Retina co-morbidity for the anterior segment surgeon
Pharmaceutical focus
Therapy on the anti-VEGF frontier

Update on retinal sparing drugs for AMD

Anti-VEGF therapy to fight neovascular eye disease recently got a boost when on November 18, 2011, EYLEA (Regeneron Pharmaceuticals, Tarrytown, N.Y.), also known as VEGF Trap-Eye, received FDA approval for wet AMD cases. This is one new anti-VEGF gaining ground in an area that has been dominated by Avastin (bevacizumab, Genentech, South San Francisco) and Lucentis (ranibizumab, Genentech), considered breakthrough drugs in their own right for AMD patients. Investigators are also honing in on other drugs such as integrin peptide therapy. EyeWorld asked practitioners to offer their insights on these valuable drugs.
The approval of EYLEA is considered a coupe for patients since it can be administered much less frequently than other anti-VEGFs. It has an additional mechanism of action, according to Peter K. Kaiser, M.D., professor of ophthalmology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland. "EYLEA is similar to other anti-VEGF agents on the market such as Lucentis and Avastin in that it blocks isoforms of VEGF, but in addition it blocks placenta growth factor, which is in and of itself an angiogenic pathway," Dr. Kaiser said. The other difference is the way that it binds to VEGF. "It binds much tighter than Lucentis and Avastin, which theoretically would allow it to last longer in terms of its biologic activity," he said. "That was borne out in the clinical study where it went head-to-head against Lucentis given monthly." In the study, EYLEA was given after a load dose just every other month and boasted equal results in vision and safety. It had essentially identical results to Lucentis given monthly. Dr. Kaiser sees this as enabling practitioners to dose patients every other month as opposed to every month or even less. "In all likelihood since most of us don't inject Lucentis every month—we use some sort of as-needed protocol—the fact that EYLEA lasts longer will hopefully make that as-needed difference even greater," he said. No red flags were raised in the clinical study in terms of safety. He sees approval of EYLEA as a potential boon for patients and practitioners alike. He pointed out that patients who have been taking Avastin monthly could be switched to EYLEA every other month. For practitioners, he thinks that it will unclog the clinics a bit, and for patients and their families it will ultimately mean fewer injections and fewer trips to the office.
Dr. Kaiser looks to a future in which monthly anti-VEGF injections are obsolete. "Anything that reduces that treatment burden is huge," he said.

CATT and its implications

Lucentis and Avastin remain key anti-VEGF players here. The recent Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) closely examined how these two valuable agents stack up against one another. The two drugs tended to be administered differently from the start, according to Daniel F. Martin, M.D., chairman, Cole Eye Institute, Cleveland Clinic. Lucentis had been studied as a monthly injection, while the predominant treatment pattern for Avastin was on an as-needed basis. In CATT both drugs fared similarly. "We showed that Lucentis and Avastin were nearly identical for all visual acuity metrics that we looked at, at 1 year," Dr. Martin said. "We also showed that PRN dosing could produce an excellent visual result, but on average it was about two letters less than was achieved with monthly dosing." Another finding was that both drugs produced an immediate and substantial decrease in fluid on OCT, but there was a slight difference between the two. "At 1 year there were more eyes that were completely dry with Lucentis than eyes treated with Avastin," Dr. Martin said. "The absolute difference in the number of those eyes was small and the average amount of fluid that remained was extremely small—its clinical relevance was not clear."
Dr. Martin stressed that it remains unclear whether the two-letter difference between PRN and monthly dosing will be wider at follow-up or whether the fact that there was a difference in the amount of fluid between Lucentis and Avastin treated eyes will ultimately matter. In terms of safety, CATT found no difference in terms of death, myocardial infarction, or stroke. However, there were more patients who received Avastin who experienced a serious adverse event (SAE). The difference in SAEs was 24% for Avastin and 19% for Lucentis. "This may be due to chance, it may be due to an imbalance at baseline, or it may represent a real risk that we still don't understand," Dr. Martin said. "We're looking forward to a second year of follow-up and to the results of other worldwide trials comparing Lucentis and Avastin."

Integrin peptide therapy

Another VEGF-related type of therapy being looked at is integrin peptide therapy with Alg-1001 (Allegro Ophthalmics, San Juan Capistrano, Calif.) for wet AMD as well as diabetic retinopathy. The drug has a slightly different mechanism, according to Baruch D. Kuppermann, M.D., Ph.D., chief of the retina service, and professor of ophthalmology and biomedical engineering, Gavin Herbert Eye Institute, University of California, Irvine. "It does intervene with VEGF, but it also inhibits tyrosine kinase and does things to the vitreous as well," Dr. Kuppermann said. "It can cause vitreous liquefaction and that decreases intraocular VEGF levels." In addition, it may cause a posterior vitreous detachment, which some think may inhibit progression of disease. Dr. Kuppermann cited a small phase I study conducted by Peter Campochiaro, M.D., that showed promise for the drug. "This one reduced the area of neovascularization by 43%, which is similar to other anti-VEGF agents," Dr. Kuppermann said. In the study, eight out of 15 eyes with diabetic macular edema showed a three-line improvement after monthly injections at 0, 30, and 60 days. "Within 30 days there was already a reduction in OCT thickness in the eight eyes that had a three-line improvement or more," Dr. Kuppermann said. "After 90 days they withheld therapy, and all of the eyes were relatively stable from an OCT thickness over that subsequent 90 days." The seven eyes that did not show a response lost no vision. A phase II trial is now being planned. Because it uses a different mechanism of action, Dr. Kuppermann thinks that it at least theoretically may be additive to the anti-VEGF compounds. There is also the hope that it may be synergistic. At the very least it seems to have potential on its own as monotherapy, he pointed out.

Editors' note: Dr. Kaiser has financial interests with Bayer (Leverkusen, Germany), Genentech, Novartis (Basel, Switzerland), and Regeneron. Dr. Kuppermann has financial interests with Allegro and Ophthotech (Princeton, N.J.). Dr. Martin has no financial interests related to this article.

Contact information

Kaiser: 216-444-6702, pkkaiser@aol.com
Kuppermann: 949-677-6361, bdkupper@uci.edu
Martin: 216-444-0431, martind5@ccf.org