The NIH-funded Diabetic Retinopathy Clinical Research Network is starting patient enrollment in August for a clinical study on the comparative effectiveness of Genentech Inc.’s products Lucentis (ranibizumab) and Avastin (bevacizumab) and Regeneron’s Eylea (aflibercept) in diabetic macular edema (DME), a sight-threatening complication of diabetes.

While the study will focus on the clinical effectiveness and safety of these treatments and is not designed as cost-effectiveness trial, the disparity in cost for these treatments is cited as a key driver in conducting the study, and it should provide clinicians with more definitive answers than currently available as to how well the relatively inexpensive Avastin performs compared to the other two more expensive products used for treating DME.

The study aims to enroll 660 patients with diabetes and will evaluate the safety and effectiveness of the three drugs. The study protocol says it will compare .5 mg doses of Lucentis, 1.25 mg doses of Avastin and 1.50 mg doses of Eylea given at baseline and up to every 4 weeks. The primary outcome, changes in visual acuity after one year, is scheduled to be evaluated in January 2015.

Secondary outcomes, including changes in visual acuity over two years and the number of injections needed, are scheduled to be measured in January 2016. Secondary outcomes also will include two safety measures: changes in blood pressure and changes in albumin/creatinine ratio. In addition to NIH, the research is being supported by Genentech and Regeneron.

The study could be significant in clarifying whether the injectable drugs, which are all anti-vascular endothelial growth factor (VEGF) agents, are equivalent in treating DME. There is a large and growing patient population with the condition, currently estimated at 560,000 in the U.S.

The Diabetic Retinopathy Clinical Research Network highlights the cost disparity between treatments in a summary of the study’s purpose, which is posted on the website clinicaltrials.gov.

“If results from a comparative trial demonstrate improved efficacy or suggest similar efficacy of bevacizumab or aflibercept over ranibizumab, this information might give clinicians scientific rationale to substitute either one of these drugs for ranibizumab in the treatment of DME, and might thereby have substantial implications for public policy in terms of future estimates of health care dollars and possibly number of treatments necessary for anti-VEGF treatment of diabetic macular disease,” the network says.

The network further suggests “there may be barriers in place to widespread adoption of ranibizumab use given its high cost per dose and the need for multiple treatments over time,” Therefore, “prioritizing resources from a public health policy perspective could be easier if more precise estimates regarding the risks and benefits of other anti-VEGF therapies were available, especially when the difference in costs could be billions of dollars over just a few years.”

In a meeting on anti-VEGF treatments for DME last March, the Medicare Evidence Development and Coverage Advisory Committee concluded that efficacy and safety differences between Lucentis, Avastin and Eylea cannot be determined based on existing data Also see "Avastin, Lucentis Assumed Comparable In DME Absent More Data, MEDCAC Members Say" - Pink Sheet, 26 March, 2012..

The Diabetic Retinopathy Clinical Research Network points out that because of the lack of data, “there is a clear rationale at this time to explore potential anti-VEGF alternatives to ranibizumab that might prove to be as or more efficacious, might deliver equally lasting or longer-lasting treatment effects, and cost substantially less.”

Products’ Cost Differences

Lucentis is the only one of the three drugs specifically approved for DME; Avastin and Eylea are used in DME off label. FDA cleared Lucentis for DME on Aug. 10 Also see "Genentech Says Lucentis DME Product Will Ship Shortly" - Pink Sheet, 10 August, 2012.. But the drug is significantly more expensive than Avastin, which is already widely used off label in DME. The 0.3 mg monthly dose of Lucentis approved for DME costs $1,170 each, a Genentech spokesman said. By comparison, Avastin is compounded in pharmacies in microdoses and available at a cost of about $50 per injection.

However, Avastin was not developed for use as an injectable treatment of macular degeneration but for treatment of certain cancers, which may lead to safety problems when it is used off label, Genentech maintains. The firm has pointed to suggestions from the large NIH-sponsored comparison of the two drugs in wet age-related macular degeneration (wet AMD), known as the CATT study, that Avastin causes more adverse events than Lucentis. The CATT study concluded the two treatments are equally effective in treating wet AMD. The research also revealed a small increase in the number of adverse events that could be tied to Avastin Also see "Avastin Safety Questions In Wet AMD Linger With Two-Year CATT Results" - Pink Sheet, 7 May, 2012..

The cost comparison between Lucentis and Eylea is less clear. The Regeneron drug is approved for wet AMD at a cost of $1,850 per injection. Lucentis is available for AMD in a .5 mg dose at a cost of $1,950 per dose.

When Regeneron launched Eylea, the company said the overall cost of treating AMD with its drug would be notably less than Lucentis because Eylea is dosed on a less frequent bimonthly schedule versus Lucentis’ monthly dosing schedule. In addition to the difference in the actual cost of the drugs, Regeneron has said its drug ends up being cheaper because each dose of Lucentis also involves an office visit and other injection costs. Genentech has pushed back against that premise, arguing that in practice Lucentis is dosed less frequently than every month.

By pursuing approval of the smaller dose for Lucentis in DME, Genentech appears to have further clouded Regeneron’s cost advantage argument. Lucentis is priced at $780 per dose less in DME than in AMD because the approved dose is smaller – .3 mg for DME versus .5 mg for AMD. The drug is priced on a per milligram basis, the Genentech spokesman said. It remains to be seen whether Regeneron will lower the cost of Eylea if the drug is also approved for DME. The company has said it plans to seek approval for the indication.

Comparison Study Of Lucentis, Avastin And Eylea In DME Starts With NIH Funding

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