Teprotumumab for the treatment of Thyroid eye disease.

Thyroid eye disease (TED) is the most common extra thyroidal manifestation of Graves' disease (GD). It may also present in those who are hypothyroid or euthyroid. The characteristic clinical manifestations of TED: chemosis, lid swelling, proptosis and diplopia are driven by a combination of inflammation and extracellular matrix modification. It has recently emerged that one of the major drivers of this molecular signature is the over-expression of the insulin like growth factor-1 receptor (IGF-1R) on key effector cells in TED pathogenesis. The overexpression of the IGF-1R is coupled with a dysregulation of the IGF-1R axis, which links other pathways that modulate inflammation, such as fibrosis and extracellular matrix organization, in patients with TED. This overexpression is also found to persist from the acute stage into the chronic phase. Teprotumumab, a fully human immunoglobulin (Ig) G1 monoclonal antibody that inhibits the IGF-1R, recently gained approval in the US for the treatment of TED. In phase 2 and phase 3 clinical studies, teprotumumab showed efficacy in reducing inflammation, proptosis, diplopia and burden on quality of life, in patients who were treated. Post introduction studies have confirmed the results of the phase 2 and phase 3 studies. Since 2020, over 5, 800 patients have been treated with teprotumumab and it appears to be well tolerated. The American Thyroid Association and the European Thyroid Association have recommended it as first line therapy for patients with moderate to severe TED, who display features of proptosis and diplopia.

Teprotumumab improves light sensitivity in patients with thyroid eye disease.

BACKGROUND: Teprotumumab, a novel IGF-1R antibody, has been shown to significantly reduce the signs of acute and chronic Thyroid Eye Disease (TED). Light sensitivity is a reported symptom in patients with TED. There is a lack of a prospective study that has explored the effects on light sensitivity in a large cohort of patients with acute and chronic TED following treatment with teprotumumab. METHODS: Consecutive patients who were diagnosed with TED and reported light sensitivity at baseline were considered for study eligibility. All patients had measurements of Visual Light Sensitivity Questionnaire-8 (VLSQ-8), proptosis, clinical activity score (CAS), and MRD1 (distance between the upper eyelid margin and corneal reflex, mm) and MRD2 (distance between the lower eyelid margin and corneal reflex, mm) before and after treatment. RESULTS: Ninety patients (41 acute, 49 chronic) met the inclusion criteria. The mean (SD) age was 47.3 (14.3). Eighty-six (95.6%) patients completed all 8 infusions. There was a significant reduction in the total score and across all categories of the VLSQ-8 (p <  0.01 for all). Seventy-two (80%) patients had a clinically significant improvement (≥2 reduction) in at least one category. There was no significant difference in the total VLSQ-8 score between the acute and chronic group (p = 0.8). CONCLUSION: Teprotumumab improves light sensitivity in patients with acute and chronic TED. The results of this study highlight that the improvements in light sensitivity following treatment are not directly related to the mechanical changes in TED, suggesting another underlying mechanism is potentially involved.

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.

Efficacy and Safety of Teprotumumab in Patients With Thyroid Eye Disease of Long Duration and Low Disease Activity.

CONTEXT: Early inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials. OBJECTIVE: We present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED. METHODS: This randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) ≤ 1 or no additional inflammation or progression in proptosis/diplopia for ≥1 year, proptosis ≥3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab, and no steroids within 3 weeks of baseline. Patients received (2:1) intravenous teprotumumab or placebo once every 3 weeks (total 8 infusions). The primary endpoint was proptosis (mm) improvement at Week 24. Adverse events (AEs) were assessed. RESULTS: A total of 62 (42 teprotumumab and 20 placebo) patients were randomized. At Week 24, least squares mean (SE) proptosis improvement was greater with teprotumumab (-2.41 [0.228]) than with placebo (-0.92 [0.323]), difference -1.48 (95% CI -2.28, -0.69; P = .0004). Proportions of patients with AEs were similar between groups. Hyperglycemia was reported in 6 (15%) vs 2 (10%) and hearing impairment in 9 (22%) vs 2 (10%) with teprotumumab and placebo, respectively. AEs led to discontinuation in 1 teprotumumab (left ear conductive hearing loss with congenital anomaly) and 1 placebo patient (infusion-related). There were no deaths. CONCLUSION: Teprotumumab significantly improved proptosis vs placebo in longstanding/low inflammation TED, demonstrating efficacy regardless of disease duration/activity. The safety profile was comparable to that previously reported.

Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease.

CONTEXT: Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED). OBJECTIVE: We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED. DESIGN: Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials. SETTING: Multicenter. PARTICIPANTS: Patients with moderate-to-severe, active TED. INTERVENTION: In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks. MAIN OUTCOME: Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial). RESULTS: The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation. CONCLUSIONS: These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

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.

Inflammatory and Noninflammatory Thyroid Eye Disease: Comparison of Disease Signs, Symptoms, and Quality of Life in Patients in the United States.

OBJECTIVE: Thyroid eye disease (TED) is an autoimmune, inflammatory disease resulting in retro-orbital fat and extraocular muscle expansion. TED quiets ("inactivates") as inflammation wanes; however, signs/symptoms often persist. Signs/symptoms of the disease and the impact on quality of life (QoL) were examined in noninflammatory and inflammatory TED. METHODS: Data of patients with moderate-to-severe TED were collected from treating physicians. Clinical activity score (CAS, 6/7 measures available) was used to classify TED as inflammatory (CAS ≥ 3) or noninflammatory (CAS = 0 or 1). QoL impact was scored as 1 = "not at all impaired" to 7 = "extremely impaired." Patients with noninflammatory TED were further grouped into longer (>3 years) and shorter (≤3 years) disease courses. RESULTS: Patients with inflammatory (N = 307) and noninflammatory (N = 281) TED had comparable age (50.0 ± 13.3 years vs 48.3 ± 13.8 years), gender (66% men vs 64% women), TED duration (4.0 ± 4.9 years vs 4.6 ± 5.5 years), and proportion of smokers (15% vs 11%). The most common signs/symptoms of noninflammatory TED included ocular dryness/grittiness (77%), proptosis (56%), excessive tearing (43%), soft tissue edema (42%), conjunctival redness (24%) decreased vision (24%), and eye muscle involvement (22%; 14% had diplopia). All signs/symptoms were less frequently reported in these patients than in those with inflammatory TED. QoL was impacted by noninflammatory TED, although to a lesser degree than the inflammatory disease (3.6 ± 1.5 vs 4.7 ± 1.4). However, mental health issues were similarly reported. Patients with noninflammatory TED with a longer disease course (9.0 ± 6.0 years) had similar QoL impact, mental health diagnoses, and TED signs/symptoms as those with a shorter disease course (1.4 ± 1.0 years). CONCLUSION: The signs/symptoms of TED often chronically persist long after TED has "quieted," continuing to impact a patient's QoL and mental health. These data suggest that moderate-to-severe TED should be thought of as a robust symptomatic chronic disease, regardless of its inflammatory status.

Expert Consensus on the Use of Teprotumumab for the Management of Thyroid Eye Disease Using a Modified-Delphi Approach.

BACKGROUND: Teprotumumab is the first treatment for thyroid eye disease (TED), a debilitating autoinflammatory condition, approved by the Food and Drug Administration in the United States, which reduces proptosis and improves quality of life. In the absence of guidelines, clinical recommendations were developed for using teprotumumab in patients with TED in the United States. METHODS: A 3-round modified-Delphi panel was conducted between October 2020 and February 2021 with experts in the management of patients with TED. Key areas regarding the use of teprotumumab were investigated, including eligible patient populations, concomitant treatments, and assessment of response and adverse events. This used 2 survey rounds via an online questionnaire, where statements were scored using 9-point Likert scales. Statements with conflict were included in the third round, involving a consensus meeting via videoconference. RESULTS: Consensus was obtained for all statements (n = 75); of which, 56% were revised to enable agreement of the group. The consensus meeting provided agreement regarding which populations should receive teprotumumab therapy, including all adult patients with TED with a clinical activity score of ≥4. Treatment with teprotumumab can also be considered for TED patients displaying the following characteristics: a CAS of <3, lid retraction of ≥2, and mild or early optic neuropathy with close clinical observation. Further recommendations included suitability of treatment for those beyond 16 months following the initial diagnosis of TED, low CAS concomitant treatment with steroids in some cases, retreatment for those who have relapses, and finally a recommendation to continue therapy for all 8 infusions despite the lack of response by the fourth infusion. CONCLUSIONS: This work constitutes the first consensus on guidelines for the use of teprotumumab. The modified Delphi approach involved physicians with significant experience with the clinical use of teprotumumab, and recommendations were based on current evidence.

