Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands
Pharmacotherapeutic group: Immunosuppressants, monoclonal antibodies
ATC code: L04AG13
Teprotumumab mechanism of action in patients with TED has not been fully characterised. Teprotumumab binds to IGF-1R and blocks its activation and signalling.
The efficacy and safety of teprotumumab was assessed in 287 patients with thyroid eye disease in four randomised, double-blind, placebo-controlled clinical studies (TED01RV, OPTIC, OPTIC-J and HZNP-TEP-403).
In all studies, patients received teprotumumab administered as an initial 10 mg/kg intravenous infusion followed by 20 mg/kg infusions every 3 weeks for a total of 8 infusions.
Patients were to be euthyroid or had thyroxine and free triiodothyronine levels less than 50% above or below normal limits. Patients with optic neuropathy were excluded.
Patients who had received immunosuppressive therapies (including rituximab, tocilizumab, or any other non-steroidal immunosuppressive agent within 3 months prior to screening), as well as those who had used oral or intravenous steroids within 4 weeks prior to screening, were not permitted in the studies. Additionally, patients who had undergone orbital irradiation or any surgical treatment for thyroid eye disease were also excluded.
Studies TED01RV, OPTIC, and OPTIC-J enrolled 225 patients 18 years and older with active thyroid eye disease (111 randomised to teprotumumab, and 114 to placebo).
Patients with active thyroid eye disease had a mean time since diagnosis of TED of 5.74 months, mean proptosis for the study eye of 22.52 mm, and mean clinical activity score CAS for the study eye of 5.0.
The baseline demographic and disease characteristics of the study population of TED01RV, OPTIC and OPTIC-J studies were: median age 52.0 years (range: 20 to 79); 14.2% patients 65 years or older; 72.4% female; 76.0% non-smoker.
The primary endpoint in phase II study TED01RV was the overall responder rate, defined as the percentage of participants with ≥2-point reduction in CAS and ≥2 mm reduction in proptosis measurement from baseline in the study eye, provided there is no corresponding deterioration (≥2-point increase in CAS or ≥2 mm increase in proptosis in the fellow eye) at week 24.
Efficacy results of study TED01RV are summarised in table 2.
Table 2. Overview of efficacy parameters in study TED01RV at week 24 (ITT population):
| Teprotumumab (N=42) | Placebo (N=45) | Treatment Difference (95% CI) | p-value | |
|---|---|---|---|---|
| Primary endpoint | ||||
| Overall responder rate, % | 69.0 | 20.0 | 48.9 (30.2, 67.6) | <0.001a |
| Secondary endpointsb | ||||
| Proptosis in study(mm), LS Mean | -2.95 | -0.30 | -2.65 (-3.38, -1.92) | <0.001 |
| CAS in study eye, LS Mean | -4.04 | -2.49 | -1.55 (-2.17, -0.94) | <0.001 |
| Change from baseline in GO-QoL visual functioning, LS Mean | 24.31 | 9.70 | 14.61 (4.37, 24.84) | 0.006 |
CAS = Clinical Activity Score; CI = confidence interval; ITT = intent-to-treat; GO-QoL = Graves' Ophthalmopathy Quality of Life; LS = Least Squares
Note: Results shown are those for the study eye for overall responder rate and change from baseline in proptosis.
a P-value was obtained from a logistic regression model with treatment and smoking status as covariate. Odds ratio of teprotumumab over placebo was 8.86 (95% CI [3.29, 23.83]).
b For secondary endpoints, analysis results were obtained from a mixed model for repeated measures (MMRM) with an unstructured covariance matrix using treatment, smoking status, baseline value, visit, treatment by visit, and visit by baseline value interaction as fixed effects. A change from baseline of zero was imputed at the first baseline visit for patients with no post-baseline assessment.
Note: For GO-QoL analysis variables, a transformed score is the sum of scores from individual questions to a scale of 0 (worst health) to 100 (best health).
After 48-weeks off-treatment, 14 of 29 proptosis responders (48.3%) in the teprotumumab group maintained responder status, and 11 of 29 (37.9%) experienced a relapse. Relapse was defined as increase in proptosis of ≥2 mm from week 24 in the study eye.
The primary endpoint, in the phase III OPTIC and the OPTIC-J studies was the proptosis responder rate at week 24 (defined as the proportion of patients with a ≥2 mm reduction in proptosis from baseline in the study eye, without deterioration (≥2 mm increase) in proptosis in the fellow eye).
Efficacy results of the OPTIC and OPTIC-J studies are summarised in tables 3 and 4, respectively.
