Teprotumumab and TED: Sarah Cheng, MD, PhD, on orbital tissue changes

Teprotumumab-trbw (Tepezza; Amgen) has demonstrated clinical benefit in thyroid eye disease (TED), but less is known about the biological changes that occur in orbital tissue following treatment. At the American Academy of Ophthalmology (AAO) 2026 Annual Meeting in New Orleans, Louisiana, researchers presented exploratory findings from a study that used single-nuclear multiomics sequencing to compare orbital tissue from 28 patients with active, chronic, reactivated or teprotumumab-treated TED and 10 control patients, evaluating more than 281,000 individual cell nuclei.

Ophthalmology Times spoke with Sarah Cheng, MD, PhD, a clinical oculoplastic fellow at University of California San Diego and an author of the study. In the following Q&A, Cheng discusses what single-nuclear multiomics can reveal that earlier tissue studies could not, how cellular makeup and pathway activity differed across TED disease states, the orbital tissue changes observed after teprotumumab treatment, ongoing validation work and the most practical takeaway for clinicians managing TED.

This Q&A has been lightly edited for length and clarity.

Ophthalmology Times (OT): What led the team to use single-nuclear multiomics sequencing to study orbital tissue in TED, and what can this approach show that earlier tissue studies could not?

Sarah Cheng, MD, PhD: Single-nuclear multiomic sequencing allows evaluation of RNA and DNA information from individual cells, allowing analysis to show not only what genes are high in a tissue, but to show what genes are high in specific cell types and what transcription factor binding sites are increasingly accessible in specific cell types. It allows the subclassification of cells into types and subtypes, giving greater resolution to our understanding of thyroid eye disease pathogenesis and how teprotumumab augments disease biology.

OT: How did the cellular makeup and pathway activity of orbital tissue differ across active, chronic and reactivated disease compared with control tissue?

Cheng: Active and reactivated tissue are states of high inflammatory activity with high T cell populations. Chronic disease featured high adipocyte levels with increased extracellular matrix–related gene expression. Patients with chronic TED had the highest hyaluronic acid gene expression, and patients with active, reactivated and chronic TED all had increased collagen gene expression in fibroblasts. Immediate early genes are a signal for tissue inflammation, and patients with active and reactivated TED had the highest immediate early gene expression, which was elevated to a lower amount in chronic TED and was lowest in control patients.

OT: What changes appeared in orbital tissue after teprotumumab treatment, and how might they help explain the reduction in proptosis seen in clinical practice?

Cheng: Patients treated with teprotumumab had a lower proportion of adipocytes compared with untreated patients. Treated patients also had lower immediate early gene expression and decreased collagen and hyaluronic acid genes in fibroblasts. These changes point to molecular changes happening at the single-nuclei level, suggesting that teprotumumab may be a disease-modifying drug that may be influencing proptosis through changing the cellular makeup and gene expression of the orbit.

OT: Since these findings are exploratory, what are the key limitations, and what research is needed to confirm or build on them?

Cheng: The key limitation of this study is that while the findings are striking, we must validate them in tissue. We are currently undertaking high-throughput mRNA-level validation of cell types, proportions and molecular changes in orbital tissue through spatial transcriptomics, as well as testing the significance of interesting candidates in cultured orbital fibroblasts.

OT: For ophthalmologists and oculoplastic surgeons managing TED today, what is the most practical takeaway from this research?

Cheng: Prior treatments for thyroid eye disease in the form of steroids and radiation are impressive for reducing inflammation in the orbit but fall short of achieving a significant reduction in proptosis. This research shows that teprotumumab, which is known to reduce proptosis, is making molecular and cell type composition changes in the tissue that extend beyond changes in inflammatory genes.