Proptosis and Diplopia Response With Teprotumumab and Placebo vs the Recommended Treatment Regimen With Intravenous Methylprednisolone in Moderate to Severe Thyroid Eye Disease: A Meta-analysis and Matching-Adjusted Indirect Comparison.

IMPORTANCE: Thyroid eye disease can be a debilitating autoimmune disorder characterized by progressive proptosis or diplopia. Teprotumumab has been compared with placebo in randomized clinical trials, but not with intravenous methylprednisolone (IVMP), which sometimes is used in clinical practice for this condition. OBJECTIVE: To conduct a matching-adjusted indirect comparison of teprotumumab vs IVMP vs placebo. DATA SOURCES: Deidentified patient-level data from teprotumumab trials and aggregate-level data from literature on the most recommended regimen of IVMP. STUDY SELECTION: PubMed and Embase were searched for randomized/observational studies using key terms and controlled vocabulary. Full texts of eligible articles were reviewed and cataloged. DATA EXTRACTION AND SYNTHESIS: Conducted by 1 reviewer (R.A.Q.) and 1 verifier (R.B.), including study characteristics, eligibility criteria, baseline characteristics, and outcomes. MAIN OUTCOMES AND MEASURES: Changes in proptosis by millimeter and diplopia response (percentage with ≥1 grade reduction) from baseline to week 12 in patients receiving IVMP and placebo, and to week 24 in patients receiving teprotumumab. RESULTS: The search identified 1019 records, and 6 through manual searches, alerts, and secondary references. After excluding duplicates and screening full-text records, 12 IVMP studies were included in the matching-adjusted indirect comparison (11 for proptosis change [n = 419], 4 for diplopia response [n = 125], and 2 teprotumumab [n = 79] and placebo [n = 83] comparator studies). Treatment with IVMP resulted in a proptosis difference of -0.16 mm (95% CI, -1.55 to 1.22 mm) from baseline to week 12 vs placebo. The proptosis treatment difference between IVMP and teprotumumab of -2.31 mm (95% CI, -3.45 to -1.17 mm) favored teprotumumab. Treatment with IVMP (odds ratio, 2.69; 95% CI, 0.94-7.70) was not favored over placebo in odds of diplopia response; however, teprotumumab was favored over IVMP (odds ratio, 2.32; 95% CI, 1.07-5.03). CONCLUSIONS AND RELEVANCE: This meta-analysis suggests that use of IVMP is associated with a small, typically not clinically relevant, change from baseline in proptosis vs placebo, with modest changes in diplopia. While this nonrandomized comparison suggests that use of teprotumumab, compared with IVMP, is associated with greater improvements in proptosis and may be twice as likely to have a 1 grade or higher reduction in diplopia, randomized trials comparing these 2 treatments would be warranted to determine if 1 treatment is superior to the other to a clinically relevant degree.

Topical Review: An Update of Diagnostic and Management Algorithms for Acquired Blepharoptosis.

SIGNIFICANCE: Acquired ptosis is a condition of the upper eyelid that has negative cosmetic and functional effects but is likely underdiagnosed and undertreated. Given the evolving understanding of the condition and expanding therapeutic options, this review reappraised published evidence and clinical experience regarding diagnosis and treatment of acquired ptosis.The authors met over two structured virtual working sessions to review current evidence and develop timely recommendations for acquired ptosis identification, differential diagnosis, characterization, and treatment selection. Diagnostic algorithms, plus management and referral guidelines, are presented. Eyelid evaluation and, when needed, ptosis diagnostic workup are essential in the comprehensive eye examination. Acquired ptosis can be efficiently identified via patient questionnaire, history, and photograph review combined with assessment of eyelid position and symmetry using established methods. When ptosis is present, it is essential to evaluate onset, symptoms, pupil diameter, and extraocular muscle function to identify or rule out serious underlying conditions. If signs of serious underlying etiology are present, immediate referral/follow-up testing is required. After ruling out serious underlying causes, masquerade conditions, and pseudoptosis, pharmacologic or surgical treatment should be selected based on the clinical evidence. Effectively managing acquired ptosis requires practice-wide commitment to thorough eyelid evaluation, accurate diagnosis, and adoption of new treatment modalities. Aided by evolving pharmacologic therapeutic options, shifting from a "detect and refer" to a "diagnose and manage" approach can support identification and treatment of more patients with acquired ptosis, particularly mild-to-moderate cases.

