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    New Drug Targets Challenge of Thyroid Eye Disease

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    For the first time, a medication has been approved that can stop and modify the debilitating and sight-threatening pathology of thyroid eye disease. Teprotumumab (Tepezza) gained expedited approval from the FDA in January.

    The drug is a fully human monoclo­nal antibody inhibitor of the insulin-like growth factor I receptor (IGF-IR), which orbital fibroblasts and B and T cells overexpress in Graves disease and thyroid eye disease (TED).1

    TED “is really burdensome for patients. It impairs their vision, in ad­dition to causing their facial disfigure­ment and double vision. Teprotumumab is the first medication that reverses all of those things, and with mild to moderate side effects,” said Raymond S. Douglas, MD, PhD, one of the principal investigators in OPTIC, the study that led to the FDA’s approval. “My patients are just thrilled. This has been a real game-changer.”

    Effect of Treatment

    EFFECT OF TREATMENT. A patient with thyroid eye disease before and after treatment with teprotumumab. The drug was administered intravenously once every three weeks during the 24-week trial; evaluation of effectiveness is continuing beyond that point.

    OPTIC results. Earlier this year, re­searchers published results of OPTIC, a phase 3 trial.2 In this study, 41 patients with TED received a total of eight in­travenous infusions of teprotumumab, spaced three weeks apart. They showed significantly greater improvement in their disease at 24 weeks than did the 42 participants who received placebo.

    The trial achieved its primary out­come—a reduction in proptosis of 2 mm or more—in 83% of the treated patients at 24 weeks. This compared to 10% in the placebo group (p < 0.001).

    Early disease improve­ment. More than half of the treated patients (56%) reached this study marker in as few as six weeks, and they continued to improve through 24 weeks, said Dr. Douglas, at Cedars-Sinai Medical Center in Los Angeles.

    Additional findings. The study also found significantly greater improvements in the treated patients’ secondary outcomes (p ≤ 0.001 for all), the researchers reported. These clinical measures in­cluded overall response (78% of treated patients vs. 7% of the placebo group); Clinical Activity Score of 0 or 1 (59% vs. 21%); the mean change in proptosis (−3.32 mm vs. −0.53 mm); and diplo­pia response (68% vs. 29%).

    In addition, improvement was noted in a 16-item quality of life (QoL) questionnaire specific to Graves disease (mean change of 17.28 points in treated patients vs. 1.80 points in the placebo group). This self-administered ques­tionnaire includes questions on visual and psychosocial functioning; a mean change of at least 6 points is considered clinically significant.

    Side effects. Adverse events associ­ated with the drug were mild to moder­ate in most cases and included muscle spasms (32%), alopecia (20%), nausea (15%), fatigue (12%), and diarrhea and headache (both 10%), the researchers reported. There were two serious ad­verse events: an infusion reaction that resolved with corticosteroid treatment, and pneumothorax that was considered unrelated to the drug.

    Mechanism of action. Previous research has shown that teprotumumab blocks the pathologic immune responses of active TED by reducing signaling by both IGF-IR and thyrotropin receptors.1 Unchecked, the activated receptors lead to the formation of physical and func­tional molecular complexes that trigger hyaluronan accumulation and expres­sion of cytokines, which in turn cause inflammation, edema, and expansion of extraocular muscle and adipose tissue, Dr. Douglas said.

    It is not clear how long the drug’s ability to inhibit the receptors will per­sist beyond 24 weeks, Dr. Douglas said. The drug manufacturer is conducting a postmarketing study intended to help clarify this issue, he said.

    A new paradigm? Looking ahead, the approval of teprotumumab rep­resents “a pivotal moment” in the treat­ment of TED, Dr. Douglas said. “I con­sider this a generational medication. I think our fellows who are training now will be hard-pressed to remember the times before teprotumumab came on the market for TED, much like the times before biologics came on the market for rheumatoid arthritis” and revolutionized treatment for that disease.

    —Linda Roach


    1 Smith TJ, Janssen JAMJL. Endocr Rev. 2019;40(1):236-267.

    2 Douglas RS et al. N Engl J Med. 2020;382(4):341-352.


    Relevant financial disclosures—Dr. Douglas: Horizon Therapeutics: C.

    For full disclosures and the disclosure key, see below.

    Full Financial Disclosures

    Dr. Dishler Carl Zeiss: C.

    Dr. Douglas Horizon Therapeutics: C.

    Mr. Han Support from the University of Queensland Research Training Scholarship and Queensland Institute of Medical Researcher Berghofer PhD Top Up Scholar­ship.

    Dr. Lam None.

    Disclosure Category



    Consultant/Advisor C Consultant fee, paid advisory boards, or fees for attending a meeting.
    Employee E Employed by a commercial company.
    Speakers bureau L Lecture fees or honoraria, travel fees or reimbursements when speaking at the invitation of a commercial company.
    Equity owner O Equity ownership/stock options in publicly or privately traded firms, excluding mutual funds.
    Patents/Royalty P Patents and/or royalties for intellectual property.
    Grant support S Grant support or other financial support to the investigator from all sources, including research support from government agencies (e.g., NIH), foundations, device manufacturers, and/or pharmaceutical companies.


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