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: