Thursday, June 28, 2012

AMD Update 20: How Fovista Works to Increase Vision in the Treatment of Wet AMD

Because I was denied the opportunity to tell you how the combined therapy works, as told by Dr. Pravin Dugel (see AMD Update 19), I decided to take another tack. With the permission of Ophthotech, I would like to explain and illustrate how the combined therapy of anti-VEGF and anti-PDGF works to provide improved vision compared to monotherapy with anti-VEGF drugs alone, for those suffering from neovascular, exudative wet AMD.

Some Background

AMD is a disease characterized by progressive degenerative abnormalities in the macula of the eye, a small area in the central portion of the retina. AMD is characteristically a disease occurring in patients older than 50 years of age and has long been recognized as the leading cause of severe and irreversible loss of central vision in adults over the age of 50 in the U.S. and other developed countries around the world. AMD is exceptionally common, currently affecting about 8 million Americans and an additional 8 million Europeans.

Of those affected, approximately 10% are afflicted with the wet form of AMD. (Dry AMD can and usually does progresses into the wet form of the disease.)

It has been estimated that there are approximately 200,000 new cases of wet AMD each year in the U.S. This type of AMD results when abnormal blood vessels proliferate under and/or within the retina. These blood vessels leak blood and fluid into and under the retina, which results in vision loss. The natural history of wet AMD is that of scarring with progressive destruction of the central retina and loss of vision.

Until 2005, there was no treatment for wet AMD that could stop its progression and provide some improved vision for those suffering from the disease. In mid-2005, Dr. Phil Rosenfeld, of Bascolm Palmer in Miami, presenting at Retina 2005, told an enthralled audience about his experiments with Avastin, an anti-VEGF agent used in cancer treatment, and how he was able to stop the progression of wet AMD. The following year, Genentech introduced the FDA-approved anti-VEGF Lucentis and history was made. (Avastin, also made by Genentech, a similar molecule approved for cancer treatment, was and still is used off-label for treating wet AMD, primarily because of its much lower cost.)

Figure 1 illustrates a normal, disease-free retina. Figure 2 shows a retina with signs of neovascular, exudative wet AMD.

Figure 1

Figure 2

Monotherapy Anti-VEGF Treatment

Monotherapy with an anti-VEGF agent (Lucentis, Avastin or Eylea) is the current standard of care for wet AMD. Anti-VEGF agents mediate their efficacy primarily through their potent anti-permeability effect. However, limitations of anti-VEGF strategies include lack of disease modification (neovascular regression). Therefore, a therapeutic regimen that induces disease modification would likely result in enhanced visual outcome for patients.

Further, as pointed out by Dr. Dugel in his blog in OSN, as shown by several studies, despite giving injections on a monthly basis for up to two years, the size of the neovascular membrane does not decrease. In fact, in some cases, despite excellent visual acuity results, the size of the neovascular membrane actually increased, leading to the questions, why was there anti-VEGF mono-therapy resistance and what was the biological basis for this?

It turns out there is an answer to these questions, which was found in the study of cancer treatments. As explained by Dr. Dugel, “As it turns out, the neovascular complex does not expand in a random fashion but rather expands with a specific, specialized group of cells known as the tip cells. These are the only naked endothelial cells in the neovascular complex.”

“These cells act as scout or lead cells in expanding the size of the neovascular membrane. These are the only naked endothelial cells in the neovascular complex. And they produce platelet derived growth factor (PDGF), which matures and recruits pericytes that back cover the neovascular complex. The pericytes act as a “protective armor” against anti-VEGF monotherapy. This simple but eloquent set of events explains a lot of the clinical observations that have been made in retina over the last 5 years.”

“With anti-VEGF monotherapy, it is clear that treatment needs to be given on a strictly monthly basis forever (bi-monthly with Eylea) because only the tip cells are killed. While the pericyte coverage of the neovascular complex provides a protective armor, the anti-VEGF treatment stops it from expanding. However, once anti-VEGF monotherapy stops, then the lead cells will grow and the complex will continue to expand. Therefore, treatment has to be given strictly on a monthly basis forever.”

