Teprotumumab Improves Bulging, QOL in Thyroid Eye Disease

Nancy A. Melville

November 05, 2019

CHICAGO — Teprotumumab, a monoclonal antibody inhibitor of the IGF1 receptor, shows efficacy, including improvements in quality of life, in the treatment of moderate to severe thyroid eye disease.

"In the largest placebo-controlled evaluation thus far conducted in patients with active to severe thyroid eye disease, teprotumumab reduced proptosis, inflammation, and diplopia, resulting in marked quality of life improvements as compared with placebo at 24 weeks," said co-author George J. Kahaly, MD, PhD, who presented the findings of a combined evaluation of phase 2 and 3 data at the 89th American Thyroid Association (ATA) Annual Meeting.

"This is the first drug that seems to be disease modifying for thyroid-eye disease and for reducing proptosis," said Kahaly, of the Thyroid Research Lab at Gutenberg University Medical Center, Mainz, Germany.

Kahaly has consulted for Horizon Therapeutics, which is developing teprotumumab and funded the trials.

Thyroid eye disease occurs in up to 50% of people with Graves disease, potentially causing proptosis, or bulging of the eye, and vision-threatening complications, yet there are currently no approved treatments specific for the condition, with therapy typically involving steroids, or in severe cases, surgery.

Teprotumumab's biologics license application with the US Food and Drug Administration (FDA) has been granted breakthrough therapy, orphan drug, and fast-track designations for Graves ophthalmopathy. A decision on approval is expected by March 2020.

Asked by an audience member if teprotumumab could potentially replace steroids for treatment or be used as a combination therapy, Kahaly said that, if approved, it "will probably become the frontline treatment for thyroid eye disease," but a better picture of the role the drug could play will emerge with more trials.

"We need head-to-head studies to compare teprotumumab with other therapies, but we know that steroids have notable side effects. We have to await the follow-up and long-term results, but what you can say is we have never seen such convincing results with other drugs," he noted.

Asked to comment, Leonidas H. Duntas, MD, PhD, agreed that, although these results are promising, more rigorous comparisons are needed.

"We really need more studies," he told Medscape Medical News. "We must evaluate the drug in comparison with other treatment modalities and not just placebo."

Duntas is a professor at the University of Athens Medical School, Greece.

Integrating Study Results for Largest Dataset in Thyroid Eye Disease

Teprotumumab inhibits the IGF1 signaling pathway, which is key in activating thyroid eye disease and drives the expansion of orbital tissue, fat cells, and muscle that occurs with the disease.

Kahaly presented findings from two 24-week randomized controlled trials of patients with active and severe eye disease of recent onset who had not received treatment. The study received funding from Horizon Therapeutics.

The 88 patients in the phase 2 study, published in 2017 in the New England Journal of Medicine, and 83 patients in the phase 3 OPTIC trial, first presented in April 2019, as reported by Medscape Medical News, were divided about half-and-half to treatment either with teprotumumab infusion or placebo every third week, for a total of eight infusions.

There were no significant differences between the groups in characteristics including age, gender, race, tobacco use, or duration of disease.

Overall, 73.8% of patients in the trials' two teprotumumab groups (n = 84) were responders, with significant improvements in proptosis and on the seven-item clinical activity score, compared with 13.8% of those in the placebo groups (n = 87) at week 24 (P < .001).

In terms of proptosis, specifically, 77.4% of teprotumumab-treated patients had at least a 2-mm or more reduction in eye bulging compared to 14.9% in the placebo group (P < .001), with a mean reduction of 3.14 mm in the treatment group versus 0.37 mm in the placebo group over the 24 weeks.

And among those with baseline diplopia, or double vision, 69.7% had at least a one-grade improvement at week 24, compared with 30.5% in the placebo group (P < .001).

Improvement in the Graves ophthalmopathy quality of life scores changed from baseline by 15.6 points in the teprotumumab group compared with 5.9 in the placebo group (P < .001). Significant improvements were also observed in visual functioning and appearance for those treated with teprotumumab compared with placebo (both P < .001).

Treatment-emergent adverse events that occurred in 5% or more of patients included muscle spasms, occurring in 25% of teprotumumab-treated patients versus 7% of placebo; nausea, in 17% versus 9%; and alopecia, in 13% versus 8%.

There were seven (8.3%) reports of serious adverse events in the teprotumumab group versus one in the placebo group, with two of the seven in the teprotumumab group believed to be related to treatment including diarrhea and infusion-related reactions, and those events led to discontinuation of the study drug.

One case of Hashimoto's encephalopathy was possibly related to the study drug and led to treatment interruption.

A Good Choice for Treatment-Resistant Thyroid Eye Disease?

Duntas told Medscape Medical News, "Many patients with thyroid eye disease are treatment-resistant, and especially for those [teprotumumab] could be a very good therapeutic advancement."

Kahaly agreed, noting, "We are aiming to look at the efficacy of the drug not just in those who are untreated but those who are resistant to other drugs," and in addition, "patients with chronic thyroid eye disease as well."

89th ATA Annual Meeting. Abstract #6. Presented November 2, 2019.

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