Eye for an eye

It’s no longer debatable: for treatment of wet age-related macular degeneration (AMD), the inexpensive Avastin (at $50 a dose) is just as good as Lucentis (at $2,000 a dose), according to the report from the Comparison of AMD Treatments Trials (CATT), which was published online in the New England Journal of Medicine on Sunday, May 1.

Doctors are being incentivized to use the more expensive drug, remember? Medicare reimburses physicians 6 percent of the sales price for the drug they use. On top of that, Genentech started a rebate program for high-volume Lucentis users.

In an earlier issue of Palm 2 Jupiter, Bascom Palmer ophthalmologist, Philip Rosenfeld pointed out the money side of this debate, as well as outlining research phases with these two drugs. At that time, he said  he was anxiously awaiting the CATT results.

And here they are: Results from the first year of the two-year clinical trial, funded by the National Eye Institute, showed that Avastin, a drug approved to treat some cancers and that is commonly used off-label to treat AMD, is as effective as the Food-and-Drug-Administration-approved drug, Lucentis, for the treatment of AMD.

Wet AMD, the leading cause of blindness of the elderly, occurs when certain proteins (vascular endothelial growth factor or VEGF) cause abnormal blood vessel growth in the back of the eye. As the blood vessels grow, they can leak blood and fluid, which damage the macula—the part of the retina that lets one see color and fine detail.

Rosenfeld, who was the lead investigator in phase 1 trials for Lucentis in 2001, said that Lucentis was revolutionary. “The way Lucentis works, it binds to VEGF, stopping the growth of abnormal blood vessels. It changed everything. Rather than simply showing down vision loss, we got dramatic vision improvement in a day or two. Patients were seeing better.”

Then, in 2003, Rosenfeld who also has a Ph.D. in genetics, began studying Genentech’s literature on Avastin, a drug that also blocks abnormal blood vessel growth.

“Both Avastin and Lucentis are derived from the same molecule, which was a mouse antibody. The mouse antibody was then humanized (made to look like a human antibody) and then Lucentis was made as a fragment of the antibody. So, both Avastin and Lucentis bind VEGF exactly the same way, only Avastin is a larger molecule and Lucentis is a fragment of this larger molecule.”

He suggested to Genentech that Avastin could be used systemically for AMD, but the company was not interested, so he raised money for a trial. He found that Avastin used systemically was effective, but had a 1-percent risk for heart attacks and strokes that he and his colleagues did not want to take.

“Then we had a Eureka moment.” Rosenfeld said. “We realized that if we injected the same amount of Avastin as Lucentis, we would have the same amount of inhibitory activity, and it worked.

“We presented this to meetings and it spread all over the world, and Avastin was ready before Lucentis was available.”

In 2004, the FDA approved Avastin for the systemic treatment of metastatic colon cancer. Also that year, some doctors started to give Avastin systemically as an intravenous infusion.

In 2005, ophthalmologists began injecting AMD patients with low doses of Avastin, due to its similarity to Lucentis and its availability. Many physicians saw a beneficial treatment effect and Avastin’s use grew rapidly. In 2006, two Genentech-sponsored clinical trials established Lucentis as highly effective for the treatment of wet AMD.

Ophthalmologists used Avastin primarily as needed when there was evidence of active disease. Also, most clinicians adopted as needed dosing for Lucentis, which was a departure from FDA-approved labeling and the monthly dosing schedule evaluated in the Genentech-sponsored clinical trials.

In 2008, the National Eye Institute decided to fund CATT to compare the two drugs. “Over 250,000 patients are treated each year for AMD, and a substantial number of them receive Avastin. Given the lack of efficacy data regarding Avastin for AMD treatment, the NEI had an obligation to patients and clinicians to conduct this study,” said Paul A. Sieving, M.D., Ph.D., director of the NEI.

The CATT study has now reported results for 1,185 patients treated at 43 clinical centers in the United States. AMD 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.

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. The as needed groups received subsequent treatment when there were signs of disease activity, such as fluid in the retina.

Change in visual acuity served as the primary outcome measure for CATT.  Some of the main findings are as follows:

●      Thus far, visual acuity improvement was virtually identical for either drug when given monthly. Also, when each drug was given on an as needed schedule, there also was no difference between drugs. As needed dosing required four to five fewer injections per year than monthly treatment and overall visual results were still excellent.

●      Adverse events indicate development or worsening of a medical condition. They may or may not be causally associated with the clinical trial treatment, but they are always monitored and reported in any clinical trial. The median age of patients in CATT 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.

