A Paradigm Shift in the Management of Thyroid Eye Disease How Teprotumumab Has Changed the Therapeutic Interface

Teprotumumab, a monoclonal antibody that blocks the insulin-like growth factor-1 receptor, has recently been approved by the US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED). Since its approval, aside from data on the safety and clinical efficacy of teprotumumab from Phase-2 and Phase-3 trials, only a handful of reports have been published regarding its use in the wider population.

State-of-the-Art Review Section Editors: Fiona Costello, MD, FRCP(C) Sashank Prasad, MD A Paradigm Shift in the Management of Thyroid Eye Disease How Teprotumumab Has Changed the Therapeutic Interface Shoaib Ugradar, MD, Andrea L. Kossler, MD, Raymond Douglas, MD PhD, Kimberly Cockerham, MD Background: Teprotumumab, a monoclonal antibody that blocks the insulin-like growth factor-1 receptor, has recently been approved by the US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED). Since its approval, aside from data on the safety and clinical efficacy of teprotumumab from Phase-2 and Phase-3 trials, only a handful of reports have been published regarding its use in the wider population. In this review, we briefly describe the mechanism of action of teprotumumab and review the literature to provide an overview of published clinical experience. This information was used to provide recommendations for patient selection, management of patient expectations, infusion details and site options, tips to optimize the authorization process, and how to monitor and mitigate side effects. Evidence Acquisition: A systemic review of the literature was performed regarding teprotumumab, focusing on its mechanisms of action and published reports on its use on patients with TED. A review of Embase, Medline (PubMed), Web of Science, and Google Scholar was conducted. Results: Clinical experience following the approval of teprotumumab has confirmed its efficacy in reducing inflammation and proptosis in patients with acute TED (,2 years). The reduction in proptosis occurs due to a reduction in orbital fat and muscle volume. Furthermore, there is evidence for its use in patients with compressive optic neuropathy. There are also reports that show its effiDepartment of ophthalmology (SU), the Jules Stein Eye Institute, University of California, Los Angeles, California; Byers Eye Institute at Stanford University School of Medicine (ALK, KC), Palo Alto, California; Cedars Sinai Medical Center (RD), Los Angeles, California; Central Valley Eye Medical Group (KC), Stockton, California A. L. Kossler: Horizon Therapeutics, Osmotica; R. Douglas: Horizon Therapeutics, Osmotica, ValenzaBio, Viridian; K. Cockerham: Horizon Therapeutics, Viridian. The remaining author reports no conflict of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Shoaib Ugradar, MD, Department of ophthalmology, the Jules Stein Eye Institute, UCLA, Los Angeles, CA 90025; E-mail: [e-mail] 26 cacy in reducing proptosis, inflammation, and diplopia in patients with chronic TED (.2 years). Teprotumumab was associated with side effects, such as muscle spasm, hearing loss, and hyperglycemia. To date, 2 case reports have shown a possible association with flares of inflammatory bowel disease. Conclusions: Teprotumumab is a powerful therapeutic option for the treatment of TED. Clinical experience following FDA approval has demonstrated efficacy in treating patients with acute and chronic TED. It is the only therapeutic option that has been shown to reduce orbital soft tissue expansion in TED. However, it is expensive, and sometimes, obtaining insurance authorization can be time consuming and difficult. Further work will reveal its full side effect profile and help to establish its role in the armamentarium used to treat TED. Journal of Neuro-Ophthalmology 2022;42:26–34 doi: 10.1097/WNO.0000000000001515 © 2022 by North American Neuro-Ophthalmology Society eprotumumab is the first and only Food and Drug Administration (FDA)–approved medication for the treatment of thyroid eye disease (TED). At the time of writing, aside from the clinical information from the original trials on the safety and efficacy of teprotumumab (1–4), only a handful of clinical reports have been published (5– 17). This review discusses the mechanism of action of teprotumumab and provides an overview of real-world experience with teprotumumab 21 months after the approval. T EVOLVING CONCEPTS IN THE MANAGEMENT OF THYROID EYE DISEASE The pathophysiology and natural history of TED are discussed in Supplemental Digital Content 1 (See Supplement 