Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials

Abstract

Summary Background Thyroid eye disease manifests inflammation and treatment-resistant proptosis and diplopia. Teprotumumab, an insulin-like growth factor-1 receptor inhibiting monoclonal antibody, was approved in the USA on Jan 21, 2020, on the basis of two randomised trials. In this analysis we evaluated the short-term and long-term aggregate response to teprotumumab from the two trials, focusing on proptosis and diplopia. Methods We analysed integrated outcomes and follow-up data from two randomised, double-masked, placebo-controlled, multicentre, trials done at a total of 28 academic referral tertiary specialised centres offering joint thyroid eye clinics, or orbital clinics or practices, or both, in Europe and the USA. Participants were adult patients with a diagnosis of Graves' disease and active moderate-to-severe thyroid eye disease (clinical activity score [CAS] ≥4). Patients received eight intravenous infusions of either teprotumumab (10 mg/kg body weight for the first infusion, 20 mg/kg for subsequent infusions) or placebo every 3 weeks. The final study visit was at week 24, 3 weeks after the final infusion. In our analysis, the prespecified primary outcome was the between-group difference from baseline to week 24 in the proportion of patients with a proptosis response (≥2 mm reduction in the study eye without similar deterioration in the fellow eye at week 24) stratified by tobacco non-use and current use. Secondary endpoints at week 24 were the proportion of patients with improved diplopia (≥1 Bahn–Gorman grade), an overall response (reduction of ≥2 mm in proptosis and reduction of ≥2 points in CAS), mean change from baseline in proptosis measurement in the study eye, mean change from baseline in Graves' ophthalmopathy quality of life (GO-QOL) questionnaire scores (overall, visual functioning, and appearance), and the proportion of patients with disease inactivation (ie, a CAS score of 0 or 1). We also assessed data for the primary and secondary outcomes by patient subgroups (tobacco use; age Findings The pooled ITT population consisted of 84 patients assigned teprotumumab and 87 assigned placebo. More patients receiving teprotumumab achieved a reduction of at least 2 mm in proptosis at week 24 versus placebo (65 [77%] of 84 patients assigned teprotumumab vs 13 [15%] assigned placebo; stratified treatment difference 63%, 95% CI 51–75; p Interpretation Teprotumumab markedly improved the clinical course of thyroid eye disease in all patient subgroups examined from the two trials, with most patients maintaining responses in the long-term. Analyses of the effect of teprotumumab retreatment on non-responders and those who flare after response, as well as further studies in a broader population of thyroid eye disease are ongoing. Funding Horizon Therapeutics.