Reimbursement Review

Teprotumumab (Tepezza)

Sponsor: Amgen Canada Inc.

Therapeutic area: Thyroid Eye Disease (TED), active

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information on the Application Submitted for Review

NOC = Notice of Compliance.

Sources: Sponsor’s Summary of Clinical Evidence;¹ product monograph.²

Introduction

Thyroid eye disease (TED), also called Graves ophthalmopathy (GO) (or Graves orbitopathy), dysthyroid eye disease, or thyroid-associated orbitopathy, is a serious autoimmune disease associated with Graves autoimmune thyroid disease.^3,4 The pathogenesis of TED is driven by inflammation that is caused by autoantibodies targeting insulin-like growth factor-1 receptor (IGF-1R) on fibroblasts in and around the orbital cavity (“eye socket”).⁵ This inflammation causes expansion of muscle tissues and fat, which leads to orbital swelling, pain, proptosis (bulging eyes), diplopia (double vision), and potentially vision-threatening compression of the optic nerve (dysthyroid optic neuropathy [DON]).⁶ Older age, male sex, smoking status, radioiodine therapy, and high levels of thyroid-stimulating hormone (TSH) receptor antibodies (TRAbs) are considered as risk factors for TED.^7-9 The estimated incidence of TED is 4.83 cases per 100,000 population, while its prevalence is 89.7 cases per 100,000 population, with 94.82% of cases involving adult patients (≥ 18 years).¹⁰ There is no disease marker for TED.⁷ The evaluation of a patient with TED can include laboratory assessments (TSH, TRAbs, free thyroxine [T4], total triiodothyronine [T3]), examination of the eyes, assessment of disease severity and activity (i.e., clinical activity score [CAS] and vision, inflammation, strabismus, and appearance [VISA] assessments), and imaging (i.e., CT scans or MRI).⁷ The natural course of TED varies, but it progresses along a continuum of 2 phases: an active inflammatory phase (CAS ≥ 3 points) and a chronic phase (CAS of 0 or 1; i.e., little or no inflammation).¹¹ Active TED involves progressive inflammation and orbital tissue expansion that rapidly progress to maximal disease severity (based on signs and symptoms) and fibrotic changes in the orbit.^11,12 After inflammation has ameliorated, TED progresses to a chronic stage with persistent structural and appearance changes (due to underlying fibrosis).^11,12 The severity of TED is broadly categorized by the European Group on Graves Orbitopathy (EUGOGO) as mild (i.e., minor impacts on daily life that do not warrant immunosuppression or surgery), moderate to severe (i.e., TED that does not currently threaten vision, but affects the patient’s life sufficiently to justify intervention), or sight-threatening (i.e., DON, corneal breakdown, and/or globe subluxation).¹³ Health-related quality of life (HRQoL) is severely affected in both the active and chronic phases due to pain, proptosis, and diplopia^14,15 as well as the potential need for surgical procedures to correct the structural and appearance changes caused by TED.^16-18

Several options for pharmaceutical management are available for moderate to severe active TED, as per the published EUGOGO guidance from 2021 and the American and European Thyroid Associations Guideline from 2022.^11,19 According to the experts consulted by Canada’s Drug Agency (CDA-AMC), current treatments for patients with active TED include IV methylprednisolone (IVMP) and orbital radiation, IVMP and mycophenolate mofetil (MMF), rituximab, and tocilizumab. IVMP, MMF, rituximab, and tocilizumab are used off label in Canada.²⁰ The experts further highlighted that glucocorticoids (GCs) are the traditional therapy choices, and that these can be combined with radiotherapy (with risk of retinopathy and cataracts). The experts also reported that statins appear to have some benefit with GCs, but are likely underutilized.^20,21 Surgery is considered effective for patients with active TED with sight-threatening orbitopathy that is unresponsive to GCs.

Surgery is usually not performed until after the active phase of TED. However, in cases of acute optic nerve compression or corneal exposure, early surgery is performed. In the chronic stages, orbital decompression surgery may decrease at least 2 mm of proptosis per orbital wall removed, according to the experts. The experts reported that strabismus surgery is required for the correction of diplopia but is an option only once the orbit is stabilized.¹¹ Nonsurgical options for large-angle diplopia include Fresnel prism, translucent occluder, or patching. Small-angle diplopia may respond to prism grind glasses. Botulinum toxin may not be effective for the fibrotic changes of TED, according to the experts.

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of teprotumumab 500 mg IV in the treatment of adult patients with moderate to severe active TED. The focus will be on comparing teprotumumab to relevant comparators and identifying gaps in the current evidence. Teprotumumab has not been previously reviewed by CDA-AMC.

Perspectives of Patient, Clinicians, and Drug Programs

The information in this section is a summary of the input provided by the patient and clinician groups that responded to our call for input and from clinical experts consulted by for the purpose of this review.

Patient Input

• One patient group, the Thyroid Foundation of Canada (TFC), submitted input for this review. TFC is a nonprofit, registered volunteer organization and charity with a mission to awaken public interest in and awareness of thyroid disease; lend moral support to patients with thyroid diseases and their families; and assist in fundraising for thyroid disease research. The information in this submission was gathered by TFC through 1 online survey and 3 telephone interviews. The data collected from the survey and telephone interviews were anonymized when aggregated for analysis. A total of 42 participants (37 patients and 5 caregivers) responded to the online survey. The majority of the patient respondents (almost 95%) were from Canada, with the remainder from the UK and the US. Telephone interviews gathered information from patients receiving teprotumumab, all of whom were living in the US.

• Patients with TED indicated that they experienced a range of symptoms, with light sensitivity, bulging eyes, dry, irritated eyes, and eye bags reported as occurring “always” by more than 40% of respondents. Double vision and eyelid retraction were most often cited as always occurring by caregivers. The respondents reported that dry and/or gritty eyes, light sensitivity, bulging eyes, and pressure or pain behind the eyes were the most burdensome ocular symptoms.²² They noted that TED negatively affected their daily lives and/or quality of life, with the most frequent issues being emotional and/or psychological well-being, social life, work or school life, ability to pursue hobbies, financial situation, family life, and ability to travel.

• Key outcomes noted as important by patients included improvements in signs and symptoms (i.e., less swelling, less eye pain, reduced redness, and no sensitivity to light), reduced side effects, and reversal of disease.

• Three patients who were treated with teprotumumab shared their experiences and noted positive (though not instantaneous) responses and manageable side effects.

Clinician Input

Input From Clinical Experts Consulted for This Review

Unmet Needs

Clinical experts reported that active TED is associated with conjunctival injection, chemosis, caruncular injection, worsening proptosis, pain on eye movement, diplopia, and vision loss.

The functional goals of treatment, as identified by the clinical experts, are reduction in inflammation, preservation of vision, avoidance of diplopia, and comfort. According to the experts, a decrease in orbital inflammation is often reflected by a decrease in proptosis, although proptosis may remain in patients who become quiescent. The experts also reported that decreasing proptosis often decreases corneal exposure and improves patient appearance, which can benefit patients psychologically.

The clinical experts reported that the limitations associated with current treatments include not being wholly effective, not being disease modifying, and posing a risk of recurring thyroid-associated orbitopathy despite treatment. The experts also noted that immunosuppressants cannot be used in patients with liver failure or tuberculosis, and that GC therapy can be associated with systemic adverse events (AEs) that can be short-term or long-term. Access to safer and more convenient immunosuppressives delivered through oral, nasal, or subcutaneous administration would increase convenience, according to the experts. High costs of therapies, especially for teprotumumab and less so with tocilizumab, were highlighted by the experts.

Place in Therapy

The experts stated that teprotumumab should not be considered as a first-line treatment. Rather, its use should be conserved for patients with moderate to severe active TED if there has been incomplete or no response to methylprednisolone and other currently available treatment options.

Patient Population

All of the clinical experts engaged reported that patients with new-onset disease and a CAS equal to or higher than 4 would respond best to treatment with an immunosuppressive (e.g., teprotumumab, tocilizumab, or IVMP). The experts highlighted that patients with marked proptosis, vision loss, or progressive diplopia would also benefit from immunosuppression. According to the experts, patients with chronic thyroid-associated orbitopathy usually do not respond to immunosuppressive therapy, and surgery is becoming more widely available across Canada for patients with chronic TED, with techniques continuing to be refined to minimize diplopia and maximize outcomes.

Of note, the experts highlighted that teprotumumab should be used with increased caution in patients with existing hearing loss or diabetes and should not be used in pregnant patients or those still growing. The following considerations before initiating teprotumumab therapy were highlighted by the experts: patients with an absolute contraindication to corticosteroids (e.g., previous psychosis), differentiation of active versus chronic disease, and mitigation of risk factors (such as considerations for smoking cessation).

Assessing the Response Treatment

The clinical experts agreed that the outcomes of interest include vision, double vision (diplopia), corneal exposure, dry eye, and socialization. One expert reported that a clinically meaningful response to treatment might correspond with a reduction in proptosis of greater than 2 mm.

Regarding the assessment of treatment response, the experts stated that a basic eye exam can be performed every 3 to 6 weeks before infusion, and more detailed exams can be performed at 24 and 48 weeks. Throughout treatment, patients should be monitored for systemic side effects by an endocrinologist or rheumatologist, according to the experts.

Discontinuing Treatment

The clinical experts agreed that teprotumumab should be discontinued if no evidence of a meaningful benefit is observed (i.e., no decrease in inflammation assessed through CAS, no decrease in proptosis, absence of reduction in double vision). All experts agreed that the drug should be suspended in case of certain AEs, such as poorly controlled diabetes mellitus, hearing loss, or infection.

Prescribing Considerations

The clinical experts agreed that ophthalmologists specializing in orbital pathology and TED (or neuro-ophthalmologists) would be required for diagnosis, determination of treatment eligibility, initiation of treatment, and monitoring for and treating possible AEs. The experts also suggested that teprotumumab treatment should not be managed by otolaryngologists, endocrinologists, or general ophthalmologists. According to the expert clinical panel, consideration should be given to screening audiometry before commencing therapy. The experts noted that teprotumumab should be administered in an outpatient setting and, ideally, within a multidisciplinary clinic with access to specialists experienced in managing TED, including an oculoplastic surgeon or neuro-ophthalmologist, an endocrinologist, and a rheumatologist. Regarding restrictions to access in remote areas or smaller centres across the country, the experts reported that initial treatment decisions, initiation of therapy, and final evaluation post-treatment would require a specialist at the level of a tertiary care centre, but that the actual treatment over the 24 weeks of therapy could be administered and monitored through local IV or home care clinics.

Clinician Group Input

The following points summarize the input received from clinician groups (not from the clinical experts consulted by CDA-AMC for the review):

• The Canadian Society of Oculoplastic Surgery (CSOPS) provided input for this submission. CSOPS represents a group of ophthalmic surgeons who have additional training and experience in the highly specialized fields of eyelids, orbits, the nasolacrimal system, and facial aesthetics. A total of 29 clinicians provided input.

• The clinician group indicated that the ideal treatment would avoid disease onset, delay progression, reduce signs and symptoms, preserve intact vision, and avoid negative impacts on quality of life.

• The clinician group noted that patients with active TED will most likely respond to teprotumumab. Patients who respond inadequately to steroids or who are unable to tolerate treatment with steroids, and those with proptosis and/or diplopia, would be in most need of an alternate intervention. Regarding patients’ response to treatment, a clinically meaningful response would need to be assessed using trial outcome metrics, namely proptosis reduction of greater than or equal to 2 mm at week 24 of treatment. In the clinical setting, ophthalmologists would assess patients for a decrease in inflammation seen on clinical exam, stability or improvement of diplopia, proptosis, lid retraction, lid swelling, visual acuity, and redness.

• The clinician group highlighted that severe infusion reactions may necessitate discontinuation of treatment.

• The clinician group noted that the drug could also be prescribed by an endocrinologist, internal medicine physician, or immunologist; however, patients receiving treatment should be followed by an ophthalmologist to assess response.

Drug Program Input

Input was obtained from the drug programs that participate in the reimbursement review process. The following were identified as key factors that could potentially affect the implementation of a recommendation for teprotumumab:

• relevant comparators

• considerations for the initiation of therapy

• considerations for the continuation or renewal of therapy

• considerations for the discontinuation of therapy

• considerations for prescribing of therapy

• generalizability

• system and economic issues.

