Real-World Experience With Teprotumumab in Patients With Dysthyroid Optic Neuropathy

Background: Teprotumumab, an insulin-like growth factor I receptor inhibitory antibody, improved proptosis, diplopia, inflammatory signs/symptoms, and quality of life in patients with active thyroid eye disease (TED) in clinical trials. The trials excluded patients with dysthyroid optic neuropathy (DON). Recently, many case reports and case series have reported the successful use of teprotumumab to treat DON. Here, we review the data from published cases and our clinical experience in treating patients having DON with teprotumumab. Methods: A literature search was conducted of patients with DON treated with teprotumumab from January 2020 through September 2022. Data from DON patients from the authors' (M.A.T. and C.A.B.) clinical practice were included. Primary outcome measure was mean (SD) improvements for visual acuity, color vision, and visual fields. Improvements in proptosis and clinical activity score (CAS) and diplopia were compared before and after teprotumumab administration. Results: Ten observational studies/case reports were identified along with 2 patients in our practice. In all, there were 24 active TED patients with DON (37 eyes) who were treated with teprotumumab. Mean (SD) age was 66.5 (13.6) years and 13 (54%) were females, disease duration ranged from 2 months to >15 years. 22/24 patients had none, minimal improvement or progression of visual loss with intravenous/oral corticosteroids, orbital decompression (n = 9), and orbital radiation (n = 2). There were 2 patients who received teprotumumab as the only therapy. Overall, 88% (21/24) reported improvement in visual acuity after teprotumumab and in 75% (18/24), improvement in vision was observed after just 2 infusions of teprotumumab. Three eyes had decompression surgery in close proximity to teprotumumab infusions and were excluded from analyses. Mean (SD) improvement in visual acuity was 3.73 lines (SD 3.74), range 2-15 lines in 33 eyes. The mean (SD) improvement in the mean deviation on visual field testing in 15 eyes was 5.6 db (3.0 db). Mean (SD) improvement in proptosis was 4.37 mm (SD: 2.11) (20 patients, 32 eyes); and clinical activity score: mean reduction of 5.1 (1.3) for 18 patients. Teprotumumab was well tolerated in all but one patient. Adverse events reported included fatigue, dysgeusia, hearing loss, nausea, hyperglycemia, and muscle spasms. Conclusions: Teprotumumab is an effective treatment for DON in our experience and in published cases in whom treatment with steroids, surgery, or orbital radiation was unsuccessful.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Real-World Experience With Teprotumumab in Patients With Dysthyroid Optic Neuropathy Madhura A. Tamhankar, MD, Tejus Pradeep, MD, Yuanyuan Chen, BS, César A. Briceño, MD Background: Teprotumumab, an insulin-like growth factor I receptor inhibitory antibody, improved proptosis, diplopia, inflammatory signs/symptoms, and quality of life in patients with active thyroid eye disease (TED) in clinical trials. The trials excluded patients with dysthyroid optic neuropathy (DON). Recently, many case reports and case series have reported the successful use of teprotumumab to treat DON. Here, we review the data from published cases and our clinical experience in treating patients having DON with teprotumumab. Methods: A literature search was conducted of patients with DON treated with teprotumumab from January 2020 through September 2022. Data from DON patients from the authors’ (M.A.T. and C.A.B.) clinical practice were included. Primary outcome measure was mean (SD) improvements for visual acuity, color vision, and visual fields. Improvements in proptosis and clinical activity score (CAS) and diplopia were compared before and after teprotumumab administration. Results: Ten observational studies/case reports were identified along with 2 patients in our practice. In all, there were 24 active TED patients with DON (37 eyes) who were treated with teprotumumab. Mean (SD) age was 66.5 (13.6) years and 13 (54%) were females, disease duration ranged from 2 months to .15 years. 