●      Serious adverse events (primarily hospitalizations) occurred at a 24-percent rate for patients receiving Avastin and a 19-percent rate for patients receiving Lucentis. These events were distributed across many different conditions, most of which were not associated with Avastin in cancer clinical trials where the drug was administered at 500 times the dose used for AMD. The number of deaths, heart attacks, and strokes were low and similar for both drugs during the study. CATT was not capable of determining whether there is an association between a particular adverse event and treatment. Differences in serious adverse event rates require further study. Investigators in the CATT study will continue to follow patients through a second year of treatment. These additional data will provide information on longer-term effects of the drugs on vision and safety.

The outcome of this study will not sway doctors one way or the other, Rosenfeld said. “They had already made up their minds. And these results won’t make a difference to Medicare, which does not have a mandate to recommend treatments based on cost. But, thank goodness, we now have two excellent AMD drugs.

“”However, if we had rerun the phase 3 Lucentis trials and replaced Lucentis with Avastin, the results would have been identical,” Rosenfeld said. “The frustrating part is this: Avastin could have been available for clinical trials in 2000. We could have run the trials with Avastin and, no doubt the FDA would have approved it for AMD for 2003 and 2004. Just think of all the blindness we could have prevented.”

For a November 2011 story on VEGF Trap Eye’s FDA approval, go here:

As Lucentis Avastin debate ends, will pocketbooks be affected?

Noticing that her sight had become fuzzy, Lois Otto of Stuart thought she might need new glasses. She went to the doctor’s for what she thought would be a routine visit, and found out she had wet macular degeneration in both eyes.

Otto is in her mid 70s, lives alone and still works; she needs her eyesight. Luckily, because of recent advancements in treatments for this disease, she still has her vision.

Presently, Otto is part of a clinical trial testing a new drug, VEGF Trap-Eye. (If it weren’t for the drug, I’d be blind,” she said. “I go every month to Retina Care Specialists and they check my eyes. Sometimes I need an injection in the eye that is part of the study, and sometimes I need it in the other eye.

“I can tell when I need an injection because my vision gets blurry. After I get an injection, I go home and sleep, and in a couple of days, I’m seeing pretty well again.

“I can drive, I see road signs, the lights, the traffic. I’m told I’m a pretty good driver.”

Age-Related Macular Degeneration (AMD), the disease

A genetic disease affecting about 13 million people in the United States more than 40 years old, most patients diagnosed as having macular degeneration have the mild or intermediate form of the disease (dry macular degeneration). Only 6-8 percent of patients 75 years or older has the advanced form, wet macular degeneration (Otto is one of them).

Wet AMD, the leading cause of blindness of the elderly, occurs when certain proteins (vascular endothelial growth factor or VEGF) cause abnormal blood vessel growth in the back of the eye. As the blood vessels grow, they can leak blood and fluid, which damage the macula—the part of the retina that lets one see color and fine detail.

Medication timeline

For the most part, laser treatment, which eliminates the abnormal blood vessels, is no longer used to treat AMD because it causes scar tissue.  Another treatment, using light to activate the medication, Visudyne, is seldom used either. Newer medicines – first Eyetech’s Macugen, then Genentech’s Lucentis and Avastin, are far more effective, explained ophthalmologist Philip Rosenfeld with Bascom Palmer Eye Institute with offices in Miami and Palm Beach Gardens.

“In 2001, I was the lead investigator in phase 1 trials for Lucentis. The paradigm shifted. Lucentis changed everything. Rather than simply slowing down vision loss (with Macugen), we got dramatic vision improvement in a day or two. Patients were seeing better.”

Lucentis binds VEGF, stopping the growth of abnormal blood vessels (When a cut heals, it’s thanks to VEGF. In cancer, when a tumor grows, it’s also because of VEGF).

Around that same time, a new imaging modality, Optical Coherence Tomography (OCT), became available. With a light, doctors could see into the back of the eye. “This was great technology. After a patient was treated with these new drugs, with OCT, we could see where the blood vessels were and if leakage was occurring, and we could see that we were getting rid of the fluid in a day.”

Then, in 2003, something “truly miraculous” happened, he said. “And I can take credit for it.” Rosenfeld, who also has a Ph.D. in genetics, began studying Roche-owned Genentech’s literature and found that Avastin, a drug that Genentech was developing for cancer that also blocks abnormal blood vessel growth, uses the same molecule as Lucentis to bind VEGF.

Lucentis VS. Avastin

“I went to Genentech and said, patients don’t like having a needle stuck in their eye, so let’s use Avastin systemically and they said, no. They did not want to use Avastin for eye disease.

