The disease is characterized by inflammation and a buildup of tissue around the eyes that cause them to bulge painfully from their sockets.

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There has never been a safe and effective treatment for Graves' eye disease, also known as thyroid eye disease (TED), for the 1 million Americans with the condition. Anti-inflammatory medicines offer inconsistent benefits. Orbital decompression surgery helps give some patients a more natural appearance, but only after the disease has run its course.

But a clinical trial led by the University of Michigan Kellogg Eye Center offers hope for those with moderate to severe active TED. Patients had a significant reduction in symptoms after treatment with teprotumumab, a study drug the Food and Drug Administration designated a "breakthrough therapy."

Most patients in the trial who got the active drug instead of a placebo had reduced eye bulging, eye pain and swelling and improved quality of life.

For some, the therapeutic benefit was rapid, occurring within six weeks of intravenous infusions of the drug that blocks what researchers say is an autoimmune attack on the muscles around the eyes.

Published in the New England Journal of Medicine, the clinical trial data represent a key milestone in research led by study principal investigators from the Kellogg Eye Center, Terry J. Smith, M.D., (pictured above) an endocrinologist and a professor of ophthalmology and visual sciences, and Raymond Douglas, M.D., Ph.D., a Graves' eye disease specialist and renowned oculoplastics surgeon.

The drug, however, cannot be prescribed to TED patients except in clinical trials. A follow-up clinical trial is underway but is not recruiting participants. It is expected to be complete in 2018.

"The findings suggest that teprotumumab may provide substantial benefit to patients and offer a therapy for avoiding complex surgery and preventing vision loss," says Smith, the lead study author.

Causes and action

TED is a rare condition associated with Graves' disease, an autoimmune disorder that causes an overproduction of thyroid hormone, or hyperthyroidism. Symptoms include swelling of the eyelids, constant stare, bulging eyes, eyelid retraction, optic neuropathy and double vision.

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About 25 to 50 percent of people with Graves' disease will develop TED, most of them women.

Previous findings in Smith's laboratory suggest that an insulinlike growth factor 1 receptor (IGF-1R) plays an important role in Graves' disease and other autoimmune diseases.

"Specifically, we have found that there is an unusually high presence of IGF-1 receptors on cells surrounding the eye in TED," says Smith, who is widely recognized for his groundbreaking research on treatments for TED and related autoimmune disorders.

Building on this discovery, an outgrowth of basic science research conducted at UCLA and then at the Kellogg Eye Center, Smith and colleagues initiated the study of thyroid-associated ophthalmopathy.

"The eyes are particularly susceptible to Graves' disease because the autoimmune attack often targets the eye muscles and connective tissue surrounding the eye," Douglas says. "This occurs as a consequence of these tissues containing proteins that are shared with the thyroid gland."

Study mechanics

The phase 2 clinical study, lasting 24 weeks and involving 88 patients, was the largest randomized, placebo-controlled multicenter TED trial. Patients were recruited between July 2, 2013, and Sept. 23, 2015, from 15 sites across the United States, as well as Italy, Germany and the United Kingdom.

Study investigators examined the benefit of teprotumumab, a monoclonal antibody shown to inhibit IGF-1 function. It was originally developed as a cancer drug.

Although teprotumumab failed to exhibit efficacy in patients with cancer, the team thought it might be useful in interrupting the TED disease process.

At the end of the trial, 69 percent of study patients receiving infusions of teprotumumab once every three weeks had reduced eye bulging (proptosis), improved vision and increased quality of life compared with 20 percent in the placebo group.

Patients were randomly assigned to receive either a placebo or an active drug. Neither participants nor researchers knew which substance was being used so they could describe what happened in the trial without bias.

Promising results

Many participants showed improvement within six weeks when, according to the study, a reported 43 percent of patients in the treatment group had a response, compared with 4 percent in the placebo group.

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Patients who responded to treatment reached the study's primary end point of a reduction by 2 points or more in the severity of the disease, which was measured on a 7-point clinical activity score, and reduction by 2 mm or more in the degree of proptosis. Secondary end points included better quality of life.

Those in the treatment group had a baseline clinical activity score of 5.1. The marked reduction in proptosis is similar to results surgical patients would expect, authors note.

"The findings have implications for other autoimmune diseases in which IGF-1 reception has already been implicated, such as rheumatoid arthritis," Smith says.

The most common side effect of treatment was nausea. Muscle spasms and diarrhea were also reported, particularly among patients with gastrointestinal disease. The only drug-related adverse event was hyperglycemia in patients with diabetes; these events were controlled by adjusting medication for diabetes.

The results provide inroads for a new therapy to safely minimize the severity of the eye condition.

"The study is an important step in achieving registration of teprotumumab as the first approved therapy to prevent TED symptoms," says Guido Magni, chief medical officer of River Vision Development Corp.

River Vision sponsored the study and collaborated with academic researchers on the study design. Researchers received grants from the National Institutes of Health, the National Eye Institute, the Bell Charitable Foundation, Research to Prevent Blindness and others. River Vision received an orphan drug grant from the FDA.