22/24 patients had none, minimal improvement or progression of visual loss with intravenous/oral corticosteroids, orbital decompression (n = 9), and orbital radiation (n = 2). There were 2 patients who received teprotumumab as the only therapy. Overall, 88% (21/24) reported improvement in visual acuity after teprotumumab and in 75% (18/24), improvement in vision was observed after just 2 infusions of teprotumumab. Three eyes had decompression surgery in close proximity to teprotumumab infusions and were excluded from analyses. Mean (SD) improvement in visual acuity was 3.73 lines (SD 3.74), range 2–15 lines in 33 eyes. The mean (SD) improvement in the mean deviation on visual field testing in 15 eyes Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania. was 5.6 db (3.0 db). Mean (SD) improvement in proptosis was 4.37 mm (SD: 2.11) (20 patients, 32 eyes); and clinical activity score: mean reduction of 5.1 (1.3) for 18 patients. Teprotumumab was well tolerated in all but one patient. Adverse events reported included fatigue, dysgeusia, hearing loss, nausea, hyperglycemia, and muscle spasms. Conclusions: Teprotumumab is an effective treatment for DON in our experience and in published cases in whom treatment with steroids, surgery, or orbital radiation was unsuccessful. Journal of Neuro-Ophthalmology 2024;44:74–79 doi: 10.1097/WNO.0000000000001994 © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the North American Neuro-Opthalmology Society. I n 2020, teprotumumab, an insulin-like growth factor 1 receptor inhibitory antibody became the first drug approved by the US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED) in adults.1 Two randomized placebo-controlled, doublemasked clinical trials of subjects with moderate TED and with a clinical activity score (CAS) of 4 and above treated with teprotumumab demonstrated clinically significant reductions in inflammation, proptosis, and diplopia over 24 weeks.1,2 The clinical trials excluded patients with dysthyroid optic neuropathy (DON). Since the approval of teprotumumab, there have been several case series and single case reports that have reported successful use of this drug in the treatment of DON that were refractory to treatment with corticosteroids, orbital decompression surgery, and orbital radiation therapy (ORT).3–13 The objective of this study was to review the data from published case reports along with our own clinical experience in treating patients with DON with teprotumumab. Supported by Research to Prevent Blindness. M. A. Tamhankar and C. A. Briceño are consultants for Horizon Therapeutics. The remaining authors report no conflicts of interest. METHODS Address correspondence to Madhura A. Tamhankar, MD, 51 North, 39th Street, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 215-316-5151; E-mail: [e-mail] A literature search was conducted for published reports of DON treated with teprotumumab from January 2020 through September of 2022. Data from patients with DON from the authors’ (M.A.T. and C.A.B.) clinical practice were also included. Data extraction included details on patient age, gender, duration and phase of TED, laterality of DON, details of This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. 74 Tamhankar et al: J Neuro-Ophthalmol 2024; 44: 74-79 Original Contribution previous treatment including intravenous (IV)/oral steroids, orbital decompression, and ORT. Active TED was defined as CAS $ 3. The number of infusions of teprotumumab that the patients received along with the number of infusions required to see a therapeutic benefit were recorded. Details of the eye examination included visual acuity at baseline and after treatment, color vision at baseline and after treatment, presence of relative afferent pupillary defect (RAPD) with subsequent resolution, proptosis reduction, improvement in CAS, improvement in Gorman diplopia score (GDS),1 and improvement in mean deviation on visual field testing. Orbital imaging data when available from published reports and authors’ own cases before and after teprotumumab were collected. DON was defined when there was decrease in visual acuity and/or deficits in color vision, presence of RAPD, presence of visual field deficits, and presence of apical compression of the optic nerve by enlarged extraocular muscles and/or stretching of the optic nerves noted on neuroimaging. Follow-up in weeks was calculated after completion of therapy. In addition, we attempted to contact authors of case reports to provide information on long-term follow-up data