Disclosures: Kahaly reports his institution received research-associated funding from Horizon Therapeutics for the study. Please see the study for all other authors’ relevant financial disclosures.
April 23, 2021
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Teprotumumab improves short- and long-term clinical outcomes in thyroid eye disease

Disclosures: Kahaly reports his institution received research-associated funding from Horizon Therapeutics for the study. Please see the study for all other authors’ relevant financial disclosures.
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Most adults with thyroid eye disease receiving an infusion of teprotumumab every 3 weeks for a 24-week period had a reduction of at least 2 mm in proptosis, with a long-term response observed in 67% of participants, according to study data.

George J. Kahaly

“These analyses provide insight into both the short-term and long-term efficacy and safety of teprotumumab and are clinically relevant as all objective signs and symptoms of thyroid eye disease, especially proptosis and diplopia, which can be resistant to medical therapy, were markedly and significantly improved with teprotumumab,” George J. Kahaly, MD, PhD, a professor of medicine, endocrinology and metabolism at Johannes Gutenberg University Medical Center in Mainz, Germany, and colleagues wrote in a study published in The Lancet Diabetes & Endocrinology. “The responses are probably due to a reduction in orbital fat and extraocular muscle volume, which characteristically expand in thyroid eye disease, as shown with orbital imaging.”

More than three-fourths of participants in the teprotumumab treatment group had a proptosis reduction of 2 mm or greater after 24 weeks. Data were derived from Kahaly GJ, et al. Lancet Diabetes Endocrinol. 2021;doi:10.1016/S2213-8587(21)00056-5.

Kahaly and colleagues conducted two randomized, double-masked, placebo-controlled trials of similar design. One trial was conducted with adults aged 18 to 75 years at 15 specialized centers in Europe, and the second trial involved adults aged 18 to 80 years from 13 centers in the U.S. Participants in both studies had a diagnosis of Graves’ disease and recent-onset, active thyroid eye disease. Patients were randomly assigned to eight IV infusions of teprotumumab (Tepezza, Horizon Therapeutics) or placebo every 3 weeks, with the final study visit taking place at week 24.

Teprotumumab reduces proptosis, improves diplopia

The two studies combined had 84 participants randomly assigned to teprotumumab and 87 in the placebo group. More patients receiving teprotumumab had at least a 2 mm reduction in proptosis compared with placebo at 24 weeks (77% vs. 15%; P < .0001). The teprotumumab group had a mean proptosis reduction of –3.14 mm vs. a reduction of –0.37 mm for placebo. All subgroups had a greater integrated proptosis response with teprotumumab vs. placebo, and the mean proptosis reduction was similar in all subgroups.

In the teprotumumab group, 70% had a one grade improvement in diplopia response at 24 weeks vs. 31% in the placebo group. There was also a greater proportion of people with diplopia resolution in the teprotumumab group vs. placebo (53% vs. 25%; P = .0007). The diplopia response was different in all subgroups except tobacco users and those with a thyrotropin-binding inhibiting immunoglobulin concentration of less than 10 IU/L at baseline.

Participants receiving teprotumumab had improved overall response in clinical activity score and proptosis at every time point. Those in the teprotumumab group also had a greater improvement in Graves’ ophthalmopathy quality of life score compared with placebo.

In participants with long-term follow-up data available at 51 weeks in the European trial and who remained in follow-up in the U.S. trial, 67% retained proptosis reduction at follow-up, 69% were diplopia responders, and improvements in composite ophthalmic outcome were observed in 83%. Improvements in quality of life scores remained through week 72 for patients who took teprotumumab.

Few serious adverse events reported

At 24 weeks, most of the adverse events in the placebo and teprotumumab groups were mild to moderate. Seven of 84 patients receiving teprotumumab had serious adverse events, with three serious adverse events possibly related to teprotumumab leading to study discontinuation. In the teprotumumab group, the risk for muscle spasms was 18% higher than placebo, the risk for hearing loss was 10% higher, and hyperglycemia risk was 8% greater.

“The efficacy of teprotumumab is accentuated by a positive benefit-risk profile, which was further shown in our integrated and follow-up analyses and further safety analyses are ongoing,” the researchers wrote. “Adverse events were generally transient and well managed, with no new events identified during the follow-up of the two clinical trials.”

The researchers wrote that further research is needed in patients with chronic eye disease as well as larger, more diverse populations. However, the trial results provided evidence that the drug could improve thyroid eye disease outcomes in the long term.

“Given that teprotumumab selectively targets the insulin-like growth factor I receptor and based on the clinical results reported here, this treatment has the potential for substantially modifying the clinical course of thyroid eye disease,” the researchers wrote.