Frequency and Patterns of Hearing Dysfunction in Patients Treated with Teprotumumab.

PURPOSE: To better characterize the frequency and patterns of hearing dysfunction in patients who have received teprotumumab to treat thyroid eye disease. DESIGN: Noncomparative case series. PARTICIPANTS: Patients who underwent audiology testing before and after completion of teprotumumab infusions. METHODS: A review of patients who underwent audiology testing before and after completion of teprotumumab infusions was carried out. Additional audiogram testing during treatment was included when available. Hearing function was analyzed using audiogram data measuring threshold hearing levels at specific frequencies. Basic demographic data as well as information regarding otologic symptoms also were obtained and analyzed. MAIN OUTCOME MEASURES: Hearing loss demonstrated by a significant change in decibel hearing thresholds or that meets criteria for ototoxicity. RESULTS: Twenty-two patients (44 ears) were included in the study, with baseline and most recent audiology testing after treatment ranging from 84 days before to 496 days after treatment. Fifteen patients (30 ears) also underwent testing during treatment starting after the second infusion up until the day of, but before, the eighth infusion. Hearing loss after treatment met criteria for ototoxicity in 17 of the 44 ears (38.6%), with 11 of the 22 patients (50.0%) meeting criteria in at least 1 ear. The pure-tone average decibel hearing levels (HLs) across all 44 ears demonstrated hearing loss after treatment (P = 0.0029), specifically at high (P = 0.0008) and middle frequencies (P = 0.0042), but not at low frequencies (P = 0.8344). Patients who were older also were more likely to experience hearing loss after treatment (P = 0.0048). CONCLUSIONS: Audiometric data demonstrate that teprotumumab influences hearing function, most significantly at higher frequencies and in older patients. Audiometric testing is critical for counseling patients regarding teprotumumab treatment. A protocol for monitoring hearing during treatment is needed to detect and manage hearing changes associated with teprotumumab use. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Rate of Re-treatment in Patients Treated with Teprotumumab: A Multicenter Study of 119 Patients with 1 Year of Follow-up.

PURPOSE: To determine the rate of re-treatment in patients who receive a full course of teprotumumab therapy for thyroid eye disease (TED) and drivers of re-treatment. DESIGN: Multicenter retrospective study. PARTICIPANTS: All patients who received a full course of treatment and had available data at 1 year after initial treatment were included. METHODS: Charts were reviewed for the following information: age, sex, months since diagnosis of TED, smoking status, and prior treatments. Further, the clinical activity score (CAS), proptosis, and the Gorman diplopia score were reviewed at baseline, at the end of the first course, and at baseline for the second course in those who received it. A logistic regression model was created to review the drivers of re-treatment. MAIN OUTCOME MEASURES: Rate of re-treatment and the drivers of re-treatment. RESULTS: One hundred nineteen patients were included from 3 centers across the United States. The overall re-treatment rate was 24% (29/119). No difference was found among the 3 sites (P = 0.6). In univariable analyses, at baseline, no difference was found in proptosis (P = 0.07), diplopia score (P = 0.4), or duration of TED (P = 0.4) between patients who were re-treated and those not re-treated. From the re-treated group, 82% showed a significant proptosis response (≥ 2-mm reduction from baseline) after the initial course, whereas 68% of patients who were not re-treated showed a clinically significant proptosis response (P = 0.16). The mean ± standard deviation difference between the end of the first treatment and at baseline before the second treatment (in those who received it) was 2 ± 2 for CAS, 2 ± 4 mm for proptosis, and 1 ± 1 for diplopia score. Age was the only significant driver of re-treatment (P < 0.05). Re-treated patients were 7 years older than patients who were not re-treated (60 years vs. 53 years; P < 0.05). CONCLUSIONS: In patients receiving a full course of teprotumumab therapy, the rate of re-treatment was 24%. Age was the only driver of re-treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

Teprotumumab-Related Adverse Events in Thyroid Eye Disease: A Multicenter Study.