1, http://links.lww.com/WNO/A557). Traditionally, the active phase of TED has been treated medically with Ugradar et al: J Neuro-Ophthalmol 2022; 42: 26-34 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review corticosteroids or orbital radiation therapy (ORT). Intravenous (IV) corticosteroids have been found to be more effective and better tolerated than oral corticosteroids (1–3). Corticosteroids may reduce inflammatory signs and symptoms but do not improve proptosis. Additionally, side effects to corticosteroids are common, and serious complications, such as hepatotoxicity, have been reported in patients receiving a cumulative dose greater than 8 g of methylprednisolone. Contraindications to steroid therapy include recent hepatitis, liver dysfunction, cardiovascular morbidity, severe hypertension, poorly controlled diabetes, and severe steroid-responsive glaucoma. Biologic agents such as rituximab and tocilizumab have also been tried. Rituximab is a chimeric monoclonal antibody targeting CD20, and it depletes CD20-carrying B cells. Two small clinical trials reviewed the impact of rituximab in TED. In the first study, 15 of 15 patients had a clinically significant decrease in the clinical activity score (CAS) ($2 points in CAS and ultimately, CAS ,3) after 24 weeks; however, at this stage, none of the patients receiving rituximab had $2 mm reductions in proptosis (18). In a second study of 25 patients, rituximab did not significantly improve CAS, proptosis, diplopia, or quality of life, and failed to reduce orbital soft tissue volume. The use of rituximab is also further complicated by the potential for serious adverse events (19). Tocilizumab, an interleukin-6 receptor monoclonal antibody, is under consideration as a potential treatment for TED. Interleukin-6 is a proinflammatory cytokine produced by a variety of cells, including monocytes, and T and B lymphocytes (20). In a recent, randomized, clinical trial (RCT) (NCT01297699) (21), 93% of patients treated with tocilizumab vs 58.8% receiving placebo had a reduction in the CAS of $2 points at Week 16 (P = 0.04; odds ratio, 9.8; 95% confidence interval, 1.3–73.2). However, tocilizumab failed to significantly improve diplopia. Furthermore, the median reduction in proptosis at Week 16 was only 1.5 mm, which may not be clinically significant (22). Furthermore, 93 adverse events were reported among 27 patients: the most common being headache (11 tocilizumab vs 4 placebo) and infection (17 vs 7). ORT remains controversial but can be helpful in the early active phase of disease in select patients. The longterm benefit from ORT is debated, as a prospective RCT found no clinically significant improvement in the volume of extraocular muscles and fat, proptosis, or retraction with ORT at 6 months and 12 months in patients with mild-tomoderate TED (4). A review of 5 observational studies and 9 RCTs concluded with Level 1 evidence that proptosis, eyelid retraction, and soft tissue changes do not improve with ORT (23). While the aforementioned therapies reduce inflammation in active moderate-to-severe TED, they do not have a sustainable, significant effect on disease outcomes, including proptosis and diplopia. Once signs of the active phase have Ugradar et al: J Neuro-Ophthalmol 2022; 42: 26-34 subsided, patients typically undergo a staged surgical approach to address proptosis, strabismus, and eyelid changes. Surgery in the active phase is usually limited to cases of sight-threatening disease. MECHANISM OF ACTION OF TEPROTUMUMAB Teprotumumab is a monoclonal antibody that blocks the insulin-like growth factor-1 receptor (IGF-1R), which can form a physical and functional association with the thyroidstimulating hormone receptor (TSHR). Studies have shown that the IGF-1R is overexpressed in TED orbital fibroblasts (OFs) (24). Autoantibodies activate the IGF-1R and TSHRsignaling complex, which stimulates OFs and leads to the release of inflammatory cytokines and increased hyaluronan production. Once activated, OFs function as key effector cells in the TED orbit, contributing significantly to the expansion of soft tissue (fat and muscle) behind the globe. Teprotumumab blocks signaling that upregulates proinflammatory cytokines and hyaluronan release. Unlike other therapeutic options, teprotumumab has been shown to reverse soft tissue (fat and muscle) enlargement in TED, evidenced objectively by computed tomography (CT) and magnetic resonance (MR)–based volumetric studies (25–28). UNDERSTANDING THE FOOD AND DRUG ADMINISTRATION SCOPE OF APPROVAL The FDA approval for teprotumumab is for adult TED patients, who