Clinical Evidence

Systematic Review

Description of Studies in Active TED

Three multicentre, double-masked, randomized controlled trials (RCTs) (the TED01RV phase II study [N = 87], the TEP-301 phase III study [N = 83], and the TEP-303 phase III study [N = 54]) assessed the efficacy and safety of teprotumumab relative to placebo in patients with moderate to severe active TED with CAS values greater than or equal to 3 (the TEP-303 study) or 4 (the TED01RV and TEP-301 studies). The primary outcome of the TED01RV study was overall responder rate (ORR), defined as the proportion of patients with at least a 2 mm reduction in proptosis and at least a 2-point reduction in CAS from baseline to 24 weeks in the study eye without corresponding deterioration in the fellow eye. In the TEP-301 and TEP-303 studies, the primary outcome was proptosis responder rate, defined as the proportion of patients with at least a 2 mm reduction from baseline to 24 weeks in proptosis in the study eye without corresponding deterioration in the fellow eye. The trials were conducted across 39 sites, with 24 centres in Europe, Japan, and the US; there were no sites in Canada. Regarding baseline characteristics, across the studies, the mean ages were 50 and 51 years in the teprotumumab and placebo groups, respectively. More than 65% of patients were females and approximately 30% were males in the teprotumumab group across the active TED trials. In the placebo group, more than 70% were females and less than 30% were males across the active TED trials. In the TED01RV and TEP-301 studies, more than 85% of patients were white, and less than 10% were either Asian, Black or African American, or Native Hawaiian or other Pacific Islander [categories are as reported in study]. The TEP-303 study was conducted in patients of Asian ethnicity. Regarding tobacco use, the proportions of people who were currently smoking in the TEP-301 and TEP-303 studies were generally balanced between the study groups (22% versus 19% for teprotumumab versus placebo in the TEP-301 study; 14.8% versus 14.8% for teprotumumab versus placebo in the TEP-303 study), whereas in the TED01RV study, there were more patients who were currently smoking in the placebo group (40.9%) than in the teprotumumab group (25.6%). The mean time since diagnosis of TED was approximately 5 months across the 2 treatment groups in the TED01RV and TEP-303 studies and approximately 6 months across the 2 treatment groups in the TEP-301 study.

Efficacy Results in the TED01RV, TEP-301, and TEP-303 Active TED Trials

Overall Responder Rate

At week 24, the proportions of patients experiencing overall response across the teprotumumab and placebo groups, respectively, were 69.0% and 20.0% (in the TED01RV study), 78.0% and 7.1% (in the TEP-301 study), and 77.8% and 3.7% (in the TEP-303 study). In the TED01RV, TEP-301, and TEP-303 studies, the corresponding differences in ORR between the teprotumumab and placebo groups at 24 weeks were 50.32% (95% confidence interval [CI], 32.11% to 68.52%; P < 0.0001), 70.82% (95% CI, 55.89% to 85.75%; P < 0.001), and 74.07% (95% CI, 56.9% to 91.3%; P < 0.0001), respectively.

Proptosis Responder Rate

At week 24, the proportions of patients experiencing response in proptosis in the study eye across the teprotumumab and placebo groups, respectively, were 71.4% and 20.0% (in the TED01RV study), 82.9% and 9.5% (in the TEP-301 study), and 88.9% and 11.1% (in the TEP-303 study). The reported differences in proptosis responder rate between the teprotumumab and placebo groups at 24 weeks were 52.45% (95% CI, 34.39 to 70.51; P < 0.0001), 73.45% (95% CI, 58.89% to 88.01%; P < 0.001), and 77.78% (95% CI, 60.7% to 94.8%; P < 0.0001) for the TED01RV, TEP-301, and TEP-303 studies, respectively.

Diplopia Responder Rate

At week 24, the proportions of patients experiencing response in diplopia across the teprotumumab and placebo groups, respectively, were 68.4% and 25.6% (in the TED01RV study), 67.9% and 28.6% (in the TEP-301 study), and 63.6% and 45.0% (in the TEP-303 study). In the TED01RV trial, the integrated summary of efficacy analyses demonstrated a between-group difference in diplopia responder rate of 39.51% (95% CI, 17.78% to 61.24%; P = 0.0004). In the intention-to-treat (ITT) population of the TEP-301 study, the difference in diplopia responder rate in the study eye between the teprotumumab and placebo groups at 24 weeks was 39.29% (95% CI, 15.55% to 63.02%; P = 0.001). In the ITT population of the TEP-303 study, the difference in binocular diplopia responder rate between the teprotumumab and placebo groups at 24 weeks was 16.82% (95% CI, −11.4% to 45.1%; P = 0.2430).

Complete Diplopia Responder Rate at Week 24

Complete diplopia response was not analyzed in the TED01RV and TEP-301 studies. In the ITT population of the TEP-303 study, the proportions of patients experiencing response in complete binocular diplopia at week 24 were 50.0% in the teprotumumab group and 20.0% in the placebo group. The difference in complete binocular diplopia responder rate between teprotumumab and placebo group at 24 weeks was 29.09% (95% CI, 0.9% to 57.3%; P = 0.043).

Change From Baseline in GO-QoL VF Score

At week 24, the mean changes from baseline in Graves Ophthalmopathy Quality of Life questionnaire (GO-QoL) Visual Functioning (VF) subscale scores across the teprotumumab and placebo groups, respectively, were 21.10 (standard error [SE] = 2.90) and 6.80 (SE = 2.66) (TED01RV study), 12.39 (SE = 2.98) and 4.21 (SE = 3.03) (TEP-301 study), and 16.22 (SE = 3.96) and 4.39 (SE = 3.97) (TEP-303 study). Trial findings assessing change from baseline in GO-QoL VF subscale demonstrated differences of 14.30 (95% CI, 6.66 to 21.94; P < 0.001), 8.18 (95% CI, 0.59 to 15.76; P = 0.035), and 11.83 (95% CI, 1.82 to 21.83; P = 0.0215) for the comparison of teprotumumab to placebo in the TED01RV, TEP-301, and TEP-303 studies, respectively.

Change From Baseline in GO-QoL Appearance Score

At week 24, the mean changes from baseline in GO-QoL Appearance (AP) subscale scores across the teprotumumab and placebo groups, respectively, were 12.92 (SE = 2.84) and 6.60 (SE = 2.66) (TED01RV study), 14.43 (SE = 2.40) and 4.22 (SE = 2.41) (TEP-301 study), and 19.35 (SE = 3.93) and 8.69 (SE = 3.93) (TEP-303 study). The results assessing changes from baseline in GO-QoL AP subscale scores demonstrated differences of 6.32 (95% CI, −1.25 to 13.90; P = 0.101), 10.21 (95% CI, 4.10 to 16.32; P = 0.001), and 10.66 (95% CI, 1.04 to 20.28; P = 0.0306) for the comparison of teprotumumab to placebo in the TED01RV, TEP-301, and TEP-303 studies, respectively.

Harms Results in the TED01RV, TEP-301, and TEP-303 Active TED Trials

In the active TED trials, most patients experienced more than 1 treatment-emergent adverse event (TEAE) during the treatment period (teprotumumab group range, 74.4% to 92.6%; placebo group range, 69.0% to 77.8%). Serious TEAEs were more common across the teprotumumab groups (range, 3.7% to 11.6%) than the placebo groups (range, 0% to 2.4%) across the studies. Discontinuation of treatment due to AEs was reported in 5 (11.6%), 1 (2.4%), and 1 (3.7%) patient in the teprotumumab arms of the TED01RV, TEP-301, and TEP-303 studies, respectively. One patient from the placebo group of each study discontinued treatment due to an AE (TED01RV study: 2.3%; TEP-301 study: 2.4%; TEP-303 study: 3.7%). No deaths were reported in any of the trials conducted in patients with active TED. The rates of notable harms were higher in the teprotumumab group (range, 18.6% to 48.8%) than in the placebo group (range, 2.3% to 23.8%).The specific notable harms reported across the trials were muscle spasm (teprotumumab group: 11.1% to 31.7%; placebo group: 0% to 9.5%), infusion-related reaction (teprotumumab group: 3.7% to 14.6%; placebo group: 0% to 9.5%), diarrhea (teprotumumab group: 9.8% to 14.0%; placebo group: 3.7% to 11.9%), and hyperglycemia (teprotumumab group: 4.9% to 22.2%; placebo group: 0% to 4.5%). Hearing impairment was reported in the TEP-301 and TEP-303 studies (teprotumumab group: 9.8% to 14.8%, placebo group: 0% to 3.7%).

Critical Appraisal of the TED01RV, TEP-301, and TEP-303 Active TED Trials

Three randomized, double-masked, multicentre studies in patients with active TED were submitted by the sponsor for the current review. Treatment allocation was performed appropriately through central interactive voice and web response systems (for the TED01RV and TEP-301 studies) or through electronic data capture (for the TEP-303 study). However, there were notable imbalances in key prognostic factors (e.g., uneven distribution of patients with smoking status in the TED01RV study and variability in patient sex in the TED01RV and TEP-303 studies) between the teprotumumab and placebo groups, which could have affected the intervention effects observed.

Risk of performance bias due to knowledge of treatment assignment might have been present in all the trials, despite the double-masked design, given that patients in the teprotumumab groups experienced more notable harms (such as hyperglycemia, hearing impairment, or muscle spasms) compared to those in the placebo groups.

The clinical experts consulted noted 2 issues with the measurement of outcomes in the trials. First, there was potential inaccuracy and low reproducibility of Hertel measurements for proptosis (that said, masking of observers would have ensured that any measurement error was evenly distributed across the 2 groups, with observed differences not completely attributed to errors). Second, the measurement of diplopia was subjective in nature.

Multiplicity control using hierarchical testing procedures was adopted across the trials. However, the following outcomes were assessed only descriptively due to the failed hierarchy: GO-QoL AP subscale (TED01RV study); diplopia responder rate, complete binocular responder rate, GO-QoL overall score, and VF and AP subscale scores (TEP-303 study). Subgroup analyses were conducted in the TEP-301 and TEP-303 studies (for smoking status, age, and sex), but none of the subgroup comparisons were adjusted for multiplicity.

Overall, the clinical experts consulted for the review noted that the results from the 3 sponsor-submitted trials were generalizable to the Canadian context, despite some potential issues. First, from the perspective of real-world clinical practice, the eligibility criteria of the 3 trials may not be aligned with those of the anticipated target population for teprotumumab. The experts indicated that, ideally, the effects of teprotumumab treatment should have been tested in patients with more severe disease, those with sight-threatening disease, or those for whom prior therapies were inadequate. Second, preservation of vision is an important treatment goal identified by the patients, clinicians, and clinical groups consulted, but it was not assessed in the studies. Instead, the primary outcomes included measures of proptosis, which — even though these were identified as important by some patients and clinical groups and could influence quality of life — were considered of limited clinical relevance, according to the panel of clinical experts consulted. Third, the duration of the trials (i.e., 24 weeks) was not long enough to assess the effectiveness and long-term safety of teprotumumab. Lastly, most of the study populations in the TED01RV and TEP-301 studies were white, and the study population in the TEP-303 study was Asian, which does not reflect the multicultural setting of Canada.

GRADE Summary of Findings and Certainty of the Evidence

Following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, certainty in the evidence from the RCTs started as high and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and its location relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

For the GRADE assessments, findings from active TED trials were considered together and summarized narratively per outcome and per comparison because these studies were similar in populations, interventions, designs, and outcome measures.

The selection of outcomes for the GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• proptosis responder rate

• ORR

• diplopia responder rate and complete binocular diplopia responder rate

• HRQoL outcomes (i.e., based on the GO-QoL VF and AP subscales)

• harms (specifically, hyperglycemia and hearing impairment).

Additional findings from the CAS measures in the active TED trials are provided as supportive evidence in the Systematic Review section of this report.

Table 2: Summary of Findings for Teprotumumab Vs. Placebo for Patients With Active TED

AP = Appearance; CAS = clinical activity score; CDA-AMC = Canada’s Drug Agency; CI = confidence interval; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; HRQoL = health-related quality of life; LS = least squares; MID = minimal important difference; NR = not reported; RCT = randomized controlled trial; TED = thyroid eye disease; VF = Visual Functioning; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aThe TED01RV study analyzed responder rates using a logistic regression model. To increase consistency and enable comparison between different studies in active TED, the sponsor conducted additional efficacy analyses of data in the TED01RV study using the Cochran-Mantel-Haenszel test (adjusted for tobacco use status).

^bNot rated down for concerns with study limitations. Imbalances in patients’ baseline characteristics were observed for smoking status and sex (the TED01RV study) and for sex (the TEP-303 study), suggesting possible impacts on randomization. According to the clinical experts consulted, inaccuracy in Hertel measurements of proptosis is common and reproducibility of measurement with this instrument is low. However, the CDA-AMC team deemed that the magnitude of differences in the response rates observed cannot be largely attributed to sampling or measurement error.

^cNot rated down for indirectness. Clinical experts consulted reported that teprotumumab treatment should have been tested in patients with more severe disease, those with sight-threatening disease, or those whose disease responded inadequately to prior therapies, which would be more aligned with the anticipated population of interest in the clinical setting in Canada. Even though some patient and clinical groups identified proptosis as an important outcome influencing quality of life, the clinical experts consulted considered proptosis to have limited clinical relevance.

^dNot rated down for imprecision. According to the clinical experts consulted by the review team, a between-group difference > 2 mm in proptosis is considered clinically important (i.e., MID). However, there are no established MIDs for between-group difference in proptosis responder rate; hence, the threshold of null was used.

^eNot rated down for indirectness. Clinical experts consulted reported that teprotumumab treatment should have been tested in patients with more severe disease, those with sight-threatening disease, or those whose disease responded inadequately to prior therapies, which would be more aligned with the anticipated population of interest in the clinical setting in Canada.