PURPOSE: To assess the duration, incidence, reversibility, and severity of adverse events (AEs) in patients with thyroid eye disease (TED) treated with teprotumumab. DESIGN: Multicenter, retrospective, observational cohort study. PARTICIPANTS: Patients with TED of all stages and activity levels treated with at least 4 infusions of teprotumumab. METHODS: Patients were treated with teprotumumab between February 2020 and October 2022 at 6 tertiary centers. Adverse event metrics were recorded at each visit. MAIN OUTCOME MEASURES: The primary outcomes measure was AE incidence and onset. Secondary outcome measures included AE severity, AE reversibility, AE duration, proptosis response, clinical activity score (CAS) reduction, and Gorman diplopia score improvement. RESULTS: The study evaluated 131 patients. Proptosis improved by 2 mm or more in 77% of patients (101/131), with average proptosis improvement of 3.0 ± 2.1 mm and average CAS reduction of 3.2 points. Gorman diplopia score improved by at least 1 point for 50% of patients (36/72) with baseline diplopia. Adverse events occurred in 81.7% of patients (107/131). Patients experienced a median of 4 AEs. Most AEs were mild (74.0% [97/131]), 28.2% (37/131) were moderate, and 8.4% (11/131) were severe. Mean interval AE onset was 7.9 weeks after the first infusion. Mean resolved AE duration was 17.6 weeks. Forty-six percent of patients (60/131) demonstrated at least 1 persistent AE at last follow-up. Mean follow-up was 70.2 ± 38.5 weeks after the first infusion. The most common type of AEs was musculoskeletal (58.0% [76/131]), followed by gastrointestinal (38.2% [50/131]), skin (38.2% [50/131]), ear and labyrinth (30.5% [40/131]), nervous system (20.6% [27/131]), metabolic (15.3% [20/131]), and reproductive system (12.2% [16/131]). Sixteen patients (12.2%) discontinued therapy because of AEs, including hearing loss (n = 4), inflammatory bowel disease flare (n = 2), hyperglycemia (n = 1), muscle spasms (n = 1), and multiple AEs (n = 8). CONCLUSIONS: Adverse events are commonly reported while receiving teprotumumab treatment. Most are mild and reversible; however, serious AEs can occur and may warrant treatment cessation. Treating physicians should inform patients about AE risk, properly screen patients before treatment, monitor patients closely throughout therapy, and understand how to manage AEs should they develop. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Effects of teprotumumab and role of HLA markers in patients with thyroid eye disease.

OBJECTIVE: To evaluate the effects of teprotumumab on ophthalmological and biochemical findings and assess potential genetic markers for TED responses. METHODS: This is a retrospective study. Participants were 18-76 years old. All subjects were treated with teprotumumab. The primary outcome was the change in proptosis before and after teprotumumab treatment. Secondary outcomes include change in other ophthalmic measures and thyroid laboratory tests. Human leukocyte antigens (HLA) were also analyzed as markers for response to teprotumumab. RESULTS: Twenty-six patients were included in the final analysis. There was a significant decrease in TSI and TRAb levels and significant increases in HbA1c, fasting glucose, and total T3 levels. There was also significant reduction in proptosis, clinical activity score (CAS), retinal nerve fiber layer (RNFL) thickness, ganglion cell thickness (GCA), and intraocular pressure (IOP). HLA haplotypes were distinct between responders and non-responders, with HLA-DRB3*02:02:01G, HLA-DRB4*neg, and HLA-DQB1*02:01:01G demonstrating better response to teprotumumab and HLA-A*23:01:01G strongly correlating to non-response. CONCLUSIONS: Patients with both acute and chronic TED treated with teprotumumab had a significant reduction in TSI and TRAb levels and improvement in proptosis, CAS, RNFL and GCA thickness, and IOP. HLA may predict responders vs. non-responders. Further studies with longer duration and larger population comparing teprotumumab with steroids or other immunomodulatory agents (tocilizumab, rituximab, etc) may be helpful.