are not pregnant or lactating. The indication does not designate disease stage, probably due to the heterogenous phenotypes of the disease. The introduction of teprotumumab has been uniquely instructive about the pathophysiology and immunology of the TED orbit. We now know that overexpression of the IGF-1R persists beyond the acute stages into the chronic phase (13). This likely explains why patients with chronic TED also gain a significant clinical improvement following treatment with teprotumumab (13). The pivotal, Phase-2 and Phase-3, double-masked (29,30), randomized, controlled studies treated adult TED patients with recent onset of disease (,9 months; Table 1. Clinical activity score (CAS) definition 7 Point Score (One Point for Each of the following Intermittent or Constant Symptoms/Signs) Conjunctival injection Conjunctival chemosis Caruncular or plica hyperemia Eyelid erythema Eyelid edema Pain (spontaneous retrobulbar) Pain (on attempted eye movement, upward, side to side, and downward gazes) 27 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Table 2. Key clinical trial inclusion and exclusion criteria Inclusion Adults 18 yr or older CAS = 4 or more Moderate-severe disease TED duration of 9 mo or less Free T3 and T4 within 50% of normal Women with negative serum pregnancy test Exclusion Prior surgical intervention or orbital radiation for TED Cumulative steroid use (IV or oral) equivalent to $1 g Corticosteroid use for conditions other than TED within 4 wk Any previous rituximab or tocilizumab use. Use of any nonsteroid immunosuppressive agent within 3 mo prior to screening Pregnant or lactating women Biopsy-proven or clinically suspected inflammatory bowel disease Optic neuropathy CAS, clinical activity score; FT3, free triiodothyronine; FT4, free thyroxine; IV, intravenous; TED, thyroid eye disease. average, 6 months), with CAS of 4 or more (Table 1) and normal thyroid function (defined as free thyroxine [FT4] and free triiodothyronine [FT3] levels ,50% above or below the normal limits). The studies excluded patients who had cumulative steroid use equivalent to $1 g, prior surgery, or evidence of optic neuropathy (Table 2). The primary outcome measure was a reduction of 2 mm or more in proptosis. Diplopia was not measured objectively, rather patients were asked to subjectively rate their diplopia using the Gorman score (Table 3). Overall, 171 subjects were enrolled, and 43 were randomized to receive teprotumumab in Phase-2 and 41 in Phase-3 studies. The treated and placebo subjects were similar in age, gender, smoking history, and ethnicity (29). Just more than 90% of subjects completed all infusions in the combined clinical trials. Seventy-seven percent of the active moderate-to-severe TED subjects treated with teprotumumab demonstrated an improvement in proptosis of $2 mm compared with 15% in the placebo group at 24 weeks. Fifty-five percent of patients had rapid improvement in proptosis within 6 weeks. The mean change in proptosis in the combined Phase 2 and Phase 3 baseline to 24 weeks was 3.14 mm (similar to what can be achieved via a 2-wall orbital decompression) (31). The proptosis response was Table 3. Gorman diplopia score 0. No diplopia 1. Diplopia in primary position of gaze when tired or awakening (intermittent) 2. Diplopia in extreme gaze (inconstant) 3. Constant diplopia in primary position or when reading 28 similar across age groups, gender, tobacco use, time to diagnosis of TED, and Graves disease, as well severity of disease (13,29,32). In the pooled Phase-2 and Phase-3 data, diplopia improved by $1 grade (based on Gorman score not objective measurements) in 70% vs in 31% with placebo and 53% had complete resolution of diplopia at 24 weeks (7,13,20). There was significant improvement in inflammatory symptoms and signs with 62% having disease inactivation (CAS of 0/1) compared with 22% for placebo by Week 24. The overall response (a reduction of $2 in the CAS plus a reduction in proptosis $2 mm) was 74% in treated subjects compared with 14% with placebo at 24 weeks. Following FDA approval, a subsequent case series of 9 chronic (mean duration, 6.25 years) TED patients with CAS of 0–1 revealed a mean (SD) reduction in proptosis of 4.2 (2.8 mm) (16). Subsequent published reports demonstrated that teprotumumab was also effective in treating TED-related compressive optic neuropathy (CON) (5,7). Sears et al reported objective improvement in visual acuity, relative afferent pupillary defect, color vision, proptosis, and visual field testing as early as 4 weeks after initiating teprotumumab for steroid resistant