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.

Teprotumumab for thyroid eye disease: early response is not required for benefit.

PURPOSE: In recent trials, 50% of patients treated with teprotumumab for thyroid eye disease had significant improvements in proptosis at 6 weeks. However, a small subgroup of patients did not have a significant response by week 12. We examine the outcomes at week 24 in patients from both trials who had little or no proptosis response at week 12. DESIGN: In this post hoc analysis, data from teprotumumab-treated patients in the placebo-controlled randomized phases 2 and 3 trials were reviewed. METHODS: Patients treated with teprotumumab or placebo with a ≤2 mm reduction from baseline in proptosis at week 12 and completed assessments at both the weeks 12 and 24 visits were included. The main outcome measures were a change in proptosis, clinical activity score (CAS) and diplopia in response to teprotumumab therapy at baseline and weeks 6, 12, 18, and 24. RESULTS: From the phases 2 and 3 studies, 24 patients from the treated and placebo groups were included for analysis (48 total). In the teprotumumab group, of the 24 who had no improvement in proptosis (≥2 mm from baseline) at 12 weeks, 15 (63%) demonstrated a clinically significant improvement at week 24. No patients from the 24 placebo patients had a clinically significant improvement in proptosis at 12 weeks, and 24 weeks. At week 12, 22 patients (92%) in the teprotumumab group had a significant reduction in the CAS (≥2 points) and at 24 weeks all patients achieved this reduction. At week 12, 11 (46%) patients from the placebo group had a significant improvement, while 10 (42%) had a significant improvement at 24 weeks. 22 of the 24 patients (92%) in the teprotumumab group had a diplopia grade > 0 at baseline. At week 12, 12 of the 22 (55%) had improvement in diplopia ≥ 1 grade. By week 24, 16 patients (73%) had an improvement in diplopia ≥ 1 grade. In the placebo group, 15 (63%) had significant diplopia. At week 12, 3 (20%) from this group had improvement in diplopia ≥ 1 grade, while at 24 weeks this number rose to 4 (27%). CONCLUSIONS: There is variability in the time taken to manifest a clinically significant response to teprotumumab, some patients my need a longer time to respond.

Angioleiomyoma of the nasolacrimal duct: case report and literature review.

Angioleiomyomas are benign tumors composed of smooth muscle and vascular endothelium. While infrequent in overall prevalence, they are exceptionally rare in the head and neck. Herein, we describe the case of a 65-year-old female who was found to have an angioleiomyoma of the right nasolacrimal duct. Endoscopic excision of the lesion along with medial maxillectomy and dacryocystorhinostomy was performed without complication. The current report is one of the few reported cases of angioleiomyoma of the lacrimal drainage system.

Teprotumumab for the treatment of chronic thyroid eye disease.