^fStatistical testing for this outcome was not adjusted for multiplicity. The results are considered as supportive evidence.

^gRated down 1 level for serious concerns with study limitations. According to the clinical experts consulted, the subjective measurement of outcome adopted in the trial is inappropriate for assessing the effects of teprotumumab on diplopia. Moreover, imbalances in baseline characteristics of patients were observed for smoking status and sex (the TED01RV study) and for sex (the TEP-303 study), suggesting possible impacts on randomization.

^hNot rated down for indirectness. Clinical experts consulted reported that teprotumumab treatment should have been tested in patients with more severe disease, those with sight-threatening disease, or those whose disease responded inadequately to prior therapies, which would be more aligned with the anticipated population of interest in the clinical setting in Canada. Clinical experts consulted by CDA-AMC reported that complete binocular diplopia is an outcome of high importance among patients with TED.

ⁱNot rated down for imprecision. According to the clinical experts consulted by the review team, there are no established MIDs for between-group differences in diplopia responder rate; hence, the threshold of null was used. The lower bound of the 95% CI of the LS mean change from baseline in diplopia responder rate in the TEP-303 study included the null and the possibility of favouring placebo.

^jRated down 1 level for serious concerns with study limitations. According to the clinical experts consulted, the subjective measurement of outcomes adopted in the trial is inappropriate for assessing the effects of teprotumumab on diplopia.

^kRated down 1 level for imprecision, given that the results were based on 1 study, with a limited sample size; the lower bound of the 95% CI was close to the value of null, indicating the possibility of no benefit.

^lRated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of 6 points was considered clinically important (i.e., MID). The lower bound of the 95% CI of the change from baseline in the GO-QoL VF subscale score was close to the MID (TED01RV study) or crossed the MID (TEP-301 and TEP-303 studies).

^mRated down 1 level for imprecision: According to the clinical experts consulted by the review team, a between-group difference of 6 points was considered clinically important (i.e., MID). The lower bound of the 95% CI of the change from baseline in GO-QoL AP subscale score included the possibility of favouring placebo (TED01RV study) or of trivial benefit (TEP-301 and TEP-303 studies).

ⁿRated down 1 level for serious indirectness. The 24-week duration of follow-up is inadequate for capturing notable adverse events of teprotumumab, as per clinical expert panel input.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence, the TED01RV Clinical Study Report, the TEP-301 Clinical Study Report, and the TEP-303 Clinical Study Report.^1,23-25

Long-Term Extension Studies

Description of Studies

Two off-treatment follow-up periods (1 connected to the TED01RV study and 1 to the TEP-301 study) and 1 open-label extension (OLE) of the TEP-301 study (the OPTIC-X study) are summarized in this section.

TED01RV Study: Follow-Up Period

This was an off-treatment follow-up period of 48 weeks (weeks 28 to 72) after the 24-week double-masked treatment period of the TED01RV study. Patients were not allowed to be on additional treatment for TED during at least the first 12 weeks, unless medically indicated. The primary efficacy end point was ORR, analyzed at week 28 and week 72 (defined as a decrease in overall CAS ≥ 2 points; a reduction in proptosis of ≥ 2 mm; and no deterioration in the nonstudy eye [i.e., an increase in CAS of ≥ 2 points or in proptosis of ≥ 2 mm]). A total of 76 patients (39 patients [86.7%] in the placebo group and 37 patients [88.1%] in the teprotumumab group) completed the study treatment (i.e., to week 24). Of these, 74 patients (38 patients [84.4%] in the placebo group and 36 patients [85.7%] in the teprotumumab group) completed the off-treatment follow-up week 72 visit. Baseline characteristics were similar to those in the main trial, given that those patients entered the follow-up period.

TEP-301 Study: Follow-Up Period

This was an off-treatment follow-up period of 48 weeks after the 24-week double-masked treatment period in the TEP-301 study. Proptosis “responders” — as well as “nonresponders” who chose not to enrol in the OPTIC-X study — entered a follow-up period during which the study drug was not administered. (Responder and nonresponder were the outcomes used in the study.)

Patients who completed the 48-week treatment-free follow-up period had been off the study drug for a total of 51 weeks at the time of the final visit at week 72. The primary efficacy end point was proptosis responder rate (defined as patients with a ≥ 2 mm reduction from baseline in proptosis in the study eye, without deterioration [i.e., ≥ 2 mm increase] of proptosis in the fellow eye). A total of 79 patients (40 patients [95.2%] in the placebo group and 39 patients [95.1%] in the teprotumumab group) completed the study treatment period (i.e., to week 24). Of these, 23 patients (3 patients [7.1%] in the placebo group and 20 patients [48.8%] in the teprotumumab group) completed the follow-up period (i.e., to week 72). Relapse was defined as an increase in proptosis of greater than or equal to 2 mm in the study eye since week 24 or an increase in CAS of greater than or equal to 2 points after week 24, with an absolute CAS of greater than or equal to 4 points following the week 24 visit. Relapse was measured as the number of days from the week 24 visit date to the date on which relapse criteria were met. In addition, patient symptomology was considered by the investigator to ensure relapse had occurred (e.g., new onset of double vision). Ten of the 41 patients (24.4%) who received teprotumumab relapsed and were discontinued from the follow-up period; of these, 9 enrolled in the OPTIC-X study. Among the 4 patients in the placebo group for whom data were collected in the follow-up period, 1 met the relapse criteria and was enrolled in the OPTIC-X study.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

The OPTIC-X study was a phase III, multicentre, OLE trial of the safety and efficacy of teprotumumab in patients who completed the 24-week double-masked treatment period of the TEP-301 study and were either proptosis nonresponders or proptosis responders at week 24 but met the criteria for re-treatment due to relapse during the follow-up period of the TEP-301 study. Relapse was defined in a similar manner to that previously stated. The baseline (day 1) visit of this extension trial occurred within 14 days of the final visit of the TEP-301 study (i.e., week 24 for proptosis nonresponders and up to week 72 for proptosis responders who relapsed). Patients who were proptosis nonresponders or had received placebo in the TEP-301 study and entered the OLE study completed a 24-week treatment period followed by a 24-week off-treatment follow-up period. For patients who entered the OPTIC-X study because they were responders who had subsequently relapsed in the TEP-301 study, there was no follow-up period after the OPTIC-X treatment period. For these patients, the last clinic visit was at week 24 of the open-label treatment period

Patients who had previously received placebo in the TEP-301 trial before entering the long-term OPTIC-X study were referred to as “first-course” patients (henceforth, “first-course group”), and those who were proptosis nonresponders at week 24 of the TEP-301 study or who relapsed during the follow-up period of the TEP-301 study and enrolled in the OPTIC-X study were referred to as “second-course” patients (henceforth, “second-course group”). A total of 8 infusions of teprotumumab (10 mg/kg on day 1 followed by 20 mg/kg every 3 weeks for the remaining infusions) were administered during the 24-week treatment period. The primary efficacy end point was proptosis responder rate (percentage of patients with a ≥ 2 mm reduction from baseline in proptosis in the study eye without deterioration [i.e., ≥ 2 mm increase] of proptosis in the fellow eye) at week 24.

Of the 37 patients in the first-course group (who received placebo in the TEP-301 study), 36 patients (97.3%) were proptosis nonresponders in the TEP-301 study, and 1 patient (2.7%) relapsed during the TEP-301 study follow-up period. Of the 14 patients in the second-course group, 5 patients (35.7%) were proptosis nonresponders in the TEP-301 study and 9 patients (64.3%) relapsed during the TEP-301 study follow-up period. One patient in the second-course group did not complete the treatment period and did not continue in the follow-up period due to hospitalization (for a serious adverse event [SAE] of cerebral hemorrhage). Fifty-one patients (37 in the first-course group and 14 in the second-course group) were included in the OPTIC-X study. Most patients were female (first-course group: 73.0%; second-course group: 78.6%), white (first-course group: 89.2%; second-course group: 78.6%), and tobacco nonusers (first-course group: 78.4%; second-course group: 78.6%). The mean times since diagnosis of TED were 12.26 months in the first-course group and 16.5 months in the second-course group.

Efficacy Results

Overall Responder Rate

TED01RV Study: Follow-Up Period

At week 72, the proportion of overall responders was 45.2% (19 of 42 patients) in the teprotumumab group compared to 22.2% (10 of 45 patients) in the placebo group, with a between-group difference of 23.0% (95% CI, 3.7% to 42.4%; P = 0.023).

TEP-301 Study: Follow-Up Period

The proportion of sustained overall responders declined over time during the follow-up period relative to week 24 responders. Of the 32 patients in the teprotumumab group, 56.3% (18 of 32 patients) were overall responders at week 72. Of the 3 patients in the placebo group, 66.7% (2 of 3 patients) were sustained overall responders at week 72.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

Of the 24 patients in the first-course group who were overall responders at week 24 relative to study baseline, 22 patients (91.6%) had a sustained response at week 48 of the OPTIC-X study. Of the 5 patients in the second-course group who were overall responders at week 24 relative to the study baseline (including 1 proptosis nonresponder in the TEP-301 study and 4 patients who relapsed in the follow-up period of TEP-301), only 1 patient (initially a proptosis nonresponder in TEP-301) had a sustained response at week 48 of the OPTIC-X study.

Proptosis (Responder Rate, Change From Baseline)

TED01RV Study: Follow-Up Period

The proportion of proptosis responders was the same as the proportion of overall responders in both the teprotumumab and placebo groups at week 72. The mean change from baseline in the teprotumumab group was −2.11 mm compared to −1.13 mm in the placebo group at week 72.

TEP-301 Study: Follow-Up Period

Of the 34 patients who were proptosis responders at week 24 of the double-masked treatment period, only 19 patients (55.9%) remained proptosis responders at week 72 in the teprotumumab group, suggesting a decline in proptosis response over time. The mean change from baseline in proptosis was −3.62 mm (mean percentage change from baseline: −16.27% [n = 21]) in the teprotumumab group and −2.67 mm (mean percentage change from baseline: −12.27% [n = 3]) in the placebo group at week 72. While the observed mean changes from baseline in proptosis were clinically meaningful at week 72, the sample sizes were small in both groups.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

The proportions of proptosis responders at week 24 relative to study baseline were 89.2% (33 of 37 patients) and 53.8% (7 of 13 patients) in the first-course and second-course groups, respectively. Of those entering the OPTIC-X study from the TE-301 study, 29 of the 32 patients (90.6%) in the first-course group and 1 of the 2 patients (50.0%) in the second-course group had a sustained proptosis response at week 48 of the OPTIC-X study. Additionally, of the 1 patient in the first-course group and 9 patients in the second-course group who relapsed during the follow-up period, all patients except 3 in the second-course group were responders at week 24 relative to baseline in the OPTIC-X study. The mean changes from study baseline to week 24 in proptosis in the study eye were −3.47 mm in patients in the first-course group and −1.77 mm in patients in the second-course group. No additional results for change in proptosis were available during the follow-up period of the OPTIC-X study.

Diplopia Responder Rate

TED01RV Study: Follow-Up Period

Of the 36 patients in the teprotumumab and the 36 patients in the placebo group, 58.3% and 28.9% of patients, respectively, were considered responders at week 72.

TEP-301 Study: Follow-Up Period

Of the 19 patients in the teprotumumab group who were diplopia responders at week 24 in the double-masked treatment period, 57.9% (11 of 19 patients) were sustained diplopia responders at week 72. Of the 8 patients in the placebo group, 1 patient (12.5%) was a sustained diplopia responder at week 72.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

The proportions of diplopia responders at week 24 relative to study baseline were 60.9% (14 of 23 patients) and 75.0% (3 of 4 patients) in first-course and second-course groups, respectively. Of the 14 patients in the first-course group who were considered diplopia responders at week 24 relative to study baseline, 85.7% (12 of 14 patients) had a sustained diplopia response at week 48 of the OPTIC-X study. For the 3 patients in the second-course group who were diplopia responders at week 24 relative to study baseline, diplopia response was not sustained at week 48.

CAS (Responder Rate, Change From Baseline)

TED01RV Study: Follow-Up Period

At week 72, the mean change in CAS scores from baseline was −3.8 points in both the teprotumumab and placebo groups, indicating no difference between the groups at the end of the follow-up period.

TEP-301 Study: Follow-Up Period

Of the 24 patients who were CAS responders at week 24 of the double-masked treatment period, 50.0% were sustained CAS responders at week 72 in the teprotumumab group.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

The proportion of CAS responders at week 24 relative to study baseline was 65.6% (21 of 32 patients) and 36.4% (4 of 11 patients) in the first-course and second-course groups, respectively. In the first-course group, of the 21 CAS responders at week 24 relative to study baseline (proptosis nonresponders in the TEP-301 study and CAS responders in OPTIC-X at week 24), 20 patients (95.2%) had sustained CAS response at week 48 of the OPTIC-X study. None of the patients in the second-course group had a sustained CAS response at week 48 of the OPTIC-X study.