Impact of Teprotumumab on Clinical Practice in Thyroid Eye Disease.

BACKGROUND: Following its Food and Drug Administration approval in January 2020, we examined the impact of teprotumumab on thyroid eye disease (TED) clinical practices. METHODS: Across 3 referral centers from January 1, 2018, to December 30, 2022, we retrospectively analyzed demographics, clinical features, treatment choices, and insurance status of patients with active, moderate to severe TED. RESULTS: Of 74 patients recommended for medical therapy, 53% received collaborative recommendations from endocrinologists and ophthalmologists in a TED clinic. Prior to teprotumumab availability, 19 patients were recommended medical therapy, and all received medical therapy (100%), which consists of corticosteroids (14, 73.7%) or tocilizumab (5, 26.3%). After teprotumumab became available, out of 55 patients that were recommended medical therapy, only 41 (74.6%) received medical therapy, mostly teprotumumab (33, 60%), followed by corticosteroids (5, 9.1%) or tocilizumab (3, 5.4%), while 14 (25.4%) did not receive medical therapy. Discordance between physicians' recommendations and therapy received or lack thereof was explained by patients' refusal (9, 64.3%), mostly due to side effect concerns (8, 88.9%), and insurance denial (5, 35.7%). Teprotumumab use was mostly associated with otic changes (10, 30.3%), weight loss (9, 27.3%), and hyperglycemia (6, 18.2%), but 2 (6.1%) patients developed serious infections. Corticosteroids were associated with insomnia (4, 21.1%), and 1 patient in the tocilizumab group had an infusion reaction requiring hospitalization. CONCLUSION: Teprotumumab introduction increased TED therapy evaluations, yet not all received recommended treatment due to safety concerns or accessibility issues. Enhancing collaborative care, medication accessibility, and adverse effect management is crucial.

Teprotumumab for thyroid eye disease in patients with hypothyroid/euthyroid state: a multicenter case series.

BACKGROUND: Teprotumumab, a novel IGF-1R antibody was recently shown to significantly reduce the signs of acute and chronic thyroid eye disease (TED) related to hyperthyroidism. Given the lower incidence of TED associated with hypothyroidism / euthyroidism, there is a paucity of data regarding the efficacy of teprotumumab in this group. METHODS: In this multicenter study, consecutive patients who had been diagnosed with TED, presenting with either hypothyroidism or euthyroidism as their baseline thyroid dysfunction and treated with teprotumumab were included. All patients had measurements of proptosis, clinical activity scores (CAS), diplopia scores and four-point strabismus scores before and after therapy. RESULTS: Twenty-six patients met the inclusion criteria. Mean age was 48 ± 14 years old and mean duration of TED prior to treatment was 31 ± 43 months. All patients received 8 infusions. Mean (SD) reduction in proptosis for study orbits was 2.7 mm (1.8) (p < 0.05) and 1.8 mm (2.0) for the fellow orbit (p < 0.05). In the study orbit, mean (SD) CAS was 2.3 (1.3) before therapy and 1.0 (1.0) following therapy (p < 0.05). At baseline, mean (SD) diplopia score was 1.2 (1.1) and 0.9 (1.1) following therapy (p < 0.05). CONCLUSION: Teprotumumab reduces proptosis and inflammation in patients presenting with TED associated with hypothyroidism and euthyroidism. The results of this study highlight the potential for teprotumumab therapy in this subgroup and also provide a unique insight into the potential role of the IGF-1R in these patients.

A comparison of proptosis reduction with teprotumumab versus surgical decompression based on fat-to-muscle ratio in thyroid eye disease.

