Teprotumumab, an insulin-like growth factor-1 receptor antagonist antibody, in the treatment of active thyroid eye disease: a focus on proptosis.
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SUBMITTER: Douglas RS
PROVIDER: S-EPMC6367366 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
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Teprotumumab, an insulin-like growth factor-1 receptor antagonist antibody, in the treatment of active thyroid eye disease: a focus on proptosis.
Eye (London, England) 20181221 2
Thyroid eye disease is a disabling autoimmune disease associated with orbital inflammation and tissue remodeling which can result in significant proptosis, leading to visual alterations and is potentially sight threatening. Current evidence indicates that autoantibodies to the insulin-like growth factor 1 receptor (IGF-1R), along with the thyroid-stimulating hormone receptor (TSHR), mediate the pathogenesis in susceptible individuals. Teprotumumab, a monoclonal IGF-1R antagonist, has demonstrate ...[more]
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Project description:Background and objectiveThyroid eye disease (TED) is characterized by inflammation/expansion of orbital tissues, proptosis, and diplopia. Teprotumumab is the first US Food and Drug Administration-approved therapy for TED, administered as an initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks for an additional seven infusions. The objective of this article is to discuss the pharmacokinetics and exposure-response profile for teprotumumab in patients with TED.MethodsA population pharmacokinetic analysis was performed to characterize pharmacokinetics and select dosing in patients with TED. Exposure-response was evaluated for efficacy (proptosis response, clinical activity score categorical response, and diplopia response) and safety (hyperglycemia, muscle spasms, and hearing impairment) parameters.ResultsTeprotumumab pharmacokinetics was linear in patients with TED, with low systemic clearance (0.334 L/day), low volume of distribution (3.9 and 4.2 L for the central and peripheral compartment, respectively), and a long elimination half-life (19.9 days). The approved dosing regimen provided > 20 µg/mL for > 90% insulin-like growth factor 1 receptor saturation throughout the dosing interval. Model-predicted mean (± standard deviation) steady-state area under the concentration-time curve, peak, and trough concentrations in patients with TED were 131 (± 30.9) mg∙h/mL, 643 (± 130) µg/mL, and 157 (± 50.6) µg/mL, respectively. Female patients had a 15% higher steady-state peak concentration but a similar steady-state area under the concentration-time curve vs male patients. No other covariates affected teprotumumab pharmacokinetics. No meaningful correlations between teprotumumab exposures and efficacy or safety parameters were observed.ConclusionsTeprotumumab pharmacokinetics was well characterized in patients with TED, and generally consistent with other IgG1 antibodies. Efficacy was consistent across the exposure range with a well-tolerated safety profile supporting the current dose regimen for patients with TED.
| S-EPMC8332554 | biostudies-literature
Project description:Abstract Introduction: Teprotumumab treatment resulted in statistically and clinically meaningful improvements across multiple facets of active TED and was generally well-tolerated in Phase 2 and 3 trials.1,2 An initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks was selected based on in vitro activity and clinical PK profile, to maintain pharmacologically active exposures and >90% saturation of IGF-1R over dosing intervals and to achieve efficacy at a well-tolerated dose for this vision-threatening disease. Methods: Population PK analysis were performed on data from a Phase 1 oncology study (n=60)3 and Phase 2 and 3 trials in active TED (N=83)2,3 and covariate effect on PK was assessed. Exposure-response relationship was evaluated in TED studies for key efficacy endpoints (proptosis response rate, % patients with a clinical activity score value of 0 or 1, and diplopia responder rate) and selected safety variables (hyperglycemia and muscle spasms). Results: Teprotumumab PK was linear in TED patients and consistent with other immunoglobulin G1 monoclonal antibodies (IgG1 mAbs), with low systemic clearance (0.334 L/day), low volume of distribution (3.9 L for central compartment and 4.2 L for peripheral compartment), and long elimination half-life (19.9 days). 