Varying ranibizumab therapy may improve DME results

Take-home:

A switch from bevacizumab to ranibizumab and, in some patients, a subsequent higher dose of ranibizumab, resulted in further improvement for patients with diabetic macular edema in a recent study.

Dr. Dhoot

By Nancy Groves; Reviewed by Dilsher S. Dhoot, MD

Santa Barbara, CA-Patients with persistent diabetic macula edema (DME) who have partial or no response to treatment with bevacizumab (Avastin, Genentech) may achieve improved vision after a medication change to ranibizumab (Lucentis, Genentech), show results of a small investigator-sponsored study.

Further, if patients continue to have an incomplete response to treatment with 0.5-mg ranibizumab, injections of 2 mg may achieve results.

“On average, we found that patients in this study (REEF: Open Label, Phase 1/II, Residual Edema Evaluation with 0.5 mg and 2.0 mg Ranibiuzumab Formulations)-regardless of whether they had few or many previous bevacizumab injections-had an improvement in vision of approximately 8.7 letters,” said Dilsher S. Dhoot, MD, California Retina Consultants and Research Foundation, Santa Barbara, CA.

About the REEF Study

The 12-month, prospective, multicenter, open-label pilot clinical trial of intravitreal ranibizumab 0.5 and 2 mg in patients with DME enrolled 43 patients who had at least 2 consecutive bevacizumab injections (mean 4.7 injections) administered less than 7 weeks apart within 1 year of the baseline study visit and showed partial or no response.

During the study, all patients received 3 mandatory 0.5 mg injections of ranibizumab at baseline, month 1, and month 2. Patients who had a complete response received additional 0.5 mg injections as needed through month 12. Those with partial or no response received 3 mandatory doses of 2 mg of ranibizumab at months 3, 4, and 5 and as-needed dosing (PRN) through month 12.

The primary outcome measure was mean change in visual acuity at 6 and 12 months. The secondary outcome measures were mean change in central retinal subfield thickness (CST) and rates of partial and complete response to either ranibizumab dose.

The mean age of the subjects was 64 years (42-85); there were 23 males and 20 females. The mean ETDRS vision was 59 letters (33 to 73), and the mean CST was 501 µm (301 to 828 µm). Mean retinal volume was 9.89 mm³ (6.72 to 14.41 mm). The mean number of previous lasers of the macula was 2.5 (0 to 7), and the mean number of intravitreal triamcinolone injections was 0.26 (0 to 4). Twenty patients had proliferative diabetic retinopathy and 23 had nonproliferative diabetic retinopathy.

Among the non-responders, the mean CST before the two consecutive intravitreal bevacizumab injections was 459 µm; afterward the mean was 461 µm.

Visual acuity outcomes

Results of the REEF study showed a mean gain of +8.8 letters in visual acuity from baseline through 6 months. The mean change in CST was a decrease of –165 µm. About 60% of patients achieved a reduction of greater than 25% in CST to less than 300 µm on optical coherence tomography.

“When we stratified visual acuity based on pre-trial bevacizumab, we found that there was no difference between patients who had 4 or less pre-trial injections of pre-trial bevacizumab (gain of +9.1 letters) and those who had 5 or more (gain of +8.3 letters) (p = 0.538),”Dr. Dhoot said.

“There was also no difference in mean retinal thickness stratified by pre-trial bevacizumab; patients with 4 or less injections had mean decrease of –189 µm, and those with 5 or more injections had mean decrease of –122 µm (p = 0.404),” he said.

Among the 43 subjects in the study, 30 were non-responders and 13 were partial responders to bevacizumab. After receiving the 3 mandatory 0.5-mg ranibizumab injections, 22 of 29 were partial responders (75.9%), 6 were non-responders (20.7%), and 1 was a complete responder (3.4%).

The partial and non-responders then received 3 monthly injections of 2-mg ranibizumab; 15 of 28 (53.6%) had an additional CST reduction of greater than 10%, and 13 (46.4%) had less than 10% reduction. At month 6, 10 of 28 patients (35.7%) required no further treatment.

Looking more closely at the patients who had not responded to the three ranibizumab 0.5-mg doses and then received 3 injections of the higher dose, 3 of the 6 achieved a reduction of more than 10% in CST through month 6.

The safety data from the study showed no Anti-Platelet Trialists Collaboration events during follow-up through 6 months. One patient died of pneumonia 9 weeks after the last ranibizumab 0.5-mg injection. No cases of endophthalmitis were reported.

The study is now complete, and the investigators are analyzing 12-month data. Results have not yet been reported.

The small number of patients and lack of a control group limited the study, Dr. Dhoot said. However, the results support further investigation comparing the safety and efficacy of ranibizumab versus bevacizumab in the treatment of DME.

Dilsher S. Dhoot, MD

P: 661/325-4393

E: ddhoot@yahoo.com

Dr. Dhoot has served as a consultant for Regeneron and ThromboGenics. The investigator-sponsored study was partially funded through a grant from Genentech.

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