VEGF Inhibitors Work Equally Well in Diabetic Macular Edema

Neil Osterweil

September 18, 2014

LONDON — Different vascular endothelial growth factor (VEGF) inhibitors offer comparable treatment gains in patients with diabetes treated for macular edema, according to the results of a comparison of phase 3 randomized trials.

The cross-trial comparison, a method that study investigators acknowledged here at the 14th EURETINA Congress is fraught with pitfalls, suggests that ranibizumab (Lucentis, Genentech), aflibercept (Eyelea, Bayer), and bevacizumab (Avastin, Genentech) produced comparable improvements in best-corrected visual acuity and were equally effective in reducing the severity of diabetic macular edema.

"We have so much new data and so many new therapeutic options, we're trying to get a handle on all of this," said Baruch Kupperman, MD, professor of ophthalmology and biomedical engineering at the University of California, Irvine.

Dr. Kupperman and his team examined results from four trials of ranibizumab in diabetic macular edema (Protocol I, RESTORE, RISE, and RIDE). They looked at two trials of aflibercept (VIVID DME and VISTA DME), and one trial in the United Kingdom using bevacizumab (BOLT). Bevacizumab is not approved in the United States for intravitreal injection.

The data from the analysis need to be interpreted with caution, Dr. Kupperman emphasized, because of differences in patient populations, study size, comparison or control treatments, retreatment criteria, analysis methods, and patient retention and dropout rates.

He reported that although the magnitude of the effect varied, each trial and each drug showed a steep improvement in visual acuity during the first 12 months of therapy.

Treatment Gains Occurred Early

After the first year, vision either stabilized or declined slightly with the exception of the BOLT study, in which patients continued to gain vision during the second year at a pace similar to that seen in the first year. In RISE, the 0.3-mg dose group continued to see slower but steady gains in acuity in years 2 and 3.

The percentage of patients who gained 15 letters of more from baseline on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart was lowest among patients in the ranibizumab Protocol I study, although these patients had generally better acuity at baseline, Dr. Kupperman said.

In all other studies except BOLT, about a quarter of patients had gained 15 or more letters by the first year. By the second year, roughly one third had achieved this level of improvement, including the patients on bevacizumab.

The investigators also found that the proportion of patients with at least a 2-step improvement in the Diabetic Retinopathy Severity Score at 1 year was comparable between RIDE/RISE (ranibizumab) and VIVID/VISTA (aflibercept), ranging from 28% to 34% of patients.

In the Protocol I study, 21% of patients at both the 0.3- and 0.5-mg doses of ranibizumab had a substantial improvement in retinopathy severity scores, and in BOLT, only 7.5% had a 2-step improvement or better.

The mean (or in the case of Protocol I, median) number of intravitreal injections ranged from a low of 7, in RESTORE, to a high of 12 in VIVID and VISTA. In Protocol I and RESTORE, patients received 4 and 3 loading doses followed by additional injections as needed. In RISE and RIDE, injections were monthly, and in VIVID and VISTA, patients received intravitreal aflibercept injections either every 4 weeks or every 8 weeks after 5 initial monthly doses.

Borja Corcostegui, MD, founder and medical director of the Institute of Ocular Microsurgery in Barcelona, Spain, who was not involved in the study, commented that in clinical practice, as opposed to clinical trials, the number of anti-VEGF injections required to control diabetic macular edema can vary significantly among patients. He asked Dr. Kupperman when clinicians should decide whether an individual requires additional injections or could benefit from laser photocoagulation.

"That's a very important question, and we're still struggling with that," Dr. Kupperman said.

Evidence from the RISE and RIDE datasets suggests that patients who were treated immediately had the best response, he pointed out. Patients who were crossed over from macular photocoagulation to drug in the third year of study did not respond as well, "suggesting that there's a change in the dynamic of diabetic retinopathy over time."

He recommended assessing each patient's response to therapy during the first 3 to 6 months of treatment, and adjusting accordingly.

This study was funded by Genentech. Dr. Kupperman disclosed receiving research support and serving as a consultant to the company and several other drug and device manufacturers. Dr. Corcostegui reported no relevant financial relationships.

14th EURETINA Congress. September 11, 2014.

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