after completion of infusion on their reported patients. RESULTS Ten observational studies/case reports were identified along with 2 of our own patients.3–13 In total, there were 24 patients (37 eyes) with DON. Mean (SD) age was 66.5 (13.6) years, 13 (54.1%) were females, and disease duration ranged from 2 months to .15 years. All patients were classified as having active disease. There were 13 patients with bilateral DON, 8 with left eye and 3 with right eye involvement. There were 22 patients who were initially treated with corticosteroids (18 intravenous and 4 oral) of whom 18 reported no improvement after receiving steroids, whereas 4 reported “minimal”, “mild,” or “some” improvement. In 4 patients, steroids were given briefly, but were discontinued because of intolerable side effects (elevated liver enzymes, agitation, hyperglycemia, and insomnia).4,6,9 In sum, in 22 patients, there was progression of disease despite steroid treatment or after discontinuation (Table 1). There were 9 patients who had worsening of vision despite previous orbital decompressions (3 bilateral and 6 unilateral). Four of those patients had decompression over a year before teprotumumab (range 1–15 years prior), one had the decompression 8 months before, 3 patients had the decompression one to several weeks before, and in one patient the duration was unknown. Orbital decompression surgery was deferred because of medical comorbidities in 2 patients.3,6 In one patient with bilateral DON, orbital decompression was performed in the left eye and teprotumumab was initiated a week before the orbital decompression. At 2-week follow-up visit visual improvement was Tamhankar et al: J Neuro-Ophthalmol 2024; 44: 74-79 noted in the unoperated right eye. In one of our own patients, orbital decompressions were performed bilaterally one week after teprotumumab infusions. Teprotumumab was continued because of failure of visual improvement after the decompression surgeries (Table 1). Two patients underwent orbital radiation. In one, the timing of orbital radiation is unknown and in the other it was given to treat the DON along with IV steroids and orbital decompression. Table 2 shows the improvement in visual acuity, color vision, proptosis, CAS, and GDS in DON eyes. Excluding 2 patients (3 eyes) who had orbital decompression surgery within 1 week of teprotumumab infusions, mean improvement in visual acuity was 3.7 lines (SD 3.7), range 2–15 lines in 33 eyes with DON. One eye did not have improvement in visual acuity from baseline of 20/25, but had improvement in visual fields. The mean improvement in the mean deviation on visual field testing in 15 eyes of patients was 5.6 db (SD 3.0 db) (Table 3). In addition, in 2 patients (4 eyes), authors reported improvement in the visual field without providing mean deviation data before and after teprotumumab. Mean proptosis measurement before teprotumumab (reported in 32 DON eyes) was 24.9 mm (SD 4.8 mm, range 18–35 mm). Mean improvement in proptosis was 4.37 mm (SD 2.11 mm); mean GDS improvement was 0.75 (SD 1.1), graded in 8 patients; and mean CAS improvement for 18 patients was 5.1 (SD 1.3) (Table 2). Color vision improved in 26 eyes after teprotumumab infusion. It stayed unchanged in 1 eye, was normal preteprotumumab in 4 eyes, could not be measured because of poor visual acuity in 4 eyes, and due to congenital dyschromatopsia in 2 eyes. Of the 22 patients in whom RAPD was assessed, 13 patients had RAPD. After teprotumumab infusion, RAPD improved or resolved in 11 patients, remained unchanged in 4, and was not reported in 7 patients. Overall, in the 24 patients with DON, teprotumumab led to improvement in visual acuity and/or color vision and visual fields in 21 patients. Of these, 9 patients had improvement in visual acuity after the first infusion of teprotumumab, 9 had improvement after 2 infusions, 2 had improvement after 3 infusions, and 1 patient improved after 6 infusions. Seventeen patients received all 8 infusions of teprotumumab, whereas 7 patients had 2-6 infusions. It is unclear whether the 7 patients did receive all 8 infusions because the reports mention the last follow-up when the patients regained their vision. There were 3 patients who had minimal response to teprotumumab. All 3 had long standing DON with poor vision (hand motions) at baseline and optic atrophy.3 However, these 3 patients had improvement in proptosis and decrease in apical compression on orbital imaging. The authors surmised that the lack of improvement was because of long-standing disease that caused optic atrophy from compression and/or stretch of the optic nerve. 