Non-responders of anti-VEFG treatments for AMD identify certain genetic variants in the VEGF pathway

Researchers at the Department of Ophthalmology at Ghent University Hospital have reported that the identification of genetic variants from wet AMD patients do not provide benefit for anti-VEFG treatments (ranibizumab and bevacizumab).  The researchers identified several SNPs (single nucleotide polymorphisms) associated with anti-VEFG treatments that did not respond to drug therapy, particularly three genes – FLT4, KDR and VEGFC.  As there is a significant proportion of patients that do not respond to such treatment, other strategies may need to address alternative anti-VEGF treatments, or require other novel targets for drug development.

 

It is estimated that about 10%-20% of wet AMD patients fail to respond anti-VEGF medication and this provides a significant challenge given that the wet AMD population could reach an estimated 2M patients by 2050.  The current clinical research has recently aimed to identify a common tagging SNP study in genes encoding VEGF pathway components from 281 patients treating anti-VEGF treatment. The association of genotypes with treatment response showed seven SNPs with a significant association with treatment outcome after 3 months, and 10 SNPs with outcome after 12 months. The primary outcome measure of the change in central foveal thickness (CFT) was at 3 months after treatment onset.  Seven SNPs were identified, including three genes – FLT4 (s7691507), KDR (rs2305945) and VEFGC. Only association with rs55667289 in FLT4 appeared to survive multiple testing correction.   FLT4 is encoded by VEGF receptor 3 (a tyrosine kinase receptor of VEGFC and VEGFD) and this was previously linked to a reduced response to sunitinib in clear cell renal cell carcinoma.

 

According to the research, the study in the report suggested that “neovascularisation in these non-responsive patients could be driven by angiogenic pathways other than the VEGF pathway”.   There could be other pathways in the current pathophysiology or rare genetic lesions that are not yet clearly identified.  In addition, there may be additional anti-VEGF treatments to capture other non-responder populations outside this study, including aflibercept, abicipar pegol or brolucizumab, and other agents not yet approved.

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