Go-QoL Scores

TED01RV Study: Follow-Up Period

Only transformed scores for the VF and AP subscales were available. Patients in both groups for both subscales experienced improved GO-QoL scores, with changes of greater than 10 compared to baseline values (except for the AP subscale scores at week 72 in the teprotumumab group).

TEP-301 Study: Follow-Up Period

For the 21 patients receiving teprotumumab who were evaluated at week 72, a mean increase from baseline in the GO-QoL overall transformed score was observed (21.19 points). For the subscales, mean increases from baseline of 18.37 points for the GO-QoL VF subscale (n = 33) and of 27.98 points (n = 21) for the AP subscale were observed for patients in the teprotumumab group.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

There was clinically meaningful improvement in GO-QoL overall scores for both groups. The mean increase from study baseline in GO-QoL transformed overall score was similar among patients in the first-course and second-course groups in the OPTIC-X study (13.39 and 14.73, respectively). For the VF subscale score, the mean increases from study baseline were 11.73 and 23.21 in patients in the first-course and second-course groups, respectively. For the AP subscale score, the mean increases from study baseline were 15.10 in patients in the first-course group and 6.25 in patients in the second-course group. These results suggest that improvements in overall scores in the first-course and second-course groups were driven mainly by the AP and VF subscales, respectively.

Relapse

TED01RV Study: Follow-Up Period

Of the 30 patients who received teprotumumab, 11 patients (36.7%) who were proptosis responders at week 24 did not maintain improvement relative to baseline (experienced reversal of ≥ 2 mm) during the off-treatment follow-up period at week 72.

TEP-301 Study: Follow-Up Period

Among the 33 patients who received teprotumumab, were week 24 proptosis responders, and entered the follow-up period, 10 patients (30.3%) relapsed during the follow-up period.

Harms Results

TED01RV Study: Follow-Up Period

The safety profile of teprotumumab did not change during the off-treatment follow-up period. No serious SAEs or deaths were reported, and no AEs led to study discontinuation in the follow-up period.

TEP-301 Study: Follow-Up Period

SAEs (intercostal neuralgia and optic neuropathy) were experienced by 2 patients (5.6%) in the teprotumumab group during the follow-up period. These were considered severe in intensity but not related to the study drug. One patient in the teprotumumab group experienced a severe but nonserious event of hypothyroidism (considered unrelated to teprotumumab) during the follow-up period. None of the AEs in the teprotumumab group led to discontinuation from study. Three patients in the teprotumumab group had an AE of special interest during the follow-up period (diabetes mellitus, muscle spasms, and hypoacusis were experienced by 1 patient receiving teprotumumab each).

Among the 4 patients in the placebo group in the follow-up period, 3 patients (75.0%) experienced at least 1 AE that was mild or moderate in intensity. None of the AEs in the placebo group were considered serious or related to the study drug, and none led to discontinuation from study. No patients in the placebo group had an AE of special interest during the follow-up period.

No patient in either treatment group died during the follow-up period.

TEP-302 Study (OPTIC-X): OLE of the TEP-301 Study

Of the 37 patients in the first-course group, 32 patients (86.5%) reported greater than or equal to 1 TEAE; 26 patients (70.3%) reported greater than or equal to 1 treatment-related TEAE; 1 patient (2.7%) reported greater than or equal to 1 TEAE leading to withdrawal of the trial drug; and 1 patient (2.7%) reported greater than or equal to 1 TEAE leading to permanent withdrawal of the trial drug. Similarly, among the 14 patients in the second-course group, 11 patients (78.6%) reported TEAEs, 7 patients (50.0%) reported treatment-related TEAEs, 1 patient (7.1%) reported a serious TEAE (cerebral hemorrhage; considered not drug-related), and 1 patient (7.1%) reported a TEAE leading to permanent withdrawal of the trial drug.

The most common TEAEs in patients in the first-course group (≥ 10.0%) included diarrhea, muscle spasms, dysgeusia, and muscle spasms. The most common TEAEs in patients in the second-course group were nasal dryness and dry skin. Among the 40 patients who entered the follow-up period, 7 patients (17.5%) had AEs that were considered treatment related. TEAEs that occurred in at least 2 patients (≥ 5.0%) during the follow-up period were muscle spasms (3 patients, 7.5%) and onycholysis (2 patients, 5.0%).

No deaths were reported in the treatment or follow-up period of the OLE.

TEAEs of special interest that occurred at any time during the treatment were hearing impairment (14.3% versus 10.8% in patients in the second-course versus first-course groups, respectively), muscle spasms (28.6% versus 48.6%), diarrhea (7.1% versus 13.5%), and hyperglycemia (0 versus 8.1%). Two patients (1 first-course and 1 second-course patient) experienced AEs associated with hyperglycemia during the OPTIC-X study follow-up period. One patient in the first-course group experienced neurosensory deafness during the follow-up period; this was considered unrelated to teprotumumab.

Critical Appraisal

In the 2 off-treatment follow-up periods of the TED01RV and TEP-301 studies, the proportion of responder rates (proptosis, diplopia, and overall) in the teprotumumab group decreased over time. The reduced sample sizes over time suggest a risk of attrition bias and raise concerns regarding the robustness of the follow-up efficacy outcome results. The impact of the use of concomitant medications on efficacy results during the follow-up period is unknown.

The OPTIC-X study was a phase III, multicentre, OLE of the TEP-301 study with a 24-week treatment period and no comparator group. The lack of a control group precludes the ability to make causal statements about benefits and harms. The open-label nature of the study may increase the risk of bias in determining the magnitude of the subjective outcomes because the lack of masking may affect patients’ expectations of the treatment, particularly with respect to subjective measures (such as quality of life). There was a decrease in both response and sample sizes over time in patients in the first-course group, which raises concerns regarding the long-term efficacy of the results. The data suggested that patients in the second-course group experienced a lack of sustained response, making it challenging to evaluate whether nonresponders may benefit from an additional course of teprotumumab in the long term; these results require confirmation. There was a risk of attrition bias because the number of patients contributing to the analyses declined steadily over time; the final outcome measures at week 48 were based on a limited sample size. Given that there were no follow-up data for patients who relapsed in the TEP-301 study and were re-treated in the OPTIC-X study, no conclusions can be drawn regarding sustained responses for those patients. Many patients used concomitant medications during the treatment period (i.e., sulphur-containing imidazole derivates, thyroid hormones, or GCs); the effect of these on efficacy outcomes cannot be determined.

None of the trial sites were in Canada. This reduces the generalizability and applicability of the results to clinical practice in Canada.

Indirect Treatment Comparisons

Description of Studies

The sponsor submitted 2 unanchored matching-adjusted indirect comparison (MAIC) analyses comparing the effects of teprotumumab versus IVMP on proptosis, diplopia, and HRQoL in patients with active TED. The first indirect treatment comparison (ITC 1) leveraged individual patient data (IPD) from 2 teprotumumab trials (the TED01RV and TEP-301 studies) that were matched to the IVMP group of the 8 published studies, pooled through random-effects meta-analysis.^26-33 Comparative treatment effects on outcomes of interest were reported, including the mean difference in the change from baseline for proptosis and the odds of diplopia response (i.e., reduction in diplopia of ≥ 1 grade). The base-case scenario incorporated 4 variables in the MAIC analyses (smoking status, baseline diplopia, baseline proptosis, and radioiodine therapy). Matching to the IVMP trials for the MAIC analyses reduced the initial sample size in the teprotumumab trials (N = 84) to effective sample sizes (ESSs) of █████ (for proptosis MAIC) and █████ (for diplopia MAIC). The second ITC (ITC 2) used IPD from the same 2 teprotumumab trials (the TED01RV and TEP-301 studies) matched to IVMP group data from 5 published studies to compare the effects of teprotumumab versus IVMP on quality of life using a random-effects meta-analysis.^32,34-37 Changes in GO-QoL overall and subscale scores from baseline to week 24 in patients receiving teprotumumab versus changes in GO-QoL scores from baseline to week 12 in patients receiving IVMP were compared indirectly using an unanchored MAIC analysis. The covariates included in the adjustment were severe diplopia, proptosis, smoking status, baseline GO-QoL scores, female sex, and age. Given that CAS was deemed prognostically important for predicting GO-QoL changes, a sensitivity analysis was conducted. After matching to the IVMP studies, the ESSs in the base-case analysis were 48 for the GO-QoL overall score, 47 for the GO-QoL AP subscale score, and 49 for the GO-QoL VF subscale score; in the sensitivity analysis, these were 36 for the GO-QoL overall score, 36 for the AP subscale score, and 36 for the VF subscale score.

Efficacy Results

For ITC 1, the base-case adjusted MAIC analyses demonstrated a mean difference favouring teprotumumab for the proptosis outcome, with a reported change from baseline in proptosis of █████ ██ (95% CI, █████ ██ █████). For diplopia response, an adjusted odds ratio (OR) favouring teprotumumab was observed, with a reported value of ████ (95% CI, ████ ██ ████) for the teprotumumab versus IVMP comparison.

For ITC 2, the results of the MAIC for the primary analysis (i.e., moderate IVMP dose only) showed a mean difference in change from baseline of 13.26 (95% CI, 7.44 to 19.09) for GO-QoL overall scores, favouring teprotumumab versus IVMP. Results for the GO-QoL AP subscale (mean difference in change from baseline: 7.50; 95% CI, 0.35 to 14.64) and VF subscale scores (mean difference in change from baseline: 17.66; 95% CI, 7.86 to 27.47) also favoured teprotumumab versus IVMP.

Harms Results

The sponsor-conducted ITCs did not evaluate the comparative safety of teprotumumab.

Critical Appraisal

Indirect Treatment Comparison 1

In the absence of a common comparator, an unanchored MAIC was conducted by the sponsor. Limitations that are inherent to an unanchored MAIC include the inability to preserve randomization within each study and the chance of bias in the comparative efficacy estimate due to possible imbalances in prognostic factors across the trial populations. Furthermore, the sample size available for the analyses was reduced due to the matching across groups. Although key baseline covariates were well balanced across the teprotumumab and IVMP cohorts following adjustment, the adjustment considered only 4 out of 11 variables that were preidentified by the sponsor as relevant. According to the experts consulted by CDA-AMC, important prognostic factors, such as diabetes, disease duration, and vision, were not included for the adjustment in the MAIC analyses. Thus, concerns remain that not all prognostic and effect-modifying factors were accounted for in the unanchored comparisons. Input from the clinical expert suggested that certain important treatments of interest for clinical practice in Canada (e.g., tocilizumab) were not considered in the ITC analyses. Considering everything discussed to this point, it is likely that the MAIC estimates are subject to an unknown amount and direction of bias, leading to challenges with respect to interpretation and uncertainty in the MAIC findings.

Indirect Treatment Comparison 2

The sponsor-funded ITC followed standard systematic review methods; however, limitations included a lack of risk of bias assessments, unmasked IVMP studies, and the absence of a sensitivity analyses to explore potential biases. Considerable methodological heterogeneity observed across the IVMP studies — such as differences in dosing, disease duration, baseline characteristics, and study designs — introduced uncertainty in the pooled effect estimates, particularly for the VF subscale score. Due to limited availability of data and restrictions on the sample sizes available, not all relevant prognostic variables could be included (such as the presence of gaze-evoked orbital pain). Additionally, there was no consideration of effect modifiers nor any investigation of the potential extent of residual confounding, which may be substantial. Residual confounding remains likely, and the reduced ESSs further decrease the reliability of the results. The lack of a protocol or statistical analysis plan increased the potential for selective outcome reporting. As a result, the ITC findings are highly uncertain. In addition, the comparisons were limited to teprotumumab and IVMP, with no information on effects versus other relevant comparators used in clinical practice in Canada (i.e., tocilizumab, rituximab).

Studies Addressing Gaps in the Evidence From the Systematic Review

The study by Lo et al.³⁸ was a published retrospective population cohort study that aimed to assess the long-term safety outcomes of teprotumumab versus IV or oral GCs for the management of TED.

Population

The study included patients aged 18 years and older with TED with a treatment code for teprotumumab or GCs from January 1, 2020, to December 1, 2024, from 80 health care organizations in the US (using the TriNetX database). Patients with TED were defined as those with a diagnostic code for thyroid diseases (teprotumumab) or at least 1 diagnostic code for hyperthyroidism and at least 1 diagnostic code for eye symptoms related to TED (i.e., GC groups) using International Classification of Diseases, 10th revision (ICD-10) codes (Table 44). Patients with treatment codes for teprotumumab, IV GCs, and oral GCs following a TED diagnostic code were included in the teprotumumab arm, IV GC arm, and oral GC arm, respectively. Patients who were pregnant were excluded from all groups.