75 Original Contribution TABLE 1. Patient demographics and response to steroids, orbital decompression surgery, and orbital radiation therapy Age/Sex Eye IV Steroids Oral Prednisone Orbital Decompression Orbital Radiation Sears 1 76/F OU Y Y N None 2 3 4 84/F 62/F 73/F OU OU OS Y N N N N N None None None 5 6 7 8 9 10 Gorrell Cheng 45/M 55/F 73/M 57/M 40/M 76/M 65/F 51/F OU OS OD OU OS OU OU OD Y Y Y (several months before) Y Y N Y Y Y N Y N Y Y N Y Y Y Y OD N N OU N N N N None Progression Yes None None None None None Chiou 68/F 68/F 65/M 83/F 90/F OS OU OS OS OS Y Y Y Y Y N N Y N N N N N N N None “Mild” None “Minimal” None 81/F 61/M 78/M 50/F 50/M OU OU OU OS OU N N Y Y Y Y Y N Y N Y (OU .1 year before) N N Y (OD .1 year before) N N N Y (OU) N Y (OD) Y (OD) Y (OD 10 years before) N N Y (OS) N Y (OS 15 years before) N N N N Y (OU) N N N N M None “Some” Progression Progression Progression Publication Diniz Hwang Lopez Paton Tamhankar Improvement IV, intravenous; N, No; OD, right eye; OS, left eye; OU, both eyes; ORT, orbital radiation therapy; Y, Yes. Two patients in the study received teprotumumab as monotherapy and noted complete resolution of DON after just 2 infusions.8,12 In 9 patients, there were orbital imaging data available before and after infusion with teprotumumab that showed reduction in extraocular muscle volume and decompression of the orbital apex that was radiographically documented before and after the administration of teprotumumab (Fig. 1). Overall, teprotumumab was well-tolerated in all except one patient. Adverse events included fatigue, dysgeusia, hearing loss, nausea, hyperglycemia, and muscle spasms. Only one patient, a 90-year-old woman, could not tolerate teprotumumab with discontinuation after 3 infusions, although she noted improvements in DON, proptosis, and CAS.6 Follow-up data after teprotumumab infusions was reported in 10 patients with average follow-up of 23 weeks (range 5–33 weeks). Three authors further reported longterm follow-up data on 6 patients, which was for 12–24 months after infusion with no flare up of disease. Three patients in this series had flare up of TED (2 previously published).7,13 In one patient, although she was stable for 30 weeks after completing teprotumumab, she had a flare up 2 weeks after receiving COVID vaccine and was subse76 quently treated with orbital decompression. In the patient reported by Paton et al,7 24 weeks after completion of teprotumumab, the patient started to notice decrease in vision in the left eye because of recurrent DON. This coincided with change in his medication dosing of levothyroxine with labs showing low T4 levels. In another of our own patients, recurrence with worsening double vision and eyelid edema occurred 32 weeks after completion of teprotumumab. The patient moved out of the state and was lost to follow-up. DISCUSSION DON is a serious vision threatening complication observed in 1%–8% of patients with TED.14 Affected patients present with decreased visual acuity, RAPD, dyschromatopsia, visual field deficits, and possibly optic nerve swelling. DON is believed to result from compression of the optic nerve at the orbital apex because of enlargement of the extraocular muscles and/or expansion of orbital fat volume.15 The optic nerve may also appear stretched in some cases.16 This may result in optic nerve ischemia or inhibition of axoplasmic flow and irreversible vision loss because of optic neuropathy if left untreated. Tamhankar et al: J Neuro-Ophthalmol 2024; 44: 74-79 Original Contribution TABLE 2. Teprotumumab response in dysthyroid optic neuropathy eyes Publication VA Preinfusion of Laterality Teprotumumab Age/Sex of DON OD/OS Sears 1 76/F OU 2 84/F OU 3 62/F OU 4 5 73/F 45/M OS OU 6 7 8 55/F 73/M 57/M OS OD OU 9 10 40/M 76/M OS OU Gorrell 65/F OU Cheng Chiou 51/F 68/F 68/F OD OS OU Diniz Hwang 65/M 83/F 90/F 81/F OS OS OS OU Lopez 61/M OU Paton 78/m OU Slentz Fasano 62/M 83/M OD OU Tamhankar 50/F 50/M OS OU HM HM HM HM 20/200, 20/200 20/30 20/40 20/125 20/100 20/25 20/100 20/60 20/40 20/100 HM 20/60 20/50 20/40 