Retina Society 2023: A comparison of the antiangiogenic profile of tyrosine kinase inhibitors vorolanib, axitinib, and sunitinib

At the 56th annual Retina Society congress in New York, Sophie Bakri, MD, MBA, gave a presentation titled, "Comparison of the Antiangiogenic Profile of Tyrosine Kinase Inhibitors Vorolanib, Axitinib, and Sunitinib." She spoke with our team to share some key insights from her research and this presentation.

Video Transcript

Editor's note - This transcript has been edited for clarity.

David Hutton: I'm David Hutton of Ophthalmology Times. The Retinas Society's annual meeting is being held in New York, and Dr Sophie Bakri made a presentation at that meeting. She's joining us here today to tell us about her presentation. Thanks for joining us. Tell us about your presentation.

Sophie Bakri, MD, MBA: This morning, I presented a comparison of the antiangiogenic profile of 3 tyrosine kinase inhibitors: vorolanib, axitinib, and sunitinib. Now, just as background, current treatments for wet macular degeneration target specific ligands of cell membrane receptors upstream of cellular pathways involved in angiogenesis and vascular permeability. And these receptors can include VEGF receptors 123, as well as others that remain active following treatment with current anti-VEGF therapies. And, what we know is that the current anti-VEGF antibodies, they quench VEGF ang-2 or placental growth factor in a ligand trap, but they're eliminated rapidly requiring frequent retreatment.

There are also small molecule pan VEGF receptor inhibitors in development, and these block all VEGF receptors 123, they block pdgf receptor beta, and other receptors. And if we deliver these via zero order release kinetics that may allow retreatment every 6 to 12 months.
So what we sought to do was look to see what the differences were. So we performed an anti angiogenic assay comparing the 3 tyrosine kinase inhibitors: vorolanib, sunitinib, and axitinib, to bevacizumab, and the concentrations used were the 50% inhibitory concentration or the IC 50 for VEGF receptor 2, and we exposed the blood vessels in the assay to the drug, and then looked at the number of blood vessels of using a sponge and the count. And the results showed that all 3 drugs inhibited angiogenesis more effectively than the positive control, which was Bevacizumab. And when we increase the dose 200 times we also have similar results, showing us that the initial IC 50 dose was sufficient.

So what we sought to do was look to see what the differences were. So we performed an anti angiogenic assay comparing the 3 tyrosine kinase inhibitors: vorolanib, sunitinib, and axitinib, to bevacizumab, and the concentrations used were the 50% inhibitory concentration or the IC 50 for VEGF receptor 2, and we exposed the blood vessels in the assay to the drug, and then looked at the number of blood vessels of using a sponge and the count. And the results showed that all 3 drugs inhibited angiogenesis more effectively than the positive control, which was Bevacizumab. And when we increase the dose 200 times we also have similar results, showing us that the initial IC 50 dose was sufficient.

We also did a kinase screening experiment, where we looked at the ability of the tyrosine kinases as well as aflibercept and OPT-302 to inhibit receptors, and we found that only the tyrosine kinase inhibitors inhibited the VEGF receptors, 1, 2 and 3, whereas aflibercept and OPT-302 didn't. But interestingly, of these 3 TKIs tested, it was only axitinib that showed a strong inhibition of the type 2 receptor, which is important for vascular stability and ideally shouldn't be inhibited. And we did IC 50 measurements using VEGF receptors 1, 2, 3 and also confirmed those kinase screening results. And lastly, we looked at melanin binding because we know melanin is present in the iris choroid and RPE. And we found that only sunitinib bound at melanin. And here we used Chloroquine as a positive control. So in summary, what we found is that all 3 tyrosine kinase inhibitors can inhibit all VEGF receptors better than bevacizumab. We also found that vorolanib was able to inhibit them without impacting type-2 function or binding melanin. Thank you.