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N Engl J Med. 2017 May 4;376(18):1748-1761. doi: 10.1056/NEJMoa1614949.

Teprotumumab for Thyroid-Associated Ophthalmopathy.

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From the Department of Ophthalmology and Visual Sciences, Kellogg Eye Center (T.J.S., R.S.D.), and the Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; the Department of Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany (G.J.K.); Moorfields Eye Hospital, London (D.G.E.); the University of Tennessee Health Science Center, Memphis (J.C.F.); the Oculofacial Plastic Surgery Division, Oregon Health and Science University, Portland (R.A.D.); Eye Wellness Center, Neuro-Ophthalmology of Texas, Houston (R.A.T.); the Department of Ophthalmology, Medical College of Wisconsin, Milwaukee (G.J.H.); the Department of Clinical and Experimental Medicine, University of Pisa, Pisa (A.A.), and the Endocrinology and Diabetology Unit, Fondazione IRCCS Ca' Granda, University of Milan, Milan (M.S.) - both in Italy; the Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles (R.A.G.); the University of Nebraska Medical Center, Omaha (J.W.G.); Barnes-Jewish Hospital, Washington University, St. Louis (S.M.C.); the Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City (E.M.S.); the Department of Ophthalmology, Emory University, Atlanta (B.R.H.); the Department of Ophthalmology, University of Colorado, Aurora (E.M.H.); and River Vision Development, New York (R.M.W., K.G., G.M.).



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.


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.


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.


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; number, NCT01868997 .).

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