BACKGROUND: Thyroid-associated ophthalmopathy, a condition commonly associated 
with Graves' disease, remains inadequately treated. Current medical therapies, 
which primarily consist of glucocorticoids, have limited efficacy and present 
safety concerns. Inhibition of the insulin-like growth factor I receptor 
(IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune 
pathogenesis of ophthalmopathy.
METHODS: We conducted a multicenter, double-masked, randomized, 
placebo-controlled trial to determine the efficacy and safety of teprotumumab, a 
human monoclonal antibody inhibitor of IGF-IR, in patients with active, 
moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned 
to receive placebo or active drug administered intravenously once every 3 weeks 
for a total of eight infusions. The primary end point was the response in the 
study eye. This response was defined as a reduction of 2 points or more in the 
Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating 
active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in 
proptosis at week 24. Secondary end points, measured as continuous variables, 
included proptosis, the Clinical Activity Score, and results on the Graves' 
ophthalmopathy-specific quality-of-life questionnaire. Adverse events were 
assessed.
RESULTS: In the intention-to-treat population, 29 of 42 patients who received 
teprotumumab (69%), as compared with 9 of 45 patients who received placebo 
(20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at 
week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 
patients in the placebo group (4%) had a response (P<0.001). Differences between 
the groups increased at subsequent time points. The only drug-related adverse 
event was hyperglycemia in patients with diabetes; this event was controlled by 
adjusting medication for diabetes.
CONCLUSIONS: In patients with active ophthalmopathy, teprotumumab was more 
effective than placebo in reducing proptosis and the Clinical Activity Score. 
(Funded by River Vision Development and others; ClinicalTrials.gov number, 
NCT01868997 .).