CON. The orbital MRI showed significant improvement in extraocular muscle size and resolution of likely optic nerve compression at 8 weeks (5). Slentz et al also reported an objective improvement in visual acuity, proptosis, optic nerve edema, and optical coherence tomography (OCT) retinal nerve fiber thickening 2 weeks after initiating teprotumumab in steroid-naive CON (7). Sears et al subsequently reported 10 patients with optic neuropathy who were treated with teprotumumab. All had a proptosis reduction of $2 mm and a CAS reduction to 0– 1. Three of 6 patients with diplopia had a reduction in diplopia. One patient had worsening of ocular deviation following teprotumumab. Patient with large-angle deviations in primary gaze were least likely to demonstrate an improvement in dysmotility. Both chronic and active patients were included in the case series (2 months–10 years and 3.95 years of mean duration). Mean reduction in proptosis was 4 mm, and improvement in optic nerve function was noted by Week 6 in all cases. By the second infusion at Week 6, 70% had significant improvement in visual acuity, color vision, and resolution of relative afferent pupillary defect. Recalcitrant (failed corticosteroids and/or surgery) patients with advanced and long-standing visual loss due to CON and significant optic atrophy had limited recovery of visual function (6). Chiou et al also reported 2 cases of mild TED CON that resolved with teprotumumab therapy. Both had received IV corticosteroids before treatment with incomplete improvement in TED CON. Following treatment with teprotumumab, both had complete resolution of visual field defects (17). Given the overexpression of the IGF-1R persisting into the chronic phase of TED, teprotumumab may be effective Ugradar et al: J Neuro-Ophthalmol 2022; 42: 26-34 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 1. Nine-Gaze photograph of a patient before and after teprotumumab. in patients with longer durations of TED. In the largest cumulative study to date, Ugradar et al treated 31 TED patients (8 male and 23 female subjects) with a mean disease duration of 81 months with teprotumumab. The pretreatment CAS was 2.3 in the study eye and 0.5 in the fellow eye. Mean proptosis improvement was 3.5 mm in the study eye and 3 mm in fellow eye. The change in proptosis was based on both Hertel exophthalmometry measurement and on 3D reconstructions of CT/MRI. Sixty-seven percent had improvement in diplopia; 47% had complete resolution based on both subjective Gorman score, and objective 4 gaze photograph documentation (Fig. 1). The CAS response was 90% in the study eye and 87% in the fellow eye (postinfusion CAS of 0–1) (14). Other smaller series have shown similar efficacy in patients with chronic TED (8,16). Ugradar et al also performed an objective assessment of soft tissue volume change using 3D volumetric analysis. Using CT and MRI, 3D models were created by voxel FIG. 2. Coronal CT scan of the orbit of a patient before and after the use of teprotumumab for TED. Panel below shows the muscle and fat volumes for each patient before and after teprotumumab (9). CT, computed tomography; TED, thyroid eye disease. Ugradar et al: J Neuro-Ophthalmol 2022; 42: 26-34 29 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Table 4. Clinical trials, case series, and case reports First, Author No. of Patients Treated with Teprotumumab CAS Smith, 2017 (30) 42 Active CAS $4 Douglas, 2020 (29) 41 Active CAS $4 Ozzello, 2020 (8), Ozzello, 2021 (16) 1patient received 3 doses of teprotumumab prior to Expedited Publication 9 10/84 pooled phase 2 and 3 data in patients with asymmetric TED 1 patient with optic neuropathy Inactive CAS 1 Inactive CAS 0–1 Ugradar, 2020 (13) Sears, 2020 (5) Sears, 2020 (6) Slentz, 2020 (7) 10 patients with optic neuropathy 1 patient with TED CON Ugradar, 2021 (14) 31 patients Diniz, 2021 (33) 21 patients Chiou, 2021 (17) Lopez, 2021(15) 2 patients 1 patient with TED CON First, Author Prior XT Prior SX Smith, 2017 (30) No No Douglas, 2020 (29) No No Ozzello, 2020 (8), Ozzello, 2021 (16) No No Ugradar, 2020 (13) No No Sears, 2020 (5) No No Sears, 2020 (6) Yes Yes Slentz, 2020 (7) No No 30 Mean TED Duration Prior CS Acute 9 mo or less (mean 6 mo or less) Acute 9 mo or less (mean 6 mo or less) Chronic Three yr duration with 2 yr of stability Chronic mean duration 6.25 yr Acute 9 mo or less No 22 mo No Yes Heterogeneous Mean CAS 3.7 ± 1.5 Heterogeneous 3 mo–12 yr Recent 6 mo Chronic all greater than chronic with mean 81 mo Mean 22 mo with range of 3–129 mo CAS 0 4m Active CAS .4 Active CAS .4 Active CAS .3 Active CAS 