AMD Risk Genes Do Not Predict Response to Therapy

Linda Roach

February 19, 2013

Four genetic risk alleles strongly associated with the development of neovascular age-related macular degeneration (AMD) cannot be used to predict how patients will respond to drug therapy, according to a new analysis of data from a landmark federal study comparing ranibizumab and bevacizumab.

Researchers from the Comparison of AMD Treatments Trials (CATT) Research Group reported their results in an article published online January 21 in Ophthalmology.

The investigators genotyped 834 (73%) patients in the study, all of whom had neovascular AMD, for 4 known AMD-associated, high-risk single nucleotide polymorphisms (CFH, ARMS2, HTRA1, and C3).

"These [genes] most consistently have been shown to have the strongest association with the development and progression of macular degeneration. So we thought they might, at the beginning, be the heavy hitters, so to speak, in terms of the response to therapy based on a person's genetic background," said lead author Stephanie A. Hagstrom, PhD, a medical geneticist and associate professor of ophthalmology at the Cleveland Clinic in Ohio, in an interview with Medscape Medical News.

"We looked at many different patient outcomes [at 1 year] and compared them to the genotypes. And we saw no statistically significant difference in therapeutic response by genotype for any of the measures that we looked at," Dr. Hagstrom said. "So the take-home message is that it looks like these alleles clearly do not predict the response to anti-VEGF therapy," Dr. Hagstrom added.

The researchers also did not find an association between genotype and therapeutic outcomes by treatment regimen in CATT: monthly ranibizumab (Lucentis, Genentech), monthly bevacizumab (Avastin, Genentech), as-needed ranibizumab, and as-needed bevacizumab.

The analyses performed in the study included tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes, longitudinal analyses using all the treatment response data measured at multiple visits in 1 year, and stepwise analysis to look for possible additive effects in participants based on their total number of genetic risk variants (0 - 1, 2, 3, 4, and ≥5 risk alleles). Because they were doing multiple comparisons, the researchers raised the threshold for statistical significance to P ≤ .01.

Despite the negative results, this pharmacogenetic study was an important first step toward gaining insights into improving AMD treatment, Michigan retinal specialist David N. Zacks, MD, PhD, told Medscape Medical News in an interview.

"This was a very important aspect of the CATT project. If they had found something, it would have been important to know," said Dr. Zacks, who is an associate professor of ophthalmology at the University of Michigan Kellogg Eye Center in Ann Arbor.

He pointed out that ophthalmologists who treat AMD commonly see patients who respond better to bevacizumab than ranibizumab, and vice versa, but no one knows why. "So now, if somebody doesn't respond to the first drug, we switch them quickly to the second drug, and sometimes we get a good response. It's very much an empirical process," he noted.

"We need to just keep plugging away at the science of what causes AMD and how people respond to treatment. As we get new insights into response then we can test for other things down the road," Dr. Zacks concluded.

Indeed, Dr. Hagstrom and colleagues currently are investigating whether the presence of 2 other polymorphisms correlated with therapeutic response among the CATT participants. One polymorphism is in the gene for VEGF's most active isoform, VEGF-A, and the other is in the gene for VEGF-A's highest affinity receptor, KDH. They plan to present the results at a scientific meeting in May 2013, she said.

The research was funded by the National Eye Institute. The authors have disclosed no relevant financial relationships. Dr. Zacks has received research funding from the National Eye Institute, the Foundation Fighting Blindness, and the Beckmann Foundation. He has patent/royalty interests based on work done at Massachusetts Eye and Ear Infirmary and the University of Michigan, and he owns equity in ONL Therapeutics.

Ophthalmology. Published online January 21, 2013. Abstract