Aflibercept: A Comprehensive Monograph on a Dual-Indication VEGF-Trap Fusion Protein

Executive Summary

Aflibercept represents a significant achievement in rational drug design, a recombinant fusion protein engineered to act as a high-affinity "VEGF Trap." This unique molecular architecture has enabled it to forge two distinct, and starkly contrasting, therapeutic identities. As the ophthalmic formulation, Eylea®, it has become a blockbuster therapy, transforming the standard of care for a range of neovascular retinal diseases, including neovascular (wet) age-related macular degeneration (nAMD) and diabetic eye diseases. Its primary clinical advantage lies in its potent and sustained inhibition of the VEGF pathway, which translates into less frequent intravitreal injections compared to its predecessors, thereby reducing the treatment burden for patients with chronic conditions. The development of a higher-dose formulation, Eylea HD®, further extends this benefit, pushing dosing intervals to four months or longer for many patients.

Conversely, the systemic formulation, Zaltrap®, has carved out a much smaller niche in oncology. Approved for second-line treatment of metastatic colorectal cancer (mCRC), it demonstrated a modest but statistically significant survival benefit in patients who had progressed on prior therapy. However, the high systemic doses required to achieve this effect unmask a formidable toxicity profile, including boxed warnings for severe hemorrhage, gastrointestinal perforation, and impaired wound healing. This challenging safety profile has limited its broader application and stands in sharp contrast to the generally well-tolerated local administration of Eylea®.