5 Inactive CAS 0–3 Percentage With Reduction of Proptosis $2 mm 71% with proptosis reduction at wk 24 (52% with proptosis reduction at wk 6) 69% proptosis reduction plus reduction of $2 Points in CAS 83% proptosis reduction 78% proptosis reduction plus $2 Points in CAS 6-mm reduction in proptosis corresponding with CT scan EOM reduction. CAS 0 After dose 3 at 9 wk 4.2-mm reduction 70% improved asymmetry 90% had CAS of 0 or 1 in both eyes Resolution of optic neuropathy after 4 wk MRI showed EOM reduction Resolution or improvement of ON with CT of orbits showing EOM reduction Resolution of optic neuropathy OCT improvement at 2 wk No No No No Yes Yes Yes Yes Percentage With Improved Diplopia (Gorman Score) 68% Gorman score 68% Gorman Score N/A 80% N/A 37.5% Not applicable Ugradar et al: J Neuro-Ophthalmol 2022; 42: 26-34 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review (Continued ) First, Author Prior XT Prior SX Ugradar, 2021 (14) Yes Yes Diniz, 2021 (33) Yes Yes Chiou, 2021 (17) Lopez, 2021(15) No No No No Percentage With Reduction of Proptosis $2 mm 90% by Hertels and volumetric orbital imaging assessment Mean reduction 3.5 mm 90% had CAS of 0–1 71.4% Mean reduction 2.5 mm Resolution of TED CON Improvement of TED CON CF to 20/50 20/50 to 20/30 4 mm OD, 3 mm OS Percentage With Improved Diplopia (Gorman Score) 67% improved 47% had complete resolution Gorman score and clinical assessment of ductions See table 5 for detailed assessment N/A CAS, clinical activity score; CON, compressive optic neuropathy; EOM, extraocular muscle; N/A, not applicable; OCT, optical coherence tomography; Prior cs, prior corticosteroids; Prior XT, prior external beam radiation; Prior SX, prior decompression; TED, thyroid eye disease. addition, and soft tissue volume was expressed in millimeters cubed. Segmentation and measurements were performed independently by 2 graders to review repeatability (Fig. 2) (9,12,14). Table 4 describes clinical details of all reported cases at the time of writing. Table 5 describes the impact of teprotumumab on diplopia assessed using a prism (33). Authorization of the treatment and its economic footprint are discussed in Supplemental Digital Content 2 (See Supplement 2, http://links.lww.com/WNO/A558). A comparison of the currently available medical treatments for TED are provided in Table 6. PATIENT SELECTION AND COUNSELING Safety and efficacy have not been studied in pediatric patients or in pregnancy. Because no data exist, the manufacturer has recommended that women of reproductive potential should be counseled that teprotumumab can cause harm to a fetus and to inform their health care provider of a known or suspected pregnancy. Patients with reproductive potential should use effective contraception before initiation, during treatment with teprotumumab, and for 6 months after the last dose of teprotumumab. A urine pregnancy test must be performed before each infusion. Because there is no information regarding the presence of teprotumumab in human milk, the effects on the breast-fed infant, or the effects on milk production, lactation is contraindicated. Patients should be informed that there have been cases of new-onset inflammatory bowel disease (IBD) after therapy with teprotumumab (34). In our experience, loose stools or diarrhea are not uncommon the day following the infusion. The symptoms are usually short-lived and may be accompanied by nausea. If persistent or severe diarrhea occurs with or without blood or rectal bleeding, associated with abdominal pain or cramping/colic, urgency, tenesmus, or incontinence, infusions should be paused, and a complete medical assessment performed. A recent case report has described a patient who have developed new-onset IBD after the initiation of teprotumumab (35). Although the mechanism behind this event and potential relationship between teprotumumab and IBD remains tentative, it is advisable for patients with existing IBD who are to be initiated on teprotumumab to see a gastroenterologist. Table 5. Teprotumumab impact on TED diplopia (N = 21 Patients) 35 Mild Horizontal degree of restriction Vertical degree of restriction Horizontal PD Vertical PD Improved by 24.1 ± 4.9 22.5 ± 4.1 24.17 ± 4.9 1.3 ± 3.2 Moderate to Severe Improved by 213.3 ± 11.1 27.9 ± 15.2 213.3 ± 11.1 24.0 ± 9.3 Active Improved by 10.5 ± 19.0 25.9 ± 13.0 21.5 ± 7.9 25.9 ± 13.0 Chronic Stable Improved by 10.9 ± 12.0 21.4 ± 4.9 1.64 ± 3.4 21.45 ± 4.9 Monocular ocular ductions were measured in 4 cardinal positions ranging from 0° for no movement to 45° for full excursion. Restrictions were summated to calculate