth of the new blood vessels.

But why do these unwanted blood vessels grow?

Although not as dramatic as a severed earthworm re-growing a missing segment, all animals possess some ability to regenerate tissue, even in adulthood. New tissue is needed to repair injuries or during pregnancy, for example. The new tissue requires sustenance in the form of oxygen and other nutrients, which is provided by blood. So the body has sophisticated mechanisms to switch on the growth of new tissue, including the new blood vessels needed in those tissues.

The growth of the new tissues is stimulated by proteins known as growth factors, which are chemical messengers produced and distributed in the body under carefully regulated conditions. There are many different growth factors for many different types of tissues. Some help build bone, others nerves, skin, red blood cells, and so on. One class of growth factors called vascular endothelial growth factors, or VEGFs, triggers new blood vessel growth. Scientists call this process angiogenesis.

Sometimes, however, as in the case of wet AMD, angiogenesis gets turned on when it should not be. AMD is not the only disease associated with unwanted angiogenesis. Any cancer tumor bigger than 1 mm (about the size of a grain of sugar) requires a supply of blood in order to continue to grow [5], so like thieves tapping into an oil pipeline, tumors create their own blood vessels to feed themselves.

In the mid-1990s, the discovery of specific growth factors in the body that stimulated angiogenesis lead scientists to hypothesize that blocking these same growth factors might stop cancer from growing. One of these scientists was Dr. Napoleone Ferrara.

Ferrara is a legend at Genentech, itself a legend in the biotechnology industry. Genentech is considered to be the first true biotechnology company, founded in 1976 in South San Francisco, where it is still located. Genentech’s products are pharmaceutical products, but not typical small molecule, chemically synthesized drugs. Genentech’s drugs are proteins, which are very large molecules, and they are produced using recombinant DNA technology. Such drugs are classified as “biologics” since they are produced through the assistance of living cells such as bacteria.

The recent purchase of Genentech by pharmaceutical giant Roche makes Genentech part of a huge corporate entity. However, Genentech still operates more like a small university than a money-making machine, according to a source at Genentech. Dr. Danis, who has been involved with numerous clinical studies sponsored by Genentech, concurs. Genentech’s goal is to make drugs that make real differences in patients’ lives, according to the source at Genentech, not just “me too” drugs or drugs that extend life by a mere month. Genentech has been involved in the development of at least 15 drugs that are currently marketed in the US and worldwide [6].

Ferrara arrived at Genentech in 1988. The handsome physician originally moved to the United States from Italy in the 1980s to study a hormone involved in reproduction called relaxin [7,8]. How he ended up discovering VEGF is a lesson in the circuitous paths that science often takes. And his application of this basic discovery to develop drugs that stopped angiogenesis is an example of every scientist’s dream of a significant breakthrough.

The idea of blocking angiogenesis to treat cancer was first described in 1971 by the late Dr. Judah Folkman, considered the “father of angiogenesis” [9,10], at the Children’s Hospital Medical Center and Harvard Medical School. Scientists tried for years to isolate a specific factor necessary for new blood vessel formation that they could then try to block. They had no problem finding candidate factors; they found a plethora of similar factors that all stimulated new blood vessel formation. But blocking just one of these factors never seemed to have much effect [7]. Like many other important mechanisms in the body, redundancy had been built-in. Attempting to simultaneously block all of the different factors that could stimulate angiogenesis, seemed a daunting task.

At Genentech, Ferrara was still working on relaxin as a potential drug to induce labor. Somewhat unusually in the pharmaceutical industry, Genentech has always encouraged its scientists to work on pet projects in their off-hours, and Ferrara took the opportunity to study angiogenic factors [7,11,12]. Unlike most scientists hunting for anti-angiogenic factors, who were cancer specialists, Ferrara was an expert in hormones involved in human reproduction, some of which are produced in the pituitary gland. This background may have given him the edge. Ferrara chose to look for factors that stimulated new blood vessel formation in the pituitary gland, a tissue that the cancer experts had not considered. And he soon hit pay dirt.