PURPOSE: To explore if orbital fat-to-muscle ratio (FMR) is predictive of whether surgical decompression or teprotumumab leads to greater proptosis reduction in thyroid eye disease (TED). METHODS: A single-center retrospective cohort study comparing surgical decompression with teprotumumab according to FMR. All TED patients completing an 8-dose course of teprotumumab between January 2020 and September 2022 and all patients undergoing bony orbital decompression from January 2017 to December 2019 were included. Subjects were excluded if they were <18 years, received both surgical decompression and teprotumumab, or lacked orbital imaging. The primary exposure variable was teprotumumab or surgical decompression. The secondary exposure variable was baseline FMR. The primary outcome measure was change in proptosis (mm). RESULTS: Thirty-eight patients, mean age 53.5 years (±11.4), were included in the teprotumumab group and 160 patients, mean age 48 years (±11.1), in the surgical group. Average proptosis reduction after teprotumumab and surgical decompression was 3 mm (±1.44) and 5 mm (±1.75), respectively. The FMR was stratified at the median of 1.80. In subjects with FMR < 1.80, teprotumumab showed equivalent proptosis reduction compared to surgical decompression, -0.33 mm (SE 1.32) p = .802. In subjects with FMR ≥ 1.80, surgical decompression led to significantly more proptosis reduction than teprotumumab, 3.01 mm (SE 0.54), p < .001. CONCLUSIONS: Baseline FMR can be used to counsel patients as to proptosis reduction with teprotumumab versus surgery. Subjects with low FMR obtain comparable proptosis reduction with teprotumumab or surgery, whereas high FMR is associated with more significant proptosis reduction following surgery over teprotumumab.

Change in upper eyelid position after teprotumumab treatment for thyroid eye disease.

PURPOSE: Despite the high prevalence, treatment challenges, and significant impact of eyelid retraction on vision and quality of life among patients with thyroid eye disease, the effects of teprotumumab on eyelid retraction are not fully understood. This study evaluated change in upper eyelid position after teprotumumab. METHODS: A retrospective study of all patients who completed eight teprotumumab infusions at one institution from January 1 2020 to December 31 2022. Primary outcome was change in upper eyelid position immediately after treatment and at most recent follow-up compared to pre-treatment. RESULTS: Among 234 eyes of 118 patients, average margin reflex distance-1 (MRD1) pre-treatment was 5.25 mm (range 0-10.0, SD 1.75), 4.66 mm (1.0-9.0, SD 1.32) immediately post-treatment (p < 0.001), and 4.50 mm (0-10.0, SD 1.52) at most recent follow-up (mean follow-up duration 10.60 months). In total, 136 (58.12%) eyes of 88 patients had MRD1 reduction immediately post-treatment, averaging 1.49 mm (0.5-5.0 mm, SD 0.97). Every 1-mm increase in pre-treatment MRD1 increased the odds of MRD1 reduction by 15.03% (CI 10.52-19.72, p < 0.001) and increased the reduction amount by 0.48 mm (CI 0.39-0.57, p < 0.001). Of 154 eyes of 78 patients with most recent follow-up, 107 (69.48%) eyes had stable or further improved retraction at most recent follow-up compared to immediately post-treatment. CONCLUSIONS: This study found a modest but significant reduction in MRD1 in approximately 60% of eyes, independent of proptosis change, which was sustained by most patients over longer-term follow-up. Higher pre-treatment MRD1 corresponded with greater improvement. These results suggest an overall mild benefit of teprotumumab for upper eyelid retraction.

Dysthyroid optic neuropathy: emerging treatment strategies.