Baseline Characteristics

Before propensity score matching (PSM), the study included 923 patients with TED who received teprotumumab, 3,613 who received IV GCs, and 4,243 who received oral GC. After PSM, there were 685 patients who were teprotumumab exposed, with a mean age of 57.8 years (standard deviation [SD] = 13.9 years); this group was 72.4% female. There were also 685 patients who were propensity score (PS) matched and IV GC exposed (mean age = 57.4 years [SD = 14.7 years]; 73.9% female); 741 patients who were teprotumumab exposed (mean age = 57.0 years [SD = 14.2 years]; 73.5% female); and 741 patients who were PS matched and oral GC exposed (mean age = 57.0 years [SD = 15.2 years]; 73.5% female). The baseline characteristics of patients in each group before PSM were not described. Most baseline characteristics, including demographics, comorbidities, previous medications, socioeconomic status, health care utilization (including screening services), and laboratory data were well balanced (i.e., standardized mean difference [SMD] < 0.1). Some body measurements and laboratory data (i.e., body mass index, hemoglobin A1C, and T3) had a high frequency of missing data, and there is no evidence of how this was handled. Approximately 6% of patients with TED in the cohort had blindness or low vision, and approximately 48% of patients with TED had exophthalmic conditions. Approximately 40% of patients with TED in the cohort had been prescribed methimazole, and approximately 1.5% of patients with TED had been prescribed rituximab.

Results

Harms

Compared to IV or oral GCs, treatment with teprotumumab was associated with a lower hazard of all-cause mortality (hazard ratio [HR] for teprotumumab versus IV GCs = 0.32; 95% CI, 0.16 to 0.65; HR for teprotumumab versus oral GCs = 0.20; 95% CI, 0.10 to 0.39).

Cardiovascular Outcomes

Patients in the teprotumumab group had a lower hazard of acute myocardial infarction compared to patients in the IV or oral GC group (teprotumumab versus IV GCs: HR = 0.37; 95% CI, 0.15 to 0.95; teprotumumab versus oral GCs: HR = 0.33; 95% CI, 0.12 to 0.91). Compared to IV GCs, the point estimates favoured teprotumumab for cerebral infarction, peripheral vascular diseases, heart failure, and atrial fibrillation; however, all 95% CIs were wide and crossed 1. Compared to oral GCs, teprotumumab was associated with a lower hazard of cerebral infarction (HR = 0.33; 95% CI, 0.15 to 0.72), peripheral vascular disease (HR = 0.44; 95% CI, 0.21 to 0.91), heart failure (HR = 0.47; 95% CI, 0.26 to 0.85), and atrial fibrillation (HR = 0.46; 95% CI, 0.23 to 0.90).

Renal Outcomes

There was a lower hazard of acute kidney failure among patients who were exposed to teprotumumab compared to those exposed to GCs (teprotumumab versus IV GCs: HR = 0.54; 95% CI, 0.31 to 0.94; teprotumumab versus oral GCs: HR = 0.37; 95% CI, 0.22 to 0.63). The point estimate for chronic kidney disease favoured teprotumumab compared to IV or oral GCs; however, the CIs were wide and crossed 1.

Other Safety Outcomes

There was a higher hazard of hearing loss among patients who initiated teprotumumab compared to GCs (teprotumumab versus IV GCs: HR = 2.43; 95% CI, 1.67 to 3.55; teprotumumab versus oral GCs: HR = 2.38; 95% CI, 1.65 to 3.44). There was no significant difference in the hazard of diabetes, no inflammatory bowel disease, and no need for a hearing device.

Infectious Outcomes

Among patients treated with teprotumumab versus IV or oral GCs, there was a lower hazard of urinary tract infections (teprotumumab versus IV GCs: HR = 0.60; 95% CI, 0.41 to 0.89; teprotumumab versus oral GCs: HR = 0.58; 95% CI, 0.40 to 0.86), pneumonia (teprotumumab versus IV GCs: HR = 0.37; 95% CI, 0.22 to 0.61; teprotumumab versus oral GCs: HR = 0.33; 95% CI, 0.20 to 0.53), and severe sepsis (teprotumumab versus IV GCs: HR = 0.24; 95% CI, 0.09 to 0.64; teprotumumab versus oral GCs: HR = 0.31; 95% CI, 0.11 to 0.84).

Critical Appraisal

The real-world evidence (RWE) study by Lo et al. (2025) had several important methodological and reporting limitations, including the absence of a predefined protocol, limited information on confounder selection, data quality, and missing data handling, and no reporting of absolute effect estimates with CIs. Although an active-comparator, new-user design was described, key features such as look-back and washout periods were not included, introducing the risk of prevalent user bias. Differences in selection procedures across groups also introduced risks of selection bias and immortal time bias (particular to outcomes such as mortality). PSM reduced some imbalances, but residual confounding is likely, given issues with substantial missing data for some variables and a lack of clarity about whether the exclusion of participants with prior outcomes occurred before or after matching. Additional concerns included the potential for outcome misclassification, differing follow-up durations between groups, small event numbers, unverified model assumptions, and the lack of a prespecified analysis plan, raising the possibility of selective reporting. While the study benefits from a large US real-world sample, the generalizability of the study findings to patients with TED in Canada is unknown. In addition, key harms (such as hyperglycemia) were not assessed, and the heterogeneous population of patients with TED limits the study’s applicability to patients with moderate to severe active TED.

Conclusions

The body of evidence from 3 studies (the TED01RV phase II study and the TEP-301 and TEP-303 phase III studies) suggests that in adult patients with moderate to severe active TED, treatment with teprotumumab results in higher ORR and proptosis response rates compared to placebo. The evidence regarding diplopia outcomes suggests that the improvements in diplopia and complete binocular diplopia with teprotumumab compared to placebo are of moderate and low certainty, respectively. Although evidence of moderate certainty suggested that improvements in HRQoL outcomes (i.e., GO-QoL AP and VF subscale scores) were observed, there was imprecision due to wide CIs; a firm conclusion could not be drawn concerning the clinical meaningfulness of the observed difference. Results from the follow-up period of the TED01RV and TEP301 studies suggest a high relapse rate (i.e., approximately 30%) among proptosis responders. Evidence from the OLE of the TEP-301 (OPTIC-X) study also suggests a lack of sustained responses post-treatment. However, the certainty in the results from the follow-up periods of the TED01RV and TEP301 studies as well as the open-label OPTIC-X study is limited due to the nature of the study designs and the small sample sizes. As such, gaps in the evidence remain regarding long-term efficacy following discontinuation of teprotumumab and re-treatment with teprotumumab.

Safety data from studies on active TED suggest that teprotumumab likely results in an increase in notable harms (i.e., hyperglycemia and hearing impairment) compared to placebo. Similar concerns with the safety profile of teprotumumab were identified based on the safety results from the OPTIC-X OLE study. Clinical experts consulted on this review highlighted emerging RWE around the ototoxicity of teprotumumab and suggested that more data are needed to elucidate whether observed hearing impairments are durable and to gain better awareness and understanding of the long-term safety of teprotumumab. In addition, according to the experts, there is a need to use screening audiograms to select patients for whom the clinical benefit of teprotumumab may outweigh the risk of harm and to conduct safety monitoring throughout treatment.

In the first ITC (an unanchored MAIC) comparing teprotumumab to IVMP in patients with active TED, teprotumumab demonstrated more favourable improvements in proptosis and diplopia response. However, the comparative evidence derived from the ITC was associated with notable limitations, including incomplete adjustment of important effect modifiers and a lack of comparisons to relevant biologic treatments for TED in Canada, not to mention HRQoL and safety outcomes.

The results from the second ITC (also an unanchored MAIC) comparing teprotumumab to IVMP in patients with moderate to severe active TED favoured treatment with teprotumumab for changes in HRQoL. However, the interpretation of these findings is limited by substantial methodological concerns, including the absence of a risk of bias assessment, potential heterogeneity across the IVMP studies, incomplete adjustment of all relevant prognostic factors due to limited data availability, and the absence of consideration of effect-modifying variables. As a result, considerable uncertainty remains regarding the estimated effect of comparative treatment.

A single, nonrandomized, observational study assessed the safety of teprotumumab compared to IV or oral GCs. While the study provides RWE on patients with TED, the interpretation of the study findings remains uncertain due to multiple methodological limitations and potential sources of bias.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of teprotumumab administered through IV at the initial recommended dose of 10 mg/kg followed by 20 mg/kg every 3 weeks for 7 additional infusions in the treatment of moderate to severe active TED in the adult population.

Disease Background

The contents of this section have been informed by materials submitted by the sponsor and by clinical expert input. The following information has been summarized and validated by the review team.

TED (also called GO, dysthyroid eye disease, or thyroid-associated orbitopathy) is a serious autoimmune disease associated with Graves autoimmune thyroid disease.^3,4 Its pathogenesis is driven by inflammation caused by autoantibodies targeting IGF-1R on fibroblasts in and around the orbital cavity (“eye socket”).⁵ This inflammation causes the expansion of muscle tissues and fat, which leads to orbital swelling, pain, proptosis (protrusion of the eye anteriorly out of the orbit), diplopia (double vision [in TED, this is due to ocular misalignment]), and potentially vision-threatening compression of the optic nerve (i.e., DON).⁶ Older age, male sex, smoking status, radioiodine therapy, and high levels of TRAbs are considered risk factors for TED.^7-9

The estimated incidence of TED is 4.83 cases per 100,000 population, and the prevalence of TED is 89.7 cases per 100,000 population, with 94.82% of TED cases involving adult patients (≥ 18 years).¹⁰ In a cohort study of more than 2,000 patients, severe TED was more frequently reported in men versus women (30% versus 21%; P < 0.0001), and the median age of men with severe TED was higher than that of women with similarly severe TED (i.e., 52 years versus 40 years; P < 0.05), suggesting that gender affects TED severity.³⁹

There is no definitive disease marker for TED.⁷ The evaluation of a patient with TED can include laboratory assessments (i.e., of TSH, TRAbs, free T4, and total T3); examination of the eyes, orbit and lid retraction; assessment of disease activity (i.e., CAS and VISA assessments) and severity; and imaging (i.e., CT scans or MRI).⁷ The natural course of TED varies, but it progresses along a continuum of 2 phases: an active inflammatory phase (CAS ≥ 3 points) and a chronic phase (CAS = 0 or 1; i.e., little or no inflammation).¹¹ Active TED involves progressive inflammation and orbital tissue expansion that rapidly progresses to maximal disease severity (based on signs and symptoms) and fibrotic changes in the orbit.^11,12 After inflammation has ameliorated, TED progresses to a chronic stage with persistent structural and appearance changes (due to underlying fibrosis).^11,12 Although chronic TED involves reduced inflammation, symptoms persist, and structural damage may become permanent, with patients not typically experiencing a significant clinical improvement without surgery.^11,12 Severity of TED is broadly categorized by EUGOGO as mild (i.e., minor impacts on daily life that do not warrant immunosuppression or surgery), moderate to severe (i.e., TED that does not currently threaten vision, but sufficiently affects the patient’s life to justify intervention), or sight-threatening (i.e., involving DON, corneal breakdown, and/or globe subluxation).¹³

HRQoL is severely affected in both the active and chronic phases due to pain, proptosis, and diplopia as key manifestations,^14,15 as well as the potential need for surgical procedures to correct the structural and appearance changes caused by TED.^16-18

Standards of Therapy

The contents of this section have been informed by materials submitted by the sponsor and by clinical expert input. The following information has been summarized and validated by the review team.

Several options for pharmaceutical management are available for moderate to severe active TED, as per both the published EUGOGO guidance from 2021 and the American Thyroid Association and European Thyroid Association consensus guidelines from 2022.^11,19 According to the experts consulted by CDA-AMC, current treatments for active TED include IVMP, MMF, rituximab, and tocilizumab, all of which are used off label in Canada.²⁰ The experts further highlighted that GCs are the traditional therapy choice and can be combined with radiotherapy (albeit with risk of retinopathy and cataracts). The experts also reported that statins appear to have some benefit with GCs, but are likely underutilized.^20,21 Surgery is considered effective for patients with active TED with sight-threatening orbitopathy that is unresponsive to GCs. According to the experts, local measures (e.g., artificial tears, eyedrops) and nonpharmacological measures (smoking cessation) are important in achieving disease control.

In the chronic stages, orbital decompression surgery is effective at achieving 2 mm to 4 mm of reduction in proptosis, according to the experts. The experts reported that strabismus surgery is required for the correction of diplopia but is only an option once the condition is stabilized.¹¹

Drug Under Review

The key characteristics of teprotumumab for adults with TED are summarized in Table 3. Teprotumumab’s mechanism of action in patients with TED has not been fully characterized. It binds to IGF-1R and blocks its activation and signalling. IGF-1R plays a key role in regulating the pathological autoimmune activation of orbital fibroblasts in TED. Therefore, modulation of IGF-1R may alter the underlying immunopathogenesis that drives the orbital inflammation, excessive synthesis of extracellular matrix, and tissue proliferation that are the hallmarks of TED.⁴⁰

The recommended dosage of teprotumumab is an IV infusion of 10 mg/kg for the initial dose followed by IV infusions of 20 mg/kg every 3 weeks for 7 additional infusions.⁴⁰ Teprotumumab should be administered as a diluted IV solution over 90 minutes for the first 2 infusions.⁴⁰ If well tolerated, the minimum time for subsequent infusions can be reduced to 60 minutes.⁴⁰ If not well tolerated, the minimum time for subsequent infusions should remain at 90 minutes.⁴⁰

Teprotumumab has been approved by Health Canada for the treatment of moderate to severe active TED in adults, and the reimbursement request aligns with the Health Canada indication. The drug has not been previously reviewed by CDA-AMC. At the time of the initial review, the drug had been approved by the regulatory agency in the US⁴¹ and was under review in Australia,⁴³ the European Union,⁴² and the UK.⁴⁴

Table 3: Key Characteristics of Teprotumumab and Comparators for Active TED

CD20 = cluster of differentiation 20; CDA-AMC = Canada’s Drug Agency; Fc = fragment crystallizable; IFG-1R = insulin-like growth factor-1 receptor; IL = interleukin; IVMP = IV methylprednisolone; MMF = mycophenolate mofetil; NA = not applicable; TED = thyroid eye disease.