In 1989, he published the first paper describing the factor he found, which he dubbed “at least provisionally” as vascular endothelial growth factor, or VEGF [11]. The name stuck. And a key step towards a future miracle treatment for AMD was taken.

Around this same time, Aunt Maureen’s initial problems had resolved, her vision stabilized, and her macular degeneration had not yet progressed to the wet form. Like a ticking time bomb, though, she knew her vision could start to deteriorate at any time.

During the next decade, much work in Ferrara’s lab and others focused on learning both how VEGF works and also how to stop it from working. One approach to stopping VEGF was to make antibodies that would attack it. Antibodies are made by an animal’s immune system as a way of deactivating foreign substances that could be harmful when they enter the body. Each human has an astounding number of different antibodies, perhaps as many as 10 billion [13], with each antibody specific to a particular foreign substance or “antigen”. Antibodies work by binding very tightly to their target antigen, taking the foreign substance out of commission.

Soon after VEGF was discovered, Genentech started working on a VEGF antibody. Antibodies can be made in animals like rabbits or mice, and they can also be made in animal cells that grow in test tubes. Genentech had already developed antibodies against other proteins to use as drugs, and they knew that a VEGF antibody could be a blockbuster. Genentech was clearly developing the anti-VEGF antibody to use as a cancer therapy, the holy grail of the pharmaceutical industry. But Genentech was also, in parallel, trying to block VEGF in other diseases where VEGF was known to be involved, including wet AMD.

Antibodies administered orally do not remain active in the body, as they are proteins that the digestive system will break down just like a tiny bite of steak. For cancer patients, then, Genentech was planning to bypass the gastrointestinal tract by injecting the drug directly into the blood stream, or intravenously. For cancer, it is not always known where within the body cancer cells may lurk, so intravenous administration makes sense since the drug goes everywhere blood goes. Giving a drug intravenously, however, means there is a bigger chance of side effects since the drug can go places where it should not be. Intravenous administration also requires a lot more drug to ensure enough drug does get to the parts of the body where it is needed. More drug makes treatment more expensive.

To treat wet AMD, Genentech decided to forego intravenous administration and inject the VEGF antibodies right into the vitreous, which is the jelly-like part of the eye. Getting injected into the vitreous of the eye, or intravitrealy, sounds incredibly frightening. I asked Aunt Maureen about it.

“The first time I freaked. But honestly, it doesn’t even hurt”.

Local anesthetic is given before the injection, and the needle used is very fine, a few times thicker than a human hair. The volume delivered to the eye is about the amount of a drop of water. Aunt Maureen reports her eyes feel tender for about a day after the injection, and then everything is fine. She has had at least eight Avastin injections now, about one per month, and has had no side effects to date.

Because antibodies are such big molecules, Genentech was concerned that the VEGF antibody would not be able to move through the gelantinous layers of the eye to the retina, where the drug needed to go to work. So they decided to test how well the drug could move within the eye. Genentech used a radioactively-labeled antibody. They also used a radioactively-labeled fragment of the antibody. The fragment they chose was the part of the antibody that actually was involved with binding VEGF, which is about a third of the entire molecule. This fragment is called a Fab for “Fragment Antigen Binding”.

Genentech injected either the radioactive antibody or Fab into monkey eyes, and then looked to see where the radioactivity went [14]. Sure enough, it looked like a full-length antibody didn’t travel as well within the eye as the shorter Fab fragment. However, they took a shortcut: they didn’t use the actual full-length VEGF antibody, but a different antibody that was about the same size that was easier to track within the animal. This may have been a mistake.

At this point Genentech decided to develop the smaller Fab antibody for wet AMD and the full-length antibody for cancer. They called the full-length antibody bevacizumab, and gave it the brand name of Avastin®. The small fragment version was given the generic name of ranibizumab, with the brand name of Lucentis®.

The true rationale behind Genentech’s decision to develop Avastin and Lucentis as two separate products may never be really known. The monkey study indicates they had some scientific justification to develop the smaller antibody for use in the eye. However, Genentech also certainly realized that having two separate drugs could mean more profit.

