Tyrphostins first appeared in a scientific publication in 1988. Short for tyrosine phosphorylation inhibitor, tryphostins blocked the activity of the epidermal growth factor receptor. Now known as tyrosine kinase inhibitors (TKIs), these molecules have shown antiangiogenic and antineoplastic effects, and several are approved to treat cancers, especially solid tumors.

Tyrosine kinase inhibitors work by inhibiting enzymes from phosphorylating tyrosine residues, thereby blocking downstream activation of VEGF, platelet-derived growth factor (PDGF), fibroblast growth factor, and more than 50 other receptor tyrosine kinases. Blocking the abnormal activation of tyrosine kinases in tumors can curb progression, invasion, and growth of malignancies. It is possible to develop drugs that block a narrow spectrum of protein tyrosine kinase activity to work on specific cancers or receptors. As the field matured, multitarget TKIs specifically targeting the VEGF family of receptors were developed, including sorafenib, sunitinib, pazopanib, and axitinib; these were successively approved as first-line treatment options for metastatic renal cell carcinoma.

The initial success in oncology led several companies to use their oncology drugs in ophthalmology with poor to mixed results. The early studies either tested the oncology drug in wet age-related macular degeneration (eg, sorafenib and vorolanib), or put the small molecule TKI into solution to test the drug as an eyedrop (eg, pazopanib and TG100801). Interestingly, TG100801 failed due to the red corneal staining that occurred with the medication, despite reducing retinal fluid. Similarly, vorolanib had retinal activity when given systemically, but adverse events halted development.

We have now entered the next generation of multitarget TKIs in ophthalmology. Specific TKIs for the VEGF and PDGF receptors have been placed in various polymers or the suprachoroidal space to enhance durability and deliver the TKI directly to the eye. Blocking VEGF receptor activation has obvious benefits in retinal vascular disease, but we now must look at PDGF again. Platelet-derived growth factor has been implicated in vascular proliferative retinopathies, such as diabetic retinopathy and choroidal neovascularization, as well as in nonvascular retinopathies, such as proliferative vitreoretinopathy. Because no anti-VEGF agent has been shown to shrink choroidal neovascularization or prevent fibrosis, the addition of PDGF inhibition by these new multitarget TKIs may work especially well in patients whose disease is refractory to anti-VEGF therapy. You may be thinking that you have heard this before with the phase 3 pegpleranib–anti-VEGF combination studies, but those studies required superiority outcomes and we never learned about any anatomic or long-term outcomes, because the studies were halted when the primary outcome was not met.

In this issue, we have assembled a group of experts in the field of TKI and polymer technology to look at the current landscape in retina. Early phase 1 studies have shown reduced treatment burden and definitive biologic effects. Anti-VEGF agents are now commonly used with TKIs in oncology, and it is exciting to watch these drugs move down the regulatory pathway as possible additional treatments to anti-VEGF for our patients with retinal vascular diseases. RP