Teprotumumab for non-inflammatory thyroid eye disease (TED): evidence for increased IGF-1R expression

Abstract

Purpose Teprotumumab, a blocking antibody to the insulin like growth factor 1 receptor (IGF-1R) has been shown to significantly reduce proptosis in recent phase 2 and 3 trials in patients with inflammatory thyroid eye disease (TED). Herein, we investigate the impact of teprotumumab on patients with non-inflammatory TED. We also investigate the expression of the IGF-1R on orbital tissues from patients with inflammatory and non-inflammatory TED compared to controls. Methods Consecutive patients with non-inflammatory TED (clinical activity score, CAS ≤ 1, for at least 4 months, were treated with teprotumumab. They received a complete course (total eight infusions) of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for subsequent infusions every 3 weeks). The primary outcome was a proptosis response at week 24. Further, IGF-1R α and β expression was evaluated on orbital tissue from patients with inflammatory and non-inflammatory TED, as well as healthy controls. Non-biased histological analysis of IGF-1R expression was performed using ImageJ. Results Four patients met eligibility criteria for the clinical study, with a mean (SD) CAS of 0 (0). Following teprotumumab treatment, there was a mean (SD) reduction in proptosis of 2.6 mm (1.2). Five patients were included for each group of the histological study; inflammatory TED, non-inflammatory TED and controls. IGF-1Rα and IGF-1Rβ expression was significantly greater in the orbital tissues of patients with inflammatory TED and non-inflammatory TED, when compared to controls. Conclusion Our findings demonstrate for the first time, that teprotumumab, a blocking antibody to the IGF-1R reduces proptosis in a series of patients with non-inflammatory TED. Overexpression of the IGF-1R in orbital tissue from patients with non-inflammatory disease compared to controls may be an important consideration for effect.

Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment

“…Additional support for this conclusion derives from finding that patients with chronic TED maintain an IGF-1R overexpression. 18 Integrated findings from those patients who were treated with an 8-infusion course of teprotumumab during the previously published pivotal trials indicate similar efficacy to those observed in the OPTIC-X study during the 24-week active treatment period. Likewise, follow-up results seen in OPTIC placebo patients who received teprotumumab initially during the OPTIC-X study, reported here, were similar to those identified in the integrated off-treatment period (7 to 51 weeks) from the earlier trials.…”

“…Recent evidence suggests that the increase in IGF-IR expression in acute TED persists into the chronic, non-progressive phase. 18 Teprotumumab (currently marketed as TEPEZZA®), a novel, fully human monoclonal IGF-1R inhibitory antibody, binds to IGF-1R, inhibits downstream signalling, and provokes internalization of the antibodyreceptor complex. Phase 2 and 3 randomized, placebo-controlled trials (NCT01868997 19 and NCT03298867 20 respectively) demonstrated marked improvement in proptosis, diplopia, and inflammation in patients with moderate-to-severe, active TED following 8 infusions of teprotumumab over a 24-week period.…”

Facial and Eyelid Changes in Thyroid Eye Disease Are Reversed by Teprotumumab

“…Recent work has shown that the overexpression of the IGF-1R on OFs persists into the chronic stages of TED. 22 It is possible that this overexpression may also be present within the extraorbital tissues of patients with chronic TED. Though further work will be required to elucidate this, the present study adds further evidence to the concept that teprotumumab may have efficacy even in patients with chronic TED.…”

Efficacy and Safety of Teprotumumab in Thyroid Eye Disease

“…CAS improved from 1 to 0 with the resolution of orbital pain after 3 infusions. 37,38 Currently, chronic, inactive TED is predominantly managed with surgical rehabilitation as needed. The reports above suggest the potential of teprotumumab as disease-modifying in chronic inactive TED.…”

“…The reports above suggest the potential of teprotumumab as disease-modifying in chronic inactive TED. 37,38 While the initial findings of Ugradar et al showed IGF-IR overexpression in orbital fibroblasts of "non-inflammatory" TED compared to controls, 37 Slentz 32 Hwang 33 Chiou 34 Diniz 35 Diniz 35 Sears 36 Sears 36 Sears 36 Sears 36 Sears 36 Sears 36 Sears 36 Sears 36 Sears 36 teprotumumab in treating patients with chronic inactive TED is currently in the recruitment process. 39…”