CATT Study Update 14: One-Year Study Results Show Equivalency Between Avastin and Lucentis

The Comparison of AMD Treatment Trials (CATT Study) one-year results were released today in the New England Journal of Medicine (NEJM). As anticipated, the two anti-VEGF drugs, Avastin and Lucentis, both produced by Genentech, showed equivalent results in the four-arm head to head study. The 43-center, single-blind, noninferiority trial of 1208 patients with neovascular age-related macular degeneration, showed no significant difference either on a monthly injection schedule, or on an as needed injection schedule.

The National Eye Institute (NEI) launched the CATT Study in 2008 to compare Lucentis and Avastin for treatment of wet AMD. The study has now reported the one-year results for 1,185 patients treated at the 43 clinical centers in the United States. Patients were randomly assigned and treated with one of four regimens for a year. They received Lucentis monthly or as needed, or Avastin monthly or as needed. Enrollment criteria required that study participants had active disease.

Patients in the monthly dosing groups received an initial treatment and then had an injection every 28 days. Patients in the as needed groups received an initial treatment and were then examined every 28 days to determine medical need for additional treatment. As needed groups received subsequent treatment when there were signs of disease activity, such as fluid in the retina. Ophthalmologists involved in patient care did not know which study drug a patient was getting, to make sure that the data was not affected by how anyone felt about the treatment.

Change in visual acuity served as the primary outcome measure for CATT. Thus far, visual acuity improvement was virtually identical (within one letter difference on an eye chart) for either drug when given monthly. In addition, no difference was found in the percentage of patients who had an important gain or loss in visual function. Also, when each drug was given on an as needed schedule, there also was no difference (within one letter) between drugs. As needed dosing required four to five fewer injections per year than monthly treatment. Visual gains were about two letters less with as needed than with monthly treatment but overall visual results were still excellent.

In the monthly treatment arms, Avastin was equivalent to Lucentis, with 8.0 and 8.5 visual acuity letters gained, respectively, and in the as-needed arms, Avastin was equivalent to Lucentis with 5.9 and 6.8 letters gained.

Lucentis as needed was equivalent to monthly Lucentis treatments, although the comparison between Avastin as needed and monthly treatments was inconclusive.  The mean decrease in central retinal thickness was greater in the Lucentis-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance).

Rates of death, myocardial infarction, and stroke were similar for patients receiving either Lucentis or Avastin (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with Avastin than with Luentis (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.

It should be noted that the median age of patients in the CATT Study was over 80 years, and a high rate of hospitalizations might be anticipated as a result of chronic or acute medical conditions more common to older populations.

In conclusion, the CATT Research Group reported that at 1 year, Avastin and Lucentis had equivalent effects on visual acuity when administered according to the same schedule. Lucentis  given as needed with monthly evaluation had effects on vision that were equivalent to those of Lucentis administered monthly. Differences in rates of serious adverse events require further study.

Or to put it another way, Avastin and Lucentis are equivalent in treating wet AMD, as needed dosing is nearly as effective as monthly injections and, there are no major safety differences between the two drugs.

I have chosen two graphics to illustrate the study results.

Graph 1 shows the changes in visual acuity over the course of the study and illustrates the equivalency of the four arms of the study.

Graph 1

The part of Table 2 that I have chosen, again shows how close the results were for the four arms of the study, and in addition, shows the number of treatments for each arm, as well as the average annual cost to the patients, with Lucentis costing as much as 40 times the cost of Avastin. This will have an important impact on national health care costs when extrapolated to the more than 250,000 patients who are treated for neovascular AMD annually in the United States.

Table 2

(By clicking on the table, an enlarged version will become visible.)

Another important observation was made concerning adverse effects. The CATT Research Group noted that "Clinical trials of intravenous Avastin in patients with cancer have identified associations with arteriothrombotic events, venous thrombotic events, gastrointestinal perforation and hemorrhage, wound-healing complications, and hypertension. With a limited statistical power to detect important adverse events, we found no significant differences between the two drugs in rates of death, arteriothrombotic events, or venous thrombotic events, findings that are consistent with the results of a study of Medicare claims involving more than 145,000 treated patients.However, in our study, the rate of serious systemic adverse events, primarily hospitalizations, was higher among Avastin-treated patients than among Lucentis-treated patients (24.1% vs. 19.0%, P=0.04). The excess numbers of these events were distributed over many different types of conditions, most of which were not identified in cancer trials involving patients who were receiving intravenous doses of Avastin that were 500 times those used in intravitreal injections. We also did not observe increased rates of adverse events with increased exposure to the study drugs; rates were higher for the two drugs when given as needed than when given monthly. The difference in rates may be attributable to chance, imbalances in baseline health status that were not included in the medical history or multivariate models, or a true difference in risk. Resolving this issue will require many more patients than were available for this study. Results from the second year of this study and from other comparative trials will provide more information regarding the relative risks of serious adverse events."


