The angiopoietin/tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains (Tie) pathway plays a key role in regulating vascular stability and inflammation under healthy and pathological conditions, and as such, is a focus for the development of next-generation therapeutics for retinal vascular disorders.
Both Regeneron and Genentech have investigated this pathway. Regeneron’s analysis on their combined Aflibercept and angiopoietin-2 (Ang-2) inhibitor missed the primary endpoint but demonstrated a strong signal with regards to 2 step retinopathy improvement in those with diabetic retinopathy. Genentech has advanced their bispecific molecular Faricimab for the treatment of both neovascular age-related macular degeneration and diabetic macular edema. The molecule targets two distinct pathways – Ang-2 and VEGF-A.
The YOSEMITE and RHINE studies compared Faricimab to Aflibercept for diabetic macular edema. The studies each have three treatment arms, with participants randomized to receive either Faricimab or Aflibercept at fixed eight-week intervals, or Faricimab at personalized intervals of up to 16 weeks, following a loading phase.
Both studies met their primary endpoint and showed that Faricimab given every eight weeks and at personalized dosing intervals of up to 16 weeks demonstrated non-inferior visual acuity gains compared to Aflibercept given every eight weeks. Faricimab was generally well-tolerated with no new safety signals identified. Of most interest was the secondary endpoint which showed that more than half of the participants in the Faricimab personalized dosing arms achieved an extended interval of 16 weeks by the first year. That’s a remarkable achievement since most therapeutics to date have not been able to achieve this level of drug durability.
It’s important to note that a durable treatment is an important outcome especially in light of these disease states and the current pandemic. Our recent studies on patients who experienced an unintended lapse in anti-VEGF treatment (akin to what is happening in the pandemic) found worse vision and retinal anatomy despite restarting treatment. Durable therapeutics might alleviate these treatment gaps and improve long term outcomes.