Teprotumumab: interpreting the clinical trials in the context of thyroid eye disease pathogenesis and current therapies.

Abstract

Teprotumumab, a monoclonal antibody targeted against the insulin-like growth factor-1 (IGF-1) receptor, was recently approved by the United States Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED). Phase I studies of teprotumumab for the treatment of malignancies demonstrated an acceptable safety profile but limited effectivity. Basic research implicating the IGF-1 receptor on the CD-34+ orbital fibrocyte in the pathogenesis of TED renewed interest in the drug. Two multicenter, randomized, double-masked, clinical trials (phase II and phase III) evaluated the efficacy of 8 infusions of teprotumumab every 3 weeks vs. placebo in 170 patients with recent onset, active TED as defined by a clinical activity score (CAS) of at least 4. Teprotumumab was superior to placebo for the primary efficacy endpoints in both studies: overall responder rate as defined by a reduction of ≥2 CAS points and a reduction of ≥2 mm in proptosis (69% vs 20%, p<0.001, phase II) and proptosis responder rate as defined by a reduction of ≥2 mm in proptosis (83% vs 10%, p<0.001, phase III). In both studies, treatment with teprotumumab compared with placebo achieved a significant mean reduction of proptosis (-3.0 mm vs -0.3 mm, phase II; -3.32 mm vs -0.53 mm, phase III) and CAS (-4.0 vs -2.5, phase II; -3.7 vs -2.0, phase III). Teprotumumab also resulted in a greater proportion of patients with a final CAS of 0 or 1, higher diplopia responder rate, and a larger improvement in the Graves Ophthalmopathy Quality of Life (GO-QoL) overall score. Over half of patients (60%, phase II; 56% phase III) who were primary endpoint responders maintained this response at 51 weeks following the last dose of therapy. The most common adverse events reported with teprotumumab included muscle spasms (25%), nausea (17%), alopecia (13%), diarrhea (13%), fatigue (10%), hearing impairment (10%), and hyperglycemia (8%). Teprotumumab is contraindicated for those with inflammatory bowel disease and in pregnancy. Although the current dosing regimen has proven effective for TED, dose ranging studies including variable concentrations, infusion frequencies, and durations of teprotumumab therapy in the setting of TED have not been performed.