Tuesday, June 29, 2010

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

Ellex 2RT Updated Clinical Results: ARVO 2010

Following up on my April 19th writeup (ELLEX 2RT Retinal Regeneration Laser: An Update – First Clinical Results), a report on the first clinical results from the trials being undertaken in London, here are the first results of some key pilot studies undertaken in Australia and reported at the May 2010 ARVO Meeting in Ft. Lauderdale, FL.

A Pilot, Prospective, Randomized Clinical Trial of a New Nanopulse Retinal Laser versus Conventional Photocoagulation for the Treatment of Diabetic Macular Edema

Ellex 2RT for Proliferative Diabetic Retinopathy

The “2RT for Proliferative Diabetic Retinopathy” study is being conducted at several study sites in Australia under principal investigator Associate Professor Robert Casson, MB, BS (Hons), DPhil, FRANZCO. This clinical prospective, double blind comparative investigation aims to compare the efficacy of Ellex 2RT with retinal laser photocoagulation for the treatment of diabetic retinopathy.

Test Sites: Royal Adelaide Hospital, Adelaide, Australia; Vision Eye Institute, Coburg & Footscray, Melbourne, Australia

Investigators: Ass. Prof Robert Casson (principal investigator), Dr Grant Raymond, Dr Henry Newland, Dr Jolly Gilhotra, Dr N Jaross.

Associate Professor Casson presented the completed 6-month study results at the ARVO 2010 Annual Meeting: Paper Session 542. Diabetic Retinopathy IV | Thursday, May 6, 2010 11:15 AM - 1:00 PM

Purpose: The Retinal Regeneration Therapy laser (2RT) is a new nanopulse retinal laser that experimentally causes minimal injury to sensory retina at clinically relevant settings. Our aim was to compare the safety and efficacy of 2RT with photocoagulative (control) laser in a prospective, randomized, multicentre, non-inferiority study.

Methods: Patients with previously untreated diabetic macular edema (DME) were randomized to receive either 2RT or control laser. Retinal thickness and LogMAR acuity (VA) were recorded at baseline and 3 and 6 months after treatment (3-month data is shown in this Abstract). The primary outcome was the change in retinal thickness in the 2RT group (2RT) compared to the change in retinal thickness in the control group (c). Non-inferiority was defined as the one-sided 95% confidence interval (CI) of (2RT – c = OCT) > -25 μm (reduction in thickness after control laser no more than 25 μm than that after 2RT): an ANCOVA model (adjusting for regression to the mean) was used to determine the CI for OCT. Similar analysis was used to determine the difference in VA change between groups (VA). The control laser was applied in a conventional focal/grid pattern based on ETDRS protocol. 2RT was applied in a grid pattern within 500 μm of the fovea such that a just discernible retinal reaction was visible.

Results: There were 22 patients in the 2RT group and 18 in the control group. Age and gender profiles were not significantly different. The baseline mean retinal thickness was 339 ± 96 μm in the 2RT group and 318 ± 70 μm in the control group; 2RT was -44 ± 94 μm, and c was -23 ± 52 μm. The treatment difference (Δ) by ANCOVA was 2.5 μm (in favour of 2RT) with a one-sided 95% CI of -24.7 μm. The baseline mean VA was .21 ± .23 in the 2RT group and .12 ± .23 in the control group; the corresponding 3-month mean VAs were .18 ± .27 and .12 ± .24, respectively. The ΔVA by ANCOVA was 0.03 (in favour of 2RT) with a one-sided 95% CI of -.03 (at least within 2 letters of the control laser). The safety profile of 2RT was excellent.

Conclusions: In this small, randomized study after 3 months of follow-up, 2RT was safe and at least as clinically effective in the treatment of DME as conventional laser. Given the potentially greater safety profile of 2RT compared to photocoagulation and the ability to treat edema closer to the fovea, this new laser modality warrants further evaluation in a larger study.