Combined Anti-VEGF Plus Anti-PDGF Therapy

Ophthotech's anti-PDGF-B aptamer, Fovista (E10030), targets PDGF, which regulates neovascular pericytes. In pre-clinical models, Fovista successfully induced neovascular regression when administered in combination with anti-VEGF agents. This effect is further supported by published studies in which inhibition of the binding of PDGF-B to its receptor, PDGFR-ß, plus an anti-VEGF agent cause neovascular regression in ocular angiogenesis models, as shown below.

Figures 3-7 illustrate the action of Fovista and the combined therapy with the anti-VEGF agent in reducing neovascularization.

Figure 3. Action of PDGF

Figure 4. Formation of Pericytes

Figure 5. Anti-VEGF Action

Figure 6. Combination Therapy

Figure 7. Combo Therapy Regresses Neovascularization

As Dr. Dugel further pointed out, “Given this scientific explanation for anti-VEGF resistance, it would make sense that a scientifically logical combination treatment model would consist of anti-PDGF treatment combined with anti-VEGF treatment. The goal would be to have the anti-PDGF treatments chemically strip pericytes from the neovascular complex, rendering it susceptible to the anti-VEGF treatment. There is indeed a solid scientific foundation for this treatment combination.”

Mural cells (pericytes) provide neovascular endothelial cell survival signals by juxtacrine secretion of growth factors such as VEGF and other pro-angiogenic factors. Therefore, neovascular tissue is resistant to regression during a monotherapy anti-VEGF attack.

PDGF is a molecule which regulates the recruitment and maturation of pericytes. Increased PDGF expression leads to enhanced pericyte coverage of neovascular tissue. Conversely, its inhibition has been shown to cause pericyte stripping.

Fovista strongly binds to PDGF-B resulting in pericyte stripping in ocular and oncological models of pathologic neovascularization. Co-administration of Fovista and an anti-VEGF agent, thereby targeting pericytes and endothelial cells respectively, has been shown to induce significant neovascular regression in multiple pre-clinical ocular and tumor models of angiogenesis.

The results of the recently completed Ophthotech prospective, randomized, controlled, Phase 2b clinical trial of 449 patients showed that the combined therapy was successful in producing a 62% increase in lines of vision compared to monotherpy alone.

Q&A With Samir Patel, CEO of Ophthotech:

Q. I know that your Phase 2b study of Fovista was done with Lucentis, but would you expect both Avastin and even Eylea to work as well, or in the case of Eylea, even better than Lucentis?

A. With respect to the currently available data, it is very difficult to claim superiority of one anti-VEGF over the other. Furthermore, it is apparent that we are at the ceiling of anti-VEGF efficacy as increasing the concentration of the anti-VEGF agent does not result in enhanced visual outcome. We believe all anti-VEGF agents would perform equally well in combination with Fovista.

Q. I anticipate that with the way the combined therapy works, perhaps less frequent retinal injections might be required to provide and hold the gains in vision shown in your initial study. Do you have any thoughts on the frequency of required injections?

A. The data from our large (449 patient) randomized study showed superiority of Fovista combination over Lucentis monotherapy on the basis of the pre-specified primary endpoint (Mean VA at 24 weeks) with statistical significance at 6 months. Furthermore, this relative benefit was increasing in magnitude at each time point resulting in divergence of visual acuity curves over time. Therefore, this enhanced visual outcome required continuous (every four weeks) of Fovista combination. I cannot comment on any alternative  regimen as the trial did not address that question. However, preclinical studies published in "Nature", "Archive of Ophthalmology"  and elsewhere suggest that anti-VEGF administration leads to increase in PDGF and neovascular maturation. Therefore, administration of Fovista (anti-PDGF) very time an anti-VEGF agent is used would likely be required for maximal visual benefit.

The remaining question, will further studies show that the combined therapy can effectively reduce the need for multiple injections to control the gains in vision achieved?


Anti-PDGF, anti-VEGF combination may be game changer in wet AMD treatment, Pravin Dugel, MD, Ocular Surgery News, June 14, 2012.

