A global clinical trial and new AI-driven research projects aim to elevate treatment of Graves’ orbitopathy.

Vanderbilt Eye Institute orbital disease specialists are pioneering research to improve treatments for thyroid eye disease (TED), also known as Graves’ disease.

An autoimmune condition, also known as Graves’ orbitopathy, can occur alongside TED but also may occur independently.

Treatment options for TED have been limited, but the pace of discovery is advancing rapidly as researchers home in on key targets that mediate inflammation and fibrosis in TED.

“This is an exciting time to be treating this disease,” said co-investigator Rachel Sobel, M.D. “As we better understand the underlying biology of thyroid eye disease, we’re able to take a more targeted approach to treatment. Some drugs, like satralizumab, were approved for treating other autoimmune conditions, and some are being newly created in the lab.”

“As we better understand the underlying biology of thyroid eye disease, we’re able to take a more targeted approach to treatment.”

Thyroid eye disease develops when imbalanced hormone production from the thyroid gland triggers an inflammatory attack on muscles and tissues surrounding the eye. A bulging eye, or proptosis, is a common visible symptom, causing disfigurement and visual disability.

The first treatment option offered was teprotumumab, a monoclonal antibody (MAB) that locks on to insulin growth factor 1 receptor (IGF1R), which is closely associated with the thyroid stimulating hormone receptor. By blocking the receptor closely associated with the target antigen in TED, the disease enters dormancy.  

As soon as teprotumumab (Tepezza) was approved by the U.S. Food and Drug Administration in 2020, Vanderbilt physicians began treating patients with the medicine, said Louise Mawn, M.D., lead investigator of TED research and oculoplastics division chief at VEI.  

Now, VEI has joined a global group of leading eye-research centers to investigate satralizumab, a newer and potentially more advantageous MAB treatment for TED. This drug targets interleukin-6, an inflammatory chemical or cytokine, which surges in the bloodstream with many autoimmune diseases.

“A self-administered medication like satralizumab is going to decrease the burden on patients and their families to be able to get treatment,” said Behin Barahimi, M.D., who is assisting with the study, along with nurse coordinator Tracy Powell.

Testing a New and Potentially Improved MAB

The SatraGO-2 trial is one of two identical phase III studies sponsored by drug manufacturer Genentech investigating satralizumab for treating adults with currently active or chronic inactive TED.  Spanning 40 sites in 15 countries, the two studies have a total anticipated enrollment of 120 patients.

The research will test the drug’s ability to significantly reduce proptosis associated with thyroid eye disease.

“Several unique aspects of this new trial are encouraging,” Mawn said. “For one, satralizumab is offered as an injection rather than as an infusion like teprotumumab. This means, if it’s successful, satralizumab could be self-administered by patients in the comfort of home.”

Additionally, satralizumab could be effective over a longer duration compared to teprotumumab, because it circulates in the bloodstream and binds repeatedly to the IL-6 receptor.

Mawn is pleased that, unlike many blind trials, everyone who participates in the satralizumab trial will ultimately receive the drug.

“After 24 weeks, those placed on a placebo will move on to get the treatment. So as a clinical trial, it really aligns with our research principles of justice and encourages us to invite patients to join,” she said.

“After 24 weeks, those placed on a placebo will move on to get the treatment, so it really aligns with our research principles of justice and encourages us to invite patients to join.”

As with treating any autoimmune condition, testing this new therapy risks triggering a wide range of side effects. Mawn notes that VEI’s team will evaluate and monitor participants carefully.

“MABs that target IL-6 can exacerbate diverticulosis and diverticulitis, so that is one of the conversations we have prior to treatment,” she said. “Some of these drugs can also elevate blood sugar and cause hearing problems. We will send patients for hearing evaluations before and after treatment if treated with a drug that could potentially cause hearing issues.”

Getting Ahead of TED Progression

Testing new therapeutics is not VEI’s only foray into game-changing research and treatment for thyroid eye disease.

The center will be joining a national collaborative of eye research institutions establishing a HIPAA-compliant database of TED patient images to use in artificial intelligence analysis. The project will generate predictive insights into how visual signs of TED could assist in earlier referral to specialists.

“We have patients who are hypothyroid and develop thyroid eye disease, as well as many who are in a hyperthyroid state, such as Graves’ disease, who may or may not,” Sobel said. “Then, there are some with no underlying thyroid problem, but have the autoantibodies for TED.”

The team hopes to determine which patients within this broad spectrum are most prone to getting the disease, and what signs may predict severe development.

“In the past, we’ve had to tackle these questions using epidemiological clues — for example, we know that patients who smoke have a greater likelihood of developing the disease,” Sobel said. “But it is exciting to try to garner new insights from big data.”

While recent treatment advances for TED are leaping forward, research shows the disease is analogous to other autoimmune diseases that require ongoing treatment.

“Developing additional modalities for the treatment of this disease is essential,” Mawn said. “It really has a devastating impact on patients.”

About the Expert

Louise Mawn, M.D.

Louise Mawn, M.D., is a professor of ophthalmology and neurological surgery at Vanderbilt University Medical Center. Her primary research interest is the surgical treatment of orbital disease, including advances in orbital biomaterials and development of endoscopic approaches.

Rachel Sobel, M.D.

Rachel Sobel, M.D., is an assistant professor in the Department of Ophthalmology and Visual Sciences at Vanderbilt University Medical Center. Her areas of expertise are eyelid surgery, brow lifting, Mohs reconstructive surgery, orbital tumors, tear duct surgery, thyroid eye disease, eye removal, trauma and cosmetics.

Behin Barahimi, M.D.

Behin Barahimi, M.D., is an oculoplastic, orbital and reconstructive surgeon at Vanderbilt Eye Institute.