Dr. Philip Rosenfeld (the father of Avastin) provided an editorial to accompany the CATT Study results in the NEJM. Here is the full text of his editorial:

Editorial

Bevacizumab versus Ranibizumab - The Verdict

Philip J. Rosenfeld, M.D., Ph.D.

April 28, 2011 (10.1056/NEJMe1103334)

For 5 years, patients and clinicians have wrestled with the choice between two drugs for the treatment of neovascular age-related macular degeneration (AMD), a common cause of irreversible blindness among the elderly worldwide. Vision loss results from the abnormal growth and leakage of blood vessels in the macula, a specialized portion of the retina responsible for the best visual acuity. Without this macular vision, patients become legally blind. Vascular endothelial growth factor (VEGF), the cytokine primarily responsible for blood-vessel growth, is inhibited when anti-VEGF drugs are injected repeatedly into the eye, and blindness is prevented in most patients. The majority of treated patients go on to have some improvement in vision.

The two anti-VEGF drugs most commonly used are bevacizumab (Avastin) and ranibizumab (Lucentis), both developed by Genentech. Bevacizumab, a full-length humanized monoclonal antibody, has been approved by the Food and Drug Administration (FDA) for the systemic treatment of certain cancers. Ranibizumab, an antigen-binding fragment, is a smaller molecule that was specifically developed and approved to treat eye diseases and is derived from the same anti-VEGF mouse monoclonal antibody as bevacizumab. Both ranibizumab and bevacizumab bind VEGF at the same position; however, they differ in size, affinity for VEGF, speed of clearance from the eye, and cost. Ranibizumab, the FDA-approved treatment for neovascular AMD, costs approximately $2,000 per dose, whereas bevacizumab, the off-label treatment, costs approximately $50. This cost difference, along with the perceived clinical similarities between these two drugs, has led to the widespread use of bevacizumab in the absence of level I evidence.

Editors Note: According to various sources, approximately 65% of ophthalmologists in the U.S. currently use Avastin over Lucentis as their primary treatment for neovascular AMD.

In this issue of the Journal, Martin and colleagues provide such evidence in their findings from the first year of the Comparison of AMD Treatment Trials (CATT), a large, prospective, multicenter, randomized clinical trial comparing bevacizumab and ranibizumab. Despite formidable obstacles, the investigators successfully compared the two drugs and two different dosing regimens: a monthly regimen versus an as-needed regimen (i.e., drug administration only when signs of exudation are present). A monthly regimen is considered the standard for treatment. An as-needed regimen is used less frequently and relies on clinical judgment and imaging techniques to determine when to reinject the drug. The most common imaging method that is used is optical coherence tomography (OCT), a noninvasive technique that identifies fluid leakage from blood vessels. This VEGF-mediated exudate resolves after the injection of ranibizumab or bevacizumab. An OCT-guided as-needed regimen has been shown to result in improved visual acuity, but CATT is the first prospective approach to directly compare a monthly regimen with an as-needed regimen.

Martin et al. found that the monthly use of either bevacizumab or ranibizumab results in the same visual acuity outcome. This finding holds true for the mean visual acuity and the proportion of patients who gain 15 letters (which represents a doubling of the visual acuity), lose 15 letters, or remain stable. Critics will argue that the OCT outcomes suggest differences between these two drugs. Although the OCT retinal thickness measurements favor ranibizumab, this difference is not reflected in any of the visual-acuity or angiographic outcomes. Whether this difference is associated with changes in vision should become clear during the second year of follow-up.

In addition, Martin et al. observed equivalent visual-acuity outcomes with both the monthly and the as-needed regimens of ranibizumab. This result is particularly good news for patients. The success of the as-needed regimen in a multicenter clinical trial cannot be overstated, given the intrinsic difficulties associated with the training of investigators to agree on OCT interpretation and retreatment guidelines. Given deficiencies that were reported by the reading center, it is likely that visual acuity and anatomic outcomes would have been even better with improved investigator compliance. Other strategies to improve overall treatment outcomes might include the use of newer OCT techniques with improved image resolution to help with retreatment decisions and the use of three mandated monthly injections at the start of the study.

Although the as-needed regimen with bevacizumab appeared similar to the as-needed regimen with ranibizumab, the as-needed bevacizumab regimen compared less favorably with monthly regimens for either bevacizumab or ranibizumab. One possibility may be that bevacizumab has a less durable treatment effect in a subgroup of patients and thus more frequent administration may be required. If the frequency of administration were increased, then the outcomes in such patients should approach the outcomes observed with monthly treatments.

Although CATT addresses the question of efficacy, the study was insufficiently powered to identify differences in drug-related adverse events. Although bevacizumab persists longer than ranibizumab in the systemic circulation after an intravitreal injection, Martin et al. observed none of the expected adverse events associated with systemic anti-VEGF therapy. Although more patients receiving bevacizumab had multiple systemic serious adverse events and hospitalizations than those receiving ranibizumab, these events were not associated with organ systems typically identified with systemic anti-VEGF therapy. The results from the second year of CATT and from five other large, ongoing, multicenter comparative clinical trials in Europe should help to clarify whether these adverse events are related to intravitreal anti-VEGF therapy.