4,5 Model-predicted mean (± standard deviation) steady-state area under the concentration curve (AUCss), peak (Cmax,ss), and trough (Cmin,ss) concentrations in TED patients were 131 (± 30.9) mg∙hr/mL, 643 (± 130) µg/mL and 157 (± 50.6) µg/mL, respectively, suggesting low inter-subject variability. Population PK analysis indicated no significant impact of baseline age, gender, race, weight, smoking status, renal impairment (mild/moderate), and hepatic function (total bilirubin, aspartate and alanine aminotransferases) on teprotumumab PK. Female patients had 15% higher Cmax,ss but similar AUC compared to male patients, which is not considered clinically relevant. Exposure-response analysis from the TED dose regimen indicated no meaningful correlations between exposures (AUCss, Cmax,ss and Cmin,ss) and key efficacy endpoints or selected safety variables, supporting the demonstrated, favorable benefit-risk profile of the TED dose regimen.2 Conclusion: Teprotumumab PK was characterized in TED patients by long elimination half-life, low systemic clearance and low volume of distribution, consistent with other IgG1 mAbs. There was no meaningful exposure-response relationship at the selected TED dose regimen for both efficacy and safety endpoints, supporting the teprotumumab dose regimen used in TED patients. Reference: (1) Smith TJ, et al. N Engl J Med 2017;376:1748-1761. (2) Douglas RS, et al. AACE 2019 late-breaking abstract. (3) ClinicalTrials.gov: NCT00400361. (4) Dirks NL et al. Clin Pharmacokinet. 2010;49(10):633-59. (5) Ryman JT et al. CPT Pharmacometrics Syst Pharmacol. 2017;6(9):576-88.
| S-EPMC7207720 | biostudies-literature
Project description:Thyroid eye disease (TED) can cause disfigurement and vision loss, most commonly in patients with Graves' disease. These symptoms are related to orbital inflammation subsequently cause proptosis and limited eye movement. Traditionally, TED is treated with corticosteroids to decrease inflammation and surgery once the disease stabilizes. However, multiple medications that play a role in immune modulation have been tested and found to be beneficial in treating TED, either as an adjuvant to steroids or in severe disease resistant to steroids. Teprotumumab-trbw, a novel monoclonal antibody sold under the trade name Tepezza®, is the first immune modulator to be approved by the Unites States Food and Drug Administration (FDA) for TED. Teprotumumab-trbw targets the insulin-like growth factor-1 receptor, which is upregulated on orbital fibroblasts and decreases activation in patients with TED. The FDA approved this drug for patients with less than nine months of disease duration and high levels of disease activity. Multiple studies have shown significant positive results in disease modulation, as well as limited side effects.
| S-EPMC10511347 | biostudies-literature
Project description:BackgroundTeprotumumab, 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.MethodsIn 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.ResultsThirty-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.ConclusionTeprotumumab significantly reduces proptosis, inflammation, diplopia, strabismus and orbital soft tissue volume in patients with chronic TED.
| S-EPMC9307784 | biostudies-literature
Project description:Thyroid eye disease (TED; also known as thyroid-associated ophthalmopathy) is an autoimmune condition with disabling and disfiguring consequences. Teprotumumab is the first and only medication approved by the United States Food and Drug Administration for the treatment of TED. We review the efficacy and safety of teprotumumab in TED, highlighting results from the 2 randomized, double-masked, placebo-controlled trials. Post-approval case reports of teprotumumab use in patients with compressive optic neuropathy (CON) and inactive TED were similarly favorable to those from the trials. The preliminarily results of teprotumumab for CON and inactive TED should be investigated in formal clinical trials. Teprotumumab should be avoided in pregnancy. Evidence also suggests that teprotumumab may exacerbate pre-existing inflammatory bowel disease, worsen hyperglycemia, and be associated with hearing impairment. Patients at risk for these adverse events need to be closely monitored with baseline and periodic assessments.
