Monday, April 18, 2011

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.''


At 6:49 AM, Anonymous Allan Hytowitz said...

Bless you Dr. Rosenfeld.
This is medicine at its finest.

At 6:37 PM, Anonymous Anonymous said...

Dr. Rosenfeld you Sir, are a genius.


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