The CATT results, together with the totality of global experience, support the use of either bevacizumab or ranibizumab for the treatment of neovascular AMD. An as-needed regimen is an acceptable alternative to a monthly regimen, but strict compliance on the part of both the clinician and the patient is required. Health care providers and payers worldwide will now have to justify the cost of using ranibizumab. Regulators in certain countries will be forced to reconsider their policies that make it illegal to use drugs off-label, particularly when so many of their citizens cannot afford ranibizumab. The CATT data support the continued global use of intravitreal bevacizumab as an effective, low-cost alternative to ranibizumab.

CATT Study Update 13: A First Peek

As reported by Andrew Pollack of the NYTimes, in a column published earlier today, the first results of the 1200 patient CATT Study (Comparison of AMD Treatments Trials), whose first-year results are scheduled for release at ARVO on Sunday afternoon, indicate equivalency between Avastin and Lucentis.

Speaking to two of the researchers involved in the study (and who presumably had access to the study results), Pollack basically said that the study will be interpreted in many ways, as some complicating factors may indicate that Lucentis is safer to use than Avastin.

Here are Pollack’s comments:

Test of Eye Drug Is Said to Show Success in Elderly

By ANDREW POLLACK
NY Times Prescriptions Blog
April 27, 2011, 11:40 am

A far less expensive alternative proved roughly as effective as Genentech's costly drug Lucentis in preserving or improving vision in elderly people with a common eye disease, according to two people familiar with the results of a closely watched clinical trial.

A clear showing of equivalence between the two drugs could lead to greater use of the less expensive drug, Avastin, which is also made by Genentech, saving Medicare hundreds of millions of dollars a year or more. However, some researchers said, there are some complicating factors, both in the trial data and in other studies, that would favor Lucentis.

"The data is going to be interpreted many different ways,'' said one investigator in the trial, who spoke under condition of anonymity but would not provide any trial results. Revealing trial results before they are published or presented at a conference is considered a violation of scientific protocol.

Genentech developed Lucentis to treat the wet form of age-related macular degeneration, the most common cause of severe vision loss in the elderly. While Avastin, which is a cancer drug, has not been approved for use in treating macular degeneration, it has the same mechanism of action as Lucentis. And Avastin costs only about $50 per injection into the eye, compared to roughly $2,000 for Lucentis.

Many eye doctors already are using Avastin off-label to treat macular degeneration, and many say it appears to work just as well as Lucentis. But there has never been a definitive trial to compare the two drugs.

So the National Eye Institute, part of the National Institutes of Health, sponsored a randomized trial involving 1,200 patients. Results are scheduled to be presented Sunday at the annual meeting of the Association for Research in Vision and Ophthalmology in Fort Lauderdale, Fla. The results will also be published in The New England Journal of Medicine.

Some 1.6 million Americans have advanced forms of age-related macular degeneration and the number is expected to increase as baby boomers age. In 2008, Medicare paid for 480,000 injections of Avastin to treat macular degeneration and 337,000 injections of Lucentis, according to a study led by Dr. Philip Rosenfeld of the University of Miami. Yet Medicare paid only $20 million for the Avastin compared to $537 million for the smaller number of Lucentis injections.

Investigators in the National Eye Institute trial had a day-long meeting on Tuesday in Chicago to learn the results. But they were sworn to secrecy.

But two people familiar with the data, who spoke on condition of anonymity, said that injections of Lucentis and Avastin every four weeks resulted in vision changes after one year that were essentially the same.

The result was largely expected. Under the rules of the trial, patients treated with Avastin could read on average of up to five fewer letters on an eye chart than those treated with Lucentis and Avastin would still be considered "non-inferior." It is believed the results were closer than five letters, however.

Still, doctors will be looking closely at details of the data. One person said Avastin was less effective than Lucentis in decreasing the thickness of the retina, suggesting that Avastin might not prove as effective in preserving vision over a period beyond one year. Patients in the trial are being followed for a second year.

Safety of the two drugs will also be closely watched. However, experts say that with only 1,200 patients, the trial will be able to detect only major differences in safety.

Another part of the trial compared injecting the drugs as needed, depending on the course of the patient's disease, rather than on a strict monthly schedule. One source said Avastin was slightly inferior to Lucentis, but the other said the results of the two drugs were the same.

The trial comparing the two drugs is of the type known as a comparative effectiveness study. Such studies are being encouraged under the new health reform law, though this one started before the law was enacted.

Genentech, which is owned by Roche, has already mounted a pre-emptive counterattack aimed at nullifying any results of the federal trial that would shift more patients to Avastin.

The company sponsored a study looking at records of nearly 78,000 Medicare recipients with age-related macular degeneration. The study found that those who received Avastin had an 11 percent higher risk of dying and a 57 percent higher risk of hemorrhagic stroke than those getting Lucentis, according to an abstract of the study posted on the Web site of the upcoming ophthalmology conference, where the results will be presented.