PURPOSE: Dysthyroid optic neuropathy (DON) is a rare sight-threatening complication of Graves' disease. First-line treatment for DON consists of high-dose intravenous methylprednisolone (ivMP), followed by immediate orbital decompression (OD) if the response is poor or absent as recommended by the 2021 European Group on Graves' orbitopathy guidelines. The safety and efficacy of the proposed therapy have been proven. However, consensus regarding possible therapeutic options for patients with contraindications to ivMP/OD or resistant form of disease is missing. This paper aims to provide and summarize all available data regarding possible alternative treatment strategies for DON. METHODS: A comprehensive literature search within an electronic database was performed including data published until December 2022. RESULTS: Overall, 52 articles describing use of emerging therapeutic strategies for DON were identified. Collected evidence indicates that biologics, including teprotumumab and tocilizumab, may be considered as an important possible treatment option for DON patients. Rituximab should be avoided in DON due to conflicting data and risk of adverse events. Orbital radiotherapy could be beneficial for patients with restricted ocular motility classified as poor surgical candidates. CONCLUSION: Only a limited number of studies have been dedicated to the therapy of DON, mostly retrospective with a small sample size. Clear criteria regarding diagnosis and resolution of DON do not exist, which restricts comparison of therapeutic outcomes. Randomized clinical trials and comparison studies with long-term follow-ups are necessary to verify the safety and efficacy of each therapeutic option for DON.

Change in lacrimal gland volume and aqueous tear production following treatment with teprotumumab.

BACKGROUND: Dry eye syndrome occurs in up to 85% of patients with thyroid eye disease (TED). Lacrimal gland enlargement correlates with subjective tearing and a reduction in quality of life in patients with TED. METHODS: In this prospective longitudinal study, patients presenting for the treatment of TED were considered for eligible. Primary outcomes included a change in the volume of the lacrimal gland and the production of tears following treatment with teprotumumab. The volume of lacrimal glands and proptosis was calculated using 3D volumetric analysis. Tear production was measured by Schirmer's test and associated symptoms were assessed using the VLSQ-8. The orbit with the most proptosis was designated the study orbit and the contralateral orbit was designated the fellow orbit. RESULTS: Twenty patients were included. Mean (SD) age was 61 (18) and mean duration of TED prior to therapy was 48 months (47). Lacrimal gland volume in the study orbit decreased from 768 mm3 (288) to 486 mm3 (173) (p < 0.01) following therapy. For the fellow orbit, volume reduced from 637 mm3 (261) to 379 mm3 (147) (p < 0.01). Schirmer's test reading (STR) in the study orbit increased from 14.5 mm (8.2) to 23 mm (10) (p < 0.01) (59%) following treatment. In the fellow orbit, STR increased from 12.7 mm (7) to 21 mm (9) post therapy (69%) (p < 0.01). There was a significant improvement on all parts of the VLSQ-8. CONCLUSION: Teprotumumab significantly reduces TED related expansion of the lacrimal gland, increases tear production, and improves dry eye symptoms.

Differential effects of teprotumumab treatment based on fat-to-muscle ratio in patients with thyroid eye disease.

PURPOSE: To characterize the distribution of fat-to-muscle ratio (FMR) across patients with thyroid eye disease (TED) and to assess the association between FMR and therapeutic response to teprotumumab. METHODS: A retrospective cohort study of patients completing a full course of teprotumumab for TED between January 2020 and March 2022 at a single tertiary referral center. Patients without baseline orbital imaging were excluded. Quantitative analysis of FMR was performed by manual segmentation of patients' imaging using OsiriX software. The primary outcome measure was change in clinical measurement of proptosis. Linear regression modelled change in proptosis against FMR. Statistical significance was set at p < .05. RESULTS: Twenty-two patients (3 M:19F) were included with a mean age of 49.4 ± 15.5 years. The FMR ranged from 1.11 to 6.54, mean 3.15 ± 1.30. The data did not deviate from a normal distribution (Shapiro-Wilk test for normality, p = .18). Pre- and post-treatment average proptosis measurements were 21.72 ± 3.56 mm and 18.81 ± 3.07 mm, respectively. Univariable linear regression demonstrated a 0.78 ± 0.36 mm greater reduction in proptosis for every 1 unit decrease in FMR (p = .038). CONCLUSIONS: Contrary to the traditional dichotomous characterization of TED into type 1 and type 2 phenotypes, orbital FMR may represent a continuum of disease manifestation, more closely following a normal rather than bimodal distribution. Furthermore, pre-treatment FMR is associated with response to teprotumumab; those with lower FMR experiencing a greater reduction in proptosis. This has implications for patient selection and counselling regarding the expected treatment outcome.

