Breakthrough Treatment in Management of Thyroid Eye Disease

Effective therapeutic options for Graves’ ophthalmology have been elusive, which makes the favorable outcomes of an investigation monoclonal antibody that acts on the IGF-IR pathway great news for patients with thyroid disease.

with Raymond Douglas, MD, PhD, and Elena Christofides, MD

Results of the OPTIC trial, a phase 3, interventional, randomized, quadruple-masked, multinational clinical study, established the efficacy of teprotumumab, an investigational biologic drug developed to reduce proptosis and other thyroid-related ophthalmopathy during active disease,1 was presented by co-principal investigator, Raymond Douglas, MD, PhD, director of the orbital and thyroid eye disease program at Cedars-Sinai Medical Center in Los Angeles.

These investigators introduced the findings in a late-breaking presentation at AACE 2019, in San Francisco, California.

First treatment for thyroid eye diseases proves effective in clinical trial.

Finally, Effective Potential Treatment to Reduce Symptoms of Thyroid Eye Disease

As many as 20,000 individuals will experience thyroid eye disease (TED) in any given year; and by some accounts, it may occur in up to 50% of patients with Graves’ disease and in an estimated 4% of those with Hashimoto’s thyroiditis.2 The main symptoms in active disease include: proptosis, inverted eyelids, dry eyes, excessive tearing of the eyes, double vision, strabismus, and in the most serious cases, vision loss.

In seeking the first therapeutic agent to confer relief of symptoms associated with thyroid-associated ophthalmopathy, participants (n=88) were randomized to receive either the biologic or a placebo every three weeks by infusion over the course of 24 weeks; the net number of treatments were eight infusions.3 Initial dosing was 10 mg/kg, which was titrated to 20 mg/kg for the second dose then kept constant for the duration of the study. This human monoclonal antibody—teprotumumab—acts by targeting the insulin-like growth factor I receptor (IGF-IR).

At the outset, all enrolled patients presented with a severe form of active thyroid eye disease, characterized by significant orbital inflammation. Dropout rates were considered low (< 5%) with 79 patients completing the phase 3 study, and 82.9% of those in the drug treatment group meeting the primary outcome of at least a 2 mm reduction in proptosis,1,3 said Dr. Douglas.

Based on the results, the OPTIC phase 3 trial also met all secondary outcomes, including responder rate and clinical activity score of 0 or 1, a reduction in double vision of at least one grade, and improvement in quality of life scores.3

Dr. Douglas added that while the duration of the phase 3 clinical trial was 24 weeks,3 the investigators had evaluated patients in the earlier phase 2 study,which at 72 weeks showed that 53% of participants maintained at least a 2 mm reduction in orbital inflammation.

The phase 2 trial that also showed significant reduction in proptosis response (reduction of ≥ 2 mm), and clinical activity scores were similar in both studies,3,4 he said.

Pursuit of an effective treatment has focused on patients with active thyroid eye disease. When approved, teprotumumab will represent the first and only therapeutic to manage the active phase of Graves’ eye disease that occurs more often in women, as is typical in autoimmune disorders.

New Drug Blocks IGF-IR Mitigating Thyroid Eye Disease Symptoms

Unlike many other biologic drugs that target the immune system, teprotumumab works by different pathway, acting on the IGF-inhibition receptors, until a final FDA review is completed, it is not known whether there will be a need to advise monitoring of blood glucose, liver and cardiac function levels. However, adverse effects were minimal and the drug was well tolerated.3

While Graves’ eye disease is not life threatening, Dr. Douglas reports being the reciptient of hugs from patients once they begin treatment and experience favorable results. “Patients’ quality of life can suffer significantly due to this disease. It causes them to look different and they often withdraw from almost all of their social activity and avoid leaving the house. This drug is a game changer.”

When the trial was designed, a key question was dosing: “how much is enough” of the drug, Dr. Douglas told EndocrineWeb. “We figured that the [orbital] inflammation might improve, but the more problematic cases might require more intensive treatment.”

It is possible that the correct dosage may need to be customized to individual patients. “We might find out that some people need more, and some need less,” he said, “but for now, this [20 mg/kg] seems to be a sweet spot.

With release of the favorable outcomes data from the OPTIC trial,3 the investigators anticipate Food and Drug Administration approval of teprotumumab in the next year, during which physicians and patients have the opportunity to learn about the potential for treating active thyroid eye disease.

Raising Awareness of Need to Seek Treatment for Graves’ Ophthalmic Symptoms

In a survey conducted by Edmunds and Boelaert,5 the authors reported that patients with TED may lack the necessary knowledge about the symptoms and need for treatment, typically presenting late to ophthalmologists, often as long as nine months after their symptoms first appear.6

To gather responses, patients with a diagnosis of thyroid eye disease, Graves’ disease, and sex- and age-matched controls received a 20-question survey about TED. While the patients demonstrated better knowledge than did controls, there were some notable misconceptions about the condition.5 Thyroid eye disease patients scored a mean 14.25/20, Graves’ patients scored 13.71/20, and the controls scored 11.53/20.

There was, for example, a poor understanding among these patients regarding the impact that inadequate hyperthyroid management as well as cigarette smoking were major factors leading to increased risk of thyroid eye disease, and greater severity of symptoms.5

Only 40% of survey participants who had TED and 50% of patients with Graves’ disease realized that the disease may arise even in people who do not have hyperthyroidism. Also, patients believed that having a thyroidectomy would not only address their hyperthyroidism but also reduce their risk of developing TED.5

While the study findings seemed to emphasize the lack of knowledge, Elena Christofides, MD, FACE, an endocrinologist with Endocrinology Associates of Columbus, Ohio, said she was impressed at the level of knowledge that many of the participants had achieved. “It’s probably higher than a lot of residents-in-training with regard to Graves’ [thyroid] eye disease,” Dr. Christofides told EndocrineWeb.

Patients should be informed that thyroid eye disease may develop “at any time, and in anyone, whether they have thyroid disease or not,” she said. “Clinicians should stress the benefits of adopting or maintaining a healthy lifestyle [reducing stress, not smoking] is always the right answer to lessen the risk.”

Any time a patient has any concern about compromised vision, they should be referred to an eye care specialist. Both optometrists and ophthalmologists have the training to assess any symptoms, discuss preventive strategies, address concerns, and if appropriate, determine if thyroid eye disease is present.

“If patients complain that their eyes feel puffy, red, irritated or overly dry, these can be symptoms that should be evaluated.” They aren’t very specific symptoms, but those are usually the first that a patient has, Dr. Christofides said.

The phase 3 OPTIC Trial was sponsored by the drug manufacturer, Horizon Pharma USA.

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Liver Failure: A Turning Point in Graves' Disease Treatment
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