Genentech arranged for the lead investigator of this study, Dr. Emily W. Gower of Johns Hopkins University, to brief Congressional staffers on the results on Tuesday.

If this finding is considered valid, it could render the results of the National Eye Institute trial somewhat moot by raising safety questions about Avastin.

"Once you plant that seed of doubt in patients' minds it's very difficult to overcome that,'' said one retina specialist, who spoke on condition of anonymity. "I would say it changes the landscape.''

However, experts have not been able to scrutinize the data of this study. One obvious potential flaw is that people who get the cheaper Avastin are more likely to be poor and uninsured and might therefore have worse health to begin with than those who get Lucentis. The study tried to correct for this but whether it did so adequately is a subject of debate.

Roche sells Lucentis in the United States and Novartis in other countries. Sales of the drug for each company were about $1.5 billion last year.

Avastin/Lucentis Update 46: Avastin — The Rest of the Story

I decided to begin this online Journal for two reasons, the first was to put some of my published columns and reports online and make them available to ophthalmic researchers and historians, and the second was because I became interested in the potential for some of the new drugs I had been reading about to stop macular degeneration cold in its tracks. During the summer of 2005, I read a review by Lynne Peterson, of Trends-in-Medicine, of what had happened at the American Society of Retina Specialists (ASRS) Meeting held that summer in Montreal.

As I wrote in one of my first original pieces for this blog (Avastin: A New Hope for Treating AMD)  in late January 2006, Lynne had reported about two drugs from Genentech – Lucentis and, for the first time, its sister drug, Avastin – and how they had the ability not only to stop the progression of AMD, but to actually improve vision for those afflicted with the disease.

As she wrote, “Word spread like a tsunami through the American Society of Retina Specialists (ASRS) meeting about the newly discovered benefits in wet age-related macular degeneration (AMD) from the off-label – and very inexpensive – use of a chemotherapy agent for colorectal cancer. At the beginning of the meeting, only a handful of doctors knew about intravitreal injections of Genentech’s Avastin (bevacizumab), but by the end of the meeting, most doctors questioned said they plan to go home and try it.”

“In fact, Avastin stole the show from Genentech’s Lucentis (ranibizumab), a  fragment of the Avastin molecule that is being developed specifically as an intravitreal injection for AMD. The data presented on Lucentis was outstanding, but it did as much to convince doctors of the value of Avastin as to build anticipation for Lucentis. There have been no studies of Avastin, just case reports and personal experiences, but that was enough to make doctors want to use it – particularly in patients who have failed photodynamic therapy and/or Eyetech’s Macugen (pegaptanib).”

Well, the doctor that spread the word at that meeting and was the first to use Avastin in the eye was Dr. Philip Rosenfeld of Bascolm Palmer Eye Institute in Miami. That was the first part of the story.

In June 2010, I received a request from a university student, Wendy Bedale, for the background information for the above report, for a paper she was writing for a journalism course at the University of Wisconsin. After reading her finished paper, I asked for and received permission to reproduce it, as it described “the story behind the story” about the invention of Avastin and Lucentis at Genentech. This was Avastin/Lucentis Update 41: The Story Behind the Invention of Avastin and Lucentis, and was part two of the story.

Then last week, I heard from a colleague blogger, Dr. David Khorram (The Retina Blog), with a question. Did I recall a story about how Dr. Philip Rosenfeld had come up with the idea to try Avastin in his patients in the first place? I didn’t remember reading this story, but David found an online version, in of all places, a diabetes online forum. I knew that that wasn’t the origin of the story so I decided to ask Dr. Rosenfeld about this story and he was kind enough to send me a copy of the original. It had been written in November 2006 by Jacob Goldstein, then working for the Miami Herald. (Jacob went on to write the WSJ Health Blog, and is currently a blogger for NPR.)

As soon as I read the piece, I realized that this was the missing piece to complete the story that I had started in January 2006.

And, with the expected release of the first year results of the CATT Study – a controlled head to head study of Avastin and Lucentis – at the opening session of the ARVO Meeting on May 1st, I decided to request permission from both the Miami Herald and from Jacob Goldstein to reproduce the Avastin story here, or, as I ‘ve called it, “the rest of the story.”

(Editor’s note: I did find the story on the Miami Herald website, but it is behind a pay to view wall, so I have not provided a link.)


Two Drugs: How a Miami Doctor Found a Cheap Way to Save People’s Sight – and Got a Lesson in  Medicine & Money

November 14, 2006
Jacob Goldstein, Miami Herald

Dr. Philip Rosenfeld had the epiphany that would save the vision of thousands of people -- and may save billions of dollars in healthcare costs -- one evening last year, as he drove home over the Rickenbacker Causeway. He realized that a cancer drug could be injected directly into the eye to fight wet macular degeneration, which leaves thousands of Americans legally blind every year.

'As soon as I got home, I said to my wife, `You're not going to believe this,' '' Rosenfeld says.