20/25 20/25 20/25 20/150 20/50 ,20/400 20/100 CF 3 feet 20/150 20/40 20/70 20/250 20/25 20/25 20/40 20/100 20/30 20/25 Color VA Postinfusion of Vision Color Vision Proptosis Teprotumumab Deficit Improved Improvement CAS GDS OD/OS Preinfusion Postinfusion (mm) OD/OS Improvement Improvement 20/800 20/800 20/800 20/800 20/50 20/30 20/20 20/20 20/20 20/25 20/20 20/25 20/30 20/20 20/70 20/200 20/25 20/25 20/20 20/25 20/25 20/25 20/20 20/60 20/50 20/40 20/30 20/25 20/20 20/30 20/40 20/20 20/25 20/30 20/25 20/25 20/30 NA NA 3/2 6 NA NA NA 3/3 4 NA OU Yes 4/5 4 2 OS OS Yes Yes 6 3/6 5 5 0 0 OS NA OU Yes NA Yes 3.5 7 1/1 4 7 4 0 1 0 OS OD Yes No 4 3/3 7 6 0 3 OU Yes 3/3 NR NR OD OS OD Yes Yes Yes 8 3 5/6 6 6 3 NR NR NR OS OS OS OU Yes Yes Yes Yes NR NR NR 5/4.5 NR NR NR 6 NR NR NR NR OU Yes 7/8 NR OU Yes 6/8 7 Improved diplopia NR None OU None Yes 5 NR 5 NR 0 NR OS N/A Yes NA 5 5/2 7 3 NR NR CAS, clinical activity score; DON, dysthyroid optic neuropathy; GDS, Gorman diplopia score; NR, not reported; OD, right eye; OS, left eye; OU, both eyes. There is no consensus on the best treatment strategy for DON. In general, affected patients are treated with some combination of IV and/or oral corticosteroids with or without orbital decompression and ORT. However, efficacy of the corticosteroids, orbital decompression surgery, and ORT used alone or in combination is variable. In a consensus statement made by the European Group of Graves Ophthalmopathy (EUGOGO), DON should be managed with high-dose intravenous methylprednisolone (IVMP) (0.5–1.0 g) for 3 consecutive days or on every second day, titrated based on improvement in visual acuity and visual field.17 Urgent orbital decompression is recommended for no improvement or worsening visual function after 1 week or limited improvement after 2 weeks of treatment. However, steroids have variable results and are believed to mask the inflammatory effects without altering the natural course of the disease.18 Tamhankar et al: J Neuro-Ophthalmol 2024; 44: 74-79 Orbital decompression surgery is performed to help relieve the compression of the optic nerve at the orbital apex, although some reports mention that it may be less effective as monotherapy. Moreover, surgical decompression also carries with it the risk of orbital hemorrhage, enophthalmos, hypoglobus, and diplopia.19 In certain cases, surgical decompression has been shown to exacerbate the disease.20 Typically, there is little or no improvement in the CAS after surgery.20 ORT has had variable efficacy in treating DON and is found to be less effective with long-standing disease and as a monotherapy.21 Published reports recommend ORT in combination with oral steroids as an effective option for DON vs. ORT alone.22 Many different immunosuppressives and biologics including mycophenolate mofetil, tocilizumab, rituximab, infliximab, anakinra, adalimumab, and etanercept 77 Original Contribution TABLE 3. Mean deviation on Humphrey visual field observed in 15 eyes before and after teprotumumab infusion in 15 eyes Author Sears case 5 (OD) Sears case 5 (OS) Sears case 6 (OD) Sears case 6 (OS) Slentz (OD) Gorrell (OD) Gorrell (OS) Hwang (OD) Hwang OS Chiou (OS) Chiou (OD) Diniz (OS) Diniz (OS) Diniz (OS) Tamhankar (OS) Preteprotumumab HVF MD (db) 26.89 210.06 21.65 23.09 23.21 24 212.32 210.6 26.29 23.7 22.8 27.5 28.07 211.33 217.42 Post-teprotumumab HVF MD (dB) 20.84 21.53 0.45 0.82 20.1 0.54 20.43 23.75 23.75 0.4 20.86 20.84 0.81 27.95 28.11 Average change in MD SD Change in MD (db) 6.05 8.53 2.1 3.91 3.11 4.54 11.89 6.85 2.54 4.1 1.94 6.66 8.88 3.38 9.31 5.59 db 3.02 db, Decibels; HVF, Humphrey visual field; MD, mean deviation; OD, right eye; OS, left eye. have shown variable efficacy in DON with studies being limited to case reports and small case series.22 Currently, there is no consensus on superiority of any one of the aformentioned drugs vs. another. In analyzing the results of the published cases and our own clinical experience, teprotumumab seemed to be a rapid and effective treatment for DON when steroids, orbital decompression surgery, and ORT failed. Most had complete resolution of DON (88%) and the effect of teprotumumab was noticed after just 2 infusions in over 75% of patients. In addition, there were 2 patients who received teprotumumab as monotherapy and had complete resolution of DON.8,12 In yet