horizontal and vertical total degrees of restriction. Strabismus in primary was measured at distance with alternating prism cover test in prism diopters (PD). Minus numbers reflect improvement in motility, and positive numbers reflect worsening of motility. Note: Only 7 of 21 patients had completed all 8 infusions. No durability data are reported. Ugradar et al: J Neuro-Ophthalmol 2022; 42: 26-34 31 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Table 6. A comparison medical treatments for TED Therapy RCT Double Masked FDA Approved for TED Medicare Will Pay Active Recent Onset TED Corticosteroids External beam radiation Rituximab anti-CD20 on B cells Tocilizumab anti-IL6 on T cells Teprotumumab anti-IGF1 No No Yes Yes Yes Therapy Corticosteroids External beam radiation Rituximab anti-CD20 on B cells Tocilizumab anti-IL6 on T cells Teprotumumab anti-IGF1 No No No No Yes Chronic Inactive TED No No No No Yes Yes Yes No No Yes Improves CAS Improves Diplopia Yes Yes Yes Yes Yes Yes Yes No No Yes Improve Proptosis .2 No No No No .90% at 48 wk Yes Yes Yes Yes Yes Decreases EOM and Intraconal Fat Volume No No No Not reported Yes Cost $ $$ $$$ $$$ $$$$ CAS, clinical activity score; EOM, extraocular muscle; FDA, Food and Drug Administration; OCT, optical coherence tomography; RCT, randomized clinical trial; TED, thyroid eye disease. Teprotumumab can cause hyperglycemia in patients with diabetes or glucose intolerance. Patients should be informed about the risk of hyperglycemia and, if they have diabetes, discuss with their primary health care provider to adjust glycemic control medications as appropriate. Patients should be encouraged to follow diet and medication recommendations. If the patient finds it difficult to check their glucose or are not adherent with their medications, they may not be suitable for teprotumumab therapy. In addition, some patients with limited access to health care may unknowingly have diabetes. A HbA1C and 2-hour postprandial glucose should be obtained before pursuing therapy in those clinically suspected of having diabetes (36). A pretreatment questionnaire can be helpful to identify risk factors for side effects and adverse events. In the Phase2 and Phase-3 clinical trials, approximately 10% of patients experienced hearing dysfunction, which was reported as mild to moderate and reversible (11,29). A recent study of 28 TED patients treated with teprotumumab found that a large portion of patients developed otologic symptoms. While most symptoms were mild, 3 patients were noted to have sensorineural hearing loss or patulous eustachian tube on audiometry and tympanometry. Until risk factors for hearing loss are better understood, providers should discuss the risk of otologic symptoms and hearing loss with patient. We also recommend baseline hearing evaluation for all patients, especially those with preexisting hearing loss, those older than 60 years, or with a history of frequent ear infections as a child (37,38). There is a single case report of a patient with rapidly progressive cognitive decline following teprotumumab; given the multifactorial etiology of cognitive decline, the role of IGF1 and brain function is unclear (39). 32 The prescribing physician should explain the 24-week infusion plan and provide a description of what to expect. A handout that specifically lists a calendar of visits, laboratory monitoring, and other pertinent details related to infusions is helpful. If the dosing protocol is delayed, the therapy can be reinstituted off cycle. Teprotumumab should not be utilized in patients who are not able to cooperate with monitoring and follow-up. EVOLVING DATA ON DURABILITY OF Effect, RE-TREATMENT, AND IMPACT ON SUBSEQUENT SURGICAL INTERVENTIONS Follow-up results from the Phase-2 and Phase-3 trials were integrated and reported (where available) at Weeks 28, 36, 48, 60, and 72 (11). All patients who entered the follow-up period were assessed (as observed) at the last visit for proptosis, diplopia, and a composite outcome response. At Week 28, short-term follow-up of proptosis (n = 71), diplopia (n = 58), and ophthalmic composite outcome (n = 72) responses were noted in 87%, 66% (with baseline diplopia), and 92% of teprotumumab-treated patients, respectively. For longer-term follow-up at 51 weeks after last dose, 67%, 69% (with baseline diplopia), and 83% were proptosis (n = 57), diplopia (n = 48), and composite outcome responders (n = 58), respectively. After completion of the Phase-3 clinical trial, the placebo treated patients and the 5 teprotumumab nonresponders were treated with 8 infusions of teprotumumab