Rosenfeld, a retina specialist at the University of Miami's Bascom Palmer Eye Institute, may have guessed that night how effective the drug would be, and he had some sense of the possible cost savings. But he could not have foreseen that his idea would spread around the world in a matter of months, with eye doctors from Santa Barbara to Beirut launching their own studies; nor could he have predicted that a biotechnology company's reluctance to get involved would draw him into the quagmire of the rising cost of new drugs.

The story properly begins five years earlier, when the results began to come in from the first clinical studies of an experimental drug called Lucentis. At that time, there was no way to prevent a gradual loss of vision for the vast majority of patients with wet age-related macular degeneration, or wet AMD, which affects more than 100,000 Americans each year.

''We knew since 2000 that everything was going to change with Lucentis,'' says Rosenfeld, who was one of the leaders of the early trials. ``We saw dramatic effects -- effects we'd never seen before with any other drug.''

Lucentis, developed by the biotechnology giant Genentech, prevents the formation of new blood vessels associated with wet AMD. The drug is very similar to Genentech's cancer drug Avastin, which prevents the formation of new blood vessels associated with lung and colorectal cancer. Indeed, Lucentis is essentially a smaller version of the molecule used in Avastin; it was developed after early studies at Genentech suggested a molecule the size of Avastin would not penetrate the retina as well as a smaller molecule.

By 2004, Lucentis was in the final stage of clinical trials. But it would be two more years before the FDA approved the drug, and in the meantime only those patients lucky enough to be included in the Lucentis trials were able to get it. For other patients, doctors were limited to far less effective treatments which usually failed to stop the loss of vision.

That prompted Rosenfeld to try Avastin. At first, he gave the drug the same way it is given to cancer patients -- with an IV infusion into the patient's bloodstream. ''The results were spectacular,'' Rosenfeld says. But studies of Avastin in cancer patients showed it increased the risk of heart attack and stroke. And when Rosenfeld shared his Avastin results with other eye doctors in early 2005, it became clear they didn't like those risks.

Then Rosenfeld learned researchers had shown that a molecule similar to Avastin could penetrate the retina -- and as he drove home to Key Biscayne one night not long after, he realized that, by sheer coincidence, the liquid preparation of Avastin sold for cancer treatment was the perfect concentration to inject into the eyes of wet AMD patients. He also realized that the amount needed for an injection to the eye would be a tiny fraction of the amount given with an IV infusion to cancer patients. That would likely reduce not only the risk of heart attacks and stroke, but also the cost. Indeed, an Avastin injection would cost about $50 -- compared to $1,000 for Macugen, the main macular degeneration drug used before Lucentis. And when Lucentis was released, it would cost $2,000 per monthly dose.

''Whoa, wait a second,'' Rosenfeld thought. ``Another lesson in healthcare economics.''

The next day, Rosenfeld asked Serafin Gonzalez, Bascom Palmer's chief pharmacist, if he could transfer Avastin from the glass vials it came in into syringes suitable for injecting people in the eye.

By the end of the week, he had injected his first patient, who showed improvement within days. That was in May. At a conference in July, (the ASRS Meeting) he presented the successful results of his first few patients, and other doctors started using the technique on their own patients. The next month, an ophthalmology insurance company posted an Avastin consent form online.

''He just started a revolution,'' says Dr. Robert Avery, a Santa Barbara ophthalmologist who was one of the first to begin using Avastin. ``He did the lion's share of the work and had the guts to make the first injection.''

Not only did ophthalmologists around the world begin using Avastin within a matter of months; they also began studying it, trying to answer all the questions usually resolved by drug company research.
Doctors in Lebanon and Brazil launched clinical trials. An Israeli scientist used rabbits to test whether Avastin was toxic in the eye -- then FedExed a box of rabbit eyeballs to Avery, who showed that the drug did in fact penetrate the retina. The effort had the spirit of open-source software development, where new computer programs are created without the aid of software companies by programmers working in their spare time, each contributing a piece of the puzzle.

Early on, Rosenfeld had flown to Genentech's California headquarters to discuss his Avastin findings. Scientists there were impressed with his findings, he said, but the company never got involved in testing Avastin for the eye.

''We're not developing Avastin for ophthalmic use,'' said Genentech spokeswoman Dawn Kalmar. “We specifically designed and stand behind our decision to design Lucentis for use in the eye. . . Our mission is to meet unmet medical needs and we believe that Lucentis is doing that today.''

By the time Lucentis was approved in June of this year (2006), Medicare covered Avastin for wet AMD in more than 30 states, including Florida. The approval of Lucentis has presented doctors and patients with a choice: a $2,000 drug that has been thoroughly studied in the eye, or a $50 drug that has been studied in an ad-hoc fashion but has become widely used.

Both drugs seem to be similarly effective, slowing or stopping the loss of vision in many patients and improving the vision of some. Serious side effects appear to be very rare for both -- although long-term studies of the effects of Avastin in the eye have not yet been done. A head-to-head study of the two drugs, funded by the National Institutes of Health and Medicare and set to begin in the next few months, should provide a clearer picture of how they compare.