BACKGROUND: Teprotumumab, a novel IGF-1R antibody was recently shown to significantly reduce the signs of active Thyroid eye disease (TED). The current study reviews its efficacy in chronic TED. METHODS: In this retrospective review, consecutive patients with chronic stable TED (>2 years), who had received ≥3 infusions of teprotumumab were included. All patients had measurements of proptosis, and calculation of the CAS and diplopia scores before and after therapy. Five-point strabismus scores were also calculated. Patients who had imaging within 4 months prior to therapy and 6 weeks post therapy underwent orbital 3D volumetric analysis. RESULTS: Thirty-one patients met the inclusion criteria. The mean (SD) duration of TED was 81 months (56) and the mean (SD) number of infusions received by each patient was 7 (2). Mean (SD) reduction in proptosis for each study orbit was 3.5 mm (0.4) and 3 mm (0.3) for the fellow orbit. The CAS response was 90% for the study orbit and 87% for the fellow orbit. Of the 15 patients who had diplopia at baseline, 67% had a clinically significant response, while 47% had complete resolution following treatment. Following teprotumumab, mean (SD) reduction of muscle tissue was 2011 mm3 (1847) in the study orbit and 1620 mm3 (1759) in the fellow orbit. The mean (SD) reduction of fat volume was 2101 mm3 (1681) in the study orbit and 1370 mm3 (1181) in the fellow orbit. CONCLUSION: Teprotumumab significantly reduces proptosis, inflammation, diplopia, strabismus and orbital soft tissue volume in patients with chronic TED.

Facial and Eyelid Changes in Thyroid Eye Disease Are Reversed by Teprotumumab.

Thyroid eye disease (TED) causes orbital soft-tissue expansion. Recent studies have suggested that brow and temple changes may also occur. Teprotumumab, a monoclonal antibody to the insulin-like growth factor 1 receptor reduces soft-tissue swelling in TED. In this study, we quantified the changes to pan facial soft-tissue volumes and eyelid position, following treatment with teprotumumab. METHODS: In this prospective study, consecutive patients who were treated with teprotumumab were appraised for study eligibility. All patients had 3D facial imaging using the Vectra H2. Soft-tissue volume changes in the upper face, periorbita, temples, midface, and lower face were quantified before and after teprotumumab therapy. Furthermore, the marginal reflex distance (MRD)1, MRD2, and intercanthal distance were also measured pretreatment and posttreatment. RESULTS: Twenty-three patients were included in the study. The mean duration of TED was 29 months (38). Following teprotumumab therapy, the mean (SD) decrease in volume for each region was 0.75 mL (0.84) in the upper face, 1.8 mL (1.3) in the periorbital region, 0.17 mL (0.5) in the temples, 1.62 mL (3.16) in the midface, and 2.67 mL (4.6) in the lower face. The mean (SD) decrease in the volume of the full face was 8.9 mL (8.7). There was also a significant reduction in MRD1, MRD2, and the intercanthal space following treatment. There was no relationship between previous steroid use and total body weight reduction and changes in facial volume. CONCLUSION: TED may cause significant tissue expansion across the entire face and this may be reduced following teprotumumab therapy.

Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials.

