What is the mechanism of action of Tepezza (teprotumumab) in thyroid eye disease, specifically for exophthalmos?

Mechanism of Action of Tepezza (Teprotumumab) in Thyroid Eye Disease and Exophthalmos

Teprotumumab binds to and blocks the insulin-like growth factor-1 receptor (IGF-1R), preventing its activation and downstream signaling that drives orbital tissue inflammation, fibroblast proliferation, and tissue expansion in thyroid eye disease. 1

Primary Molecular Target

• Teprotumumab is a fully human IgG1 monoclonal antibody that specifically targets IGF-1R, which is overexpressed on orbital fibroblasts in patients with both inflammatory and non-inflammatory thyroid eye disease compared to healthy controls. 2
• The drug blocks IGF-1R activation and signaling, though the complete mechanism of action in thyroid eye disease has not been fully characterized by the FDA. 1
• IGF-1R forms a signaling complex with the thyroid-stimulating hormone receptor (TSHR), and teprotumumab's inhibition of this IGF-1R/TSHR complex reduces orbital fibroblast differentiation and inflammatory responses. 3

Direct Effects on Orbital Tissues Causing Exophthalmos

• Teprotumumab reduces extraocular muscle size and orbital fat volume, which are the primary anatomical drivers of proptosis in thyroid eye disease. 4
• In patients with chronic thyroid eye disease, teprotumumab produces a mean reduction of 2011 mm³ in muscle tissue volume and 2101 mm³ in fat volume per orbit, directly addressing the mechanical cause of exophthalmos. 5
• The drug achieves mean proptosis reduction of 3.5 mm in the study orbit and 3 mm in the fellow orbit in chronic disease, with similar efficacy demonstrated in active disease. 5

Receptor Saturation and Pharmacologic Profile

• The approved dosing regimen (10 mg/kg initial infusion followed by 20 mg/kg every 3 weeks for seven additional infusions) maintains serum concentrations above 20 µg/mL, providing greater than 90% IGF-1R saturation throughout the dosing interval. 6
• Teprotumumab exhibits linear pharmacokinetics with low systemic clearance (0.334 L/day), low volume of distribution (3.9 L central, 4.2 L peripheral), and a long elimination half-life of 19.9 days, consistent with other IgG1 antibodies. 6
• Steady-state peak concentrations average 643 µg/mL and trough concentrations average 157 µg/mL, ensuring sustained receptor blockade. 6

Efficacy Across Disease Stages

• IGF-1Rα and IGF-1Rβ expression is significantly elevated in orbital tissues from patients with both inflammatory and non-inflammatory thyroid eye disease compared to controls, explaining teprotumumab's efficacy even in chronic, stable disease. 2
• In non-inflammatory thyroid eye disease (clinical activity score ≤1 for at least 4 months), teprotumumab still produces a mean proptosis reduction of 2.6 mm, demonstrating that IGF-1R blockade addresses tissue remodeling beyond acute inflammation. 2
• The drug reduces both soft tissue congestion and the underlying fibroblast proliferation that drives chronic orbital expansion, making it effective across the disease spectrum. 4, 3

Clinical Implications of the Mechanism

• By targeting IGF-1R rather than general immunosuppression, teprotumumab addresses the specific pathophysiology of thyroid eye disease, including the unique orbital fibroblast activation that distinguishes this condition from other autoimmune disorders. 3
• The mechanism explains why teprotumumab reduces not only proptosis but also diplopia (67% response rate in chronic disease) by decreasing extraocular muscle volume and improving muscle function. 5
• No meaningful correlations exist between teprotumumab exposure levels and efficacy parameters, indicating that standard dosing achieves adequate receptor saturation in virtually all patients without need for individualized dosing. 6

Common Pitfalls Related to Mechanism Understanding

• Do not assume teprotumumab only works in active, inflammatory disease—IGF-1R overexpression persists in chronic disease, making the drug effective even years after disease onset (mean 81 months in one study). 5, 2
• Do not expect immediate results—the mechanism requires sustained receptor blockade over multiple infusions to reverse established tissue expansion, with maximal effect typically seen at week 24. 2
• Do not overlook that IGF-1R blockade affects glucose metabolism systemically, explaining the hyperglycemia adverse effect that requires monitoring even in non-diabetic patients. 7, 1