By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
Earlier this year, the FDA approved the first drug for the treatment of thyroid eye disease (Graves’ orbitopathy or thyroid-associated ophthalmopathy). Teprotumumab is a fully human IgG1 that is an inhibitor of insulin-like growth factor-1 receptor (IGF-1R).1 It received priority review and fast track, breakthrough, and orphan designations. Teprotumumab is distributed as Tepezza.
Teprotumumab should be prescribed to treat thyroid eye disease.1
The recommended initial dose is 10 mg/kg by IV infusion, followed by 20 mg/kg every three weeks for seven additional infusions.1 Infusion should occur over a 60- to 90-minute period (90 minutes for the first two infusions). Teprotumumab is available as 500 mg lyophilized powder in a single-dose vial.
Teprotumumab is the first FDA-approved treatment for thyroid eye disease.
Teprotumumab can harm the fetus, cause infusion reactions, and exacerbate inflammatory bowel disease and hyperglycemia.1 Patients with diabetes should be under appropriate control before initiating treatment with teprotumumab. The most frequent adverse reactions (vs. placebo) include muscle spasm (25% vs. 6%), nausea (17% vs. 9%), alopecia (13% vs. 8%), diarrhea (12% vs. 8%), and fatigue (12% vs. 7%).1
Thyroid-associated ophthalmopathy (TAO) is a rare autoimmune disease of the thyroid gland.2 It is a disfiguring and potentially sight-threatening condition as the soft tissue around the eyes become inflamed and undergoes remodeling. This results in disfigurement and disability from proptosis and diplopia. IGF-1R is overexpressed in several cell types in TAO and may be involved in the disease process.2
Teprotumumab’s efficacy and safety were evaluated in two randomized, double-masked, placebo-controlled studies.1,3,4 Subjects (86% white, 73% female) with thyroid eye disease and who were euthyroid or had thyroxine and free triiodothyronine levels less than 50% above or below normal limits were randomized to teprotumumab (n = 42 in study 1; n = 41 in study 2) or placebo (n = 45 in study 1; n = 42 in study 2). Proptosis ranged from 16 mm to 33 mm, and 73% had diplopia at baseline.
The primary outcome was a proptosis response, defined as a reduction of ≥ 2 mm from baseline in the study eye without a corresponding increase of ≥ 2 mm at week 24 in the nonstudy eye.
Diplopia was evaluated in a subgroup of subjects with diplopia at baseline. Proptosis responses were 71% in study 1 and 83% in study 2 compared to 20% and 10%, respectively, for placebo. The mean changes from baseline were -2.5 mm (vs. 0.2 mm for placebo) in study 1 and -2.8 mm (vs. -0.5 mm) in study 2. Improvement in proptosis was observed in week 6 and continued to improve through week 24. Diplopia improved in 53% of subjects compared to 25% for placebo. In study 1, 53% of responders maintained their proptosis response 51 weeks after the last dose, and 67% of diplopia responders maintained their response.1
TAO is a rare condition affecting more women than men. Before approval of teprotumumab, there were no FDA-approved medical therapies for TAO. Mild disease is characterized by dry eyes, lid retraction, and modest ocular prominence.5 Generally, this is managed with local supportive measures, such as topical ocular solutions and short-course oral steroids with or without nonsteroidal anti-inflammatory agents.5
With moderate to severe disease, periorbital tissue remodeling occurs; corticosteroids usually are administered alone or with orbital radiotherapy, but with limited success. The active disease course is usually one to three years, followed by stable disease.5 These patients often undergo multiple surgical and cosmetic procedures.5
Teprotumumab is the first treatment for TAO that ameliorates several manifestations of TAO, including those that were previously amenable only to surgical rehabilitation.2 The cost is $14,900 per vial. A treatment course (six months) is estimated to be $343,000.6
- Horizon Therapeutics USA, Inc. Tepezza prescribing information. January 2020.
- Smith TJ, Janssen JAMJL. Insulin-like growth factor-I receptor and thyroid-associated ophthalmopathy. Endocr Rev 2019;40:236-267.
- Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 2017;376:1748-1761.
- Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med 2020;382:341-352.
- Smith TJ. Challenges in orphan drug development: Identification of effective therapy for thyroid-associated ophthalmopathy. Annu Rev Pharmacol Toxicol 2019;59:129-148.
- Inserro A. FDA approves biologic teprotumumab, first drug for thyroid eye disease. AJMC. Jan. 21, 2020.