Monday, June 25, 2012

Josef Bille, Laser Surgery Pioneer, Wins Lifetime Achievement Award from European Patent Office

The following writeup was taken from the website, with just a few changes.

I first met Professor Bille when he was at Intelligent Surgical Lasers (ISL), developing a picosecond laser for intrastromal ablation. I’ve since followed his career through successive startups, including Technolas Perfect Vision and then 20/10 Perfect Vision.

This Lifetime Achievement award is richly deserved.

EPO recognizes Josef Bille at annual ceremony

Josef Bille's development of the technology that underpins personalized laser eye surgery has won the University of Heidelberg researcher and entrepreneur a "lifetime achievement" award from the European Patent Office (EPO).

At the EPO's annual "European Inventor Awards", held in Copenhagen, Denmark, on June 14, Bille was recognized for more than three decades of work on wavefront correction techniques that have revolutionized the field of vision correction, created several start-up companies and now employ around one thousand people around the world.

Laser-assisted in situ keratomileusis (LASIK), the most common method of refractive eye surgery to correct common defects such as myopia, was a relatively crude technique when first introduced in 1989. But thanks in large part to research work covered in patents filed by Bille, LASIK has evolved into a "tailor-made" technology, where the precise re-shaping of a patient's cornea is determined in much greater detail with the use of aberrometers to measure tiny defects, known as higher-order aberrations, in each eye.

Subsequent developments have included all-laser LASIK - where femtosecond laser pulses are used in place of the traditional knife to create a "flap" under which the cornea is re-shaped, meaning more precise vision correction - and more recently the emergence of femtosecond laser cataract surgery, which is set to open up a much larger market for the technology.

In his acceptance speech after winning the award, Bille said that he and his colleagues had tried to convey an atmosphere of entrepreneurship at Heidelberg. As well as five start-ups with which Bille was directly involved, his former PhD students have started up another twenty firms.

"We described ourselves as the 'tip of the arrow' [Pfeilspitze]," Bille said. "Because we saw each other as a group of young people who can change the world."

Industry experience

Bille first started working on wavefront sensing and correction in the early 1980s, after becoming a professor at the University of Heidelberg in Germany following a five-year stint in the chemicals industry.

His original idea for wavefront correction emerged from work to develop a retinal imaging system that was first presented in 1982, and which led to a US patent filed in collaboration with the German optics giant Zeiss.

Two years later, Bille co-founded Heidelberg Instruments, initially working on prototype ophthalmology systems - although the company, which is still going strong, is now firmly focused on laser-based lithography systems.

Toward the end of the 1980s, Bille and his PhD student Andreas Dreher first demonstrated that adaptive optics could be performed on eyes in vivo, before making a key breakthrough in 1991. With another PhD student, Junzhong Liang, Bille demonstrated wavefront refraction with a Shack-Hartmann aberrometer for the first time - a development that has come to underpin the personalization of laser eye correction surgery.

Patent strategy

All in all, Bille has applied for 74 patents since 1982 - mostly relating to ophthalmology and eye surgery. Some of those have proved critical to gaining venture capital funding and protecting inventions that have led to the creation of several successful start-ups.

In fact, says Bille, patents have been essential for the cross-over of those technologies into the commercial world. "To set up a firm there is a need for venture capital," he says. "But it would not be possible to obtain such capital if we had no patents. In fact, one could say that writing a business plan equates to writing patents."

The Heidelberg professor has largely taken on that responsibility himself - even with the more recent emergence of university technology transfer specialists intended to speed the process.

"Being professional at university technology transfer offices - fast, unbureaucratic - is an issue for a lot of universities in Europe and also in the US," he says, adding that part of the reason he writes his own patent applications is simply that it is fun to do.

Nowadays, Bille adds, because of the increasing backlogs at patent offices, it has become the patent applications - and not so much the granted patents - that carry more influence. His strategy has typically been to patent first in the US with priority filings, largely because this is where the majority of venture capital firms are based, but also because US patent law has broader applicability, particularly for methods such as surgical procedures.

