Endocrine Abstracts

JOINT1221

Background: TED is a heterogenous disease, with symptoms that can burden daily life. Patients with chronic TED may be particularly challenging to diagnose and treat. Insulin-like growth factor-1 receptor (IGF-1R) plays a key role in TED pathogenesis. Teprotumumab, a fully human monoclonal IGF-1R inhibitor antibody, recently demonstrated proptosis improvement in a trial of patients with chronic, low disease activity TED. This trial represents a significant step for a population traditionally treated with decompression surgery and recalcitrant to pharmacotherapy. To further understand teprotumumab’s impact on biomarkers and signaling pathways, we examined serum proteomics to elucidate global pathways impacted by teprotumumab in chronic TED.

Methods: Patients in the trial (NCT04583735) had clinical activity score (CAS) ≤1 and TED duration 2-10 years. Serum samples were collected from placebo (n = 20) and teprotumumab (n = 41) patients at baseline and weeks 3, 12 and 24 and analyzed on the Olink Explore 3072 platform. Serum IGF-1 levels were analyzed with the R&D Quantikine assay.

Results: In samples from teprotumumab-treated patients, drug target engagement was validated and confirmed through the IGF-1 immunoassay. Modulation of IGF-1 pathways (i.e., soluble IGF-1R, and insulin-like growth factor binding proteins [IGFBPs] 1-3) was also observed post-teprotumumab treatment in the Olink assay. Additionally, teprotumumab treatment inhibited key proteins that are elevated in tissues of TED patients. These included proteins involved in collagen formation and extracellular matrix (ECM) production, such as COL1A1, OMD, and MMP1; decreased by 2.07, 1.82 and 1.60-fold compared to placebo after 24-week treatment, respectively.

Conclusion: Previous studies have demonstrated that collagen accumulation results in expansion of the ECM that causes destructive tissue remodeling,^1,2 a hallmark of TED. Our findings underscore the pivotal role of IGF-1R activation in TED and confirm target engagement and modulation with teprotumumab in these patients with low CAS, chronic TED. Global proteins associated with the disease were altered by teprotumumab, particularly in pathways related to IGF-binding and ECM which ultimately may lead to disease modification. These insights strengthen our understanding of teprotumumab’s therapeutic mechanisms and its role in the management of chronic TED.

References: 1. Roztocil E, Hammond CL, Gonzalez MO, et al. Sci Rep. 2020;10(1):8477.

2. Lehmann GM, Feldon SE, Smith TJ, et al. Thyroid. 2008;18(9):959-965.