“So I raised money for a trial in Miami and Palm Beach Gardens on Avastin, systemically, and it worked great. I was convinced it would work just as well as Lucentis, without a patient needing to get a needle stuck in their eye.”

But, his colleagues didn’t want to take the 1-percent risk of heart attack or stroke with a systemic treatment (that a cancer patient would be willing to take because it would prolong life).

“Then we had the Eureka moment. We realized if we injected the same amount of Avastin as Lucentis, we would have the same amount of inhibitory activity, and it worked.

“The big difference? Once we prepared Avastin, it cost about $10 compared to Lucentis, which was $2,000.

“This was in 2005. We presented this to meetings and it spread all over the world, and Avastin was ready before Lucentis was available. Avastin got FDA approval (for colon cancer) in February 2004. We first used Avastin as an injectible into the eye in 2005, and Lucentis was approved in 2006.”

Avastin spread globally because it was affordable and it worked, he said. In the meantime, since Genentech would not do a trial for Avastin to be used for macular degeneration, the National Institutes of Health sponsored a trial to compare Lucentis and Avastin head-to-head. Results should be published either in late April or early May. “We are anxiously awaiting the results.”

Doctors are being incentivized to use Lucentis, he said. Medicare reimburses physicians 6 percent of the sales price for the drug they use, and Genentech started a rebate program for high-volume Lucentis users.

“Although that amounts to being paid double and a good sum of money, up until now 60 percent of U.S. doctors use Avastin over Lucentis,” he said. “That’s really a credit to our profession that so many doctors are concerned with saving money.”

Other countries – The United Kingdom, France, Germany, Germany, Austria, Norway and Brazil – are also conducting trials comparing the two drugs. “In early March this year, in the UK, NICE (National Institute for health and Clinical Excellence) decided that Lucentis would not be covered for diabetes (diabetic macular edema), and that’s the first example of a national health organization saying, ‘No, it’s too expensive and we are not going to cover it,” Rosenfeld said.

VEGF Trap-Eye

Meanwhile, other drugs are also in trials. One of them is VEGF Trap-Eye by Regeneron.

Dr. Adrian Lavina, an investigator in Regeneron’s VIEW 1 study, offers his patients the choice to use VEGF Trap-Eye at his practice, Retina Care Specialists in Palm Beach Gardens.

“This drug is similar to Lucentis in that it represses VEGFs, but it has a higher affinity, he said.  “It binds more tightly to VEGF molecules and another molecule, Placenta Growth Factor.”

While Lucentis is given every four weeks for two years, longer periods of time can go between doses of VEGF Trap-Eye, and even though Lavina’s patient, Otto, said that the injection is painless, people don’t like getting an injection in their eye.

For the VIEW 1 study, which started about a year and a half ago, after a loading dose of three monthly injections the patient gets a VEGF Trap-Eye injection every two months, rather than once a month. Initial results were released in November 2010, and VEGF Trap Eye was found to be just as good as giving Lucentis every single month after one year of the trial.

The results of a sister study, VIEW2, were released at the same time and mirrored the results of the VIEW1 study. Now is the right time to present the drug for FDA approval, Lavina said.

Lavina uses Lucentis and Avastin for patients who are not candidates or interested in taking part in a trial. He also uses Eyetech’s Macugen, a company headquartered in Jupiter, in select cases – for high risk patients who’ve had a recent stroke, or patients already stable on Lucentis. “It’s a niche market. It also binds VEGFs, but only one isoform of it. There are five active isoforms, and medicines like Lucentis, and VEGF Trap-Eye bind to all five. “

Now, Lavina is in the second year of the two-year study, where injections are given every three months, more if needed.

“It’s very exciting to give the very best and to be able to offer medicines that are up and coming and might be better than what is currently available and we have a duty to move our field forward and be on the forefront of developing treatment,” Lavina said.

Rosenfeld, too, finds the advancements in treating AMD exciting, and he agrees that less frequent dosing is a real benefit, but he asks, what will VEGF Trap Eye cost?

That’s a big question – Lavina said, because pricing would not be released until after FDA approval.

(for follow up on costs for VEGF Trap Eye and FDA approval, go here.)

(for follow-up story on Lucentis and Avastin, go here.)

In the meantime, Rosenfeld is turning his attention to dry macular degeneration. An FDA-approved drug to block another disease (PNH or paroxysmal nocturnal hemoglobinuria), Alexion’s Soliris is under trial in his Palm Beach Gardens and Miami offices. “It’s already shown to be a safe drug, and we know the appropriate dosage and the dosing interval.”

written for palm2jupiter