Development of the VEGF antibody for cancer proceeded rapidly, and in February of 2004, Genentech received FDA approval to sell Avastin for colon cancer [7]. The development of Lucentis for wet AMD was going well, but slower. By the following year, three clinical studies with Lucentis had been completed. The results were spectacular. 95% of the subjects showed stable or improved vision following one year of treatment with Lucentis [15].

By this time, Aunt Maureen’s AMD had progressed to the wet form. Her vision became so bad she had trouble reading and was driving over sidewalks. Her doctor tried laser therapy. He told Aunt Maureen she was lucky, as she was one of the 10% of patients who responded well to it, at least initially.

Genentech announced the Lucentis results at the meeting of the American Society of Retina Specialists in Montreal of July 2005. It was intended to be the springboard for Lucentis. However, to Genentech’s probable surprise, a different Genentech drug stole the show [15].

That drug was Avastin. As word starting leaking about the miraculous results with Lucentis, a handful of trailblazing ophthalmologists, who couldn’t wait for FDA approval of Lucentis, took matters into their own hands. Some began using intravenous Avastin in patients with wet AMD. And a few brave doctors began injecting the drug, approved only for colon cancer, into eyes of patients who had wet AMD [16,17].

The Avastin results reported at the Montreal meeting, although representing only 18 patients, of whom only one received an intravitreal injection [15], were comparable to the Lucentis results reported at the same meeting, according to an article later that year in the Los Angeles Times [18]. The earlier experiment in monkeys may have mislead Genentech into thinking Avastin would not work in the eye, but these new results in humans showed that it clearly could.

The Montreal meeting was pivotal for Avastin use in AMD, according to Irv Arons, a long-time consultant to the ophthalmology industry [19]. The excitement generated among retinal specialists was tremendous.

“Word spread like a tsunami” according to Lynne Peterson, writing in Trends-in Medicine after the Montreal meeting [15]. Within 3 months more than 1000 wet AMD patients had received intravitreal injections of Avastin, according to the Los Angeles Times [18].

To understand the significance of the use of Avastin in wet AMD at that time, it helps to understand a little about the FDA approval process for drugs. When the FDA approves a drug, it is always for a particular disease or “indication”. Approval means that the FDA has reviewed all of the pertinent animal and human studies of that drug and has agreed that the drug is both effective in treating that disease and safe for use in that disease.

Although the FDA approves a drug for a specific disease or “indication”, it is legal and not unusual for a physician to prescribe and use the drug for other indications. For example, a drug approved for breast cancer might be tried in a patient with a different type of cancer. This type of prescription for a disease other than the official approved FDA indication is called “off-label” usage.

Because a drug used off-label has not gone through the rigorous testing and FDA scrutiny for that disease that the approved indication has, certain barriers exist to help limit widespread off-label usage. The FDA puts strict gags on companies to prevent them from advertising their drugs for unapproved indications. Insurance companies may refuse to pay or reimburse for off-label treatments.

According to Lynne Peterson, writing just after the Montreal meeting, Genentech was alarmed about the flood of off-label Avastin use. Officially, Genentech was concerned about the possible safety problems associated with using Avastin in the eye [15]. Avastin was not manufactured initially to meet the rigorous requirements for use in the eye. In addition, unlike Lucentis, Avastin has to be diluted before it is injected into the eye.

This dilution can only be done by a special compounding pharmacy. There is no formal inspection or quality control required after the dilution step, and errors in dilution or contamination are therefore possible and probably more likely than in the production of the carefully controlled, single-use containers of Lucentis produced entirely within Genentech’s hands. Genentech has no ability to control Avastin compounding once it is sold, yet the company might still be held liable if a patient received an eye infection, for example, after treatment with off-label Avastin.

Dr. Danis at the University of Wisconsin-Madison was one of many caught by the wave of Avastin excitement following the initial reports presented in Montreal prior to the approval of Lucentis. His first experience using Avastin was in Donna, his patient with the long history of AMD who had run out of therapeutic options.

“She came to me waving this newspaper clipping,” said Danis. She demanded that he try Avastin on her. So he did.

