Teprotumumab, an insulin-like growth factor-1 receptor antagonist antibody, in the treatment of active thyroid eye disease: a focus on proptosis

Abstract

Thyroid eye disease is a disabling autoimmune disease associated with orbital inflammation and tissue remodeling which can result in significant proptosis, leading to visual alterations and is potentially sight threatening. Current evidence indicates that autoantibodies to the insulin-like growth factor 1 receptor (IGF-1R), along with the thyroid-stimulating hormone receptor (TSHR), mediate the pathogenesis in susceptible individuals. Teprotumumab, a monoclonal IGF-1R antagonist, has demonstrated previously in a 24 week, randomized, controlled trial to produce significant changes in composite outcomes of proptosis and clinical activity score as compared with placebo. Further examination of the proptosis results reported here, indicate that the proptosis outcome (≥ 2 mm reduction) was met in 71.4% of the teprotumumab-treated patients as compared with 20% of the placebo-treated patients (p < 0.001). Additionally, the proptosis benefit was observed early in the trial (study week 6), and all individual patients demonstrated some benefit at week 24. Improvement was noted among smokers, non-smokers, men and women, and particularly those with higher levels of proptosis at baseline. The level of proptosis reduction with teprotumumab reported here is similar to that seen with decompression surgery. If these results are confirmed in the ongoing Phase 3 trial, teprotumumab will offer an alternative to surgery and its associated complications.

Fig. 1

Diverse presentations of thyroid eye disease [24, 25]

Fig. 2

a Pathogenic autoantibodies stimulating the orbital fibroblasts resulting in production of hyaluronan and giving rise to symptoms of thyroid eye disease. b Teprotumumab (an IGF-1R antagonist) blocks the stimulatory effects of pathogenic autoantibodies on the orbital fibroblasts TSI thyroid stimulating immunoglobulins, GD-IgG Graves’ disease immunoglobulins, TSHR thyroid stimulating hormone receptor, IGF-1R insulin-like growth factor-1 receptor

Fig. 3

Study design. ^ǂExcluding local supportive measures and oral steroids if the maximum cumulative dose is less than 1000 mg methylprednisolone or equivalent. There must be at least 6 weeks between last administration of steroids and study randomization. ^aOne patient underwent randomization and withdrew prior to dosing. ^bIn total, 37 patients completed therapy, 5 discontinued teprotumumab due to an adverse event. ^cIn total, 39 patients completed therapy, 6 discontinued placebos (one had an adverse event and five had other reason)

Fig. 4

Proptosis responders (percent of patients with a decrease ≥  2 mm)

Fig. 5

Individual patients’ proptosis and CAS over time

Fig. 6

Proptosis reductions according to baseline proptosis measurements. Note: 1 patient did not receive the full course of treatment but had measurements at week 24

Fig. 7

Proptosis response with teprotumumab stratified by race, gender and smoking status. Note: 1 patient did not receive the full course of treatment but had measurements at week 24

Fig. 8

Reduction in Proptosis in smokers and non-smokers