SAT-554 Teprotumumab in Graves' Orbitopathy: Extended Outcome Analyses

Objective A multicenter, double-masked, randomized, placebo-controlled, phase two trial of 88 patients with active, moderate-to-severe Graves’ orbitopathy (GO) has demonstrated a significant and rapid response to teprotumumab, an insulin-like growth factor 1 receptor inhibitory monoclonal antibody, when compared with placebo after 24 weeks (N Engl J Med 2017; 376:1748). We now report extended primary and secondary outcome analyses. Methods Seven weeks after final dose of study medication (week 28), the primary and secondary endpoints were analyzed in teprotumumab intent-to-treat patients as compared with placebo to assess possible relapse. This included the primary composite endpoint of percentage patients with ≥2 points reduction in clinical activity score (CAS, seven-point scale) and a reduction of ≥2 mm in proptosis, secondary endpoints of proptosis, CAS, diplopia grade, specific GO quality of life questionnaire (GO-QoL), and exploratory analyses of clinical severity, all in the study (more severely affected) eye. Results Thirty-one of 42 (74%) teprotumumab- and six of 45 (13%) placebo- treated patients reached the primary outcome at treatment week 28 (p<0.001). Response was maintained from end of treatment period (week 24) in 93% of those teprotumumab-treated patients who responded. Proptosis response was similar to the primary outcome, with 55% of those receiving teprotumumab having a high response (≥3mm decrease). Gender, race, smoking or baseline proptosis values did not impact proptosis response. At week 28, 37/42 (88%) of those receiving teprotumumab and 27/45 (60%) getting placebo reached the CAS outcome (p=0.003). All individual CAS components were different from placebo (p≤0.04) except eyelid erythema (p=0.06). Assessment of CAS and severity of GO favored teprotumumab: chemosis (percent of patients ≥1 grade reduction; p=0.11), swelling of eyelid (percent of patients ≥1 grade reduction; p=0.01) and lid aperture (percent of patients ≥2 mm reduction; p=0.09). From baseline there was a reduction in constant diplopia (36% vs 9.5%) and increase in those with no diplopia (9.5% vs. 50%) in the teprotumumab group. At week 24, significantly more teprotumumab-receiving patients had improved by ≥one grade than placebo (62% vs. 22%, p<0.001). Improvement of diplopia grade remained significant at week 28 off drug. Overall GO-QoL was higher in those receiving teprotumumab than in patients getting placebo (p<0.001). Teprotumumab did not affect thyroid function, which was stable in both study groups through the treatment phase and follow-up. Conclusions Teprotumumab reduced the composite primary outcome of proptosis and CAS, as well as improved diplopia and GO-QoL significantly at seven weeks following study treatment discontinuation. This analysis also indicates that proptosis can serve as a primary and sensitive outcome for future trials of therapeutic response in GO.