FDA Approves First Drug for Thyroid Eye Disease

The new drug is a game changer for patients with TED

With Raymond Douglas MD PhD and Andrew Harrison MD

The drug reduces the telltale orbital swelling that is a symptom of Graves' disease.

Thyroid Eye Disease (TED) is an autoimmune inflammatory disease of the eye most often found in patients with Graves' Disease and hyperthyroidism. About 25-50% of Graves' patients develop TEDand there may be a bimodal emergence of it. A large number of patients are diagnosed in their 40’s while another group is diagnosed in their 60’s. Several environmental factors are associated with an increased risk for TED, most notably smoking.


TED is visible by a bulging of the eyeballs (proptosis), periorbital edema, and eyelid retraction. Beneath the physical appearance, there is orbital inflammation and fibrosis, reduced eye motility and alignment (strabismus), and a breakdown of corneal epithelium due to lack of moisture (exposure keratopathy). Severe cases can lead to chronic fibrosis and damage to the optic nerve.

TED can be active or quiescent, often alternating between the two states. During active TED, the proptosis, edema, and other symptoms are readily apparent. Active stages usually self-resolve over the course of months or years.


Most TED patients, besides maintaining an euthyroid state, can be treated with supportive care during the active state, including:

  • ocular lubrication
  • topical cyclosporine
  • sodium restricted diet
  • selenium support
  • sunglasses if photophobic
  • elevating the head during sleep


Smoking can prolong the active TED state as well as make it more severe, with enhanced proptosis and more frequent episodes of double-vision (diplopia). Even though many cases are ultimately mild and resolve, TED can diminish the quality of life and early treatment can prevent permanent damage to the eye and optic nerve.

Autoimmune disorders, such as Graves' and TED, are complex and sometimes difficult to treat. Understanding the cellular and molecular components, even in part, can help develop effective treatments.

It is generally agreed that the orbital fibroblasts are the major effectors behind the autoimmune inflammatory effects of TED. Unlike other fibroblasts, those found in the tissues supporting the eye express thyroid stimulating hormone receptors (TSHR), insulin-like growth factor-1 receptors (IGF1-R), and the CD40 receptor. TSH1-R and IGF1-R stimulate fat production (adipogenesis) and the production of extracellular matrix proteins, like hyaluron and glycosaminoglycans, resulting in enlargement of the surrounding orbital tissues. Further, IGF1-R is involved with cytokine production and regulators of oxidative stress, which further stimulates the inflammatory response surrounding the eye. CD20 receptors respond to T-cells and B-cells, enhancing the inflammation.

Corticosteriod treatments have historically been used to treat TED for their powerful anti-inflammatory effects. However, a new treatment was approved by the FDA, one which targets the role of IGF1-R in TED. When asked why TED patients need a new drug, Raymond Douglas MD, Ph.D of the Departments of Surgery and Ophthalmology at Cedars-Sinai Medical Center in Los Angeles told Endocrine Web, “Corticosteroids treat the inflammation only. They do not change the disease: the bulging, swelling, and changes in vision. These are corrected by surgery. Teprotumumab, though, reverses the disease.”

A new targeted TED therapy against IGF1-R

In January of 2020, Teprotumumab was approved by the FDA for the treatment of TED in Graves' Disease patients. Teprotumumab is a human-derived monoclonal antibody against IGF1-R, effectively blocking the inflammatory responses of IGF1-R on orbital fibroblasts and reducing the effects of TED.

We asked Dr. Douglas why IGF1-R was the therapeutic target over TSH-R. He replied, “IGF1-R is expressed at higher levels in the orbital tissues than TSH-R, and in TED patients, its expression is even higher. Early studies showed that stimulating the IGF1 receptor was the most likely candidate for producing the tissue effects of TED.”

Successful clinical trials lead to FDA approval

In the Phase 2 random, double-blind, placebo-controlled clinical study, Teprotumumab or a saline-placebo were given intravenously (IV) once every three weeks for 24 weeks to patients with Graves' Disease. Inclusion criteria were:

  • Active TED with an onset less than 9 months
  • Clinical Activity Score (CAS) ≥ 4
  • Euthyroid
  • No previous surgical treatment for TED
  • No oral/IV steroids for non-TED reasons in the previous 3 months

Patients were excluded if they had optic neuropathy, unresponsive corneal compensation, poorly controlled diabetes, low hemoglobin, or platelet count < 100x10^9/L.

The primary outcome compared the number of responders in each group, or those patients that had a reduction in CAS score of at least 2 points and a reduction in proptosis of at least 2 mm by 24 weeks.

TED patients respond to Teprotumumab treatment

Significantly more patients were classified as responders in the Teprotumumab group (69%) than in the placebo group (20%). Furthermore, the average CAS score dropped by 3.4 points and proptosis was down by 2.46 mm in the treated group.

The Graves' Ophthalmology Quality of Life (GO-QoL) scores, a secondary outcome, also showed a significant improvement with Teprotumumab treatment, both in the overall score and in the visual functioning subscale.

Details of the Phase 2 results were published by Smith et al. in the New England Journal of Medicine (NEJM), where they report that Teprotumumab treatment was effective in some patients as early as 6 weeks.

The Phase 3 clinical study supported all results of its predecessor study, with 82.9% of Teprotumumab treated patients falling into the responder category.

Further analysis of the Teprotumumab results

Recently, the patient data of the Phase 2 and 3 studies were analyzed in a single study to determine if specific TED patients were more likely to benefit from Teprotumumab treatment. TED does not affect patients evenly: women are affected more than men, smokers have prolonged and more severe active TED states, and those diagnosed over 50 years old tend to have a poorer prognosis.  

In the re-analysis of the combined data sets, it was found that Teprotumumab was equally beneficial to all subgroups. Proptosis was reduced by 3.1 mm in women and 3.3 mm in men. Smokers had a 2.99 mm reduction while non-smokers had a 3.2 mm reduction. Lastly, older patients (>65 years old) had the greatest benefit at 3.6 mm reduction in proptosis. Despite some variation, there were no statistically significant differences between the groups.

A game changer for TED patients

By treating patients early in an active state of TED, chronic fibrosis and potential optic nerve damage can be avoided. Andrew R. Harrison MD, Director of Oculoplastic and Orbital Surgery at the University of Minnesota is enthusiastic about Teprotumumab and what it means for his patients. He says:

“The use of this drug is a game changer for treating TED. For 20 years I have said to my patients, ‘One day there will be a magic bullet for your disease.’ This drug is just that. It provides results as good, or better, than our surgical treatments, such as orbital decompression. By treating early, we are able to spare these patients years of misery due to the functional limitations and physical appearance changes caused by TED.”

Dr. Douglas reports receiving consulting fees from Horizon Therapeutics. Dr. Harrison reports no current conflicts with regard to discussing this study.

Continue Reading:
Duration of Graves' Disease Remission Following Anti-thyroid Drug Therapy
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