another unpublished data (poster presentation ASOPRS meeting 2022), there is a report of 8 patients with DON who responded to teprotumumab monotherapy with stability documented 8 months after completion of infusion further lending support for its use in DON.23 Given the complete resolution of DON observed in most reported cases, these patients were able to avoid urgent orbital decompression surgery and its potential for adverse effects and morbidity. The side effect profile of teprotumumab was minor and all, but one patient tolerated the medication well. The 3 patients who were nonresponders had long-standing optic atrophy, implying that once there is atrophy of retinal ganglion cell axons, visual recovery may not occur despite improvement in the apical crowding after teprotumumab therapy. In contrast, a full recovery of DON was observed in patients who did not develop optic nerve pallor despite not responding to steroids for several weeks, indicating that the optic nerve is resilient to the effects of compression by enlarged extraocular muscles and that full visual recovery can be expected in most patients. Given that in most patients, improvement in DON was observed sometimes as early as after the second 78 infusion, one can wait for the therapeutic response of teprotumumab to take effect without emergently having to do decompression surgery. A reduction in volume of extraocular muscles was documented by neuro imaging before and after teprotumumab for 9 patients. This lends support for the efficacy of teprotumumab in that decrease in muscle volume demonstrated by neuro imaging led to resolution of compression of the optic nerve (Fig. 1). This is similar to the orbital imaging data from the 2 previous clinical trials that showed reduction in extraocular muscle volume, FIG. 1. T1 axial MRI images of the orbit show enlarged extraocular muscles with apical crowding (top) and decrease in the extraocular muscle enlargement (bottom) in a 79-year-old man with bilateral dysthyroid optic neuropathy after teprotumumab infusions. Tamhankar et al: J Neuro-Ophthalmol 2024; 44: 74-79 Original Contribution orbital fat, or both, before and after the use of teprotumumab.1,2 The imaging data showing improvement in the above parameters support the use of teprotumumab as a potential therapeutic option for patients with DON. Many questions arise when trying to decide the best treatment paradigm for DON. Our study had limitations inherent to all retrospective studies along with selection bias in that it is unknown whether there were patients with DON who did not respond to teprotumumab or those who responded to steroids and other interventions and were not reported. Because 92% of patients with DON were treated with corticosteroids before initiation of teprotumumab, it is difficult to conclude that teprotumumab alone was beneficial for DON except in the 2 reports where it was given as monotherapy. There were also time-dependent factors such as time to insurance approval causing delay in the initiation of teprotumumab and the time for therapeutic response, which likely had a larger role to play in patients being concurrently treated with steroids and surgery while awaiting approval. Currently, there are no studies comparing teprotumumab to IV steroids and/or orbital decompression or ORT. There are limited follow-up data because of the reports that were published immediately after completion of the teprotumumab infusions. It is therefore unclear whether the effect of teprotumumab was sustained over the long-term in some of these patients. Although well-designed clinical trials, comparison studies, and long-term data to test the efficacy of novel agents are important, the rarity of DON and the need for urgent treatment when evaluating such patients make level 1 data difficult to obtain. Based on the existing data, teprotumumab presents a promising option as an adjunctive or even first-line therapy especially in those who are unresponsive to conventional therapies, have intolerable steroid-related adverse effects, or those who are poor surgical candidates. Its effectiveness in this setting will help to perhaps provide better evidence for its superiority in the treatment of DON. STATEMENT OF AUTHORSHIP Conception and design: T. Pradeep, C. A. Briceno, M. A. 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