Teprotumumab for Thyroid-Associated Ophthalmopathy

Abstract

BACKGROUND Thyroid-associated ophthalmopathy, a condition commonly associated with Graves’ disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy. METHODS We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves’ ophthalmopathy–specific quality-of-life questionnaire. Adverse events were assessed. RESULTS In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes. CONCLUSIONS In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997.)

Factors associated with the efficacy of intravenous methylprednisolone in moderate‐to‐severe and active thyroid‐associated ophthalmopathy: A single‐centre retrospective study

“…15 In the present study, we did not find a significant correlation between smoking and therapeutic efficacy either. 6,29 The other two retrospective studies mentioned above did not take passive smoking into account either. In the observational study, patients were divided into never-smokers, active smokers and passive smokers.…”

Antibodies to watch in 2020

“…Teprotumumab was granted Fast Track, Breakthrough Therapy and Orphan Drug designations for Graves' orbitopathy by the FDA. 34 Based on positive data from both Phase 2 (NCT01868997) 35 and Phase 3 (NCT03298867) studies, Horizon Pharma submitted a BLA to the FDA for teprotumumab as a treatment for TED. The BLA was granted priority review, and FDA's PDUFA target action date is March 8, 2020.…”

Cambridge Ophthalmological Symposium 2018: introduction and reflections on the day

“…Others find little evidence for IGF1R autoantibodies being elevated in TED [8], while Neumann and co-workers suggest that cross-talk between TSHR and IGF1R, following the activation of TSHR, has a central role in TED pathogenesis [9]. This model could be compatible with the dramatic improvements in proptosis following treatment with an IGF1R antagonist, teprotumumab, reported by Smith et al [10].…”

“…Teprotumumab is a human monoclonal antibody that binds with IGF1R and was originally developed to treat cancer. When applied to the treatment of TED it improves proptosis and thus must affect adipogenesis, proliferation, fibrosis and/or ECM production either directly or indirectly [10]. I was delighted that Prof. Terry Smith accepted our invitation to describe this seminal clinical trial and the science that underpins it.…”