At six months Ellex 2RT nanosecond laser treatment had produced very similar reductions in macular edema as compared to conventional retinal photocoagulation, whilst using approximately 500 times less laser energy and inducing no collateral damage.

(Editors note: Dr. Casson is in the process of publishing the six-month results in a clinical research paper. Following publication of this paper, the six-month results will be available for posting in this forum.)

Novel Nanosecond Laser Treatment To Prevent Vision Loss From Age-related Macular Degeneration

Ellex 2RT for Early AMD

The “2RT for Early AMD” study is being undertaken in partnership with the Centre for Eye Research Australia (CERA) and the Royal Victorian Eye and Ear Hospital. Preeminent AMD researcher and Head of Macular Research at CERA, Professor Robyn Guymer, MB, BS, PhD, FRANZCO, is leading the prospective, comparative study to investigate the efficacy of Ellex 2RT for the treatment of early AMD.

“Currently, when a patient is diagnosed with early AMD, they’re told that nothing can be done until the disease reaches its late stages, by which time some patients have suffered irreversible vision loss,” Professor Guymer said.

According to Professor Guymer, "The initial results suggest that the application of Ellex 2RT to the affected eye eliminates the yellow deposits known as drusen which are present in the retinal tissue of people with AMD. By getting rid of the drusen from a patient’s retina, we hope to reverse the degenerative processes caused by the disease.”

Principal Investigator: Prof Robyn Guymer

Dr. Robyn Guymer

Poster Session 121. AMD II | Sunday, May 2, 2010 11:15 AM - 1:00 PM

Purpose: To provide proof of concept for a pilot study using a new nanosecond laser based treatment in early Age-related Macular Degeneration (AMD) to reduce progression or even cause regression of disease.

Methods: The study design involved treating one eye with the nanosecond retinal regenerative therapy (2RT) laser in patients with bilateral high risk early AMD, using the contra-lateral eye as a control. Subjects underwent a full clinical evaluation and undertook novel visual function testing: dark adaptation, flicker and colour thresholds, VA or drusen resolution in both eyes at baseline, prior to treatment and then at 1, 3, 6 months and 12 months post laser. The laser was applied in one session with twelve, subthreshold, 400um spots placed in a clock hour distribution, 1400um from the fovea in one eye.

Results: 20 patients have been recruited and treated in one eye. 14 patients have been tested out to 6 months. Of these, 10 treated eyes improved in either visual function (6) or drusen reduction (10). Of great interest is that (10) fellow eyes also improved in either function (4) or drusen resolution (8). All 14 patients showed the parafoveal area (1-3 degrees eccentricity) to be the region with greatest dysfunction. This is the area where GA often commences. In our first 14 patients, 7 treated and 1 fellow eye improved in this areas of greatest dysfunction.

Conclusions: At 6 months post-laser a large number of treated eyes and untreated eyes were showing some signs of overall retinal function improvement. The dramatic effect seen in some subject’s fellow eye was not expected, and the treatment effect was often not seen until 6 months post treatment. Drusen decreased in 70% of treated eyes and 56% of non-treated eyes. Central visual function improved in 50% of treated eyes and 36% of non-treated eyes. In addition, retinal imaging confirmed that there was no evidence of laser damage to the photoreceptor cells.

Drusen Reduction

Improvement in Para-Foveal Visual Function

The improvement in visual function in the region of greatest pre-treatment dysfunction, and the level of drusen reduction, suggests that this treatment may be reversing the drivers of the disease.

We aim to treat 50 high risk eyes over the next year to complete the pilot study. It is anticipated that the 2RT laser will address the underlying cause of AMD which appears to be reduced flux across Bruch’s membrane. The laser design should enable the positive features of previous laser studies for early AMD to be harnessed without entertaining any of the negative effects such as neovascularization.

Professor Guymer expects to present the 12-month results at this Fall’s AAO Meeting.

