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New Treatment Breakthrough for Thyroid Related Eye Disease

Published on August 1, 2017

Thyroid Eye Disease
The thyroid gland can be the target of autoimmune disease. For reasons not well understood, the soft tissues around the eyes can also be affected. There are two different conditions produced by autoimmune diseases that affect the thyroid gland and involve the soft tissues around the eyes. One is Hashimoto’s disease and the other is Graves’ disease. Graves’ disease is more common and can cause severe disfigurement and dysfunction. Graves’ disease more commonly affects women and it usually presents in the 20-40 year old age range. It does occur in both men and women and may appear at any age. The incidence of Graves’ hyperthyroidism is as high as 200 cases per 100,000. Commonly the incidence is quoted as 20-50 cases per 100,000. Hyperthyroid symptoms are related to over-activity of the thyroid gland. These included weight loss, heat intolerance, palpitations, as well as mood disorders and anxiety. Treatments are far from ideal and are associated with significant side effects. Treatments including the use of corticosteroids and radiation therapy to control the inflammation of the eye tissues have been less than ideal. Surgery is often necessary to address the changes to the eyes.

A New Treatment
Research in the past decade has focused on an immune therapy to interrupted disease process in Graves’ disease. One the factors that seems to be active in Graves’ disease is an insulin-like growth factor (IGF-I) and its corresponding cell receptor (IGF-IR). Investigators reasoned that this receptor is over-expressed in Graves’ disease. This prompted the clinical study of a molecule that blocks the insulin-like growth factor receptor. An experimental compound from the family of monoclonal antibodies was chosen. The compound, R1507, has been shown experimentally to successfully block fibroblast over activity seen in Graves’ disease. This compound is now known as teprotumumab. It has received orphan drug status by the FDA. Teprotumumab has also been given fast track designation for wider study in patients suffering from Graves disease. Raymond Douglas and Terry Smith at the University of Michigan are at the center of much of this work.

Investigating Teprotumumab
These investigators along with co-workers at 15 other institutions recently published a promising double blind study in the New England Journal of Medicine in May of 2017. Their study examined patients with recent onset of thyroid related ophthalmopathy with clinical activity scores of at least 4 on a 7-point scale. They excluded patients with prior surgical treatment or who had received significant doses of steroids. Patients who met these basic criteria were screened initially and randomized to 24 weeks of treatment with teprotumumab or placebo. A change of 2 points on a 7-point scale was considered a response to treatment. Other measures included exophthalmometry, which measures how prominent the eyes are, and an assessment of double vision. A questionnaire was also administered (GO-QOL) that assesses the subjective impact of the disease. During the 24 weeks of treatment, study participants received an infusion of either a placebo of injectable sterile salt water or teprotumumab (10 mg per kg for the initial infusion, and 20 mg per kg thereafter). Investigators at the study site were unaware if the participant was receiving placebo (salt water) or teprotumumab. These treatments were performed every 3 weeks during the 24 weeks of study.

Study Outcome
Following treatment, there was a 48-week follow-up period. A response was defined to be a 2 mm or more reduction in proptosis and also a reduction in the clinical activity score of at least 2 points when measured at week 24. In total, there were 39 patients in the placebo group and 37 teprotumumab group patients who completed the treatment. Overall, 9 of 45 of the placebo treated patients and 29 of 42 of the teprotumumab treated patients had a response at 24 weeks (statistically significant at the P<0.001 level). Of those responding, patients receiving teprotumumab had a faster onset of response, and more had reductions of 3 mm or more in proptosis, a reduction of 3 or more points in their clinical activity score, and improvement in visual functioning measured with a quality of life scale adapted for Grave’s disease. Adverse events associated with teprotumumab include elevations in blood sugar in individuals without diabetes. This was seen in more than 5% of study patients. There were no study deaths. Six patients discontinued treatment in each treatment group (placebo and teprotumumab). Authors attributed two serious adverse events (diarrhea and mental confusion) as possibly related to teprotumumab infusion.

Study Implications
The study suggests teprotumumab is a significant and potentially breakthrough treatment for thyroid eye disease. In contrast to prior treatment options, which have demonstrates limited or no reduction in proptosis, teprotumumab produced a reduction in proptosis that rivaled surgical decompression. There are significant limitations to the study including the fact that no study related imaging was performed and there is no long-term follow up of these patients. However, this study is encouraging and this treatment offers the possibility of medically managing thyroid eye disease without the complications of steroids and the need for surgical management. Larger confirmatory studies will help clarify the role of teprotumumab for the treatment of thyroid eye disease but there is sufficient data here to recommend this treatment for individuals with new onset thyroid eye disease and activity scores of 4 or more.

1. Pritchard J, Han R, Horst N, et. al. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves’ disease is mediated through the insulin-like growth factor I receptor pathway. J Immunol. 2003; 170:6348-54.
2. Smith, TJ, Kahaly GJ, Ezra DG, et. al. Teprotumumab for thyroid-associated ophthalmopathy. NEJM. 2017; 376: 1748- 1761.

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