Table 3. Overview of efficacy parameters in study OPTIC at week 24 (ITT population):
| Teprotumumab (N=41) | Placebo (N=42) | Treatment Difference (95% CI) | p-value | |
|---|---|---|---|---|
| Primary endpoint | ||||
| Proptosis responder rate, % | 82.9 | 9.5 | 73.5 (58.9, 88.0) | <0.001a |
| Secondary endpoints | ||||
| Overall responder rate, % | 78.0 | 7.1 | 70.8 (55.9, 85.8) | <0.001a |
| CAS responder rate, % | 58.5 | 21.4 | 36.0 (17.4, 54.7) | <0.001a |
| Change from baseline in proptosis (mm) through week 24, LS mean | -2.82 | -0.54 | -2.28 (-2.77, -1.80) | <0.001b |
| Diplopia responder rate, %c | 67.9 | 28.6 | 39.3 (15.6, 63.0) | <0.001a |
| Change from baseline in GO- QoL visual functioning, LS mean | 15.40 | 2.86 | 12.54 (3.14, 21.94) | 0.010b |
| Change from baseline in GO- QoL appearance, LS mean | 18.84 | 0.37 | 18.47 (9.95, 27.00) | <0.001b |
CAS = Clinical Activity Score; CI = confidence interval; GO-QoL = Graves' Ophthalmopathy Quality of Life; ITT = intent-to-treat; LS = Least Squares
Note: Results shown are those for the study eye for proptosis responder rate, overall responder rate, CAS responder rate, and diplopia responder rate.
Overall responder rate = Overall responders are defined as achieving ≥2 points reduction in CAS and ≥2 mm reduction in proptosis from baseline, provided there was no corresponding deterioration (≥2 points/mm increase) in CAS or proptosis in the fellow eye at week 24.
CAS responder rate = CAS responders are defined as achieving a reduction to a CAS of 0 or 1 at week 24.
Diplopia responder rate = Diplopia responders are defined as achieving ≥1 grade reduction in diplopia in the study eye without worsening by at least one grade in the fellow eye at week 24.
a Cochran–Mantel–Haenszel (CMH) test stratified by tobacco use status (smoker vs non-smoker).
b Results obtained from mixed model repeated measurements (MMRM) analysis with an unstructured covariance matrix including baseline value, tobacco use status, treatment group, visit, visit by treatment, and visit by baseline value interactions. A change from baseline of 0 was imputed at the first post baseline visit for any patient without a post-baseline value at all.
c Evaluated based on only those who presented diplopia at baseline.
Of 34 proptosis responders at week 24, 10 (29.4%) relapsed during the 48-week off-treatment follow-up. Among the 21 who had assessments at week 72, 19 (90.5%) maintained their responder status.
Table 4. Overview of efficacy parameters in study OPTIC-J at week 24 (ITT population):
| Teprotumumab (N=27) | Placebo (N=27) | Treatment Difference (95% CI) | p-value | |
|---|---|---|---|---|
| Primary endpoint | ||||
| Proptosis responder rate, % | 88.9 | 11.1 | 77.8 (60.7, 94.8) | <0.0001a |
| Secondary endpoints | ||||
| Overall responder rate, % | 77.8 | 3.7 | 74.1 (56.9, 91.3) | <0.0001a |
| CAS responder rate, % | 59.3 | 22.2 | 37.0 (12.5, 61.6) | 0.0031a |
| Change from baseline in proptosis, LS mean | -2.36 | -0.37 | -1.99 (-2.75, -1.22) | <0.0001b |
CAS = Clinical Activity Score; CI = confidence interval; ITT = intent-to-treat; LS = least squares
Note: Results shown are those for the study eye, for proptosis responder rate, overall responder rate, and CAS responder rate.
Overall responder rate = Overall responders are defined as achieving ≥2 points reduction in CAS and ≥2 mm reduction in proptosis from baseline, provided there was no corresponding deterioration (≥2 points/mm increase) in CAS or proptosis in the fellow eye at week 24.
CAS responder rate = CAS responders are defined as achieving a reduction to a CAS of 0 or 1 at week 24.
a p-value was estimated from Cochran-Mantel-Haenszel test adjusted for the randomisation stratification factor (tobacco use status).
b p-value is from mixed model repeated measurements analysis with an unstructured variance-covariance matrix including change from baseline value as the dependent variable and the following covariates: Baseline value, treatment group, tobacco use status, visit, visit-by-treatment and visit-by-baseline value interactions.
Phase IV study (HZNP-TEP-403) enrolled 62 patients with chronic thyroid eye disease (42 randomised to teprotumumab and 20 to placebo). Patients with chronic thyroid eye disease had a mean time since diagnosis of TED of 5.18 years, mean proptosis for the study eye of 24.40 mm, and mean CAS for the study eye of 0.4. The baseline demographic and disease characteristics of the study population were: median age 49 years (range: 18 to 75); 85.5% patients under 65 years, 14.5% patients 65 years or older; 80.6% female, and 87.1% non-smokers.
The primary endpoint in study HZNP-TEP-403 was the mean change from baseline in proptosis at week 24 in the study eye. The first secondary endpoint was the proptosis responder rate defined as the percentage of participants with a ≥2 mm reduction from baseline in proptosis in the study eye, without deterioration (≥2 mm increase) of proptosis in the fellow eye at week 24.
Efficacy results of HZNP-TEP-403 are summarised in table 5.