Meanwhile, Rosenfeld -- who is 49 and has spent his career in academia, largely sheltered from issues of healthcare costs -- can't stop thinking about drug prices. ''I'm a physician, a retina specialist, a molecular biologist, a geneticist. I'm not an expert in healthcare policy,'' he says. ``But certain things are becoming painfully obvious . . .

“I think people should be rewarded for developing remarkable, fabulous, miracle drugs. I'm not someone who believes in penalizing the industry, but I have become acutely aware of how these drugs appear to be excessively priced. “We need to strike a better balance between financial rewards and affordability. . . . It's percolated into my everyday life -- in how I treat patients, how I think about studies and how I pursue future treatments.''

AMD Update 14: Neurotech Pharmaceuticals NT-501 Implant Shown to Slow Vision Loss in Patients with Geographical Atrophy Associated with Dry AMD

Back in December 2009, I reproduced Dr. Philip Rosenfeld’s excellent article that presented an overview of the drugs in development to treat dry AMD. At the time, and still today, there was no drug or treatment approved for the treatment of the dry stage of AMD, that represents about 90% of AMD sufferers.

Here is what I presented (from Dr. Rosenfeld’s article) about drugs to promote the survival of photoreceptors and retinal pigment epithelium (RPE) for the treatment of dry AMD:

“No matter what the underlying cause of AMD, drugs that can preserve viable photoreceptors and maintain the RPE should preserve vision. One strategy to promote survival of photoreceptors and the RPE is to protect cells against ischemia and improve the choroidal circulation in patients with dry AMD. Two studies are currently using this strategy. In Europe, an ongoing multicenter, randomized, placebo-controlled study is investigating the use of an offlabel, generic drug known as trimetazidine (Vastarel MR, 35 mg tablet), a drug currently used for the treatment of angina pectoris. Trimetazidine improves myocardial glucose utilization by stopping fatty acid metabolism, and it is considered to have cytoprotective effects in ischemic conditions. Other uses for this drug include the treatment of vertigo, tinnitus, and vision loss and visual field loss due to vascular causes. The primary goal of this study is to slow the conversion of dry AMD to wet AMD.”

“Another drug being investigated for its vasodilatory effect is Alprostadil, also known as prostaglandin E1 (PGE1). The presumed rationale is based on the belief that improved circulation would slow the progression of AMD. This multicenter, randomized, placebo-controlled study is ongoing in Europe.”

“Another strategy to preserve the macular function is to prevent apoptosis by using neuroprotective agents. Ciliary neurotrophic factor (CNTF), a potent neuroprotective agent, has been shown to inhibit photoreceptor apoptosis in an animal model of retinal degeneration  and is being investigated as a treatment for dry AMD. Using encapsulated cell technology that permits CNTF-producing transfected cells to be implanted into the vitreous cavity, Neurotech Pharmaceuticals (Lincoln, RI) has developed a sustained-release platform that produces CNTF for a year or longer. The phase 2 study is completed and data analysis is currently under way. Other neuroprotective agents currently under investigation for dry AMD include a brimonidine tartrate intravitreal implant (Allergan, Irvine, CA) and topical tandospirone (Alcon, Fort Worth, TX).”

Well, this week, Neurotech Pharmaceuticals, Inc., announced that a report in the Proceedings of the National Academy of Sciences (PNAS) (published online March 28, 2011) showed that its product candidate NT-501, slowed progression of vision loss in patients with geographic atrophy (GA) associated with dry age-related macular degeneration (AMD) in a Phase 2 study.

The report, “Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration”,  is the first to show the benefits of a therapy to slow the progression of vision loss from this disease. The results highlight the benefit of the use of a neotrophic factor to treat geographic atrophy and provides hope to the nearly one million sufferers of this vision loss disease.

NT-501 is an intraocular implant that consists of human cells genetically modified to secrete ciliary neurotrophic factor (CNTF) - a nerve growth factor capable of rescuing and protecting dying photoreceptors. GA is a condition that destroys sharp central vision, often resulting in serious vision loss to one or both eyes, for which there is no available treatment.

The Phase 2 study was a multi-center, double-masked, sham-controlled, dose-ranging study in 51 subjects with GA. Subjects were randomly assigned to receive either a high- or low-dose NT-501 implant or sham surgery. The primary study endpoint was change in best corrected visual acuity (BCVA) at 12 months. The study results demonstrated a dose-dependent increase in retinal thickness suggesting increased photoreceptor metabolic activity. This increase was followed by visual acuity stabilization (loss of fewer than three lines of vision, or 15 letters) of 96.3% in the high-dose group compared to 83.3% in the low-dose group and 75.0% in the sham group. In a sub-group analysis of subjects with better vision at base line (20/63 or better), 100% of the high-dose group (n = 10) maintained visual acuity stabilization compared to 55.6% (p = 0.033) in the combined low- and sham-treated groups (n = 9). In this sub-group analysis, there was a 0.8 mean letter gain in the high-dose group compared to a 9.7 mean letter loss in the combined low- and sham-treated groups. Overall, there were no serious adverse events reported and the surgical procedures were well tolerated. The proof of concept study results were originally reported by the company in March 2009.

