Raymond S Douglas1, George J Kahaly2, Shoaib Ugradar3, Heike Elflein4, Katharina A Ponto5, Brian T Fowler6, Roger Dailey7, Gerald J Harris8, Jade Schiffman9, Rosa Tang9, Sara Wester10, Amy Patel Jain11, Claudio Marcocci12, Michele Marinò12, Alessandro Antonelli13, Anja Eckstein14, Dagmar Führer-Sakel15, Mario Salvi16, Saba Sile17, Megan Francis-Sedlak17, Robert J Holt17, Terry J Smith18. 1. Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: Raymond.Douglas@cshs.org. 2. Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany. 3. The Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, California. 4. Department of Ophthalmology, Johannes Gutenberg University Medical Center, Mainz, Germany. 5. Department of Ophthalmology, Johannes Gutenberg University Medical Center, Mainz, Germany; Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany. 6. Health Science Center, University of Tennessee, Memphis, Tennessee. 7. Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon. 8. The Medical College of Wisconsin Eye Institute, Milwaukee, Wisconsin. 9. Eye Wellness Center-Neuro-Eye Clinical Trials, Inc., Houston, Texas. 10. Bascom Palmer Eye Institute, University of Miami, Miami, Florida. 11. Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California. 12. Endocrine Unit 2, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy. 13. Department of Surgical, Medical and Molecular Pathology and Critical Care, University of Pisa, Pisa, Italy. 14. Department of Ophthalmology, EUGOGO Center Essen, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 15. Department of Endocrinology, Diabetes and Metabolism, EUGOGO Center Essen, University Hospital Essen, University of Duisburg-Essen. 16. Endocrinology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 17. Horizon Therapeutics plc, Deerfield, Illinois. 18. Department of Ophthalmology and Visual Sciences and Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
Abstract
PURPOSE: To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare. DESIGN: The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial. PARTICIPANTS: Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC. METHODS: OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score [CAS], or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks. MAIN OUTCOME MEASURES: Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life. RESULTS: Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, -3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during the first course of treatment, and 2 events reoccurred after re-treatment. CONCLUSIONS: Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.
PURPOSE: To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare. DESIGN: The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial. PARTICIPANTS: Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC. METHODS: OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score [CAS], or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks. MAIN OUTCOME MEASURES: Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life. RESULTS: Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, -3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during the first course of treatment, and 2 events reoccurred after re-treatment. CONCLUSIONS: Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.