^aTreatment used off label for moderate to severe active TED and currently used as standard first-line treatment.

^bTreatment used off label for moderate to severe active TED and usually an option only after IVMP.

Note: While MMF is used off label in Canada, it was identified by CDA-AMC experts as not routinely used in clinical practice in Canada for TED; therefore, it has not been added as a relevant comparator.

Sources: Draft product monographs for teprotumumab (Tepezza),⁴⁰ IVMP,⁴⁵ rituximab,⁴⁶ and rocilizumab;⁴⁷ Burch et al. (2022).¹¹

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

One patient group, TFC, submitted input for this review. TFC is a nonprofit, registered volunteer organization and charity with a mission to awaken public interest in and awareness of thyroid disease; lend moral support to patients with thyroid disease and their families; and assist in fundraising for thyroid disease research.

The information in this submission was gathered by TFC through 1 online survey and 3 telephone interviews. Telephone interviews gathered information from patients receiving teprotumumab, all of whom were living in the US. The data collected from the survey and telephone interviews were anonymized when aggregated for analysis. A total of 42 participants (37 patients and 5 caregivers) responded to the online survey. The majority of the patient respondents were from Canada (almost 95%), with the remainder from the UK and the US. Of the patient respondents from Canada, the majority (more than 58%) were from Ontario, followed by Alberta (almost 14%), Quebec (more than 8%), British Columbia (almost 6%), Prince Edward Island, Nova Scotia, Manitoba, and the Northwest Territories. The caregiver respondents were from Canada (2 from Ontario, 1 from Quebec, 1 from Alberta, and 1 from British Columbia). Approximately 30% of the patient respondents were 55 to 64 years of age; 22% were 45 to 54 years of age; 22% were 65 to 74 years of age; 16% were 35 to 44 years of age; and 5% each were 25 to 34 years of age or 75 to 84 years of age. Two of the caregiver respondents were 35 to 44 years of age. The other 3 were 45 to 54 years of age, 55 to 64 years of age, and 65 to 74 years of age. Content was supplemented with information from a published article,²² which included a 62-question survey conducted with funding provided through the Graves’ Disease and Thyroid Foundation, completed by 443 respondents (25 of whom were from Canada).

The patient group noted that TED is a debilitating, lifelong condition and that patients can experience significant disease burden, which is often the consequence of suboptimal medical management or treatment. It is associated with excess comorbidity and mortality, early retirement, loss of productivity, and decreased quality of life resulting from physical manifestations (such as eyelid retraction, ocular dryness and/or grittiness, eyelid redness, pain with eye movement, pressure sensation behind the eyes, excessive tearing, proptosis, or diplopia) and mental health issues (i.e., anxiety and depression). Patients often face incorrect diagnoses, resulting in treatment delays.

Of the patient respondents, almost 60% were aged 40 to 60 years when they were diagnosed. More than 24% were aged 18 to 39 years at diagnosis. The remainder were diagnosed when they were older than 64 years or could not recall when they were diagnosed. At diagnosis, 70% of patients were in the chronic phase, 8% were in the active phase, and 22% were not sure of the stage of their TED. Patients with TED indicated that they experienced a range of symptoms, with light sensitivity, bulging eyes, dry, irritated eyes, and eye bags being reported as “always” by more than 40% of respondents. Double vision and eyelid retraction were most often cited as “always” occurring by the caregivers. In the article survey,²² the respondents reported dry and/or gritty eyes, light sensitivity, bulging eyes, and pressure or pain behind the eyes as the most burdensome ocular symptoms. Patient respondents noted that TED negatively affected their daily lives, including quality of life, with the most frequent issues being their emotional and psychological well-being, social life, work or school life, ability to pursue hobbies, family life, ability to travel, and financial well-being. The caregiver responses were similar to these, with the addition of 2 other affected areas: personal care and housework and/or meal prep. Of the 394 respondents from the survey who answered the quality-of-life questions, approximately half (n = 179, 45%) reported feeling depressed and/or anxious, and 174 respondents (44%) expressed concerns about their appearance. Seventy-three respondents (19%) reported avoiding public situations. One hundred and ninety-two respondents (49%) reported a decline in their confidence and/or feelings of well-being. Seventy-eight of the 394 respondents (20%) experienced a decline in achieving goals.²²

Both patient and caregiver respondents noted disadvantages of using steroids, such as weight gain, mood changes and/or irritability, blurred vision, and a fast, slow, pounding, or irregular heartbeat or pulse. Additional side effects noted were insomnia, fatigue, and moon face. The respondents highlighted improvement in signs and symptoms (i.e., less swelling, less eye pain, reduced redness, no sensitivity to light), reduced side effects, and reversal of disease as important outcomes for new treatment options.

Three patients who had the opportunity to be treated with teprotumumab shared their experiences. All noted positive (though not instantaneous) responses to treatment, with manageable side effects.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). As part of the review of teprotumumab, a panel of 3 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating about situations where there are gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with TED, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this panel discussion follows.

Unmet Needs

Clinical experts reported that active TED is associated with conjunctival injection, chemosis, caruncular injection, worsening proptosis, pain on eye movement, diplopia, and vision loss. Current treatments for patients in the active phase include IVMP, MMF, rituximab, and tocilizumab, all of which are used off label in Canada. The experts further highlighted that GCs are the main choice of therapy and can be combined with radiotherapy (albeit with risk of retinopathy and cataracts). The experts also reported that statins appear to have some benefit with GCs but are likely underutilized.²¹ According to the experts, some practitioners opt to introduce oral prednisone in high doses instead of IVMP (for patients’ convenience); some may use methotrexate as well. Surgery can be effective for patients with active TED who have sight-threatening orbitopathy that is unresponsive to GCs.

In the chronic stages, orbital decompression surgery may decrease at least 2 mm of proptosis per orbital wall removed, according to the experts. The experts reported that strabismus surgery is required for the correction of diplopia but is an option only once the disease has stabilized. Nonsurgical options for large-angle diplopia include Fresnel prism, translucent occluder, or patching. Small-angle diplopia may respond to prism grind glasses. Botulinum toxin may not be an effective treatment for the fibrotic changes of TED, according to the experts.

According to the experts, treatment of hyperthyroidism as well as smoking cessation therapies are important in achieving control of disease.

The functional goal of treatment, as identified by the clinical experts, is to reduce inflammation while preserving vision, avoiding diplopia, and maintaining comfort. According to the experts, a decrease in orbital inflammation is often reflected by a decrease in proptosis, although proptosis may remain in patients who become quiescent. The experts also reported that decreasing proptosis often decreases corneal exposure and improves patient appearance, which can benefit patients psychologically. The clinical experts reported that current treatments may not be wholly effective or disease modifying and carry the risk of thyroid-associated orbitopathy recurring despite treatment. Moreover, the experts reported that it is difficult to predict which patients will develop thyroid-associated orbitopathy and would benefit from early immunosuppression.

The experts also noted that immunosuppressants cannot be used in patients with liver failure or tuberculosis, and that GC therapy can be associated with systemic AEs that can be either short-term or long-term. Access to safer and more convenient immunosuppressives through oral, nasal, or subcutaneous routes would increase the convenience of delivery, according to the experts. High costs of therapies (especially for teprotumumab; less so with tocilizumab) were highlighted by the experts.

Place in Therapy

The experts stated that teprotumumab should not be considered as a first-line treatment. Rather, use of teprotumumab should be reserved for patients with moderate to severe active TED if methylprednisolone and other currently available treatment options have failed to provoke a complete response, according to the experts.

The experts expressed concerns about the price of teprotumumab therapy, its notable side effects (i.e., hyperglycemia, hearing loss^48-50), and the high recurrence rates observed in active disease.⁵¹

Patient Population

All clinical experts engaged reported that patients with new-onset disease and a CAS equal to or higher than 4 would respond best to treatment with an immunosuppressive (e.g., teprotumumab, tocilizumab, or IVMP). The experts highlighted that patients with marked proptosis, vision loss, and progressive diplopia would also benefit from immunosuppression. According to the experts, patients with chronic thyroid-associated orbitopathy usually do not respond to immunosuppressive therapy; meanwhile, surgery is becoming more widely available across Canada for patients with chronic TED. Techniques to minimize diplopia and maximize outcomes continue to be refined.

Of note, the experts highlighted that teprotumumab should be used with heightened caution in patients with existing hearing loss or diabetes and should not be used in patients who are pregnant or still growing. The experts highlighted the following factors to consider before initiating teprotumumab therapy: patients with an absolute contraindication to corticosteroids (e.g., previous psychosis), differentiation of active versus chronic disease, and mitigation of risk factors (such as considerations for smoking cessation).

Assessing the Response to Treatment

The clinical experts agreed that the outcomes of interest include vision, double vision (diplopia), corneal exposure, dry eye, and socialization. One expert reported that a clinically meaningful response to treatment might correspond with a reduction in proptosis of greater than 2 mm.

Regarding the assessment of treatment response, a basic eye exam can be performed every 3 to 6 weeks before infusion, and more detailed exams can be performed at 24 weeks and 48 weeks. Throughout treatment, patients should be monitored for systemic side effects by an endocrinologist or rheumatologist, according to the experts.

Discontinuing Treatment

The clinical experts agreed that teprotumumab should be discontinued if no evidence of meaningful benefit is observed (i.e., no decrease in inflammation assessed through CAS, no decrease in proptosis, absence of reduction in double vision). All experts agreed that the drug should be suspended in case of certain AEs, such as poorly controlled diabetes mellitus, hearing loss, or infection.

Prescribing Considerations

The clinical experts agreed that ophthalmologists specializing in orbital pathology and TED (or neuro-ophthalmologists) would be required for diagnosis, treatment eligibility determination, treatment initiation, and monitoring for and treating possible AEs. The experts also suggested that teprotumumab treatment should not be managed by otolaryngologists, endocrinologists, or general ophthalmologists. According to the expert clinical panel, consideration should be given to screening audiometry before commencing therapy.

The experts noted that teprotumumab should be administered in an outpatient setting and, ideally, within a multidisciplinary clinic with access to specialists experienced in managing TED, including an oculoplastic surgeon or neuro-ophthalmologist, an endocrinologist, and a rheumatologist. Regarding restrictions to access in remote areas or smaller centres across the country, the experts reported that initial treatment decisions, initiation of therapy, and final evaluation post-treatment would require a specialist at the level of a tertiary care centre; however, the actual treatment over the 24 weeks of therapy could be administered and monitored through local IV clinics or local home care clinics. One expert additionally noted that smaller centres could potentially conduct initial exams through online assessments, with a specialist remotely reviewing photos, visual acuity, pupil findings, corneal staining, motility, and perimetric tests.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

CSOPS provided input for this submission. CSOPS represents a group of ophthalmic surgeons with additional training and experience in the specialized fields of the eyelids, orbit, nasolacrimal system, and facial aesthetics. The purpose of CSOPS is to advance education, research, and the quality of clinical practice in these areas of expertise. Information was gathered from the literature, product monograph, and consultations by the author of the submission with colleagues. A total of 29 clinicians provided input.

TED is an autoimmune disease affecting the eyelids, conjunctiva, extraocular muscles, fat, optic nerve, and connective tissue within the orbit. Currently, no treatments prevent or reverse the course of the disease. The clinician group noted that treatment regimens for active TED include the use of steroids in high doses; this use is associated with many side effects (i.e., liver failure, diabetes, hypertension, insomnia, and psychosis). Subsets of patients may have disease that does not respond to steroids, may be unable to continue treatment due to intolerance, or may have persistent vision problems and significant facial disfiguration despite treatment, negatively affecting their quality of life. The clinician group indicated that an ideal treatment would avoid disease onset, delay progression, reduce signs and symptoms, preserve intact vision, and avoid negative impacts on quality of life. The group highlighted that currently, no European or North American clinical practice guidelines exist that include teprotumumab.

The clinician group noted that patients with active TED will most likely respond to teprotumumab. Patients for whom steroids are not effective, who are unable to tolerate treatment with steroids, or who have proptosis and/or diplopia would be in most need of an intervention. The group additionally highlighted that patients would be identified by clinician judgment, with no requirement for companion diagnostic tests and no risk of misdiagnosis. Regarding patients’ response to treatment, a clinically meaningful response would need to be assessed using trial outcome metrics — namely, proptosis reduction of greater than or equal to 2 mm at week 24 of treatment. In the clinical setting, ophthalmologists would assess patients for a decrease in inflammation seen on clinical exam as well as for stability or improvement of diplopia, proptosis, lid retraction, lid swelling, visual acuity, and redness.