BACKGROUND: Thyroid eye disease manifests inflammation and treatment-resistant proptosis and diplopia. Teprotumumab, an insulin-like growth factor-1 receptor inhibiting monoclonal antibody, was approved in the USA on Jan 21, 2020, on the basis of two randomised trials. In this analysis we evaluated the short-term and long-term aggregate response to teprotumumab from the two trials, focusing on proptosis and diplopia. METHODS: We analysed integrated outcomes and follow-up data from two randomised, double-masked, placebo-controlled, multicentre, trials done at a total of 28 academic referral tertiary specialised centres offering joint thyroid eye clinics, or orbital clinics or practices, or both, in Europe and the USA. Participants were adult patients with a diagnosis of Graves' disease and active moderate-to-severe thyroid eye disease (clinical activity score [CAS] ≥4). Patients received eight intravenous infusions of either teprotumumab (10 mg/kg body weight for the first infusion, 20 mg/kg for subsequent infusions) or placebo every 3 weeks. The final study visit was at week 24, 3 weeks after the final infusion. In our analysis, the prespecified primary outcome was the between-group difference from baseline to week 24 in the proportion of patients with a proptosis response (≥2 mm reduction in the study eye without similar deterioration in the fellow eye at week 24) stratified by tobacco non-use and current use. Secondary endpoints at week 24 were the proportion of patients with improved diplopia (≥1 Bahn-Gorman grade), an overall response (reduction of ≥2 mm in proptosis and reduction of ≥2 points in CAS), mean change from baseline in proptosis measurement in the study eye, mean change from baseline in Graves' ophthalmopathy quality of life (GO-QOL) questionnaire scores (overall, visual functioning, and appearance), and the proportion of patients with disease inactivation (ie, a CAS score of 0 or 1). We also assessed data for the primary and secondary outcomes by patient subgroups (tobacco use; age <65 years or older; sex; time to diagnosis; CAS score 4 or 5, or 6 or 7; and thyrotropin binding inhibiting immunoglobulin [TBII] concentration <10 IU/L or ≥10 IU/L) versus placebo. Additional outcomes included short-term and long-term responses at 7 weeks and 51 weeks after the final dose, and post-hoc assessments of disease severity (more severe baseline disease defined as proptosis ≥3 mm or constant or inconstant diplopia, or both, as compared with all others), and an ophthalmic composite outcome (improvement in ≥1 eye from baseline without deterioration in either eye in ≥2 of the following: absence of eyelid swelling; CAS ≥2; proptosis ≥2 mm; lid aperture ≥2 mm; diplopia disappearance or grade change; or improvement of 8 degrees of globe motility). All outcome endpoint analyses were done by intention-to-treat (ITT) except where noted. FINDINGS: The pooled ITT population consisted of 84 patients assigned teprotumumab and 87 assigned placebo. More patients receiving teprotumumab achieved a reduction of at least 2 mm in proptosis at week 24 versus placebo (65 [77%] of 84 patients assigned teprotumumab vs 13 [15%] assigned placebo; stratified treatment difference 63%, 95% CI 51-75; p<0·0001). Numbers-needed-to-treat (NNT) were 1·6 for proptosis response, 2·5 for diplopia response (treatment difference 39%, 95% CI 23-55), 1·7 for overall response (treatment difference 60%, 48-72), and 2·5 for disease inactivation (treatment difference 40%, 27-53); all p <0·0001. The post-hoc assessment of the composite outcome showed that it was reached by 68 (81%) patients in the teprotumumab group and 38 (44%) in the placebo group (NNT 2·5, treatment difference 40%, 95% CI 26-53; p<0·0001). There were significantly more proptosis responders with teprotumumab in all subgroups at week 24; the number of diplopia responders was also significantly higher with teprotumumab for all subgroups except tobacco users and patients with TBII less than 10 IU/L at baseline. Integrated treatment differences for proptosis ranged from 47% in tobacco users (95% CI 21-73, p=0·0015; NNT=2·1) to 83% in patients aged 65 years and older (60-100, p<0·0001; NNT=1·2), and for diplopia ranged from 29% in tobacco users (95% CI -3 to 62, p=0·086; NNT=3·4) to 47% in those with baseline CAS of 6 or 7 (95% CI 23-71, p=0·0002; NNT=2·1). All other integrated subgroup results were p≤0·033. Integrated responses were observed at 7 weeks and 51 weeks after final dose for proptosis in 62 (87%) of 71 patients and 38 (67%) of 57 patients respectively; for diplopia in 38 (66%) of 58 and 33 (69%) of 48 respectively; and for the composite outcome in 66 (92%) of 72 and 48 (83%) of 58, respectively. During the 24-week study, compared with placebo, there were moderate-to-large improvements with teprotumumab for GO-QOL total scores (19 vs 6, p<0·0001), visual scores (20 vs 7, p=0·0003), and appearance scores (18 vs 6, p=0·0003), respectively, which were maintained during follow-up. Of all adverse events during the treatment period, 63 (94%) of 67 patients with teprotumumab and 59 (98%) of 60 patients with placebo were mild to moderate (grade 1 or 2), with three (4%) serious adverse events related or possibly related to teprotumumab of diarrhoea, infusion reaction, and Hashimoto's encephalopathy (co-incident with confusion) leading to study discontinuation. Of the most commonly reported adverse events with teprotumumab, muscle spasm (18%, 95% CI 7·3-28·7), hearing loss (10%), and hyperglycaemia (8%, 1·7-15·0) had the greatest risk difference from placebo. INTERPRETATION: Teprotumumab markedly improved the clinical course of thyroid eye disease in all patient subgroups examined from the two trials, with most patients maintaining responses in the long-term. Analyses of the effect of teprotumumab retreatment on non-responders and those who flare after response, as well as further studies in a broader population of thyroid eye disease are ongoing. FUNDING: Horizon Therapeutics.