Aflibercept (Eylea, Eylea HD, Zaltrap)

Aflibercept is a real, FDA-approved VEGF-trap fusion protein sold as three separate approved drugs — Eylea (2011) and Eylea HD (2023) for eye disease, and ziv-aflibercept/Zaltrap (2012) for colorectal cancer — and currently the subject of a live, multi-front biosimilar patent war that has already produced one at-risk US launch and several multi-year settlement delays.

One fusion protein, three approved drugs

Aflibercept is a recombinant fusion protein — portions of the extracellular, VEGF-binding domains of human VEGF receptors 1 and 2, joined to the Fc fragment of human IgG1 — built on the same Fc-fusion "decoy receptor" logic as romiplostim and etanercept elsewhere on this site. Rather than binding a cell-surface receptor, aflibercept acts as a soluble trap for circulating VEGF-A, VEGF-B, and placental growth factor (PlGF) before they can activate abnormal blood-vessel growth, making it useful against two very different diseases that both depend on that process: wet age-related macular degeneration (and related eye diseases) and metastatic colorectal cancer. Regeneron and Sanofi sell what is functionally the same fusion protein as distinct branded products with different formulations, doses and approved uses — the ophthalmic Eylea/Eylea HD line (Regeneron) and the oncology drug Zaltrap, marketed under the distinct generic name "ziv-aflibercept" specifically because its formulation is not interchangeable with the eye drug.

The pivotal trials behind each approval

The FDA approved the original Eylea (aflibercept, 2 mg) on 18 November 2011 for wet age-related macular degeneration, based on the twin VIEW 1 and VIEW 2 trials (Heier JS, Brown DM, Chong V, et al., "Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-Related Macular Degeneration," Ophthalmology 2012;119(12):2537-2548): 2,419 patients, finding aflibercept dosed every 8 weeks (after 3 monthly loading doses) clinically equivalent to monthly ranibizumab on the primary vision-maintenance endpoint — the basis for aflibercept's original selling point of fewer injections. Eylea's label later expanded to diabetic macular edema (29 July 2014), macular edema following retinal vein occlusion (6 October 2014), and diabetic retinopathy (2019). Separately, ziv-aflibercept (Zaltrap) was approved in August 2012 for metastatic colorectal cancer in combination with FOLFIRI chemotherapy, based on the VELOUR trial (Van Cutsem E, Tabernero J, Lakomy R, et al., "Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen," J Clin Oncol 2012;30(28):3499-3506, PMID 22949147): 1,226 previously treated patients, median overall survival 13.50 months on ziv-aflibercept plus FOLFIRI versus 12.06 months on FOLFIRI alone (hazard ratio 0.817, 95% CI 0.713-0.937, p=0.0032). A third, higher-concentration formulation, Eylea HD (aflibercept 8 mg), was approved 18 August 2023 for wet AMD and diabetic macular edema based on the PULSAR and PHOTON trials, which found vision gains equivalent to standard Eylea while allowing dosing intervals extended to every 8-16 weeks after loading doses — later expanded to retinal vein occlusion, and to monthly dosing across all its indications, in November 2025.

A live, multi-front biosimilar patent war

The FDA approved five aflibercept biosimilars in 2024 alone — Yesafili and Opuviz in May, Ahzantive in July, and Enzeevu and Pavblu in August — but Regeneron sued most of their makers for patent infringement before any could launch. Courts granted Regeneron preliminary injunctions against Samsung Bioepis and Celltrion in mid-2024, both affirmed on appeal by the Federal Circuit in early 2025, keeping those biosimilars off the US market. Amgen's Pavblu was the exception: it launched "at risk" in October 2024 after the Federal Circuit declined to enjoin it, on the strength of a formulation designed around Regeneron's asserted buffer patent — but Regeneron came back in June 2025 with a second lawsuit, over a different patent that had issued only after Pavblu was already on the market, and that fight remained unresolved as of this review. Every other biosimilar maker has instead chosen to settle: Biocon (Yesafili), Sandoz (Enzeevu) and Samsung Bioepis (Opuviz) have all reached agreements with Regeneron across 2025 and early 2026 trading a delayed, staggered US launch — variously reported for the second half of 2026 through early 2027 — for an end to litigation.

Current status

Eylea and Eylea HD remain FDA-approved and are still Regeneron's largest product franchise, but combined US net sales fell sharply in 2025 (down roughly 27% for the year, to about $4.4 billion) — driven mainly by Roche's competing anti-VEGF/Ang-2 drug Vabysmo capturing new-patient share, with real but smaller additional pressure from Amgen's Pavblu (reported at $442 million in US sales over the first three quarters of 2025) and from cheaper compounded or off-label bevacizumab. Zaltrap, by contrast, has always been a minor oncology product relative to Eylea and carries no comparable patent fight, since ziv-aflibercept has not attracted the same biosimilar interest. None of aflibercept's three approved forms has any wellness, cosmetic, or grey-market presence — it is administered exclusively by injection or infusion under direct clinical supervision.