| S-EPMC8630371 | biostudies-literature
Project description:IntroductionThyroid-associated ophthalmopathy (TAO) is a disfiguring, potentially blinding, and sub-optimally managed autoimmune condition. Current therapy of active TAO consists most frequently of glucocorticoid steroids, orbital radiation, or B-cell depletion; all of which are associated with substantial side effects. Teprotumumab (Tepezza) is a human monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR), recently evaluated in two clinical trials for active moderate-to-severe TAO that was recently approved by the United States Food and Drug Administration (FDA) for use in TAO.Areas coveredThis article reviews phase II and III placebo-controlled, double-masked, prospective, multicenter studies assessing the efficacy and safety of teprotumumab for the treatment of active, moderate-to-severe TAO.Expert opinionTeprotumumab has demonstrated substantial and rapid improvement in Clinical Activity Score and proptosis reduction in TAO compared to placebo. Subjective diplopia and quality of life were also improved in both clinical trials. Teprotumumab exhibited a favorable safety profile, with transient hyperglycemia, muscle cramps, and auditory side effects being associated with the drug; these were usually transient. The trial findings indicate that teprotumumab is a promising, potential first-line therapy for treating TAO.
| S-EPMC7529924 | biostudies-literature
Project description: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.MethodsIn 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.ResultsTwenty-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.ConclusionTED may cause significant tissue expansion across the entire face and this may be reduced following teprotumumab therapy.
| S-EPMC8443810 | biostudies-literature
Project description:PurposeIn 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.DesignIn this post hoc analysis, data from teprotumumab-treated patients in the placebo-controlled randomized phases 2 and 3 trials were reviewed.MethodsPatients 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.ResultsFrom 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%).ConclusionsThere is variability in the time taken to manifest a clinically significant response to teprotumumab, some patients my need a longer time to respond.
| S-EPMC9232498 | biostudies-literature
Project description:ImportanceThyroid 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.ObjectiveTo conduct a matching-adjusted indirect comparison of teprotumumab vs IVMP vs placebo.Data sourcesDeidentified patient-level data from teprotumumab trials and aggregate-level data from literature on the most recommended regimen of IVMP.Study selectionPubMed 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 synthesisConducted by 1 reviewer (R.A.Q.) and 1 verifier (R.B.), including study characteristics, eligibility criteria, baseline characteristics, and outcomes.Main outcomes and measuresChanges 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.ResultsThe 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 relevanceThis 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.
| S-EPMC8855315 | biostudies-literature
Project description:Teprotumumab has been shown to improve proptosis and clinical activity scores (CAS) in patients with thyroid eye disease, but little has been published regarding its effects on eyelid retraction. The purpose of this work was to evaluate changes in eyelid position in thyroid eye disease patients after teprotumumab. Eight patients completed eight cycles of teprotumumab. Data collected included exophthalmometry; clinical activity scores; margin reflex distance (MRD) 1; MRD2; and pre-, during, and posttreatment photographs. ImageJ analysis was also used to evaluate eyelid position in photographs. Proptosis significantly improved in 15 of 16 orbits [mean 4.75 ± 2.07 mm reduction (P = 0.0001) in study orbits and mean 3.00 ± 2.14 mm reduction (P = 0.0048) in nonstudy orbits]. CAS was significantly reduced (pretreatment mean 4.88 mm and posttreatment mean 1.88 mm, P = 0.006). MRD1 decreased in 11 of 16 orbits and increased in five orbits (P = 0.18 in study orbits and P = 0.22 in nonstudy orbits). MRD2 decreased in six of 16 orbits and increased in eight orbits (P = 0.49 in study orbits and P = 0.43 in nonstudy orbits). Patients exhibited variable changes in eyelid position with teprotumumab. There was a statistically insignificant decrease in MRD1 after teprotumumab. Proptosis reduction led to unpredictable changes in MRD1 and MRD2. Severity of eyelid retraction did not correlate with clinical activity score response to teprotumumab. There are inherent difficulties in evaluating eyelid position in thyroid eye disease, which may necessitate a paradigm shift in how patients are examined, measured, and photographed.
| S-EPMC9029877 | biostudies-literature