Wednesday, June 23, 2010

Avastin/Lucentis Update 40: Lucentis is Approved for Treating Macular Edema in Retinal Vein Occlusion

According to an announcement from Genentech, Lucentis has been approved by the FDA for treating macular edema following retinal vein occlusion (RVO)

Here is Genentech’s news release:

FDA Approves Genentech's Lucentis (Ranibizumab Injection) for the Treatment of Macular Edema Following Retinal Vein Occlusion

Genentech, Inc., a member of the Roche Group, announced today (6/22/10) that the U.S. Food and Drug Administration (FDA) has approved Lucentis (ranibizumab injection) for the treatment of macular edema following retinal vein occlusion (RVO). The FDA approved this new indication after a six-month Priority Review.

"This approval provides an important new medicine for people experiencing the unexpected vision loss associated with macular edema following RVO," said Hal Barron, M.D., executive vice president, Global Development and chief medical officer. "In the Lucentis RVO clinical trials significantly more people treated with monthly Lucentis showed sustained vision improvement during the six-month study with an effect seen as early as seven days."

About the Studies

The BRAVO study assessed the safety and efficacy profile of Lucentis in a total of 397 patients with macular edema following branch-RVO. The CRUISE study assessed the safety and efficacy profile of Lucentis in a total of 392 patients with macular edema following central-RVO. During the first six-month period, participants in both trials received monthly injections of either 0.3 mg or 0.5 mg of Lucentis (n=527) or monthly sham injections (n=262). The primary endpoint of both studies was mean change from baseline in best-corrected visual acuity (BCVA) at six months compared with patients receiving sham injections. The studies were not designed to compare the two doses of Lucentis.

In the BRAVO study, the percentage of patients in the Lucentis 0.5 mg study arm who gained 15 or more letters in BCVA from baseline at month six was 61 percent (compared with 29 percent in the sham injection arm). In the CRUISE study, the percentage of patients in the Lucentis 0.5 mg study arm who gained 15 or more letters in BCVA from baseline at month six was 48 percent (compared with 17 percent in the sham injection arm). At month six, patients in BRAVO who received 0.5 mg of Lucentis had a mean gain of 18.3 letters (compared to 7.3 letters in patients receiving sham injections). In the CRUISE study, at month six, patients who received 0.5 mg of Lucentis had a mean gain of 14.9 letters (compared to 0.8 letters for patients receiving sham injections).

The adverse events reported in BRAVO and CRUISE were similar to previous studies, and no new safety events were observed. In BRAVO and CRUISE, the most common ocular adverse events that occurred in the Lucentis arms included conjunctival hemorrhage (48 percent) and eye pain (17 percent). Among non-ocular serious adverse events in the BRAVO study, one arterial thromboembolic event occurred in the sham injection group and two events occurred in the Lucentis 0.5 mg dose group: one cerebrovascular accident that resulted in death and one myocardial infarction. In CRUISE, non-ocular serious adverse events were uncommon and included one case of either myocardial infarction or acute coronary syndrome in each of the three groups. No cerebrovascular accidents or deaths occurred during the six-month treatment period in CRUISE.

About RVO

RVO affects more than 1 million people in the United States(1) and is the second-most common cause of vision loss due to retinal vascular disease(2), which can develop over a long period of time or occur suddenly. It occurs when the normal blood flow through a retinal vein becomes blocked, causing swelling (edema) and hemorrhages in the retina, which may result in vision loss. Sudden blurring or vision loss in all or part of one eye is common with RVO, although loss of vision can develop over a long period of time. RVO typically affects patients who are more than 50 years old, and the incidence increases with age. People with a history of high blood pressure, hypertension, diabetes and atherosclerosis are at an increased risk for developing RVO.

There are two main types of RVO: branch-RVO, which affects an estimated 887,000 people, and central-RVO, which affects an estimated 265,000 people in the United States.(1) Branch-RVO, which is three times more common than central-RVO(3), occurs when one of the smaller veins emptying into the main vein of the eye becomes blocked. Usually, the blockage occurs at the site where an artery and a vein cross, and affects only a portion of the retina. Central-RVO, the less common form of RVO, occurs when the main vein of the eye (located at the optic nerve) becomes blocked.

About Lucentis

Lucentis is a vascular endothelial growth factor (VEGF) inhibitor which was first approved by the U.S. Food and Drug Administration (FDA) for the treatment of neovascular (wet) age-related macular degeneration (AMD) in 2006. In wet AMD clinical trials, Lucentis administered monthly demonstrated an improvement in vision of three lines or more on the study eye chart in up to 41 percent of patients at two years. Nearly all patients (90 percent) in those trials treated monthly with Lucentis maintained vision.

Lucentis is designed to bind to and inhibit VEGF-A, a protein that is believed to play a critical role in the formation of new blood vessels (angiogenesis) and the hyperpermeability (leakiness) of the vessels. In RVO, angiogenesis and hyperpermeability can lead to macular edema, the swelling and thickening of the macula, which is the portion of the eye responsible for fine, detailed central vision.

Lucentis is a prescription medication given by injection into the eye. Lucentis has been associated with detached retina and serious eye infection and should not be used in patients who have an infection in or around the eye. Increases in eye pressure have been seen within one hour of an injection. Although uncommon, conditions associated with eye- and non-eye-related blood clots (arterial thromboembolic events) may occur. Serious side effects include inflammation inside the eye and, rarely, effects related to the injection procedure such as cataract.

The most common non-eye-related side effects are nose and throat infection, headache, and respiratory and urinary tract infections. The most common eye-related side effects are the feeling that something is in the eye, and increased tears. If a patient's eye becomes red, sensitive to light, painful, or has a change in vision, they should seek immediate care from their eye doctor.

Please visit http://www.lucentis.com for the Lucentis full prescribing information, and additional important safety information.

Lucentis was discovered by Genentech and is being developed by Genentech and Novartis for diseases or disorders of the eye. Genentech (a member of the Roche Group) retains commercial rights in the United States and Novartis has exclusive commercial rights for the rest of the world.

1 Genentech data on file (Based on population-based studies/the Beaver Dam Eye Study 2000 and 2008 and the United States Census).

2 Rehak J, Rehak M. Branch retinal vein occlusion: pathogenesis, visual prognosis, and treatment modalities. Curr Eye Res. 2008;33:111-131.

3 Hamid S et al. Etiology and Management of Branch Retinal Vein Occlusion. World Applied Sciences Journal 6(1):94-99, 2009.

Saturday, June 19, 2010

Menu – Part 16: Updates for April to June 2010

Since the last menu posting in late March, I have added three updates on Avastin vs. Lucentis; five updates on AMD topics; one CATT update; and two new postings. One new posting is an update on the Ellex 2RT treatment, including the first clinical results, while the other new posting is about how Lucentis in combination with pan-retinal laser treatment is more effective than laser alone in treating diabetic retinal macular edema.

Here are the recent postings:

Avastin/Lucentis Updates

As reported in the New York Times, as part of the writeup on the use of Lucentis in combination with laser for the treatment of DME, it turned out that Avastin was not used because Genentech “paid” to have only Lucentis used in the study. The full story is presented.

As reported in APM Health Europe, the Brits also want to use Avastin instead of Lucentis in treating AMD. And, the UK’s cost-effectiveness body of NICE (the National Institute for Health and Clinical Excellence) is taking the first steps to appraise the off-label use of Avastin to replace Lucentis. A positive opinion on Avastin might just do the trick.

Dr. Phil Rosenfeld of Bascom Palmer Eye Institute and three colleagues from CMS have prepared an article showing how Medicare could save more than $500 million annually by using Avastin rather than Lucentis, but top officials at CMS have prevented them from seeking to have the study published in a peer-reviewed journal. Dr. Rosenfeld charges that the agency was trying to suppress the study to avoid antagonizing Genentech. The full story as reported by the WSJ.

