Teprotumumab for Thyroid-Associated Ophthalmopathy
- 4 May 2017
- journal article
- research article
- Published by Massachusetts Medical Society in The New England Journal of Medicine
- Vol. 376 (18), 1748-1761
- https://doi.org/10.1056/nejmoa1614949
Abstract
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; ClinicalTrials.gov number, NCT01868997.)Keywords
This publication has 42 references indexed in Scilit:
- The adverse events profile of anti-IGF-1R monoclonal antibodies in cancer therapyBritish Journal of Clinical Pharmacology, 2014
- R1507, a Monoclonal Antibody to the Insulin-Like Growth Factor 1 Receptor, in Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors: Results of a Phase II Sarcoma Alliance for Research Through Collaboration StudyJournal of Clinical Oncology, 2011
- Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?Pharmacological Reviews, 2010
- A Phase I Study of Weekly R1507, A Human Monoclonal Antibody Insulin-like Growth Factor-I Receptor Antagonist, in Patients with Advanced Solid TumorsClinical Cancer Research, 2010
- Increased Generation of Fibrocytes in Thyroid-Associated OphthalmopathyJournal of Clinical Endocrinology & Metabolism, 2010
- Reactivation of Graves’ Orbitopathy after Rehabilitative Orbital DecompressionOphthalmology, 2007
- Comparison of the Effectiveness and Tolerability of Intravenous or Oral Glucocorticoids Associated with Orbital Radiotherapy in the Management of Severe Graves' Ophthalmopathy: Results of a Prospective, Single-Blind, Randomized StudyJournal of Clinical Endocrinology & Metabolism, 2001
- Thyrotropin Receptor Expression in Graves' Orbital Adipose/Connective Tissues: Potential Autoantigen in Graves' OphthalmopathyJournal of Clinical Endocrinology & Metabolism, 1998
- Expression of thyrotropin-receptor mRNA in healthy and Graves' disease retro-orbital tissueThe Lancet, 1993
- Autoantibodies to Igf-1 Binding Sites in Thyroid Associated OphthalmopathyAutoimmunity, 1993