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The CATT team discussing results
CATT team discussing results of follow-up study. (Standing from left: Ebenezer Daniel, MBBS, MS, MPH, PHD; Maxwell Pistilli, MEd,MS; Gui-Shuang Ying, PhD; Wei Pan, MS. Seated from left: Maureen Maguire, PhD; Juan Grunwald, MD)
By Ava Kikut

Scheie Vision Annual Report 2017

On July 18, 2005, two novel treatments for neovascular age-related macular degeneration (AMD) were presented back-to-back at the American Society of Retina Specialists Annual Meeting in Montreal. The first drug, Lucentis (ranibizumab), was developed by the biotechnology company Genentech specifically for neovascular AMD. Clinical trials for Lucentis were yielding amazing results and the drug was on its way to becoming FDA approved. The second treatment presented was Avastin (bevacizumab), another Genentech product. Avastin was on the market for the treatment of colon cancer, but intravitreal injections of the drug were also helping patients with neovascular AMD. 
AMD is the leading cause of vision loss in Americans aged 60 and older. Neovascular (wet) AMD accounts for 90% of cases of severe vision loss from the disease. This form of AMD results from the growth of abnormal leaky blood vessels under the retina, due in-part to excess amounts of a protein called vascular endothelial grown factor (VEGF). Thirteen years ago, a patient diagnosed with neovascular AMD was certain to lose vision in one or both eyes within a few years.  
The introduction of Lucentis and Avastin, both VEGF inhibitors, was pathbreaking. “These anti-VEGF drugs revolutionized care and treatment for patients,” said Maureen Maguire, PhD, Director of the Scheie Eye Institute’s Center for Preventive Ophthalmology and Biostatistics. Yet many ophthalmologists were initially hesitant to use Avastin for AMD.  

Avastin vs. Lucentis 

Lucentis and Avastin are similar in use and composition. Both are administered through intravitreal injections and both are derived from the same base molecule. Originally, Genentech predicted the Avastin molecule would be too big to penetrate the retina of the eye, and the company trimmed down the molecule to make Lucentis. However, in 2005 ophthalmologists were beginning to find that Avastin could penetrate the eye successfully. 

What was remarkable about the prospect that Avastin could be equally efficacious to Lucentis was the price difference. Because Avastin was put on the market for cancer treatment, it is sold in higher quantities. An injection in the eye only requires 0.05 ml of the 16 ml package. Thus, Avastin costs $50 a dose for AMD, while Lucentis costs $2000 a dose.  
Avastin was also on the market before Lucentis. “Once a drug is approved and on the market a physician can take it and treat any condition,” explained Dr. Maguire. “It’s off-label but it’s legal.” Due to Avastin’s affordability and accessibility, it quickly became a leading first-line therapy for neovascular AMD.  


The increased off-label use of Avastin for AMD called for a clinical trial to test the drug’s long-term effects. “All the ophthalmologists wanted it to happen because, even though they were using Avastin off-label, they were worried that it might not be as efficacious and there might be some safety problems,” said Dr. Maguire.  

In January 2007, the National Eye Institute (NEI) provided funding for the Comparison of Age-Related Macular Degeneration Treatments Trial (CATT), a $26 million study designed to test the efficacy and safety of Avastin compared to Lucentis. The CATT team included Drs. Maureen Maguire, Gui-shuang Ying, Juan Grunwald, Ebenezer Daniel, and Stuart Fine of the Scheie Eye Institute; Dr. Daniel Martin of the Cole Eye Institute; and Dr. Glenn J. Jaffe of the Duke Department of Ophthalmology. Between 2008 and 2010, CATT enrolled 1185 patients with neovascular AMD, each assigned to one of four groups defined by drug (Avastin or Lucentis) and dosage (monthly or as needed).  
CATT found that Avastin and Lucentis were equally efficacious and safe. After two years of treatment, both drugs could increase visual acuity from about 20/60 to around 20/40 (the required acuity for a driver’s license in most states) or better. “[Patients] actually improved. This was a huge change. All of our treatments before kept people from getting worse, and never improved vision. So everybody is happy about that,” said Dr. Maguire. These findings were replicated by five additional clinical trials in other countries. 

The Impact of CATT  

The results of the comparison studies have had significant implications for health care services and their patients. Dr. Maguire explained, “Worldwide the CATT trial and the five other supporting trials have had a major impact in lowering the price and getting more patients treated.” In some countries, health services that previously covered Lucentis now only cover Avastin. In others, such as England, health care services have negotiated with Genentech to reduce the price of Lucentis. In poorer countries, where Lucentis is unaffordable, the acceptance of Avastin has made treatment for neovascular AMD a possibility that didn’t exist before.  

In the United States, CATT results have had less impact on prices and formal regulation than in other countries, but they have helped inform treatment decisions for physicians and patients. Because Medicare is not permitted to negotiate drug costs, the prices remain $2000 a dose for Lucentis and $50 for Avastin. While one might expect Avastin to become FDA approved for AMD, FDA approval is a process that is usually initiated by the company making the drug. Genentech does not have incentive to initiate this process, since it already has Lucentis on the market. However, FDA approval would not particularly benefit ophthalmologists or their patients. The bottom line is CATT results have increased confidence in Avastin’s effectiveness and safety; ophthalmologists can comfortably prescribe Avastin and insurance services have agreed to cover it. Avastin and Lucentis, as well as Regeneron Pharmaceutical’s anti-VEGF drug Eylea (aflibercept), which was FDA approved in 2011 and costs $1850/dose, are currently the leading therapeutic options for neovascular AMD. 
The CATT Follow-Up Study 

In 2016, CATT published results for a five-year follow up study. “We were now interested, not so much in comparing the drugs, but how do people do after long-term anti-VEGF treatment,” said Dr. Maguire. The CATT results demonstrated that after five years of anti-VEGF therapy, 50% of patients increased to and maintained 20/40 vision and 20% decreased to 20/200 or worse.  

The results of the follow-up study show a dramatic difference between anti-VEGF therapy and any previous treatment for AMD. Before anti-VEGF drugs were available, the leading treatment for AMD was photodynamic therapy. After a year of photodynamic therapy, only 15% of patients maintained 20/40 vision and 40% of patients decreased to 20/200 or worse. In untreated patients, 90% experienced vision loss within a year and 75% declined to 20/200 or worse. 
While the effectiveness of anti-VEGF treatment may decrease over time, anti-VEGF therapy helps significantly with the odds of maintaining vision. “If you continue seeing an ophthalmologist and keep getting anti-VEGF injections, you have about half a chance to keep really good vision,” stated Dr. Maguire. “If you keep being observed for treatment you can maintain vision that is much better than you would if you were not being treated.”  
There is no doubt the prospects for patients with neovascular AMD have become far more promising since 2005. The CATT trial and follow-up study results have shed light on the potential for both Lucentis and Avastin to save the vision of AMD patients, and the importance of checking in with patients after clinical trials conclude. In 2016, National Eye Institute Director Dr. Paul Sieving called CATT “the most comprehensive study of anti-VEGF therapy for AMD to date.

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