AMD Updates

In order to enter the U.S. with its breakthrough 2RT therapy, Ellex announced the sub-licensing of the Latina SRT (selective retinal therapy) patent from Massachusetts General Hospital. Now, both Ellex and Lumenis hold marketing rights to this patent. My writeup of this announcement also includes a table comparing the Lumenis SLT and SRT lasers to Ellex’s 2RT laser.

My writeup of the announcement that Notal Vision’s ForeSeeHome Device would be used in an adjunct study of AREDS2, comparing its use with the Amsler Grid in detecting the progression of dry AMD into the wet (choroidal neovascularization) stage.

Dr. Dante Pieramici wrote an excellent overview of current treatment protocols for treating wet AMD and I received permission from Refractive Eyecare to reproduce it.

I learned about a startup company, On Demand Therapeutics, that was developing a drug reservoir that could be implanted in the back of the eye and use a laser beam to open one pocket of the reservoir to deliver its drug to the retina. Here is their story.

I read about the work being done by scientists at UC Irvine on creating a three-dimensional, eight-layer, early stage retina from human embryonic stem cells. Here is the story, along with a few pictures of what the structure might look like.

CATT Study Update

I have previously written about how the CATT Study finally got started (CATT Study Update 8). The same authors have written another version, how they had to overcome Government bureaucracy in order to get the study approved and started. This article was published in the New England Journal of Medicine, which refused permission to reproduce it, so I provided a short synopsis and a link to the original online version.

The New Postings

In November 2008, Ellex released the results of its six-month clinical study of its first trial with 2RT. I requested some graphics to accompany the results, but they were never received from John Marshall in London. Finally, in April 2010, along with the announcement of additional pilot studies, of which preliminary results were to be presented at this year’s ARVO Meeting, I was provided with some graphics, and posted the original six-month results.

A news release from the NEI/NIH described how researchers have shown that the combination of retinal lasers used with Lucentis are more effective in improving vision in the treatment of diabetic retinopathy that either lasers or drugs alone. The study’s one-year results were published in Ophthalmology.

Friday, June 18, 2010

Avastin/Lucentis Update 39: And the Controversy Continues

This article was published in yesterday’s Wall Street Journal. It again illustrates how Medicare operates with one hand tied behind its back.

WSJ, June 17, 2010

By Alicia Mundy

Medicare could save more than $500 million annually by using a cheaper Genentech drug to save vision, according to a draft study by federal officials and a University of Miami eye doctor.

The study shows that the cheaper drug, Avastin, is already used in about 65% of Medicare patients with wet age-related macular degeneration and accounts for nearly 60% of their eye injections, compared with about 40% for a more expensive drug called Lucentis. However, Medicare paid $537 million for Lucentis in 2008 and only $20 million for Avastin, according to the unpublished study, which was reviewed by The Wall Street Journal.

The numbers point to a delicate problem for the federal program for the elderly, whose rising costs are often cited as among the biggest long-term factors in the federal budget deficit. Both drugs are made by Genentech, but only Lucentis is approved by the Food and Drug Administration to treat the disease, the leading cause of irreversible blindness among older people.

Clinical trials suggest that Avastin, approved by the FDA to treat some forms of cancer, is also effective in treating the eye disease. Doctors have been "voting for Avastin with their feet," said Philip Rosenfeld, a retina specialist at the University of Miami's Bascom Palmer Eye Institute and one of the study's authors. Some pharmacies take supplies of Avastin and divide it into tiny doses suitable for injection in the eye.

The study, based on data from more than 200,000 Medicare patients, found that Medicare paid on average $42 a dose for Avastin in the eye, compared with $1,593 a dose for Lucentis.

Genentech, part of Roche Holding AG, says Avastin's risks and benefits in eye disease aren't known. It says the high price of Lucentis is justified by the drug's benefits in preventing blindness and the years of research Genentech put into demonstrating efficacy. A Genentech spokeswoman declined to comment on the Medicare study.

Three of the study's four authors are officials at the Centers for Medicare and Medicaid Services, the federal agency that administers Medicare.

