Laird Harrison

July 17, 2015

VIENNA — Differences in dosing could explain why aflibercept produced better results in patients with diabetic macular edema than ranibizumab or bevacizumab in a recent trial, experts say.

"Bevacizumab or ranibizumab at higher doses may be equivalent, although that is not technically easy with either drug," David Brown, MD, from the Baylor College of Medicine in Houston, Texas, told Medscape Medical News.

The point arose after a presentation here at the American Society of Retina Specialists (ASRS) 2015 Annual Meeting of results from the Protocol T comparison study conducted by the Diabetic Retinopathy Clinical Research Network. The results were also published in the New England Journal of Medicine (2015;372:1193-1203).

In the Protocol T study, researchers randomly assigned 660 people with diabetic macular edema to intravitreal injections: 224 received aflibercept 2.0 mg, 218 received bevacizumab 1.25 mg, and 218 received ranibizumab 0.3 mg.

The mean age of the study participants was 61 years.

All patients had at least one eye with a best corrected visual acuity letter score of 78 to 24 on a 100-point scale. Higher scores indicated better visual acuity. The equivalent range on the Snellen chart would be 20/32 to 20/320.

All patients had center-involved diabetic macular edema evident on clinical examination and optical coherence tomography.

A year after treatment, patients in the aflibercept group had gained more lines of vision than those in the bevacizumab and ranibizumab groups. However, that difference was entirely attributed to the patients in each group who had the most severe vision loss.

Table. Change in Letters of Visual Acuity at 1 Year

Baseline Letter Score Snellen Equivalent Aflibercept Group Bevacizumab Group Ranibizumab Group
≤69 ≤20/50 18.9 11.8 14.2
78 - 69 20/32 - 20/40 8.0 7.5 8.3

For patients with 20/50 visual acuity or worse, the difference between aflibercept and bevacizumab was significant (P = .001), as was the difference between aflibercept and ranibizumab (P = .003). However, the difference between bevacizumab and ranibizumab was not significant (P = .21).

For patients with better vision, none of the differences between treatment groups was significant.

After the presentation here, session moderator Tarek Hassan, MD, from Oakland University in Royal Oak, Michigan, asked a panel of experts why they thought aflibercept seemed more potent in the patients with more severe disease.

In thickening retinas and worsening eyes, the drug that has much more molar VEGF blockage wins the race. Dr David Brown

"In thickening retinas and worsening eyes, the drug that has much more molar VEGF blockage wins the race," Dr Brown explained. "If you upped your bevacizumab dose to 2 mg or 5 mg, or what have you, to make it equivalent, they may be equivalent. Certainly, in this disease that is super-VEGF mediated, there seems to be a difference."

Alan Cruess, MD, from Dalhousie University in Halifax, Nova Scotia, Canada, made a similar point in conversation with Medscape Medical News.

"We don't know, but the dosing of ranibizumab might have affected the results," Dr Cruess said. "It might have reduced the incremental benefit in the worst-treated eyes."

The US Food and Drug Administration has approved ranibizumab at a dose of 0.3 mg, but its counterparts in other countries have approved a dose of 0.5 mg, he said.

Any change in ranibizumab dosing would have to be initiated by Genentech, Dr Hassan told Medscape Medical News. "Unfortunately, that's the approved dose."

In addition, in the Protocol T study, bevacizumab did not reduce central subfield thickness as much as the other two drugs, regardless of a patient's visual acuity at baseline.

"If it were my eye, I would want both the swelling to be better and to be able to see better," Dr Hassan explained. "Long-term chronic edema patients do worse."

Still, Protocol T can provide useful guidance to clinicians who follow the regimen used in that trial, said researcher Andrew Antoszyk, MD, from Charlotte Eye, Ear, Nose and Throat Associates in North Carolina.

"I think the applicability to clinical practice is excellent," he told Medscape Medical News.

In the study, patients received injections every 4 weeks unless visual acuity was 20/20 or better, central subfield thickness was below the eligibility threshold, and there was no improvement or worsening in response to the previous two injections.

Starting at 24 weeks, regardless of visual acuity or central subfield thickness, an injection was withheld if there was no improvement or worsening after two consecutive injections, but treatment was reinitiated if visual acuity or central subfield thickness worsened.

"It's a very rigid protocol, but it provides great guidance for physicians," Dr Antoszyk said.

The Diabetic Retinopathy Clinical Research Network is working on a new trial to find out which treatment works best for patients whose vision is better than 20/32, he reported.

Regeneron Pharmaceutical provided the aflibercept and Genentech provided the ranibizumab for this study. Dr Brown has disclosed no relevant financial relationships. Dr Antoszyk reports that he has consulted for Alimera Sciences and Iconic Therapeutics. Dr Cruess reports that he has consulted for Bayer, Bausch & Lomb, and Novartis. Dr Hassan reports that he has consulted for Regeneron Pharmaceutical and Genentech.

American Society of Retina Specialists (ASRS) 2015 Annual Meeting. Presented July 12, 2015.


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