Teprotumumab Effective for Thyroid-Associated Ophthalmopathy
The New England Journal of Medicine
The pathogenesis of thyroid-associated ophthalmopathy, which is commonly associated with Graves disease, is poorly understood, and current treatments are inconsistently effective and potentially unsafe. Smith et al. investigated whether teprotumumab was effective at treating active ophthalmopathy. They found that the drug, a human monoclonal antibody that inhibits insulin-like growth factor I receptor (IGF-IR), was more effective than placebo in reducing proptosis and Clinical Activity Score (CAS).
This double-masked, 3-phase multicenter trial involved 87 patients (age range, 18-75 years) with ophthalmopathy who were diagnosed within 9 months after symptom onset and had a CAS tally of ≥ 4 points (out of 7) in the study eye. During the 24-week intervention phase, patients were assigned randomly to receive either 8 intravenous infusions of teprotumumab (n = 42) or placebo (n = 45), with 1 infusion delivered at baseline (10 mg/kg) and the others (20 mg/kg) delivered at 3-week intervals. The primary outcome was response in the study eye, defined as a decrease of ≥ 2 points in CAS and ≥ 2 mm in proptosis by week 24. Secondary outcomes included proptosis and CAS results (i.e., continuous variables). Adverse events (AEs) were evaluated as safety endpoints.
By week 24, 29 of 42 teprotumumab recipients (69%) demonstrated a response, versus 9 of 45 patients (20%) in the placebo group. Onset of response occurred earlier in the teprotumumab group, with 18 of 42 patients (43%) responding by week 6, versus 2 of 45 patients (4%) in the placebo group. Between-group differences increased with time. Most AEs were mild and resolved without treatment. Hyperglycemia, the only drug-related AE, was controlled with medication adjustments.
Although 1-year follow-up is ongoing, the authors concluded that 24-week teprotumumab therapy is clinically beneficial for active moderate-to-severe thyroid-associated ophthalmopathy. The comprehensive effects suggest that the therapeutic mechanism is upstream from the orbital inflammation. The U.S. Food and Drug Administration has since designated teprotumumab a breakthrough therapy.
The original article can be found here.