Glycemic Trends in Patients with Thyroid Eye Disease Treated with Teprotumumab in 3 Clinical Trials.

PURPOSE: Assess incidence, severity, and glucose excursion outcomes in thyroid eye disease (TED) patients receiving the insulin-like growth factor-1 receptor inhibitor teprotumumab from 3 clinical trials. DESIGN: Analysis of pooled glycemic data over time. PARTICIPANTS: Eighty-four teprotumumab- and 86 placebo-treated active TED patients from the phase 2 and phase 3 (OPTIC) controlled clinical trials and 51 teprotumumab-treated patients from the OPTIC extension (OPTIC-X) trial. METHODS: Eight intravenous infusions were given over 21 weeks. Phase 2 serum glucose was measured at weeks 1, 4, 15, and 21, with fasting measurements at weeks 1 and 4. Serum glucose was measured at each study visit in OPTIC and OPTIC-X, with fasting measurements at weeks 1 and 4 (in patients without diabetes) or all visits (in patients with diabetes). In all studies, hemoglobin A1c (HbA1c) was measured at baseline, 12, and 24 weeks plus weeks 36 and 48 in OPTIC-X. MAIN OUTCOME MEASURES: Serum glucose and HbA1c. RESULTS: In the phase 2 and 3 studies, 9 hyperglycemic episodes occurred in 8 teprotumumab patients; mean HbA1c level increased 0.22% from baseline to week 24 (to 5.8%; range, 5.0%-7.9%) versus 0.04% in patients receiving the placebo (to 5.6%; range, 4.6%-8.1%). At study end, 78% (59/76) of teprotumumab patients and 87% (67/77) of patients receiving placebo had normoglycemic findings. Normoglycemia was maintained in 84% (57/68) of patients receiving teprotumumab and 93% (64/69) of patients receiving placebo. Among baseline prediabetic patients, 43% (3/7) remained prediabetic in both groups, and 29% (2/7) of teprotumumab patients and 14% (1/7) of patients receiving placebo had diabetic findings at week 24. OPTIC-X patients trended toward increased fasting glucose and HbA1c whether initially treated or retreated with teprotumumab. Fasting glucose commonly rose after 2 or 3 infusions and stabilized thereafter. Most hyperglycemic incidents occurred in patients with baseline prediabetes/diabetes but were controlled with medication. No evidence was found for progression or increased incidence of hyperglycemia with subsequent doses. CONCLUSIONS: Serious glycemic excursions are uncommon in patients with normoglycemia before teprotumumab therapy. Patients with controlled diabetes or impaired glucose tolerance can be treated safely if baseline screening, regular monitoring of glycemic control, and timely treatment of hyperglycemia are practiced. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Assessment of hearing dysfunction in patients with Graves' disease and thyroid eye disease without or with teprotumumab.

IMPORTANCE: Thyroid eye disease (TED) negatively impacts quality of life. TED occurs predominantly in Graves' disease (GD). Teprotumumab improves TED but concern for hearing adverse events (AEs) has emerged. Hearing dysfunction is reported in thyroid autoimmune disease but the background prevalence in GD/TED without teprotumumab remains uncertain. OBJECTIVE: To quantify ear-related diagnostic codes/hearing AEs in GD, TED, and patients receiving teprotumumab by examining medical claims and clinical trials. DESIGN AND PARTICIPANTS: Deidentified claims for ear/labyrinth-related ICD-10 codes (KOMODO®) were examined in GD patients without TED, and TED patients without/with teprotumumab treatment. Hearing AE incidence/severity was evaluated in teprotumumab clinical trials. Graves' Ophthalmopathy QOL (GO-QOL) scores were compared in teprotumumab TED trial patients without/with hearing AEs. RESULTS: GD (469,720), TED (38,566) and teprotumumab-treated (967) patients were identified in the claims database. Ear-related codes (including those not specific for hearing) occurred in 24% GD, 33% TED, and 32% teprotumumab-treated patients. "Sensorineural hearing loss bilateral" was most frequent: 32,961/469,720 (7%) GD, 4,279/38,566 (11.1%) TED, and 104/967 (10.8%) teprotumumab patients. Pre-teprotumumab use,165 (17.1%) patients had ear-related codes while 98 (10.1%) had new ear-related codes post-treatment.Eight teprotumumab oncology trials revealed 8.1% (51/633) had Ear/Labyrinth Disorders with 2.1% (13) considered study-drug-related and 3.8% (24) hearing impairment/tinnitus-related AEs, with 1.3% (8) considered teprotumumab-related. Similar rates occurred in TED trials.GO-QOL improved in teprotumumab-treated patients without/with hearing AEs. Incidence/severity was consistent across patients with chronic and acute TED. CONCLUSIONS: These analyses indicate similar occurrence of hearing claims in patients with GD/TED alone as following teprotumumab treatment. Future analyses of incremental hearing risk from teprotumumab should utilize a priori study designs accounting for background hearing dysfunction in patients with GD/TED.