The clinician group noted that infusion reactions during or up to 24 hours after infusion are possible; severe reactions may necessitate discontinuation of treatment. The group highlighted that prescribing physicians must consider the warnings and precautions of teprotumumab outlined in the product monograph. The drug is administered as an IV infusion in the outpatient setting by a qualified health care professional. An ophthalmologist (typically an oculoplastic surgeon), endocrinologist, internal medicine physician, or immunologist can prescribe the drug. Additionally, the group noted that patients should be followed by an ophthalmologist for treatment and response.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by for this review are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

CAS = clinical activity score; CDEC = Canadian Drug Expert Committee; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; ICUR = incremental cost-utility ratio; IVMP = IV methylprednisolone; MMF = mycophenolate mofetil; TED = thyroid eye disease; VISA = vision, inflammation, strabismus, and appearance.

Note: The categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of teprotumumab 500 mg IV in the treatment of adult patients with moderate to severe TED. The focus will be on comparing teprotumumab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of teprotumumab is presented in 3 sections, with our critical appraisal of the evidence included at the end of each. The first section, the Systematic Review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. Our assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes sponsor-submitted long-term extension studies. The third section includes indirect evidence from the sponsor.

Included Studies

Clinical evidence from the following studies is included in the review and appraised in this document:

• 3 pivotal studies or RCTs identified in the systematic review

• 3 long-term extension studies

• 1 ITC.

Systematic Review

The contents within this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5.

Table 5: Details of the Active TED Studies Included in the Systematic Review

ALT = alanine aminotransferase; AP = Appearance; AST = aspartate aminotransferase; CAS = clinical activity score; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; IBD = inflammatory bowel disease; TED = thyroid eye disease; ULN = upper limit of normal; VF = Visual Functioning.

Note: The categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and from the Clinical Study Reports for the TED01RV,²³ TEP-301,²⁴ and TEP-303 studies.²⁵

TED01RV Study

The TED01RV study is a phase II, randomized, double-masked, placebo-controlled, multicentre trial designed to evaluate the efficacy and safety of teprotumumab in patients with active TED. A total of 88 patients were randomized through an interactive web response system in a 1:1 ratio to receive either teprotumumab or placebo. Randomization was stratified by smoking status through a randomization table prepared by the contract research organization. The study was conducted across 11 centres in the US and 4 centres in Europe. One patient was randomized but not treated; hence, 87 patients received a single course of teprotumumab (n = 42) or masked placebo (n = 45) during the 24-week, double-masked treatment period. The first patient provided informed consent on June 24, 2013, and the last treatment phase visit was on March 23, 2016.

The study design is described in Figure 1, which shows a screening period of 4 weeks (for eligibility assessments), a treatment period of 24 weeks, and a follow-up period of 12 months.

Figure 1: TED01RV Study Design

FU = follow-up.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TED01RV Clinical Study Report.²³

TEP-301 Study

The TEP-301 study is a phase III, randomized, double-masked, placebo-controlled, parallel-group multicentre study designed to evaluate the efficacy and safety of teprotumumab in patients with active TED. A total of 83 patients with moderate to severe active TED were randomized in a 1:1 ratio through an interactive web response system to receive teprotumumab (n = 41) or placebo (n = 42). Randomization was stratified by smoking status through a central study-level randomization schedule. The study was conducted across 8 centres in the US and 5 centres in Europe. The first patient was enrolled on October 4, 2017, and the data cut-off date for the double-masked treatment period was February 19, 2019.

The study design is described in Figure 2, which shows a screening period of 2 to 6 weeks before the first dose (for eligibility assessments) and a treatment period of 24 weeks. At the end of the treatment period, patients who were proptosis nonresponders (i.e., the study eye had a < 2 mm decrease in proptosis) were eligible to enter an OLE study (Study HZNP-TEP-302). Proptosis responders and nonresponders who chose not to enrol in the OLE study entered a 48-week follow-up period of the TEP-301 study during which teprotumumab was not administered, but clinical assessments were performed. In addition, patients who were responders at week 24 but met the criteria for re-treatment due to a relapse during the follow-up period could enrol in the OLE study. After the end of the follow-up period, patients were contacted at 6 and 12 months (the follow-up contact phase) by phone or email to assess whether they had received new TED treatments.

Figure 2: TEP-301 Study Design

M = month; OLE = open-label extension; W = week.

Note: The categories used in the figure footnotes are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

¹Patients were randomized in a 1:1 ratio (stratified by tobacco use status) to receive either teprotumumab (10 mg/kg on day 1 followed by 20 mg/kg every 3 weeks for the remaining 7 infusions) or placebo every 3 weeks for all 8 infusions.

²Visit windows were ± 1 day for weeks 1 and 4, ± 3 days for weeks 3, 6, 9, 12, 15, 18 and 21, and ± 7 days for week 24.

³Patients who were proptosis responders or nonresponders who did not elect to participate in the OLE study entered a follow-up period. Patients who were responders at week 24 but relapsed during the follow-up period could enrol in the OLE study.

⁴Visit windows of ± 7 days.

⁵Patients who completed the week 72 visit were contacted by phone or email by research staff to inquire if any treatment for TED had been received since the last study contact.

⁶Patients who were proptosis nonresponders at week 24 of the double-masked treatment period were offered the option to enter an OLE study.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-301 Clinical Study Report.²⁴

TEP-303 Study

The TEP-303 study is a phase III, randomized, double-masked, placebo-controlled, parallel-group multicentre study conducted in Japan to evaluate the efficacy and safety of teprotumumab in patients with active TED. A total of 54 patients with moderate to severe active TED were randomized in a 1:1 ratio to receive teprotumumab (n = 27) or placebo (n = 42). Randomization was stratified by tobacco use. A randomization schedule was generated by the contract research organization before shipment of any trial drug to the clinical sites. The study was conducted across 20 centres in Japan. The first patient was enrolled on February 15, 2022, and the data cut-off date for the double-masked treatment period was June 14, 2023.

The study design is depicted in Figure 3, which shows a screening period of 4 weeks before the first dose (for eligibility assessments) and a treatment period of 24 weeks. At the end of the treatment period, patients who were proptosis nonresponders (i.e., the study eye had a < 2 mm decrease in proptosis) were eligible to enter an OLE period of 24 weeks. Proptosis responders and nonresponders who chose not to enrol in the OLE period entered a 30-day follow-up period of the TEP-303 study during which the study drug was not administered.

Figure 3: TEP-303 Study Design

BL = baseline; OLE = open-label extension; W = week.

Notes: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Patients who were proptosis nonresponders at week 24 of the double-masked treatment period were offered the option to enter an OLE study.

^aPatients were randomized in a 1:1 ratio (stratified by tobacco use status) to receive teprotumumab (10 mg/kg on day 1 followed by 20 mg/kg every 3 weeks for the remaining 7 infusions) or placebo every 3 weeks for all 8 infusions.

^bVisit windows were ± 1 day for weeks 1 and 4, ± 3 days for weeks 3, 6, 9, 12, 15, 18 and 21, and ± 7 days for week 24.

^cPatients who were proptosis responders or nonresponders who did not elect to participate in the OLE study entered a follow-up period. Patients who were responders at week 24 but relapsed during the follow-up period could enrol in the OLE study.

^dVisit windows of ± 7 days.

^ePatients who completed the week 72 visit were contacted by phone or email by research staff to inquire if any treatment for TED had been received since the last study contact.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-303 Clinical Study Report.²⁵

Populations

Inclusion and Exclusion Criteria

Studies TED01RV, TEP-301, and TEP-303 (Active TED)

The TED01RV, TEP-301, and TEP-303 studies included adult patients (aged 18 to 80 years) with moderate to severe TED (based on significant proptosis and/or diplopia) who were not planning for or did not immediately need surgical ophthalmological intervention and had not recently received treatments for TED.

The inclusion criteria required a clinical diagnosis of Graves disease and active TED, which was defined by a CAS of greater than or equal to 4 (on a 7-item scale) in the TED01RV and TEP-301 studies but by a CAS of greater than or equal to 3 (on a 7-item scale) in the TEP-303 study. According to the sponsor, the TEP-303 study CAS inclusion criteria were adopted to account for the milder signs and symptoms of TED in Asian patients. ⁵⁷ The TEP-301 and TEP-303 studies specified moderate to severe TED as an inclusion criterion (i.e., lid retraction of greater than or equal to 2 mm, moderate or severe soft tissue involvement, proptosis [exophthalmos] greater than or equal to 3 mm higher than normal, and/or inconstant or constant diplopia). Patients needed to be euthyroid or have mild hypothyroidism or hyperthyroidism for inclusion in the studies, with every effort having been made to correct the mild hypothyroidism or hyperthyroidism. In all the studies, patients were required to enrol less than 9 months from symptom onset.

The key exclusion criteria for all 3 studies mentioned a decrease in best corrected visual acuity due to optic neuropathy, corneal decompensation unresponsive to medical management in the study eye, a decrease in CAS of greater than or equal to 2 points between screening and baseline (i.e., no spontaneous improvement in disease activity), and a decrease of greater than or equal to 2 mm in proptosis between screening and baseline (for the TEP-301 and TEP-303 studies). Patients were also excluded if they had previously undergone radiotherapy or TED-related surgical procedures (i.e., orbital decompression or strabismus surgery) or if they had received TED treatment using steroids (within 4 to 6 weeks before screening), rituximab, tocilizumab (only for the TEP-301 and TEP-303 studies), or other monoclonal antibodies (within 3 months before screening; only for the TEP-301 and TEP-303 studies). Previous steroid use with a maximum cumulative dose of less than 1 g methylprednisolone or equivalent for the treatment of TED was allowed if discontinued at least 4 to 6 weeks before screening.

Interventions

Interventions in the TED01RV, TEP-301, and TEP-303 Studies

Across the active TED studies, single courses of teprotumumab or placebo were administered through IV in a double-masked manner every 3 weeks during the 24-week treatment period for a total of 8 infusions. Teprotumumab was administered at a dose of 10 mg/kg for the first infusion and 20 mg/kg for the following 7 infusions. Masking of treatment assignment was maintained by using 100 mL or 250 mL infusion bags (as appropriate, per weight-based dosing) for both teprotumumab and placebo. The pharmacists responsible for preparing the treatment or placebo solution for IV use were not masked to the treatment being administered, but the investigator and other study personnel were. In both treatment groups, the first 2 infusions were administered over approximately 90 minutes, while subsequent infusions were administered over approximately 60 minutes. Immediate infusion-associated events were managed by slowing the infusion rate, interrupting the administration, or offering symptomatic treatment, if needed.

Treatment Discontinuation in the TED01RV, TEP-301, and TEP-303 Studies

Across all the studies, study treatment discontinuation could occur in the event of an AE (if the AE posed an unacceptable risk to the patient’s health or the patient was unwilling to continue because of it), lack of efficacy, noncompliance with the study drug, protocol deviations, losses to follow-up, pregnancy, withdrawal by patients, or termination by the sponsor.

Permanent study drug discontinuation occurred in the event of a drug-related anaphylactic reaction (in the TEP-301 and TEP-303 studies), a persistently severe drug-related AE that did not become mild or moderate in intensity at least 2 weeks before the next scheduled dose (in the TEP-301 study), severe drug-related hyperglycemia (e.g., blood glucose > 250 mg/dL) that did not decrease to mild or moderate intensity with antidiabetic treatment (the dose could be skipped up to 2 times before permanently discontinuing the study drug) (in the TEP-301 study), or the diagnosis or suspicion of inflammatory bowel disease (in the TEP-301 and TEP-303 studies).

Across all the studies, patients experiencing hyperglycemia could skip their next scheduled infusions to allow for hyperglycemia treatment to take effect or for their fasting glucose rate to return to mild or moderate severity, based on the investigators’ judgment. Withholding a scheduled infusion was permitted only twice during the study.

In all studies, patients who discontinued the study drug were required to return to the clinic and undergo the scheduled end-of-treatment assessments; they were encouraged to participate in the follow-up phases. Patients who discontinued the study drug due to an AE were followed until resolution or stabilization of the AE, or until an adequate explanation for the event was obtained.

The TEP-303 study adopted a replacement policy whereby patients who discontinued from the trial prematurely for any reason (including pandemic or natural disaster and associated restrictions on movement and work) could be replaced at the discretion of the sponsor.

Concomitant Treatments in the TED01RV, TEP-301, and TEP-303 Studies

During all the trials, local supportive measures for TED, simple analgesics (e.g., acetaminophen, nonsteroidal anti-inflammatory therapies), and medications or supplements for conditions other than TED were permitted. Topical and inhaled corticosteroids for conditions other than TED were allowed, but oral and/or IV corticosteroids were not (except for patients who experienced infusion- associated AEs). Similarly, use of other immunosuppressive drugs was restricted during the trials.

