Teprotumumab therapy has been found to markedly improve the clinical course of thyroid eye disease across multiple patient subgroups, with patients maintaining this response over the long-term, according to research published in Lancet Diabetes Endocrinology.

Teprotumumab was the first drug approved by the US Food and Drug Administration (FDA) to treat thyroid eye disease. In the study, researchers sought to evaluate the aggregate response to teprotumumab from 2 pivotal trials with a focus on responses to the primary severity components of thyroid eye disease: proptosis and diplopia. The researchers drew conclusions from 17 articles published between database inception and January 2021.

Through these integrated analyses, the investigators were able to evaluate the effect of teprotumumab on multiple patient subgroups — men, smokers, older patients, those with longer disease duration, those with more progressive disease, and those with higher thyrotropin receptor antibodies — as well as off-treatment follow-up analyses 7 and 51 weeks after the final dose.

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The current analyses included integrated outcomes and follow-up data from 2 randomized, double-masked, placebo-controlled, multicenter studies in Europe and the US (Study 1, ClinicalTrials.gov Identifier: NCT01868997; Study 2, ClinicalTrials.gov Identifier: NCT03298867).

Participants included adult patients with Graves disease and active thyroid eye disease of recent onset (≤9 months duration). Patients were randomly assigned 1:1, stratified by smoking status, to receive either teprotumumab or placebo. Participants received 8 intravenous infusions of either teprotumumab (10 mg/kg bodyweight for the first infusion, then 20 mg/kg for subsequent infusions) or placebo every 3 weeks. The final study visit was at 24 weeks, which was 3 weeks after the final infusion.

The primary efficacy endpoint for these integrated analyses was the proportion of patients with a proptosis response of ≥2 mm in the study eye without deterioration in the fellow eye at week 24. Secondary endpoints included the proportion of patients with improvement in subjective diplopia, overall response to treatment, and disease inactivation.

The intent-to-treat population included 87 study participants randomly assigned to placebo and 84 participants randomly assigned to teprotumumab. In both groups, 91% of patients completed the study, and key demographic characteristics were considered to be well balanced between groups.

More patients in the integrated analysis who received teprotumumab vs placebo achieved at least a 2-mm reduction in proptosis (77% vs 15%) at week 24 (stratified treatment difference, 63%; 95% CI, 51-75). These patients also demonstrated a greater mean change from baseline at week 24 (-3.14 and -0.37, respectively; difference, -2.77 mm; 95% CI, -3.23 to -2.31).

All sensitivity analyses demonstrated a higher proportion of proptosis responders among teprotumumab-treated patients.

Integrated proptosis response was higher with teprotumumab in all subgroups and ranged from a 47% difference in tobacco users to an 83% difference in patients 65 years of age and older. All patients who completed treatment demonstrated some level of proptosis improvement from baseline with teprotumumab therapy.

At all visits, diplopia response rate was also higher in the teprotumumab group. By week 24, 70% of patients in the teprotumumab group improved by 1 grade or more (treatment difference, 39%; 95% CI, 23-55), and 53% of those in the teprotumumab group demonstrated diplopia resolution (vs 25% in the placebo group; treatment difference, 28%; 95% CI, 12-44).

Constant diplopia also improved in 71% of the teprotumumab group vs 18% of the placebo group. Across subgroups, the diplopia treatment difference was higher with teprotumumab except in tobacco users (29% difference, 95% CI, -3 to 62) and in those with thyrotropin binding inhibiting immunoglobulins (TBII) less than 10 IU/L at baseline (31% difference; 95% CI, -3 to 65). There were also more diplopia responders in the teprotumumab group than in the placebo group in the high TBII subgroup (71% vs 23%; difference, 48%; 95% CI, 15-81). No significant difference between the 2 TBII groups was noted in post-hoc analyses of diplopia response.

In terms of overall response, clinical activity score (CAS) 0 or 1 and CAS alone were significantly improved in the teprotumumab group vs the placebo group. Overall response and each CAS component were improved in each group at 24 weeks. Those in the lower and higher baseline CAS subgroups (groups 4 or 5 and 6 or 7) demonstrated improvements with teprotumumab therapy vs placebo for proptosis and diplopia endpoints.

Patients in the teprotumumab group also experienced a greater improvement in the Graves ophthalmopathy quality of life (GO-QOL) questionnaire score at 24 weeks compared with the placebo group, as reflected in mean total, visual functioning, and appearance subscales. Total GO-QOL score improved by a least-squares mean of 19.0 and 6.3 points in each group, respectively.

At week 24, improvement in visual functioning and appearance subscales was 19.7 and 17.78 points, respectively, in the teprotumumab group and 7.0 points and 5.6 points in the placebo group.

In terms of follow-up data, there was no evidence for acute disease rebound at week 28. In study 1, at 51 weeks 67%, 69%, and 83% of patients were proptosis, diplopia, and composite outcome responders. In Study 2, the investigators saw large mean increases from baseline in total GO-QOL score during the same time period.

Most adverse events that occurred during the first 24 weeks of the study were mild to moderate. Seven patients in the teprotumumab group had serious adverse events; 3 participants reported diarrhea, infusion reaction, and Hashimoto encephalopathy, which were deemed “possibly related” to teprotumumab and led to study discontinuation.

No new safety concerns were identified during follow-up. No serious adverse events during the follow-up period were related to teprotumumab, and no deaths were reported. Nine patients experienced adverse events related to teprotumumab, including diabetes, muscle spasms, skin and subcutaneous tissue disorders, hyperglycemia, and abnormal lactate dehydrogenase and alkaline phosphate concentrations.

Study limitations include the small number of patients followed through 72 weeks after treatment initiation, the paucity of follow-up visits in Study 1, and the differences in follow-up protocols between the 2 trials, as well as the inclusion of patients with concomitant Graves disease and thyroid eye diseases 9 months or less after diagnosis.

“Given that teprotumumab selectively targets the insulin-like growth factor-1 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 concluded.

Disclosure: This clinical trial was supported by Horizon Therapeutics. Please see the original reference for a full list of authors’ disclosures.


Kahaly GJ, Douglas RS, Holt RJ, Sile S, Smith TJ. Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomized, double-masked, placebo-controlled, multicenter trials. Lancet Diabetes Endocrinol. 2021;9(6):360-372. doi: 10.1016/S2213-8587(21)00056-5