Regeneron Pharmaceuticals Inc.’s Eylea (aflibercept) will benefit from results of an NIH-funded study showing the drug was more effective than Roche/Genentech Inc.’s Lucentis (ranibizumab) or Avastin (bevacizumab) in diabetic macular edema patients with more advanced vision loss.

Payers are likely to welcome results showing that Avastin, which is far less expensive than the other two drugs, was as effective in diabetic macular edema (DME) patients with less severe vision impairment.

Payers, including CMS, have expected results of the study may help clarify whether the drugs are equivalent in treating DME Also see "Comparison Study Of Lucentis, Avastin And Eylea In DME Starts With NIH Funding" - Pink Sheet, 14 August, 2012.. There is a large and growing patient population with the condition, currently estimated at 750,000 in the U.S.

The randomized clinical study, known as Protocol T, marks the first head-to-head comparison of the injectable drugs, which are all anti-vascular endothelial growth factor (VEGF) agents, in DME. Conducted by the NIH Diabetic Retinopathy Clinical Trial Network, the study enrolled 660 adults. The primary outcome measure was change in visual acuity after treatment for one year. Results were published online in the New England Journal of Medicine Feb. 19.

During the year-long study, subjects on Avastin and Lucentis received an average of 10 injections at doses of 1.25 mg and .3 mg, respectively, while those on Eylea received nine injections at a dose of 2.0 mg.

The study showed that Eylea-treated patients with moderate or worse vision loss (defined as 20/50 or worse), improved on a vision chart by almost four lines, on average. By comparison, Lucentis improved vision by an average of almost three lines and Avastin, by an average of 2.5 lines. The difference in improvement associated with Eylea was considered clinically meaningful.

In a statement on the results, lead author John Wells, Palmetto Retina Center, South Carolina, said “Eylea, Avastin and Lucentis yield substantial gains in visual acuity for most people with diabetic macular edema; however, on average, Eylea appears to provide additional benefit for patients who start treatment with moderate or worse vision loss.”

Regeneron pointed out in a release that “the improvements with Eylea relative to alternative anti-VEGF therapies were particularly apparent in the group with moderate or worse vision loss at the start of the trial, where there was a greater opportunity to demonstrate gains in vision.”

Equal Efficacy For Avastin

The study also found the three anti-VEGF inhibitors were equally effective in patients with less severe vision loss, defined as those with visual acuity of approximately 20/32 to 20/40. Vision improved on average almost two lines on an eye chart in each of the three treatment groups. That result is likely to bolster use of the much-cheaper Avastin in those patients.

It is unclear how large the patient group with less visual impairment is. Genentech says it represents the majority (75%) of those with DME. An editorial that accompanies the study in NEJM also cites the 75% figure, noting it is from a 1995 report. But Regeneron says an analysis by Vestrum Health indicates 50% of newly diagnosed patients with DME present with visual acuity of worse than 20/40. And the study population is divided pretty evenly (49% to 51%) between the milder and worse vision loss groups.

Genentech did not address Avastin in a statement on the results but said “the difference observed between Lucentis and aflibercept in a small group of patients with more severe vision loss has not been seen in previous studies and needs further evaluation to better understand the potential impact of factors such as the duration and severity of their diabetes and their overall health.”

No significant safety issues emerged for any of the treatments, which is also good news for proponents of Avastin. A prior NIH trial comparing the two Roche drugs in age-related macular degeneration suggested that Avastin might have greater systemic toxicity than Lucentis Also see "Lucentis And Avastin Stack Up In CATT, Forcing Genentech/Novartis To Play Defense" - Pink Sheet, 28 April, 2011.. Genentech seized on the findings to defend the value of its more expensive drug. However, the results were not confirmed by a subsequent meta-analysis, the authors of Protocol T pointed out.

The advantages found in Eylea treatment for some patients should add even more momentum to the drug’s sales, which have accelerated over the past year, in part reflecting expanded use from approval of the DME indication in July 2014. U.S. sales for the drug rose 23% to $1.7 billion in 2014.

On the other hand, U.S. sales for Lucentis have slowed and this study may not do much to accelerate them. Roche has said it expects sales for the drug will flatten out in 2015 as competition in the ocular treatment segment heats up. U.S. revenues for Lucentis totaled CHF 1.7 billion ($1.78 billion) in 2014, up 2% from the prior year. Lucentis was approved for DME in August 2012.

U.S. sales for Avastin reached CHF 2.68 billion ($2.8 billion) in 2014. However, Roche does not break out off-label sales for the drug, which is approved for a number of cancers but not for any ocular indications. Nevertheless, it is widely used in DME.

The study does not address the cost-effectiveness of the three agents. However, the authors note the wide disparity in the cost of Eylea and Lucentis versus Avastin. According to Medicare data, they said, the per-injection costs of each drug at the doses used in the study were about $1,950 for Eylea, $1,200 for Lucentis and $50 for Avastin.

First Line Use Of Avastin

In the accompanying editorial, Daniel Martin, Cleveland Clinic, and Maureen Maguire, University of Pennsylvania, suggest the results and cost differential support first-line use of Avastin in patients who have less severe vision loss.

“Because there were no significant differences in safety or efficacy among drugs in patients with this presenting visual acuity, cost becomes a major consideration in choosing therapy,” they said. “Given the large difference in cost to patients per dose among bevacizumab ($50), ranibizumab ($1,200), and aflibercept ($1,950), bevacizumab should be considered as first-line therapy in patients with a visual acuity of 20/40 or better.”

For patients with a visual acuity of 20/50 or worse, they continued, “aflibercept should be considered as first-line therapy in these patients, with bevacizumab as the alternative given the lack of a significant difference in visual outcome between bevacizumab and ranibizumab and the large difference in cost between the two drugs.”

“There are powerful forces in addition to efficacy and safety that affect drug selection by physicians,” the authors acknowledge. They said these include the current requirement for a patient-specific prescription, which limits or delays access to compounded Avastin in some states; rebates paid directly to physicians by drug companies; and CMS’ policy of reimbursing Medicare Part B drugs based on the average sales price plus 6%, which may offer a financial incentive to prescribe the more expensive drug.

Nevertheless, they argue that “all financial incentives and logistic barriers to providing the least expensive drug, among drugs equivalent in safety and efficacy, should be eliminated so that patients may benefit fully from the results of this Diabetic Retinopathy Clinical Research Network trial as well as those from other comparative trials.”

Eylea, Avastin Both Get A Boost From NIH Comparative Study In DME

More from Archive

More from Pink Sheet