Many of Bille's patents were written in conjunction with Technolas Perfect Vision (formerly known as 20/10 Perfect Vision, a company name referring to the way that wavefront measurements can correct eyesight to such a precise degree that patients become able to see better than the "20/20" typically considered to be perfect).

Technolas is now part of the global eyecare giant Bausch & Lomb, and is focused on the emerging field of cataract surgery using femtosecond lasers, as well as laser correction of presbyopia. In an era of ageing global population, both of those applications look set for rapid adoption in the coming years.

Of the five start-up to have been formed directly around Bille's work, three now employ around 250 employees each, and have a combined turnover of some ?300 million.

Bille's recipe for success identifies four key elements: perseverance; close interaction with the users of the invented technology; an inclination to go against the grain and challenge conventional thinking; and, of course, an intellectual property (IP) strategy. The final part of that puzzle requires strong financial backing, however. "Venture capitalists' backing is essential in this context," Bille notes.

Thursday, June 14, 2012

AMD Update 19: Combination Therapy May Be A “Game Changer” for Wet AMD

You may have seen or heard the news that a new drug, Fovista, from Ophthotech, when used in combination with Lucentis (and probably Avastin), has the potential to greatly improve the outcomes now experienced with anti-VEGF monotherapy. The results from a Phase 2b clinical study of 449 patients showed that the combination therapy resulted in a gain of 10.6 letters of vision on the ETDRS standardized chart at 24 weeks, a 62% increase over the 6.5-letter gain from Lucentis monotherapy.

Fovista is a novel anti-platlet-derived growth factor therapy. 

I did not understand the implication of this combined therapy until I read Dr. Pravin Dugel’s blog in the June 14th issue of OSN Online. Now that I’ve read this blog I understand the importance of this combined therapy and would like to share it with you.

I have asked OSN for permission to reproduce Dr. Dugel’s article, and when it comes, I will reproduce the full article in this space. In the meantime, here are excerpts from the blog.

Anti-PDGF, anti-VEGF combination may be game changer in wet AMD treatment

Pravin U. Dugel, MD

Published in Ocular Surgery News Online June 14, 2012

As noted above, I had requested permission from the editor and publisher of OSN to reproduce Dr. Dugel’s writeup in this space. That permission was denied. The reason given was that “Google severely punishes” OSN if someone duplicates their content. I hardly think that could be the case in this case, with their 30,000 subscribers compared to my 100 to 200 visitors per day, but so be it, I have complied with their demand to remove my reproduction of their article which I posted last evening.

So, I now urge you to follow the link shown above and read this important writeup on the OSN site. However, if you cannot access the OSN site, I have reproduced what Dr. Dugel’s writeup would have looked like on this site in a pdf file which I will be happy to send to anyone requesting it. Just use the “Email Me” link to the right and request AMD Update 19.

To summarize what Dr. Dugel wrote: “Anti-VEGF monotherapy will go down in history as a treatment that was both insurmountable and unsustainable.”

Tremendous gains were made in using both Lucentis and Avastin in saving, preserving, and even improving vision in people with wet AMD that previously to anti-VEGF monotherapy use would have gone blind. “We went from essentially not being able to treat our patients at all and watching them go blind, to being able to maintain vision in 90% of our patients ... we were able to improve vision in 30% to 40% ... with anti-VEGF monotherapy.”

However, with its use, it was learned that the treatment was unsustainable to achieve the best results possible – “the treatment burden (of monthly treatment) was simply too great.”

An answer was found in studying treatments for oncology. The use of an anti-PDGF treatment combined with anti-VEGF treatment is being found to provide better visual outcomes than the use of monotherapy alone. Please read Dr. Dugel’s article to find out why.

And that, ladies and gentlemen, is what Dr. Dugel had to say. Wow! Does this mean that fewer injections will be needed in the future and provide even better results? I’ve asked this question of Dr. Dugel and if he responds, I will provide his answer as a supplement to this writeup.

Editors Note: As I said upfront, I asked permission to reproduce the complete writeup and it was denied. So, it is up to you to find and read Dr. Dugel's excellent writeup.