using the same every 3-week schedule as the Phase-3 trial (OPTIC-X) (40). Of the teprotumumab nonresponders, 2 responded, 1 had a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatments early. A flare was defined as CAS worsening of 2 or more with an absolute CAS of $4 or Ugradar et al: J Neuro-Ophthalmol 2022; 42: 26-34 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review worsening in proptosis of 2 mm or more, with 9 patients meeting the criteria and being retreated. One of these patients had a delayed Week-24 visit due to COVID but had a 5-mm reduction 3 months after the last dose. Of the remaining 8, 5 (63%) were proptosis responders. The safety profile for the retreated patients was consistent with the prior studies (11). The mean duration of TED in the previous placebo treated patients from the Phase 3 study was more than 1 year in contrast to the original Phase-2 and Phase-3 studies, where the mean duration of disease was approximately 6 months. Thirty-three of 37 (89%) placebotreated patients in the OPTIC study became proptosis responders (mean [SD], 23.5 mm [1.7]) when treated with teprotumumab. In these responders, proptosis, CAS 0 or 1, and diplopia responses were maintained in 29 of 32 (90.6%), 20 of 21 (95.2%), and 12 of 14 (85.7%) patients, respectively, at Week-48 follow-up. These patients had a median TED duration of 12.9 months vs 6.3 months in those treated with teprotumumab in the OPTIC study. Greater than 90% maintained proptosis reduction (#2 mm), disease inactivation, and overall responses at 72 weeks for those treated with teprotumumab in the OPTIC study (40). Some patients will require surgical interventions for reconstructive surgery following treatment with teprotumumab. We are not aware of the influence of teprotumumab on recovery following surgery; however, it should be noted that the duration for complete washout of teprotumumab is approximately 6 months. Based on the experience in the clinical trials and those of our own patients, eyelid retraction and strabismus were the most common residual findings that may require subsequent surgery. Nonresponders and nondurable responders may still require orbital decompressions (10,12). CONCLUSIONS Teprotumumab is an exciting—yet expensive—new tool in the armamentarium against TED (41). It is the only therapeutic option that significantly reduces soft tissue expansion in the orbit and the face (42). As such, its role in reducing severity and duration of disease in minimally symptomatic patients is controversial. In the past 21 months, thousands of patients have been treated and posttrial studies confirm that teprotumumab can be effective in not only active TED of recent onset but also chronic TED of decades-long duration. Because it acts within weeks, utilization in TED patients with optic neuropathy can result in rapid relief of the compression and improvement in visual status. Inflammatory symptoms and signs including pain are also diminished quickly. Dysmotility is more complex with many patients responding favorably but with guarded expectations in those with large angle deviations. Maintenance of therapy up to 72 weeks is encouraging, but the Ugradar et al: J Neuro-Ophthalmol 2022; 42: 26-34 durability beyond that, and the role of retreatment, remain unclear (40). Teprotumumab is safe in adherent patients who are monitored. Careful patient selection and monitoring of side effects is crucial to prevent complications. Teprotumumab is ideally administered in a multidisciplinary team setting, with an oculoplastic/orbit or neuro-ophthalmologist, endocrinologist, and primary care physician. Managing expectations in advance of the infusions and then communicating clearly with the team will optimize patient experience and outcomes. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. Ugradar, K. Cockerham, A. L. Kossler, and R. Douglas; b. Acquisition of data: S. Ugradar, K. Cockerham, A. L. Kossler, and R. Douglas; c. Analysis and interpretation of data: S. Ugradar, K. Cockerham, A. L. Kossler, and R. Douglas; Category 2: a. Drafting the manuscript: S. Ugradar, K. Cockerham, A. L. Kossler, and R. Douglas; b. Revising it for intellectual content: S. Ugradar, K. Cockerham, A. L. Kossler, and R. Douglas; Category 3: a. Final approval of the completed manuscript: S. Ugradar, K. Cockerham, A. L. 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Facial and eyelid changes in thyroid eye disease are reversed by teprotumumab. Plast Reconstr Surg Glob Open. 2021;9:e3809. Ugradar et al: J Neuro-Ophthalmol 2022; 42: 26-34 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.