Quoting from an earlier safety study, published in PNAS in March 2006, the authors then noted: “This trial indicates the safety and promising utility of encapsulated cell delivery as a mode of administration of protein therapeutics to the eye. The results raise the intriguing possibility that CNTF may improve visual acuity in some eyes with advanced RP and atrophic macular degeneration. At the end of the 6-month implantation duration, all explanted capsules contained viable cells that secreted CNTF at expected levels that were therapeutic in the rcd1 dog study. Because pharmacokinetic data on preclinical studies showed continued CNTF production out to 1 year and beyond, encapsulated cell implants may provide a longer-term therapeutic release that will facilitate efficacy studies in retinal and macular neurodegenerative diseases. These results, coupled with robust implant performance, provide the basis for considering the next stages of human trials of CNTF delivered by encapsulated cell implants.”

(Editors note: Whereas the earlier safety study indicated that NT-501 might improve visual acuity in some eyes with advanced RP and GA, the Phase 2 study results, the focus of this article, indicated that the device might slow vision loss.)

The current study's lead author and one of its clinical investigators was Dr. Kang Zhang, Professor of Ophthalmology & Human Genetics, Shiley Eye Center and Director of the Institute for Genomic Medicine, University of California, San Diego. He noted, "The study findings are very promising since both structural and functional improvements were demonstrated in a disease that is currently untreatable. These results support the initiation of larger confirmatory studies of NT-501 in patients with GA."

Paul Sieving, MD, PhD, Director of the National Eye Institute and Principal Investigator of Neurotech's Phase 1 study of NT-501 in retinitis pigmentosa, commented that, "The results of this Phase 2 study suggest that CNTF delivered by the ECT platform may be a useful approach to slow the progression of vision loss in GA patients, and warrant further study in a larger trial of patients exhibiting early onset of this condition."

Ted Danse, Chief Executive Officer of Neurotech stated, "These results in GA demonstrate the significant opportunity of NT-501 to fill a much needed treatment void for sight-robbing retinal degenerative diseases. The data also provide further validation of our proprietary ECT technology and strongly support the introduction of additional product candidates from the platform."

About Dry AMD/ Geographic Atrophy (GA)

Age-related macular degeneration (AMD) is a chronic progressive disease of the macula that results in the loss of central vision. It is the leading cause of blindness in elderly people in the developed world. There are two forms of AMD - dry and wet. Dry AMD is the most common form of AMD representing approximately 90% of all AMD cases. In its advanced stages dry AMD can lead to the degeneration of photoreceptors, those cells of the retina responsible for fine central and color vision, and retinal pigment epithelial cells, those cells responsible for nourishing photoreceptors, resulting in a chronic condition called geographic atrophy (GA). There are currently no approved GA therapies for the nearly 1 million individuals affected in the United States.

About NT-501

NT-501 is one of Neurotech's lead product candidates under development and consists of encapsulated human cells genetically modified to secrete ciliary neurotrophic factor (CNTF). CNTF is a nerve growth factor capable of rescuing dying photoreceptors and protecting them from degeneration. NT-501 is designed to continually deliver a therapeutic dose of CNTF into the back of the eye in a controlled, continuous basis for up to twelve months, by means of the company's proprietary Encapsulated Cell Therapy (ECT) platform. Delivery via ECT bypasses the blood-retinal barrier and overcomes a major obstacle in the long-term treatment of retinal disease.

About Encapsulated Cell Therapy

Neurotech's core technology platform is Encapsulated Cell Therapy (ECT), a unique technology that allows for the long-term, sustained delivery of therapeutic factors to the back of the eye. ECT implants consist of human cells that have been genetically modified to produce a specific therapeutic protein and encapsulated in a semi-permeable hollow fiber membrane. The diffusive characteristics of the hollow fiber membrane are designed to promote long-term cell survival by allowing the influx of oxygen and nutrients while simultaneously preventing direct contact of the encapsulated cells with the cellular and molecular elements of the immune system. The cells continuously produce the therapeutic protein which diffuses out of the implant at the target site. ECT enables the controlled, continuous delivery of therapeutic factors directly to the retina, thereby bypassing the blood-retina barrier.

The ECT Implant

ECT implants consist of cells that have been genetically modified to produce a desired therapeutic factor that are encapsulated in a section of semi-permeable hollow fiber membrane. The implant has a suture loop at one end to anchor it to the sclera in the vitreo-retinal body inside the eye. The current product is 6 mm in length, roughly the size of a grain of rice.