Sunday, June 03, 2012

Avastin/Lucentis Update 52: Another Point of View

As you know, I have been writing about Avastin and the Avastin vs. Lucentis controversy since January 2006. There are now over 50 postings on this subject, and an additional 35 or so on various treatments for AMD, including the Comparisons of Age-Related Macular Degeneration Treatments Trials (the CATT Study). From time to time, as I’ve run across articles or blogs by others pertinent to these subjects, I’ve gotten in touch with the authors and requested permission to reproduce their words here. This is such an instance.

I recently was referred to a blog posting by Laura Newman on her Patient Point of View (POV) blog. It deals with the Avastin vs. Lucentis (and now Eylea from Regeneron) controversy, but more importantly, it asks patients with wet AMD to think about the potential biases that their eye doctor might have as to which drug treatment he/she would recommend.

I thought that Laura’s POV blog might be of interest to my audience and got in touch with her and asked for her permission to reproduce the writeup in this space.

She graciously said yes, and here it is:

Posted on May 22, 2012 by Laura Newman

Just about a year ago, I reported the one-year results for the Comparison of AMD Treatments Trial (CATT), which compared Lucentis, the high-cost injectable medication made by Genentech with Avastin, also made by Genentech. A lot has happened in the past year in macular degeneration, including the release of two-year CATT results and the approval of a new drug, Eylea, by Regeneron. 

Your Ophthalmologist’s Biases

Doctors talk about patient-centered care and I am starting to think that patients are out in the cold in terms of picking the best doctors for themselves. We know zero about physician biases, use of data, and involvement with pharma and medical device manufacturers.

If you've got wet macular degeneration and are a candidate for drug therapy, you may find yourself lost when you search for an ophthalmologist to treat you:

●  How do you pick a top-quality ophthalmologist?
●  Are the drugs affordable?
●  What are your preferences?
●  Does your ophthalmologist have preferences for specific drugs and are those preferences aligned with your's?
●  Will your ophthalmologist recommend therapy, based on the best science and safety data?
●  Is affordability important to you? Your out-of-pocket costs can be substantially higher with Lucentis, for example.

Much harder to discern is what your doctor's biases are. For all the talk about ratcheting up patient literacy, patients know next to nothing about ophthalmologists' biases. There are no uniform standards. I'd like to see more transparency. For example,  is your ophthalmologist going to pick a brand name on principle? Pharmaceutical sales reps will press safety buttons, making your physician go with brand. Is your ophthalmologist a paid consultant for the eye industry and could this bias his or her perspective? Are ophthalmology sales reps sitting in the waiting room? Are promotional literature, pens, and tissue boxes cluttering up the waiting room?  It would be nice to know their involvement with industry: speakers' bureaus, patents, involvement with drug and device companies.

It's not just your ophthalmologist.

Your Doctor and the Pharmaceutical Industry

According to a report in the Nov. 3, 2010 New York Times, Genentech used a secret rebate program for eye doctors dispensing a high-volume of Lucentis, and rebates rose as quarterly usage increased.

I am not naïve enough to think that I can find a pure eye doctor not involved with industry in any way, shape, or form. I have been to too many ophthalmology meetings and read the disclosures to expect it. I want an eye doctor attentive to my out-of-pocket costs and not recommending a drug because s/he is on a speakers' bureau or because a drug rep promoted it as the only safe option, when it is disputable.

Is it too much to ask for patients to have the same information on industry involvement available to us that medical journals require?

Five Fast Facts on Wet Macular Degeneration Drugs

1. Currently, there are 3 drugs available demonstrated to improve vision: Avastin, Lucentis, and Eylea.

2. "Lucentis accounts for 10% of Medicare Part B," state the CATT authors in the two-year trial results, a higher proportion than I ever expected.

3. Medicare reimburses ophthalmologists 6% of the average wholesale price of the injected drug, or $120 for each Lucentis injection, versus $3 for each Avastin injection.

4. Avastin (Genentech) is the cheapest, at $50 per dose, compared with Lucentis (Genentech), at $2,000 per dose. Both are designed to be given monthly, or on an as-needed basis (stopping the injection if no fluid builds up in the eye.

