CLINICAL TRIAL SPOTLIGHT

New Life for Macugen?

The first FDA-approved anti-VEGF drug for AMD seeks its own niche, this time in RVO.

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

Macugen was approved by the FDA in 2004 for the treatment of AMD, the first drug approved that blocks VEGF. Macugen binds to VEGF₁₆₅, identified as a key protein in the development of angiogenesis.

While this was a tremendous breakthrough, subsequent studies using bevacizumab and the closely related ranibizumab ultimately pushed Macugen to the side, with several clinical trials scrapped. Believers in Macugen never gave up on it, however, keeping the drug in at least one clinical trial for AMD, as well as trying it out in conditions for which it had not received FDA approval.

Among these trials is one undertaken by Jack Wells, MD, at Palmetto Retina Center, LLC, in Columbia, SC. Dr. Wells talked with Retinal Physician about the trial he and coinvestigators John Wroblewski, MD, and Christine Gonzalez, MD, conducted to evaluate Macugen for the treatment of macular edema due to branch retinal vein occlusion (BRVO).

Asked why Macugen would be considered for treatment of BRVO, Dr. Wells explained that retinal vascular diseases are quite different from AMD and are likely to be much more responsive to VEGF inhibition. “Unlike AMD, where there is considerable disease at the level of the RPE and choriocapillaris, the primary abnormality in retinal vascular disease is abnormal permeability in intraretinal capillaries,” he said. “This is probably mediated primarily by VEGF and especially by VEGF₁₆₅.”

Dr. Wells explained that several animal models have demonstrated that inhibition of VEGF₁₆₅ reduces the permeability of retinal blood vessels — a key consideration when treating CME due to RVO. “Of course,” he said, “pan-VEGF inhibitors will also work.”

The potential benefit of selective VEGF₁₆₅ inhibition in DME and CME due to RVOs is that “ischemia could potentially be exacerbated by pan-VEGF inhibition,” he said, “and there are some concerns about neuroprotection by other VEGF isoforms that could be deleterious to the retinal nerve fiber layer if all VEGF is inhibited.”

Dr. Wells conceded that much of this is theoretical, but stated that it still makes sense to inhibit VEGF₁₆₅ if you know that is effective and is the primary cause of the vascular hyperpermeability. “Macugen should be more effective in these conditions than in AMD, where the biologic soup of growth factors is more complex and affects more retinal layers,” Dr. Wells said.

Before this BRVO trial, Dr. Wells participated in the Eyetech-sponsored phase 2 randomized trial of Macugen vs placebo for macular edema due to CRVO. This study, published in the April 2009 Archives of Ophthalmology, randomized 99 patients with nonischemic CRVO and CME to Macugen given every six weeks in doses of 0.3 mg or 1.0 mg vs sham injections for a total of five injections. Results were analyzed six weeks after the last injection.

“While the prespecified primary endpoint of 15 ETDRS letters improvement showed no significant difference between the three groups, there was a statistically significant 13-letter improvement in vision in the 1.0-mg group and a 10-letter improvement in the 0.3 mg group vs sham,” Dr. Wells said. This was proof that VEGF₁₆₅ inhibition could give improved vision outcomes in CRVO and inspired the BRVO trial.

“In our open-label BRVO trial, 20 patients received either 0.3 mg or 1.0 mg of Macugen in a 3:1 ratio every six weeks for three doses. Additional doses were given through week 48 at the investigator's discretion. Our primary endpoint was letters of vision gained with a secondary endpoint of reduction in OCT-measured macular edema,” Dr. Wells said. “Our cases showed at one year on average a 14-letter improvement in vision from baseline and a 201-μm reduction in OCT-measured central macular subfield thickness. The detailed results of this trial have been accepted for publication in the American Journal of Ophthalmology.”

The current trial is still enrolling. More details can be found in this issue. RP