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Eric Wakshull, Eric Day, Jihong Yang, Xiangdan Wang, Sandeep Yadav, William Hanley; The long leap from drug affinity to efficacy: Intervening factors that strongly influence clinical outcomes. Invest. Ophthalmol. Vis. Sci. 2017;58(8):196. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The clinical efficacy of drug product is strongly impacted by multiple factors (Fig 1). We review data on the relative binding affinity and potency of 2 VEGF inhibitors used to treat retinal diseases (ranibizumab, RBZ; aflibercept, AFL), and assess their relevance to clinical outcomes.
A comparative review and analysis of key studies on the affinity and potency of VEGF inhibitors and a sensitivity modeling experiment.1,2
RBZ and AFL bind to VEGF under various lab conditions. Using Biacore, Papadopoulos et al1 reported the affinity (KD) for AFL binding VEGF as <1 pM while RBZ affinity was 46 pM. However, their RBZ affinity analysis had a major limitation due to rapid dissociation of RBZ from the capture antibody.2 Further we found that KD values from Biacore measurements were assay-format dependent.2 Data from an orthogonal method, analytical ultracentrifugation, did not support AFL having a significantly higher affinity to VEGF relative to RBZ. RBZ and AFL showed similar dose-dependent inhibition of VEGF-induced endothelial cell proliferation (IC50 ~0.088±0.032, 0.090±0.009 nM, respectively). A sensitivity analysis of RBZ and AFL clinical data indicates that, assuming the affinities reported1 and intravitreal half-life of drug are within the reported ranges, there appears to be no improvement in vision gained (Fig 2). This analysis is supported by various clinical trials where the RBZ and AFL doses given provide sufficient inhibition of VEGF and results showed comparable vision gains and dosing intervals for RBZ or AFL.
We have shown that affinity values reported for RBZ by Papadopoulos et al1 are not reliable.2 Moreover, both molecules appear equipotent in a relevant cell-based assay. Modeling of literature data show that within the range of reported affinities, dosing and pharmacokinetic considerations suggest comparable clinical outcomes. Thus, in this context, affinity is not an important driver of efficacy. Most importantly, clinical trial data from patients support the comparable efficacy and durability of RBZ and AFL.1. Papadopoulos et al. Angiogenesis 2012;15:171-85.2. Yang et al. Mol Pharmaceutics 2014;11:3421-30.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
Figure 1. Putting molecular characteristics and clinical outcomes into perspective
Figure 2. Results of sensitivity analysis using RBZ and AFL data
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