Family of Five

Management of exudative retinal diseases was forever changed with the advent of anti-VEGF pharmacotherapies, a revolution that continues to unfold with brolucizumab (Novartis) awaiting Food and Drug Administration approval and at least seven additional anti-VEGF drugs progressing through human trials. But, in light of the recent Phase II trial investigating vascular endothelial growth factor-C and -D blockade, we should clarify that these drugs primarily target vascular endothelial growth factor A. 

Recall that the VEGF family comprises five cytokine members. VEGF-A, the first to be cloned 30 years ago in 1989 by Napoleone Ferrara, appears to be predominately responsible for the pathologic angiogenesis and vascular leakage in retinal diseases. But, other members of the family have also been implicated in the pathogenesis of retinal diseases. 

Unfortunately, validation of an alternative target that delivers additive benefit beyond anti-VEGF-A monotherapy has proven remarkably challenging. While notorious failures such as anti-PDGF drugs litter our past, I believe our future is brighter. 

Multiple active clinical trials hold tremendous promise that we may break through the VEGF-A monotherapy glass ceiling. Positive results with combined VEGF-A and angiopoeitin-2 blockade in the BOULEVARD Phase II trial drove the bispecific crossmab faricimab (Roche/Genentech) into multiple ongoing Phase III trials, with readouts anticipated within two years.  

Most recently, OPT-302 (Opthea) achieved its primary endpoint of superiority in a 366-patient Phase IIb randomized trial comparing ranibizumab (Lucentis, Roche/Genentech) monotherapy to combination therapy of ranibizumab and OPT-302. OPT-302 is an engineered trap molecule based on the soluble, extracellular portion of VEGF receptor 3 designed to inhibit the activity of VEGF-C and -D. 

Among treatment-naïve patients with neovascular age-related macular degeneration, combination dosing achieved 14.2 letters gained at 24 weeks, or a statistically significant 3.4 more letters compared with ranibizumab monotherapy, while secondary endpoints, including anatomic outcomes, supported the primary outcome of superiority. (For more on OPT-302, see Clinical Trial Closeup, “Closing the escape route of anti-VEGF-A agents,” page 45.)

Ongoing Phase III trials with faricimab and anticipated registration trials with OPT-302 bring a fresh sense of hope and opportunity to the retina community. RS