Eric Nudleman, MD, PhD
Shiley Eye Institute, UCSD
Editor, RETINA Roundup
Although anti-VEGF therapy has revolutionized the management of retinal vascular diseases, there has been significant effort in recent years to identify additional targets to address the suboptimal response seen in some patients. This is particularly relevant in diabetic macular edema, where despite monthly treatment, roughly a quarter of patients have persistent edema 1-3.
Basic and clinical evidence over the last decade has implicated the tyrosine kinase receptor (Tie2) pathway as a promising therapeutic target. It has become clear that the development and maintenance of the retinal vasculature, including the stability of the blood-retinal barrier, requires activation of the Tie2 receptor by angiopoietin-1 (Ang-1). In contrast, angiopoietin-2 (Ang-2) functions as an antagonist, preventing Tie2 activation. Downstream of Tie2, an intracellular phosphatase (vascular endothelial-protein tyrosine phosphatase, VE-PTP), also functions as a negative regulator of Tie2 activity. In animal models of diabetic retinopathy, both Ang-2 and VE-PTP are upregulated, making these attractive targets for intervention.
Multiple companies agree, and several early phase trials have been completed. Last week, however, Regeneron announced that they will not pursue a phase 3 trial evaluating the combined effect of their anti-Ang2 drug in combination therapy with Eyelea. Following their phase 2 studies, it was determined that there was insufficient evidence suggesting a benefit with the combined therapy to warrant moving forward.
Additional studies are still underway. Aerpio Therapeutics has concluded a phase 2 study comparing AKB-9778, a small molecule inhibitor of VE-PTP that is delivered by subcutaneous injections, to either ranibizumab or in combination with ranibizumab, for the treatment of DME. Interestingly, the combination of both agents was significantly better than either alone. A phase 2b study is now being conducted. Genentech also has skin in the game. Their molecule, RO6867461, is a bi-specific antibody that targets both Ang2 and VEGF. Phase2 studies evaluating this molecule are underway for both DME and AMD.
While the best strategy for modulating the Tie2 pathway has not been determined, the potential is enormous. We are all eagerly awaiting the results.
- Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. 2012;119(4):789-801. doi:10.1016/j.ophtha.2011.12.039.
- Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology. 2015;122(10):2044-2052. doi:10.1016/j.ophtha.2015.06.017.
- Gonzalez VH, Campbell J, Holekamp NM, et al. Early and Long-Term Responses to Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema: Analysis of Protocol I Data. Am J Ophthalmol. 2016;172:72-79. doi:10.1016/j.ajo.2016.09.012.