Clinical Trial Updates in Biological Treatment of Thyroid Eye Disease.

Abstract

Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves' disease, causing proptosis, diplopia, and, in severe cases, vision loss. The 2020 approval of the first insulin-like growth factor 1 receptor (IGF-1R) inhibitor for TED introduced disease-specific pharmacotherapy and prompted accelerated development of additional biological agents across multiple mechanistic classes. This review summarizes the clinical trial evidence for biological agents currently approved or in late-stage development for TED, drawing on peer-reviewed publications, conference presentations, and sponsor disclosures through early 2026. Among the mechanistic classes evaluated, IGF-1R inhibition has accumulated the largest randomized trial evidence base. Multiple IGF-1R-directed agents, delivered by intravenous, subcutaneous, and oral routes, have demonstrated statistically significant reductions in proptosis in placebo-controlled trials, with responder rates that vary by agent, route, and disease activity. Interleukin-6 receptor (IL-6R) antagonism produced discordant Phase 3 primary endpoint outcomes across 2 parallel pivotal trials. Neonatal Fc receptor (FcRn) inhibition and selective interleukin-17A blockade each failed to meet primary endpoints in Phase 2 or Phase 3 studies. B-cell directed therapies and other off-label agents have produced inconsistent results in smaller, generally nonrandomized studies. In parallel, the use of orbital decompression has declined in the era following IGF-1R inhibitor approval, reflecting the changing role of surgery in pathways that initially lead with medical therapy. As comparative trial data emerge and the field moves toward treatment selection based on phenotype, clinicians will be better equipped to individualize biological therapy by disease stage, severity, safety profile, and patient preference.