Current concepts regarding Graves' orbitopathy.

Graves' orbitopathy (GO) is an orbital autoimmune disorder and the main extrathyroidal manifestation of Graves' disease, the most common cause of hyperthyroidism. GO affects about 30% of Graves' patients, although fewer than 10% have severe forms requiring immunosuppressive treatments. Management of GO requires a multidisciplinary approach. Medical therapies for active moderate-to-severe forms of GO (traditionally, high-dose glucocorticoids) often provide unsatisfactory results, and subsequently surgeries are often needed to cure residual manifestations. The aim of this review is to provide an updated overview of current concepts regarding the epidemiology, pathogenesis, assessment, and treatment of GO, and to present emerging targeted therapies and therapeutic perspectives. Original articles, clinical trials, systematic reviews, and meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, Graves' orbitopathy, thyroid eye disease, glucocorticoids, orbital radiotherapy, rituximab, cyclosporine, azathioprine, teprotumumab, TSH-receptor antibody, smoking, hyperthyroidism, hypothyroidism, thyroidectomy, radioactive iodine, and antithyroid drugs. Recent studies suggest a secular trend toward a milder phenotype of GO. Standardized assessment at a thyroid eye clinic allows for a better general management plan. Treatment of active moderate-to-severe forms of GO still relies in most cases on high-dose systemic-mainly intravenous-glucocorticoids as monotherapy or in combination with other therapies-such as mycophenolate, cyclosporine, azathioprine, or orbital radiotherapy-but novel biological agents-including teprotumumab, rituximab, and tocilizumab-have achieved encouraging results.

Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment: OPTIC-X Study.

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.

Advances in the Treatment of Thyroid Eye Disease Associated Extraocular Muscle Myopathy and Optic Neuropathy.

PURPOSE OF REVIEW: To review emerging treatments for thyroid eye disease (TED) associated extraocular muscle myopathy and dysthyroid optic neuropathy (DON). RECENT FINDINGS: Emerging targeted biologic therapies may alter the disease course in TED. Teprotumumab, a type I insulin-like growth factor receptor inhibitor, is the most recent addition to the treatments available for TED-associated extraocular muscle myopathy causing diplopia. Small studies also suggest a potential therapeutic benefit for DON. Various recent studies have also expanded our knowledge on conventional TED therapies. The therapeutic landscape of TED and its sequelae has evolved in recent years. New targeted therapies have the potential to reduce the extraocular muscle and orbital volume expansion which can lead to diplopia and vision loss from optic nerve compression. Longer term efficacy and durability data is needed to determine the role biologics, such as teprotumumab, should play in the treatment of TED patients compared to the current standard of care.

Teprotumumab for chronic thyroid eye disease.

PURPOSE: To describe the treatment of nine patients with chronic, low clinical activity score thyroid eye disease with teprotumumab. METHODS: A retrospective series of patients with chronic thyroid eye disease (TED) and low clinical activity score (CAS) treated with teprotumumab infusion therapy. Inclusion criteria: adults over 18 years of age with TED for greater than 9 months and CAS of 1 or less. All patients included in the analyses completed a full series of eight infusions. Primary outcome measures included proptosis and eyelid retraction in both eyes. Secondary outcomes included CAS, reported adverse effects, and surgery post-treatment. RESULTS: Nine patients met all inclusion criteria, seven females and two males with mean age of 50.2 years and TED diagnosis of 6.25 years. Three patients had a baseline CAS of 1 and 6 had a CAS of 0. Mean proptosis reduction in the worse eye was 4.0 ± 2.4 mm immediately post-treatment (p = .02). Five out of nine patients had extended follow-up (average 16.8 ± 5.1 weeks) with mean proptosis reduction of 4.2 ± 2.8 mm at last follow-up (p = .03). Mean reduction in eyelid retraction in the worse eye was 0.3 ± 1.6 mm post-treatment (p = .58) and 0.5 ± 0.9 mm at last follow-up (p = .30). Three patients reported infusion-related myalgias, two hair thinning, one exacerbated chronic tinnitus, and one hyperglycemia. CONCLUSIONS: We report clinically and statistically significant proptosis reduction in nine patients with chronic, low CAS TED treated with teprotumumab. Teprotumumab may be an effective treatment option for these patients.

