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Purpose: To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare. Design: The Treatment of Graves’ Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves’ Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial. Participants: Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC. Methods: OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score [CAS], or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks. Main Outcome Measures: Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life. Results: Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, –3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during first course of treatment, and 2 events reoccurred after re-treatment. Conclusions: Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.

Thyroid eye disease (TED) is a complex, debilitating autoimmune disease that causes orbital inflammation and tissue remodeling, resulting in proptosis, diplopia, and in severe cases, loss of vision. TED can lead to facial disfigurement and severely impact patients’ quality of life. Although the course of TED was identified over 60 years ago, effective treatment options have proved to be challenging. Current treatments such as glucocorticoid therapy and orbital radiation focus on reducing orbital inflammation. However, these therapies fail to modify the disease outcomes, including proptosis and diplopia. Recent advances in the understanding of the molecular basis of TED have facilitated the development of targeted molecular therapies such as teprotumumab, an insulin-like growth factor-1 receptor inhibiting monoclonal antibody. In recent phase 2 and phase 3 randomized placebo-controlled trials, teprotumumab rapidly achieved improvement in clinical endpoints defining TED, including improved proptosis and diplopia. Dramatic improvement in clinical outcomes achieved after teprotumumab therapy during active TED are heretofore singular and comparable only to surgical therapies achieved during the inactive phase of TED. The advent of effective medical therapy can lead to a paradigm shift in the clinical management of TED. This review will provide an overview of TED, its epidemiology, insight into the molecular biology of the disease, clinical characteristics and diagnosis, and current and emerging treatment modalities.