AMD risk alleles fail to predict treatment response

Feb 20 2013

By Joanna Lyford, Senior medwireNews Reporter

The major risk alleles that influence the development of age-related macular degeneration (AMD) do not predict response to therapy for the condition, a substudy of the CATT trial indicates.

The Comparison of AMD Treatment Trial (CATT) found that two anti-vascular endothelial growth factor (VEGF) therapies, bevacizumab and ranibizumab, were equally effective in improving visual acuity (VA) in patients with neovascular AMD.

For this pharmacogenetic substudy, 834 (73%) of 1149 trial participants were genotyped for four single nucleotide polymorphisms (SNPs) known to be associated with AMD susceptibility: rs1061170 in the CFH gene, rs10490924 in ARMS2, rs11200638 in HTRA1, and rs2230199 in C3.

Stephanie Hagstrom (Cleveland Clinic, Ohio, USA) and colleagues looked for correlations between genotypic frequencies and clinical measures of response to therapy at 1 year.

There were three visual outcome measures: mean VA, mean change in VA, and the proportion of patients with a 15-letter or more increase in VA. In addition, five anatomic outcome measures were evaluated: retinal thickness, mean change in total foveal thickness, presence of fluid on optical coherence tomography, presence of leakage on fluorescein angiography, and mean change in lesion size. Also assessed was the mean number of injections administered.

Writing in Ophthalmology, the authors report that they found no associations between any of the SNPs and any of the clinical measures. Furthermore, the response to therapy did not vary by the number of risk alleles present. The lack of correlation between genotype and response held true whether patients were given bevacizumab or ranibizumab and whether they were dosed monthly or as needed.

Hagstrom et al note that anti-VEGF therapy is highly effective yet there is a wide range of clinical response and variability in the number of injections required.

"Given the impact of genetic factors on disease manifestation and progression, a logical assumption would be that genetic variants play a role," they write. However, "this study found no statistically significant pharmacogenetic association between these SNPs and VA outcomes, anatomic outcomes, or the number of injections required."

Nevertheless they say they remain hopeful that gene variants that predict patient response to AMD treatments will be identified soon.

"Additional studies are underway, including investigations targeting biologic pathways that directly modulate cytokine behavior in neovascular AMD, such as VEGF and other growth factor pathways," Hagstrom and colleagues write. "Identification of markers that do affect clinical response may result in optimization of anti-VEGF therapy."

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