She came back a week later. She wanted a shot in the other eye, because she believed the drug was working. Within six months of treatment, she was driving herself to the clinic and seeing 20/40, which means she could read the 5th line down from the top of an eye chart in a vision exam.

“She likes to say she had ‘Avastin’ improvement in both eyes”, chuckles Danis.

Besides possible safety problems, Genentech also had commercial reasons to be concerned about off-label Avastin use. Avastin could steal Lucentis’s market before Lucentis was even officially launched. Genentech therefore raced to get their product approved, seeking “fast track” status to expedite the lengthy, cumbersome FDA review process, which generally takes a year. They submitted their Lucentis data later that year, and Lucentis was approved six months later, in June of 2006 [20].

As might be expected for a drug that is only injected once a month and was expensive to develop and manufacture, Genentech set a high price for Lucentis, around $2000 per injection [21]. Even with Medicare coverage, the standard 20% co-pay required by the patient was about $400 per month for Lucentis, which was too much for some. Avastin, in contrast, is given to cancer patients in doses 100 times greater than Lucentis, and is administered twice per month instead of once. For cancer indications, Avastin is still considered a very expensive drug (up to $100,000 annually per patient [22]), but the cost of the amount needed for an intravitreal injection ends up being very low, about $50, because the amount needed in the eye is so tiny [21]. Avastin could therefore make a significant dent in Lucentis’s profits.

Initially, Medicare and private insurance companies did not reimburse for Avastin when used in AMD because the drug was not approved for that indication, and no rigorous clinical studies had been conducted with the drug to formally test its effectiveness or safety. However, the full drug cost for Avastin without any reimbursement was only about 10% of the cost of Lucentis after reimbursement. So many physicians and patients opted for Avastin, including Aunt Maureen’s eye doctor.

Doctors were split on the use of Avastin or Lucentis [16,23]. Some, like Danis, preferred to use Avastin because of its lower cost. Others questioned the ethics of using Avastin for an unapproved indication after an FDA approved drug, Lucentis, was on the market.

There was also concern that safety problems might start showing up in the burgeoning number of patients receiving Avastin. While several small clinical studies with intravitreal Avastin for AMD were published at this time, no large studies had been conducted, as would have been required prior to FDA approval. Genentech, of course, had no desire to sponsor an intravitreal Avastin study, and they certainly had no incentive to seek approval for Avastin for AMD. Eye doctor associations argued that a head-to-head comparison of Lucentis and Avastin was needed, and many began lobbying for a government-sponsored study to do just that [16,21,23].

During its first year on the market, Lucentis made money, but probably not as much as Genentech had hoped. The Wall Street Journal reported that during the first 6 months of 2007, sales of Avastin in the US were $1.1 billion dollars, while Lucentis sales were about a third of that at $420 million [24].

On October 11, 2007, Genentech’s president sent a letter to members of the eye care community announcing that effective November 30, 2007, Genentech would no longer allow its distributors to sell Avastin to compounding pharmacies [25]. Perhaps realizing the potential hardship this move would make for patients of limited financial means, the communication also discussed a financial support program designed to make Lucentis available to patients who cannot afford Lucentis. This program is still operational, and Danis reports that it has worked well for his patients that qualify for it.

Genentech explained in the letter that this move to block sales to compounding pharmacies was triggered by two FDA inspections. One inspection, of a compounding pharmacy in Massachusetts, took place in late 2004, prior to the approval of Lucentis [26]. The pharmacy was specifically cited for “repackaging” Avastin for use in eye indications. The FDA was “particularly concerned” because Avastin as originally sold is a sterile solution, meaning it contains no microorganisms that might cause infection. By repackaging Avastin, it would be possible for bacteria or other microbes to contaminate the product. The introduction of microbes directly into they eye by intravitreal injection could cause serious eye infections that could lead to blindness.

The other FDA inspection noted in Genentech’s October letter was of Genentech itself. The FDA said that Genentech’s manufacturing facility and quality standards for Avastin were not adequate for making a drug designed for use in the eye [25].