ECT Device

ECT Placement

In contrast to gene therapy, ECT does not modify the host genome. The implant is surgically placed in the vitreous body of the eye as an out-patient procedure in about 15 to 20 minutes. The implant is sutured in a manner that allows for its retrieval when desired, providing an added level of safety as well as the ability to reverse or adjust therapy, if needed.

Placement in the eye

How it Delivers its Drug

The diffusive characteristics of the ECT hollow fiber membrane are designed to promote long-term cell survival by allowing the influx of oxygen and nutrients while simultaneously preventing direct contact of the encapsulated cells with the cellular and molecular elements of the immune system.

Delivery Action

ECT Applications

ECT-based products can be tailored to address the three main clinical manifestations of retinal diseases: degeneration of photoreceptors and/or ganglion cells in the neural retina, vascular proliferation and inflammation. A number of proteins have been discovered in the field of ophthalmology that possess powerful neurotrophic, anti-angiogenic and anti-inflammatory properties. These proteins have the potential to significantly slow, stabilize or halt disease processes in the eye. ECT represents a unique platform for the safe and effective delivery of many of these factors for the treatment of various chronic ophthalmic diseases as follows:

    * Neurotrophic factors for the treatment of retinal degeneration in geographic atrophy (a serious condition associated with the atrophic (dry) form of age-related macular degeneration), retinitis pigmentosa, glaucoma and others.

   * Anti-angiogenic factors for the treatment of the wet form of age-related macular degeneration, retinal vein occlusion, vascular proliferation in diabetic retinopathy and for the treatment of abnormal vascular permeability for various forms of macular edema.
 
  * Anti-inflammatory factors for the treatment of ocular inflammations such as uveitis.

The graphic below shows the status of several of the company’s programs involving its encapsulated cell technology devices.

Neurotech Device Pipeline

About Neurotech Pharmaceuticals, Inc.

Neurotech is developing sight-saving therapeutics for the treatment of chronic retinal diseases. NT-501, one of the company's lead product candidates, is currently in late-stage clinical development for retinitis pigmentosa (RP) and advanced dry age-related macular degeneration (dry AMD). The company's portfolio of product candidates also includes treatments for wet AMD, including NT-503 that delivers a VEGF antagonist. All of Neurotech's development programs are based on the company's proprietary Encapsulated Cell Therapy (ECT). ECT uniquely enables the controlled, continuous delivery of biologics directly to the back of the eye, thereby overcoming a major obstacle in the treatment of retinal disease. To learn more, please visit our web site at www.neurotechusa.com.

A Golden Retriever Named Trevor and Retinitis Pigmentosa

Trevor

Almost every day, I check on  who is looking at my online Journal, where the referrals came from, and what articles are being read most frequently. (I can do this because I use Sitemeter as a visitor counter and for viewer statistics.)

Recently, I encountered a unique referral source, goldenretrevor/pra-research. This piqued my curiosity and I went to the site and took a look. It turns out that the site is run by the owner of a Golden Retriever, Trevor, and two sibling Labrador Retrievers. It seems that Trevor had been diagnosed with photo receptor cone disease (prcd), associated with progressive retinal atrophy (PRA). This was discovered when the dog was a puppy and the owner decided to look into this disease to see if there was anything that could be done to prevent him from going blind.

In doing extensive research, the owner, Katie McCormick, discovered that there was little research being done in the field of PRA in animals, but that PRA is genetically similar to retinitis pigmentosa (RP) in humans, as one study noted, "Identical mutation in a novel retinal gene causes progressive rod-cone degeneration (prcd) in dogs, and retinitis pigmentosa in man." And, there was lots of research being done on RP.

As she put it, “Because of this genetic connection, dogs are being used as proxies to study human retinal degeneration, and to test possible therapies. So that is the ultimate irony – whereas "no one cares about treating PRA" since the best way to eliminate it is through selective breeding, finding an effective treatment for retinitis pigmentosa is huge. And dogs are right in the middle of it.”

She continued, “My research about RP convinced me that even though PRA and RP are diseases of programmed cell death (also known as apoptosis), there were ways to delay the onset (update 8-19-09: see the conclusion in this article for a discussion of how photoreceptor cell death is different from classic apoptosis). But as always, the devil is in the details.”

“Should dog owners mimic what human RP patients do to delay onset? The answer turns out to be no, not necessarily. Contact me personally if you want more background on this.”

In her blog entry on PRA Research, Katie describes how she set up a “Google Alert” using the terms “progressive retinal atrophy” and “retinitis pigmentosa” – which is how she found my Journal article on The Use of Gene Therapy in Treating RP and Dry AMD.

In any event, I thought you might find this interesting. To read more about Trevor, his accomplishments, and how he is progressing with his PRA, take a look at Katie’s blogs about him by following these links: “Welcome to Trevor's Website! “, and “PRA Research”. Katie can be reached at Katie McCormick

Postscript:

Trevor had his annual eye exam at the end of November 2010, on the eve of his 4th birthday. Katie is happy to report that his eye vet said that his eyes still look perfectly normal

Katie and Trevor

A Blue Ribbon Winner