Dr. Rosenfeld, the fourth, said the authors completed their work last year but have run into roadblocks getting top officials at the agency to allow them to submit the study to a medical journal and peer review. He charged that the agency was trying to suppress the study to avoid antagonizing Genentech and added, "I'm tired of the delaying tactics."

Medicare's chief medical officer, Barry Straube, denied any effort to hinder release of the data. He said he hadn't realized that the authors viewed the matter as pressing and said, "I think we can speed this up significantly."

Dr. Straube said he had no problem with the data collected by the authors but is waiting for more information from them about how the data can be translated into policy. He said Medicare is prohibited from doing cost-effectiveness analysis.

The purpose of the study, Dr. Rosenfeld said, was to ascertain how many doctors are using Avastin instead of Lucentis, as a measurement of the standard of care for the eye disease. "Doctors want to know if they are treating patients the way other physicians are, and this helps them," he said.

Sen. Herb Kohl, a Wisconsin Democrat who is chairman of the Senate Committee on Aging, criticized the delay in publishing the study. "It is baffling that CMS would delay the release of this data when there are hundreds of millions of taxpayer dollars at stake," he said.

Mr. Kohl said it is "puzzling to me ... that the federal government continues to reimburse Lucentis at 40 times the amount to treat the same conditions."

Dr. Rosenfeld co-authored a key study showing Lucentis's success in slowing down macular degeneration. He pioneered the use of Avastin in the eye in 2005, while awaiting the FDA's approval of Lucentis. A study of 131 patients published last week in the British Medical Journal BMJ said Avastin was safe and effective in treating macular degeneration.

(Editor’s Note: In the small study – only 131 patients, recently published in the British Medical Journal, Avastin was compared to verteporfin PDT, Macugen, and a sham laser treatment for wet AMD. The study was started before Lucentis was approved for use in the UK, and the Avastin was used off-label. I have provided a link to the original article in the BMJ.)

Dr. Rosenfeld said he was now concerned that because of Lucentis's high price to patients-Medicare covers only 80% of the cost-many can't continue treatment and some doctors don't give injections frequently enough to hold off blindness.

Last fall, the federal Medicare center tried to roll back payments to eye doctors using Avastin by more than 80%. The lower rate would have pushed doctors to prescribe more Lucentis, even at higher cost to the federal government.

Wednesday, June 09, 2010

CATT Study Update 11: More on the Story Behind the Story of the CATT Study

As we await publication of the first results of the CATT Study, probably sometime early next year, I found another interesting account of the “story behind the story” of how the CATT Study became a reality. Just published by the Health Care Reform Center of the New England Journal of Medicine, it is an account of how the investigators behind the CATT Study overcame many obstacles to get the study underway. The article was written by the same authors as my previous writeup on this subject – “CATT Study Update 8: The Story Behind the CATT Study”, by Drs. Martin, Maguire and Fine.

Because the NEJM refused permission to reproduce the article, here is a synopsis, along with a link to the original version that is available online.

Identifying and Eliminating the Roadblocks to Comparative-Effectiveness Research

By: Daniel F. Martin, M.D., Maureen G. Maguire, Ph.D., and Stuart L. Fine, M.D.

Posted by NEJM ● June 2nd, 2010

With patient-advocacy and health policy groups seeking comparative-effectiveness research (CER) as a means to reduce health care cost without compromising the quality of patient care, the Federal Government has committed $1.1 billion, under the American Recovery and Reinvestment Act to ensure that the scientific community will undertake such research. Yet major federal policy changes and innovative measures were required before one such CER study, the “Comparison of Age-Related Macular Degeneration Treatments Trials (CATT Study) could be launched.

This article describes the trials and tribulations, along with hoops to jump through, that the organizing committee had to go through to get this study underway.

An initial article on this topic, written by the same authors, appeared in the Fall 2008 issue of Retina Times, the official publication of the American Society of Retinal Specialists (ASRS). I reproduced that article in this space as CATT Study Update 8: The Story Behind the CATT Study.

The new article, whose title is shown above, can be read in its entirety in the New England Journal of Medicine at this link.