Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment

Teprotumumab Efficacy, Safety and Durability in Longer Duration Thyroid Eye Disease and Retreatment: Optic-X Study

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 for 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.

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Teprotumumab for the treatment of chronic thyroid eye disease.

Context Thyroid-associated ophthalmopathy (TAO) is an organ-specific autoimmune disease closely associated with Graves' disease (GD). IL-38, a novel cytokine in the IL-1 superfamily, has been reported to be involved in the pathogenesis of various autoimmune diseases. Objectives To evaluate the relationship between IL-38 and TAO disease activity and its role in inflammation and fibrosis in TAO. Design/setting/participants Blood samples and orbital connective tissues were collected from TAO patients and controls. Orbital fibroblasts (OFs) were isolated from patients with TAO. Main outcome Measures Enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), flow cytometry, immunofluorescence, quantitative real-time PCR and western blot analysis were performed. Results Here, we demonstrated that IL-38 levels decreased in the circulation and orbital connective tissues of patients with TAO compared to the controls, and were negatively correlated with the clinical activity score (CAS). In vitro, potent anti-inflammatory and anti-fibrotic effects of IL-38 were observed. Furthermore, we revealed that IL-38 can counteract the phosphorylation of star molecules in multiple classical pathways. Conclusions IL-38 plays a protective role in TAO and is associated with its pathogenesis. Our data suggest that IL-38 may be a promising marker of TAO disease activity and a potential target for TAO therapy.

IL-38 Exerts Anti-Inflammatory and Antifibrotic Effects in Thyroid-Associated Ophthalmopathy.

Purpose Teprotumumab, a blocking antibody to the insulin like growth factor 1 receptor (IGF-1R) has been shown to significantly reduce proptosis in recent phase 2 and 3 trials in patients with inflammatory thyroid eye disease (TED). Herein, we investigate the impact of teprotumumab on patients with non-inflammatory TED. We also investigate the expression of the IGF-1R on orbital tissues from patients with inflammatory and non-inflammatory TED compared to controls. Methods Consecutive patients with non-inflammatory TED (clinical activity score, CAS ≤ 1, for at least 4 months, were treated with teprotumumab. They received a complete course (total eight infusions) of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for subsequent infusions every 3 weeks). The primary outcome was a proptosis response at week 24. Further, IGF-1R α and β expression was evaluated on orbital tissue from patients with inflammatory and non-inflammatory TED, as well as healthy controls. Non-biased histological analysis of IGF-1R expression was performed using ImageJ. Results Four patients met eligibility criteria for the clinical study, with a mean (SD) CAS of 0 (0). Following teprotumumab treatment, there was a mean (SD) reduction in proptosis of 2.6 mm (1.2). Five patients were included for each group of the histological study; inflammatory TED, non-inflammatory TED and controls. IGF-1Rα and IGF-1Rβ expression was significantly greater in the orbital tissues of patients with inflammatory TED and non-inflammatory TED, when compared to controls. Conclusion Our findings demonstrate for the first time, that teprotumumab, a blocking antibody to the IGF-1R reduces proptosis in a series of patients with non-inflammatory TED. Overexpression of the IGF-1R in orbital tissue from patients with non-inflammatory disease compared to controls may be an important consideration for effect.

Teprotumumab for non-inflammatory thyroid eye disease (TED): evidence for increased IGF-1R expression

Purpose Teprotumumab, a specific blocking antibody to the insulin like growth factor 1 receptor, significantly reduced proptosis in patients with thyroid eye disease (TED) in recent clinical trials. Given its specificity, we expect it to demonstrate greater efficacy on the worse affected orbit, in patients with asymmetric TED. Herein, we investigate the differential impact of teprotumumab on the orbits of such patients. Methods In this pooled analysis of patients who were enrolled in the recent phase 2 (NCT01868997) and phase 3 (NCT03298867) trials, all patients with asymmetric TED (difference in exophthalmometry of ≥3 mm) were screened for eligibility. The primary outcomes of the trials, proptosis, diplopia and Clinical Activity Score (CAS) response, were evaluated in both orbits of patients who had received treatment or placebo, to examine the differential response from baseline to week 24. Results From a pooled group of 84 patients randomised to receive teprotumumab and 87 randomised to placebo, 10 (12%) and 12 (14%), respectively, met the inclusion criteria. The teprotumumab-treated patients demonstrated significant reductions in proptosis, CAS and diplopia in both orbits of each patient and this was not seen with placebo. The reduction in proptosis and CAS was significantly greater in the worse affected orbit, improving symmetry. In the placebo arm, while the mean CAS in the study eye reduced over time, proptosis and diplopia did not change in either orbit. Conclusion The findings in this study suggest the differential impact of teprotumumab on orbits that are clinically more affected by TED, suggesting that teprotumumab reduces asymmetry.

https://bjo.bmj.com/content/bjophthalmol/early/2021/02/11/bjophthalmol-2020-318314.full.pdf

Improvement of asymmetric thyroid eye disease with teprotumumab

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.

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Tunde Mester

Papers

Teprotumumab for non-inflammatory thyroid eye disease (TED): evidence for increased IGF-1R expression

Improvement of asymmetric thyroid eye disease with teprotumumab

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