This a randomized, double-masked, placebo-controlled, phase 3 multicenter trial evaluated the insulin-like growth factor I receptor (IGF-IR) inhibitor teprotumumab for treating thyroid eye disease.

Study design

Patients with active moderate to severe TED were assigned, in a 1:1 ratio, to receive intravenous infusions of teprotumumab (41 patients) or placebo (42 patients) once every 3 weeks for 21 weeks. The primary outcome measure was a proptosis reduction of 2 mm or more. Secondary outcomes measures included rate of overall response (a reduction of ≥2 points in the Clinical Activity Score [CAS] plus a reduction in proptosis of ≥2 mm) and CAS scores of 0 or 1 (indicating no/minimal inflammation), as well as proptosis improvement, diplopia response, and the mean change in Graves’ ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire scores across trial visits (mean change of ≥6 points is considered clinically meaningful).

Outcomes

At 24-week follow up, 83% of patients in the teprotumumab group had a proptosis response compared with 10% in the placebo group (P<0.001). All secondary outcomes were significantly better in the teprotumumab group, including overall response (78% vs. 7%), CAS of 0 or 1 (59% vs. 21% ), mean change in proptosis (−2.82 mm vs. −0.54 mm), diplopia response (68% vs. 29%) and mean change in GO-QOL overall score (13.79 vs. 4.43 points).

Reductions in extraocular muscle, orbital fat volume or both were observed in six patients in the teprotumumab group who underwent orbital imaging. Adverse events, which occurred in at least 5% of patients in both trial groups, were mild or moderate in severity and included hyperglycemia in two patients, hearing impairment in five patients and an infusion reaction in one patient that led to treatment discontinuation.

Limitations

Limitations include the lack of long-term follow-up to determine the drug’s durability. Of note, in the phase 2 trial previously published in the NEJM in May 2017, the efficacy of teprotumumab was maintained for up to 48 weeks in most patients. Additionally, the sample size of 41 patients is relatively small and the population included patients with active TED with a CAS of 4 or more. More studies are still needed to understand the efficacy in patients with mild, active TED or stable disease. Furthermore, studies comparing the efficacy of teprotumumab vs IV steroids, orbital radiation and other targeted therapies such as tocilizumab are necessary.

Clinical significance

Teprotumumab was approved by the FDA in January 2020 for the treatment of thyroid eye disease based on this phase 3 study and a previous phase 2 study. The results of this study show a convincing improvement in proptosis, diplopia, CAS score and quality of life in active, moderate to severe TED patients. It is possible that future studies will demonstrate that this drug will benefit patients suffering from less severe forms of TED. Additional studies are on-going and will continue to shape the treatment of TED.