Teprotumumab for thyroid-associated ophthalmopathy

Terry J. Smith, George J. Kahaly, Daniel G. Ezra, James C. Fleming, Roger A. Dailey, Rosa A. Tang, Gerald J. Harris, Alessandro Antonelli, Mario Salvi, Robert A. Goldberg, James W. Gigantelli, Steven M. Couch, Erin M. Shriver, Brent R. Hayek, Eric M. Hink, Richard M. Woodward, Kathleen Gabriel, Guido Magni, Raymond S. Douglas

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1748-1761
Number of pages14
JournalNew England Journal of Medicine
Volume376
Issue number18
DOIs
Publication statusPublished - May 4 2017

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R-1507 monoclonal antibody
Graves Ophthalmopathy
Placebos
Exophthalmos
IGF Type 1 Receptor
Safety
Graves Disease
Therapeutic Uses
Drug-Related Side Effects and Adverse Reactions
Hyperglycemia
Glucocorticoids

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Smith, T. J., Kahaly, G. J., Ezra, D. G., Fleming, J. C., Dailey, R. A., Tang, R. A., ... Douglas, R. S. (2017). Teprotumumab for thyroid-associated ophthalmopathy. New England Journal of Medicine, 376(18), 1748-1761. https://doi.org/10.1056/NEJMoa1614949

Teprotumumab for thyroid-associated ophthalmopathy. / Smith, Terry J.; Kahaly, George J.; Ezra, Daniel G.; Fleming, James C.; Dailey, Roger A.; Tang, Rosa A.; Harris, Gerald J.; Antonelli, Alessandro; Salvi, Mario; Goldberg, Robert A.; Gigantelli, James W.; Couch, Steven M.; Shriver, Erin M.; Hayek, Brent R.; Hink, Eric M.; Woodward, Richard M.; Gabriel, Kathleen; Magni, Guido; Douglas, Raymond S.

In: New England Journal of Medicine, Vol. 376, No. 18, 04.05.2017, p. 1748-1761.

Research output: Contribution to journalArticle

Smith, TJ, Kahaly, GJ, Ezra, DG, Fleming, JC, Dailey, RA, Tang, RA, Harris, GJ, Antonelli, A, Salvi, M, Goldberg, RA, Gigantelli, JW, Couch, SM, Shriver, EM, Hayek, BR, Hink, EM, Woodward, RM, Gabriel, K, Magni, G & Douglas, RS 2017, 'Teprotumumab for thyroid-associated ophthalmopathy', New England Journal of Medicine, vol. 376, no. 18, pp. 1748-1761. https://doi.org/10.1056/NEJMoa1614949
Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA et al. Teprotumumab for thyroid-associated ophthalmopathy. New England Journal of Medicine. 2017 May 4;376(18):1748-1761. https://doi.org/10.1056/NEJMoa1614949
Smith, Terry J. ; Kahaly, George J. ; Ezra, Daniel G. ; Fleming, James C. ; Dailey, Roger A. ; Tang, Rosa A. ; Harris, Gerald J. ; Antonelli, Alessandro ; Salvi, Mario ; Goldberg, Robert A. ; Gigantelli, James W. ; Couch, Steven M. ; Shriver, Erin M. ; Hayek, Brent R. ; Hink, Eric M. ; Woodward, Richard M. ; Gabriel, Kathleen ; Magni, Guido ; Douglas, Raymond S. / Teprotumumab for thyroid-associated ophthalmopathy. In: New England Journal of Medicine. 2017 ; Vol. 376, No. 18. pp. 1748-1761.
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AU - Smith, Terry J.

AU - Kahaly, George J.

AU - Ezra, Daniel G.

AU - Fleming, James C.

AU - Dailey, Roger A.

AU - Tang, Rosa A.

AU - Harris, Gerald J.

AU - Antonelli, Alessandro

AU - Salvi, Mario

AU - Goldberg, Robert A.

AU - Gigantelli, James W.

AU - Couch, Steven M.

AU - Shriver, Erin M.

AU - Hayek, Brent R.

AU - Hink, Eric M.

AU - Woodward, Richard M.

AU - Gabriel, Kathleen

AU - Magni, Guido

AU - Douglas, Raymond S.

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N2 - 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.

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