5. Eylea (Regeneron) became FDA-approved about six months ago. Eylea is administered every 2 months at about $1800 per injection. Eylea is potentially half as expensive as Lucentis.

The Avastin-Lucentis Data

Here's my summary of the key findings at one year:

1. In comparison with previous treatments, Avastin and Lucentis are the first treatments to ever improve vision in patients with age-related macular degeneration;

2. Drugs used in the past (Macugen and Visodyne) only slowed the progression of age-related wet macular degeneration.

3. Testing various regimens, including monthly injections versus variable (stopping the injection if no fluid builds up in retina), investigators learned that they could give injections into the eye less frequently than once a month because patients getting the injections did not build up fluid that quickly.  On average, patients needed injections into their eye 7 times during the year, instead of monthly (or 12 times).

4. The two drugs had about the same effects on visual acuity, when administered on the same schedule.

5. The drug's cheaper formulation (Avastin), cost $50 per injection, compared with Lucentis, at $2,000 per dose.

6. Safety considerations are still being evaluated. Serious adverse events (primarily hospitalizations) occurred in 24% of patients for patients on Avastin, compared with 19% for patients on Lucentis. According to the study, these safety concerns were not identified in previous studies of Avastin, when used to treat colon cancer. Patients are now being followed for a second year and safety will continue to be monitored.

Safety Signal Fails to Materialize

Since the one-year data was released, industry has been pushing hard to press safety issues with Avastin. The one-year trial results made the cheaper Avastin look like a reasonable first-line drug choice.

An industry-sponsored safety analysis done in conjunction with Johns Hopkins researchers using Medicare claims data came out when the first-year NEI study data surfaced, showing an 11% higher mortality risk and 57% higher risk of cerebral hemorrhage in patients using Avastin. Even though Genentech pressed hard with the results, the results didn't fly because the study was not able to ascertain other patient factors, including stroke, hypertension, and cardiovascular risks.

Notably, at two years, the trial investigators, the American Academy of Ophthalmology, and many other authorities concluded that both Avastin and Lucentis had strong efficacy. Differences in serious adverse events with the two drugs was no longer interpreted as worrisome. The investigators wrote: "There were no differences in rates of death or atherothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab [Avastin] is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF."

The AAO press release lauded the study as "seminal" in "comparative effectiveness research," a marked departure from AAO's defensive stance at year one, when they stressed the importance of MD choice and autonomy.

Donald S. Fong, MD, MPH, Director of Clinical Trials Research, Kaiser Permanente  Southern California, Pasadena, CA, told Patient POV: "As far as I am concerned, Avastin is first line. If it doesn't work, I will go to Eylea, which is half as expensive as Lucentis."

There were a few isolated issues with compounding of Avastin and industry tried to use this as a lesson in going for brand.

Patients Need to Know More About Their Doctor

Patients would benefit from knowing a lot more about their eye doctors and all other doctors that  just isn't out there. In a previous article on Patient POV, Ricki Lewis told the story of a patient with osteogenesis imperfecta (brittle bone disease), a condition which has eye manifestations. Some ophthalmologists are unfamiliar with the disorder.

I don't mean to single out ophthalmology. These issues are relevant to knowing your doctor.  Why should journals be the only place where physician disclosures are mandated? Why can't patients find reliable data on physician experience as well?

Clarification: The following was inadvertently left out of the original piece. Genentech has purposely not sought FDA approval for Avastin for the treatment of wet macular degeneration. Lucentis is a fragment of the Avastin.

Laura Newman Bio

Laura is a medical journalist and blogger. Her stories have appeared in peer-reviewed journals and on the web. She has covered ophthalmology as a reporter for several years, with both  Ophthalmology Times and Ocular Surgery News. She has also written news for Scientific American, The Lancet, and the Journal of the National Cancer Institute.

In Patient POV, she strives to bring the same rigor to telling stories about patients that she has shown in her previous work, which has featured research scientists and physicians.

Laura can be found on Twitter as: @lauramanny

Her email address is: Laura Newman