Teprotumumab: Interpreting the Clinical Trials in the Context of Thyroid Eye Disease Pathogenesis and Current Therapies.

Teprotumumab, a monoclonal antibody targeted against the insulin-like growth factor 1 (IGF-1) receptor, was recently approved by the United States Food and Drug Administration for the treatment of thyroid eye disease (TED). Phase 1 studies of teprotumumab for the treatment of malignancies demonstrated an acceptable safety profile but limited effectiveness. Basic research implicating the IGF-1 receptor on the CD-34+ orbital fibrocyte in the pathogenesis of TED renewed interest in the drug. Two multicenter, randomized, double-masked, clinical trials (phase 2 and 3) evaluated the efficacy of 8 infusions of teprotumumab every 3 weeks versus placebo in 170 patients with recent-onset active TED, as defined by a clinical activity score (CAS) of at least 4. Teprotumumab was superior to placebo for the primary efficacy end points in both studies: overall responder rate as defined by a reduction of 2 or more CAS points and a reduction of 2 mm or more in proptosis (69% vs. 20%; P < 0.001; phase 2 study) and proptosis responder rate as defined by a reduction of 2 mm or more in proptosis (83% vs. 10%; P < 0.001; phase 3 study). In both studies, treatment with teprotumumab compared with placebo achieved a significant mean reduction of proptosis (-3.0 mm vs. -0.3 mm, phase 2 study; -3.32 mm vs. -0.53 mm, phase 3 study) and CAS (-4.0 vs. -2.5, phase 2 study; -3.7 vs. -2.0, phase 3 study). Teprotumumab also resulted in a greater proportion of patients with a final CAS of 0 or 1, higher diplopia responder rate, and a larger improvement in the Graves' Ophthalmopathy Quality of Life overall score. More than half of patients (62%, phase 2 trial; 56%, phase 3 trial) who were primary end point responders maintained this response at 51 weeks after the last dose of therapy. The most common adverse events reported with teprotumumab included muscle spasms (25%), nausea (17%), alopecia (13%), diarrhea (13%), fatigue (10%), hearing impairment (10%), and hyperglycemia (8%). Teprotumumab is contraindicated for those with inflammatory bowel disease and who are pregnant. Although the current dosing regimen has proven effective for TED, dose-ranging studies including variable concentrations, infusion frequencies, and durations of teprotumumab therapy in the setting of TED have not been performed.

Teprotumumab (Tepezza): from the discovery and development of medicines to USFDA approval for active thyroid eye disease (TED) treatment.

Teprotumumab (TPT) is a type I insulin-like growth factor receptor inhibitor, marketed as Tepezza; recently USFDA approved it for the treatment of thyroid eye disease (thyroid-associated ophthalmopathy (TAO), Graves ophthalmopathy/orbitopathy) in the USA. It is a monoclonal antibody although it was initially developed in collaboration with Genmab and Roche for the treatment of the tumour, but later it was investigated by River Vision Development Corporation and Horizon Therapeutics for its ophthalmic use. The drug has been designated as an orphan drug, breakthrough designation and fast-track designation. This review summarizes the milestones in the research and development including ongoing, clinical trial of TPT till now, foremost to this primary approval for thyroid-associated ophthalmopathy (TAO).