Table 5. Overview of efficacy parameters in study HZNP-TEP-403 at week 24 (intent-to-treat population):
| Teprotumumab (N=42) | Placebo (N=20) | Treatment Difference (95% CI) | p-value | |
|---|---|---|---|---|
| Primary endpoint | ||||
| Change from baseline in proptosis at week 24, LS mean | -2.41 | -0.92 | -1.48 (-2.28, -0.69) | 0.0004a |
| Secondary endpoint | ||||
| Proptosis responder rate, % | 61.9 | 25.0 | 36.9 (5.4, 59.2) | 0.0134b |
| Change from baseline in GO-QoL visual functioning, LS mean | 8.73 | 2.41 | 6.31 (0.57, 12.06) | 0.0318a |
CI = confidence interval; GO-QoL = Graves' Ophthalmopathy Quality of Life; LS = least squares
Note: For responder rates, a participant missing the week 24 evaluation was considered a non-responder.
Note: Results shown are those for the study eye for the change from baseline in proptosis at week 24 and proptosis responder rate.
a p-value is from mixed model repeated measurements analysis with an unstructured variance-covariance matrix including change from baseline value as the dependent variable and the following covariates: Baseline value, treatment group, visit, visit-by-treatment and visit-by-baseline value interactions.
b p-value is from Fisher exact test. Placebo was the reference group for the analysis.
The European Medicines Agency has waived the obligation to submit the results of studies with TEPEZZA in all subsets of the paediatric population with thyroid eye disease (see section 4.2 for information on paediatric use).
In a randomised placebo-controlled study (OPTIC) where teprotumumab was administered intravenously over a 24-week period to participants with active TED, 4.9% (2 of 41) participants tested positive for binding anti-drug antibodies at post-baseline visits. There was no apparent impact of ADA on efficacy, safety, or pharmacokinetics.
The pharmacokinetics of teprotumumab was described by a two-compartment population pharmacokinetic (PK) model. Based on data from 10 healthy subjects (dose of 1 500 mg) single intravenous and 176 patients with TED (first infusion at 10 mg/kg followed by 7 repeated doses of 20 mg/kg Q3W), teprotumumab follows dose-proportional pharmacokinetics. Following the recommended dose regimen (first infusion at 10 mg/kg followed by 7 repeated doses of 20 mg/kg Q3W), the mean (± SD) estimates for AUCss, peak Cmax,ss, and trough Cmin,ss concentrations of teprotumumab were 139 (± 27) mg×hr/mL, 675 (± 147) mcg/mL, and 159 (± 38) mcg/mL, respectively.
Following the recommended teprotumumab dosing regimen, the population PK estimated mean (± SD) for volume of distribution of teprotumumab were 6.76 (± 1.17) L.
Metabolism of teprotumumab has not been fully characterised. However, teprotumumab is expected to undergo metabolism via proteolysis.
Following the recommended teprotumumab dosing regimen, the population PK estimated mean (± SD) for the clearance of teprotumumab was 0.27 (± 0.07) L/day and for the elimination half-life was 22 (± 4) days.
No clinically relevant differences in the pharmacokinetics of teprotumumab were observed following administration of teprotumumab based on patient's age (18–80 years), gender, ethnicity, renal function, bilirubin levels, aspartate aminotransferase (AST) levels, or alanine aminotransferase (ALT) levels. No dose adjustments are considered necessary for patients with renal and hepatic impairment (see section 4.2).
In repeat-dose toxicity studies in cynomolgus monkeys, non-adverse, reversible thymic atrophy, decreased serum alkaline phosphatase and lower body weight gains occurred in animals at exposure similar to the exposure in humans at the proposed clinical dose.
Carcinogenic or mutagenic potential of teprotumumab was not evaluated.
No male or female reproductive organ toxicity or histopathology findings were observed in repeat-dose toxicity studies in cynomolgus monkeys.
In an embryo-foetal development study, seven pregnant cynomolgus monkeys were dosed intravenously at one dose level of teprotumumab (8.3-fold the maximum recommended human dose based on AUC) once weekly from gestation day 20 through the end of gestation. The incidence of abortion was higher for the teprotumumab-treated group (2 out of 7 foetuses, 28.6%) compared to the control group (1/6, 16.7%). Teprotumumab caused decreased foetal growth during pregnancy, decreased foetal size and weight at caesarean section, decreased placental weight and size, and decreased amniotic fluid volume. Multiple external and skeletal abnormalities were observed in each exposed foetus, including: misshapen cranium, closely set eyes, micrognathia, pointing and narrowing of the nose, and ossification abnormalities of skull bones, sternebrae, carpals, tarsals and teeth. The test dose was the maternal no observed adverse effect level.
Based on the mechanism of action of teprotumumab which is the inhibition of IGF-1R signalling, exposure to teprotumumab may cause harm to the foetus.
In juvenile (11-14 months old) cynomolgus monkeys, teprotumumab treatment for 13 weeks resulted in decreased bone mass (bone mineral content and density), narrower bones with thinner cortices attributed to reduced periosteal expansion, and decreased body weight gains with some signs of reversibility after 13 weeks of recovery. These findings occurred at exposures similar to the exposure in human adults at the proposed clinical dose.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.