Efficacy and Safety of Teprotumumab in Patients With Thyroid Eye Disease of Long Duration and Low Disease Activity

Abstract

Context: Early inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials.

Objective: We present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED.

Methods: This randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) ≤ 1 or no additional inflammation or progression in proptosis/diplopia for ≥1 year, proptosis ≥3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab, and no steroids within 3 weeks of baseline. Patients received (2:1) intravenous teprotumumab or placebo once every 3 weeks (total 8 infusions). The primary endpoint was proptosis (mm) improvement at Week 24. Adverse events (AEs) were assessed.

Results: A total of 62 (42 teprotumumab and 20 placebo) patients were randomized. At Week 24, least squares mean (SE) proptosis improvement was greater with teprotumumab (-2.41 [0.228]) than with placebo (-0.92 [0.323]), difference -1.48 (95% CI -2.28, -0.69; P = .0004). Proportions of patients with AEs were similar between groups. Hyperglycemia was reported in 6 (15%) vs 2 (10%) and hearing impairment in 9 (22%) vs 2 (10%) with teprotumumab and placebo, respectively. AEs led to discontinuation in 1 teprotumumab (left ear conductive hearing loss with congenital anomaly) and 1 placebo patient (infusion-related). There were no deaths.

Conclusion: Teprotumumab significantly improved proptosis vs placebo in longstanding/low inflammation TED, demonstrating efficacy regardless of disease duration/activity. The safety profile was comparable to that previously reported.

Keywords: Graves disease; chronic; inactive; teprotumumab; thyroid eye disease.

Figure 1.

Enrollment, randomization, and completion of treatment period. Patients not meeting criteria at Day 1 were screening failed. Abbreviations: AE, adverse event, ITT, intention-to-treat population.

Figure 2.

A, LS Mean change from baseline in proptosis in mm (primary endpoint, ITT, MMRM). B, LS Mean change from baseline in proptosis in mm (per protocol, MMRM). C, percentage of patients with a proptosis response (ITT). D, percentage of patients with a proptosis response (per protocol). LS Mean change from baseline in the (E) GO-QOL Visual Function subscale and (F) GO-QOL Appearance-related subscale (MMRM). Error bars represent 95% CI. Abbreviations: AP, appearance subscale; BL, baseline; GO-QOL, Graves’ Ophthalmopathy Quality of Life questionnaire; LS, least squares; MMRM, mixed model for repeated measures, VF, visual function subscale.

Figure 3.

A, Patient characteristics and reduction in orbital muscle and fat volume in 6 patients (study eye and fellow eye) in the teprotumumab group. B, MRI at baseline and Week 24 in an individual patient (#5 in panel A) treated with teprotumumab. The green circle indicates the superior rectus and the blue circle indicates the inferior rectus of the study eye. The patient was female, aged 64 with approximately 7 years since diagnosis of TED and no diplopia at baseline. At Week 24, proptosis was reduced in the study eye and fellow eye by 3 and 2.5 mm, respectively and GO-QOL improved by 49 (overall), 75 (appearance), and 23 (visual function).

Figure 4.

A, Reduction in volume of each orbital muscle and fat for 6 patients (12 eyes) with MRI imaging at baseline and Week 24. B, GO-QOL overall, appearance, and visual function scores in the 6 patients with MRI imaging. C, muscle and fat volumes at baseline and Week 24 in an individual patient (#5 in Fig. 3A and Fig. 4B, imaged in 3B) treated with teprotumumab.