Some rationale beyond profit appears to exist, therefore, for Genentech’s October 2007 decision to block sale of Avastin to compounding pharmacies. Even so, Genentech received considerable flack from the press regarding this decision. A Wall Street Journal article published the day after the Genentech letter was released pointed out that if patients were given Avastin instead of Lucentis, the annual savings to the Medicare program (and therefore US taxpayers) could be over $1 billion [27]. This caught the attention of Senator Herb Kohl (D-Wisconsin), Chairman of the Senate’s Special Committee on Aging. He asked that the Center for Medicare and Medicaid Services look into the matter [28].

In response to the strong criticism from physicians, patients, Congress and the press, Genentech announced two weeks later that they would delay the restriction of sales to compounding pharmacies until January 2008 [29]. In this second announcement, Genentech explicitly stated that the decision to block sales was “not motivated by a desire for increased profits”, a comment that has been viewed with some skepticism in the media [30,31,32,33,34].

In December of 2007, following two months of intensive discussions between Genentech and several eye doctors’ organizations to reach a compromise to the dilemma, Genentech announced that it would allow sale of Avastin to physicians, who could then direct the drug to a compounding pharmacy [35]. Genentech also reported destroying more than $200 million worth of Avastin that would not have been suited for use in the eye, presumably to address the FDA’s concerns following their inspection [29].

In the meantime, the long-hoped for head-to-head clinical study comparing Avastin and Lucentis began in February 2008 and is still underway [36]. As expected, Genentech is not involved in the study [37], which is sponsored by the National Eye Institute and is called the CATT study (“Comparison of Age-related Macular Degeneration Treatment Trials: Lucentis-Avastin”). Results from this study, which involves 1208 participants in 59 locations throughout the US, should be available in February of 2012 [36].

The results from this study have important implications. It will at long last provide data regarding the relative effectiveness and safety of Avastin and Lucentis, which may improve treatment for patients with wet AMD. If the Avastin results are promising, billions of tax-payers’ dollars could be saved each year. The study will also address the optimal dosing frequency for both Avastin and Lucentis, which has been the subject of conflicting reports in the literature. If Avastin proves successful in this study, many countries worldwide may more formally adopt Avastin usage for wet AMD, particularly in those countries where Lucentis is not currently available, according to Danis.

Pharmaceutical companies often justify the high cost of their products by citing statistics about the risks and high costs of developing drugs, or by explaining that a large percentage of their revenues are used to fund research on the next miracle cure. But pharmaceutical companies are for-profit enterprises, and their public financial statements make it clear that if successful, they make money well beyond expenses. Do pharmaceutical companies deserve to earn money if it means making life saving or important quality-of-life enhancing drugs more expensive? Is the high cost of such drugs, reimbursed at least partly by Medicare and insurance companies, a surreptitious scheme by drug companies to make the taxpaying public support them? Should the public have access to drugs that have not been approved by the FDA when FDA-approved drugs for that disease exist? The ethical issues associated with the pharmaceutical industry are complex and continually evolving, and the Avastin-Lucentis debate highlights many of them.

No one outside of Genentech will probably ever know the whole story behind the development and marketing strategies for Avastin and Lucentis. When I asked a source at Genentech if she could provide additional insight into this area, or guide me to someone at Genentech who could, she was required to tell me that Genentech employees were forbidden to discuss the Avastin/Lucentis controversy.

What is not disputed, however, is that Genentech’s two drugs, Avastin and Lucentis, have helped many people around the world retain or regain their eyesight, a truly significant medical advance. In the words of Dr. Danis: “It’s almost like a miracle”.

Last year Christmas I received a beautiful lace-trimmed and embroidered dresser scarf that Aunt Maureen made for me. I see the dresser scarf every morning when I first get up and fumble for my eye-glasses, which I need to get me to the bathroom where I put in my contact lenses. Aunt Maureen is now well past the age of 60. And she can see.

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Wendy Bedale

A biochemist by training, Wendy currently is the Director of Regulatory Affairs for Deltanoid Pharmaceuticals and is an Assistant Scientist at the University of Wisconsin-Madison. She enjoys reading and writing about science and technology in her free time.

She can be contacted at: Wendy Bedale