AMD: Gene Variants Predict Response to Anti-VEGF Drug

Ricki Lewis, PhD

December 30, 2013

Variation in the gene that encodes the vascular endothelial growth factor 2 receptor (VEGFR2) partially accounts for the wide range of responses to ranibizumab (Lucentis, Genentech), an antiangiogenic drug used to treat neovascular (wet) age-related macular degeneration (AMD), according to a report published online December 23 in Ophthalmology.

Ranibizumab is a humanized monoclonal antibody fragment that the Food and Drug Administration approved for intravitreal treatment of wet AMD in 2006. It targets vascular endothelial growth factor A (VEGFA).

The drug preserves or improves visual acuity in many patients, but some individuals do not respond. "It depends on the definition of nonresponders (loss of vision after 1 year, no improvement after 3 injections, baseline visual acuity, etc), but about 10% to 20% of patients do not respond well," senior author Sascha Fauser, MD, a professor of ophthalmology from the Department of Ophthalmology, University Hospital of Cologne, Germany, told Medscape Medical News.

"Most patients respond very well to anti-VEGF, whether it's ranibizumab (Lucentis), bevacizumab (Avastin, Genentech), or aflibercept (Eylea, Bayer HealthCare). Overall, about 25% to 30% have significant visual gain, and most of the rest are stabilized," Shalom Kieval, MD, chief of ophthalmology at Albany Memorial Hospital in New York, told Medscape Medical News.

Lack of response can have several causes. "Vision may decline or not improve because of other factors than nonresponse to the anti-VEGF agent, such as presence of scar tissue, damage from previous hemorrhage, tears of the retinal pigment epithelium, and retinal atrophy. Not much variability is seen in clinical practice, but there is certainly a subset of poor responders," Dr. Kieval said.

Previous investigations have associated poor response to ranibizumab with polymorphisms of the complement factor H (CFH) gene and the age-related maculopathy susceptibility 2 (AMRS2) gene. "Risk variants in these genes increase the severity of the disease and, therefore, to some degree, the response to treatment. However, these genes are not directly involved in the pharmacological pathways of Lucentis response," Dr. Fauser said. Variants in these genes can predict response to zinc and antioxidants to protect against visual loss in those at high-risk for developing AMD, as reported by Medscape Medical News.

To test the hypothesis that variants in the VEGF and VEGF receptor genes predict response to ranibizumab, first author Manuel M. Hermann, MD, also from the Department of Ophthalmology, University Hospital of Cologne, and colleagues evaluated the association of single-nucleotide polymorphisms (SNPs) in these genes with drug response rate. The case series study measured visual acuity (VA) at baseline, after 3 monthly injections, and after 1 year of treatment in 366 patients with wet AMD. Patients were from the European Genetic Database.

The researchers cataloged 126 SNPs in the genes that encode VEGFA; VEGFB; VEGFC; VEGFD; placental growth factor; VEGF receptors VEGFR1, VEGFR2, and VEGFR3; and pigment epithelium-derived factor. Past studies evaluated fewer SNPs and in VEGFA and VEGFR2 only. VEGFR2 is the receptor that mediates most of the cellular response to VEGF.

Univariate analyses of variance showed that a SNP in VEGFR2 had a significant effect on VA change after 12 months (F[1,235] = 14.05; P = .02). None of the other SNPs analyzed were significantly associated with response in the univariate analysis, but a multivariate stepwise regression analysis showed that a second SNP in the VEGFR2 gene was associated with outcomes at the 1-year mark.

Patients with 3 such "minor alleles" had a mean increase in VA of 0.26 on the logarithm of the minimum angle of resolution (logMAR) scale compared with loss of 0.03 logMAR in patients who had no copies of either of the minor alleles. The researchers noted differences in VA between patients with at least 1 minor allele and those with none by 3 months; the improvements increased to 3 lines by a year. Improvement correlated to increased number of minor alleles.

A similar modulating effect on antiangiogenesis drug response is seen in metastatic pancreatic adenocarcinoma treated with bevacizumab, which is derived from the same monoclonal antibody as ranibizumab.

The investigators conclude that identification of the VEGFR2 variants might predict which patients are most likely to respond to antiangiogenic therapy. "We are currently analyzing more variants which may also predict VEGF suppression time. Maybe a combination of all these variants might give us a meaningful clinical tool in the future," Dr. Fauser told Medscape Medical News.

A limitation of the study was using 2 methods to assess visual acuity and converting one to the other. The researchers call for replication of the study and for following-up participants for longer periods because some individuals lose VA after 12 months of treatment.

Genetic testing likely will not affect prescribing because all patients with wet AMD are offered anti-VEGF therapy, Dr. Kieval said, but it could be useful in predicting relapse, which the study did not address. "Right now we have no way of determining who will and who won't maintain remission. If genetic testing could tell us who we can watch safely and who requires maintenance injections regularly, then it would have great clinical utility," he said. However, he added, if the findings are confirmed, they may shed light on the mechanisms of differential response, "and that can be helpful in deepening our understanding of the disease and in designing better treatments."

The authors and Dr. Kieval have disclosed no relevant financial relationships.

Ophthalmology. Published online December 23, 2013. Abstract

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