Symptomatic treatments (e.g., antipyretics, antihistamines, beta-agonists, GCs, oxygen, and IV fluids) could be administered to patients who experienced immediate infusion-associated AEs. In patients with immediate or delayed infusion-associated events, pretreatment for the following study drug administration was possible.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures. The summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as on any outcomes identified as important to this review, according to the clinical experts consulted for this review and input from the patient and clinician groups and public drug plans. Using the same considerations, we selected end points that were considered most relevant to inform the expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing the expert committee deliberations were also assessed using GRADE.

Additional findings from the CAS measures in the active TED trials are provided as supportive evidence in the Systematic Review section of this report.

Table 6: Outcomes Summarized From the Active TED Studies Included in the Systematic Review

AP = Appearance; CAS = clinical activity score; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; TED = thyroid eye disease; VF = Visual Functioning.

Note: The categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

^aStatistical testing for these end points was adjusted for multiple comparisons (i.e., hierarchal testing).

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TED01RV,²³ TEP-301,²⁴ and TEP-303 Clinical Study Reports.²⁵

Proptosis

Proptosis (exophthalmos or protrusion of the eyeball) was evaluated in all 3 studies. The assessments were performed by study observers for both eyes at baseline and at each assessment time point. The eye with the most significant proptosis at the baseline visit was defined as the “study eye,” while the other eye was defined as the “fellow eye.” Analyses were conducted for both eyes, but only the study eye contributed to the primary analyses of proptosis-related end points. Supplementary analyses were conducted using the fellow eye. Proptosis was measured in millimetres (with higher values indicating worse proptosis) using a Hertel exophthalmometer. Whenever possible, the same instrument and same observer were used at each evaluation for the duration of the trial. According to the sponsor, a minimal important difference (MID) in proptosis was defined as a greater than or equal to 2 mm reduction, based on prior TED trials;⁵⁸ this was validated by a panel of clinical experts consulted by CDA-AMC.

Clinical Activity Score

The CAS assesses patients with active TED (i.e., active inflammation) based on the presence or absence of inflammatory signs and symptoms. In the trials, assessments were performed by study observers using the 7-item EUGOGO-amended CAS for each eye.⁵⁹

The 7-point CAS is scored as 0 or 1 point for each of the following items, and the total score is calculated as the sum of these scores (scores range from 0 [no clinical activity] to 7 [worst clinical activity]):

• spontaneous orbital pain

• gaze-evoked orbital pain

• eyelid swelling attributed to active TED or GO (inflammatory phase)

• eyelid erythema

• conjunctival redness attributed to active TED or GO (inflammatory phase) (“equivocal” redness was not scored)

• chemosis

• inflammation of caruncle or plica.

Psychometric properties of the instrument as well as MIDs are reported in Table 7.

Diplopia

Diplopia (double vision) was graded subjectively by study observers on a scale of 0 to 3, with higher scores indicating worse diplopia. The grades were defined as 0 for no diplopia, 1 for intermittent diplopia (in the primary gaze position, when tired, or when first awakening), 2 for inconstant diplopia (at the extremes of gaze), or 3 for constant diplopia (in the primary or reading position).⁶⁰ A clinically meaningful change threshold adopted in the clinical trials and sponsor’s submission was defined as a greater than or equal to 1 grade change.⁵⁸

GO-QoL Questionnaire

The GO-QoL is a disease-specific, self-reported measure of quality of life in patients with TED. The questionnaire contains 16 items divided into 2 subscales (daily functioning as it relates to visual function and the psychosocial consequences of an altered appearance), with each item scored on a 3-point Likert scale. For each subscale, the scores for the 8 questions are summed and transformed to a 0 to 100 scale, with 0 indicating the worst health state and 100 indicating the best health state.⁶¹ Psychometric properties of the instrument as well as MIDs are reported in Table 7.

Safety

A descriptive analysis of safety was performed in all the trials. All TEAEs were coded using the Medical Dictionary for Regulatory Activities and classified using the National Cancer Institute Common Terminology Criteria for Adverse Events. A TEAE was defined as an AE that occurred on or after the date of the first infusion, and events were reported according to whether these occurred during the double-masked treatment period, the open-label treatment period, or the follow-up period.

AEs of special interest varied by study, but included infusion reactions (all 3 studies), hyperglycemia (all 3 studies), thrombocytopenia (the TED01RV study), anemia (the TED01RV study), muscle spasms (the TEP-301 study), diarrhea (the TEP-301 study), hearing impairment (the TEP-303 study), and new onset or exacerbation of inflammatory bowel disease (the TEP-303 study).

Table 7: Summary of Outcome Measures and Their Measurement Properties

AP = Appearance; CAS = clinical activity score; CI = confidence interval; GO = Graves ophthalmopathy; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; ICC = intraclass correlation; MCID = minimal clinically important difference; MID = minimal important difference; MOS-24 = Medical Outcomes Study Short-Form General Health Survey; QoL = quality of life; SIP = Sickness Impact Profile; TED = thyroid eye disease; VF = Visual Functioning.

Statistical Analysis

According to the sponsor, in general, the statistical analyses were conducted similarly between the 4 trials, with the only notable difference being in the TED01RV study, which analyzed responder rates using a logistic regression model. The sponsor conducted additional efficacy analyses on the TED01RV study data using the Cochran-Mantel-Haenszel test (adjusted for tobacco use status) to allow consistent comparison with the analyses conducted in the TEP-301 and TEP-303 studies. Descriptions of the analytical approaches used for the main outcomes in the active TED trials are reported in Table 8.

Analyses of categorical variables were generally conducted with nonresponder imputation (i.e., patients with missing week 24 data were imputed as nonresponders). Analyses of continuous variables were generally conducted using a mixed model for repeated measures; a change value of 0 (i.e., no response) was imputed for patients without any postbaseline values to avoid excluding those patients from the model.

Table 8: Statistical Analysis of Efficacy End Points

ANCOVA = analysis of covariance; AP = Appearance; CAS = clinical activity score; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; ITT = intention to treat; mITT = modified intention to treat; MMRM = mixed model for repeated measures; PP = per protocol; TED = thyroid eye disease; VF = Visual Functioning.

Note: The categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TED01RV,²³ TEP-301,²⁴ and TEP-303 Clinical Study Reports.²⁵

Sample Size and Power Calculation

TED01RV study: The sample size was planned to be 84 patients (42 patients per treatment arm), which would provide 80% power at a 2-sided alpha level of 0.05 to detect a treatment difference in the primary outcome (ORR), assuming a 30% response rate in the placebo arm and a 60% response rate in the teprotumumab arm. Up to 93 evaluable patients could be enrolled to account for up to a 10% dropout rate.

TEP-301 study: The sample size calculation was based on the TED01RV study, in which a 51% difference (71% versus 20%) in proptosis response (≥ 2 mm) was observed between the teprotumumab and placebo arms at week 24. In TEP-301, a sample size of 38 patients per group would provide 90% power at a 2-sided alpha level of 0.05 to detect a difference of 39% between teprotumumab and placebo; the sample size was adjusted to allow for a 16% discontinuation rate.

TEP-303 study: The sample size calculation assumed that a 40% treatment difference would be observed in the proptosis response rate (≥ 2 mm) (teprotumumab: 65%, which the sponsor reported to be lower than the observed response rate in the teprotumumab group from the TED01RV trial; placebo: 25%, which the sponsor reported to be higher than the observed response rate in the placebo from TED01RV trial). In the TEP-303 study, a sample size of 50 patients (25 per treatment group) was needed to provide 83% power to detect the treatment difference using a 2-sided alpha level of 0.05.

Statistical Testing

TED01RV Study

If the primary end point (ORR at week 24) reached statistical significance (i.e., a 2-sided alpha level of 0.05), then the secondary end points were evaluated for statistical significance at the same level in the following order:

• change from baseline to week 24 in the GO-QoL overall score

• change from baseline to week 24 in proptosis in the study eye

• change from baseline to week 24 in CAS in the study eye

• change from baseline to week 24 in the GO-QoL VF subscale score

• change from baseline to week 24 in the GO-QoL AP subscale score.

TEP-301 Study

If the primary end point (proptosis responder rate at week 24) reached statistical significance (i.e., a 2-sided alpha level of 0.05), then the secondary end points were evaluated for statistical significance at the same level in the following order:

• ORR at week 24

• CAS categorical response (score of 0 or 1) rate at week 24

• change from baseline to week 24 in proptosis in the study eye

• diplopia responder rate at week 24

• change from baseline to week 24 in the GO-QoL overall score.

TEP-303 Study

If the primary end point (proptosis responder rate at week 24) reached statistical significance (i.e., a 2-sided alpha level of 0.05), then the secondary end points were evaluated for statistical significance at the same level in the following order:

• ORR at week 24

• CAS categorical response (score of 0 or 1) rate at week 24

• change from baseline to week 24 in proptosis in the study eye

• diplopia responder rate at week 24

• complete binocular responder rate at week 24

• change from baseline to week 24 in the GO-QoL overall score at week 24

• change from baseline to week 24 in the GO-QoL VF and AP subscale scores at week 24.

Subgroup Analyses

Subgroups analyses were not conducted in the TED01RV study.

In the TEP-301 study, prespecified subgroup analyses were performed for the primary outcome according to race (Asian, Black, white, other), ethnicity (Hispanic or Latino, not Hispanic or Latino), tobacco use (nonuser, including “never” and “former,” versus user), age (< 65 years, ≥ 65 years), sex (female, male), and region (Europe, US). These subgroup analyses were not controlled for multiplicity.

In the TEP-303 study, subgroup analyses were performed for the primary outcome according to tobacco use (nonuser, user), age (< 65 years, ≥ 65 years), and sex (female, male) and were not controlled for multiplicity.

Analysis Populations

The analysis populations were generally aligned between the 3 studies, with the ITT populations used for the primary efficacy analyses, the safety populations used for the safety analyses, and the modified ITT and per-protocol (PP) populations used for sensitivity and supplementary analyses. It is noteworthy that the ITT and safety analyses sets in the TEP-303 study are identical, given that all randomized patients received at least 1 dose of their assigned treatment.

Descriptions of the study populations used in diverse analyses across the studies are presented in Table 9.

Table 9: Analysis Populations of the Studies Included in the Review

ITT = intention to treat; MITT = modified intention to treat; PP = per protocol; TED = thyroid eye disease.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TED01RV,²³ TEP-301,²⁴ and TEP-303 Clinical Study Reports.²⁵

Results

Patient Disposition

TED01RV Study

Reasons for patients being screened out were not reported for the TED01RV study (Table 10). A total of 88 patients were randomized in the study. One patient withdrew before receiving the first infusion of the treatment and was removed from the ITT population; however, this patient (counted as discontinuing the study) was added back to the teprotumumab group to align with the definition of the ITT population from other active TED trials (the TEP-301 and TEP-303 studies). The proportions of patients who completed treatment were 86.7% in the placebo group and 88.1% in the teprotumumab group. Discontinuation of treatment occurred in 11.9% (N = 5) and 13.3% (N = 6) of patients in the teprotumumab and placebo groups, respectively. In the teprotumumab group, reasons for discontinuation were entirely related to AEs. In the placebo group, the most common reasons for discontinuation were defined as other (occurring in 6.7% and including back surgery, optic disc edema, and vasovagal attack) and lack of efficacy (4.4%).

TEP-301 Study

Of the 107 patients who were screened for the TEP-301 study, 24 patients (22.4%) were screened out (Table 10). The most common reasons for being screened out were a CAS of under 4 in the most severely affected eye at screening and baseline (N = 8) and unwillingness to comply with the prescribed treatment protocol and evaluations for the duration of the study (N = 4). Overall, 83 patients were randomized to receive placebo (N = 42) or teprotumumab (N = 41). The proportions of patients who completed treatment in the placebo and teprotumumab groups were 95.2% and 95.1%, respectively. Discontinuation of treatment occurred in 4.8% (N = 2) and 4.9% (N = 2) of patients in the placebo and teprotumumab groups, respectively. In both study groups, the most common reasons for discontinuation were AEs (2.4%) and patient decision (2.4%).

TEP-303 Study

Of the 64 patients who were screened for the TEP-303 study, 10 patients (15.6%) were screened out (Table 10). Reasons for being screened out were a CAS of less than 4 in the most severely affected eye at screening and baseline (N = 5), lacking a euthyroid status at screening (N = 2), recent corticosteroid use for non-TED conditions (N = 1), and investigator discretion (N = 2). Overall, 27 patients were randomized to receive placebo and 27 patients were randomized to receive teprotumumab. The proportions of patients who completed treatment were 92.6% and 96.3% in the placebo and teprotumumab groups, respectively. Discontinuation of treatment occurred in 7.4% (N = 2) and 3.7% (N = 1) of patients in the placebo and teprotumumab groups, respectively. In the teprotumumab group, discontinuation occurred due to an AE, while in the placebo group, 1 patient discontinued due to an AE and 1 patient discontinued due to receipt of a restricted concomitant medication.

Table 10: Summary of Patient Disposition in the Active TED Studies Included in the Systematic Review — All Patients

CAS = clinical activity score; ITT = intention to treat; mITT = modified intention to treat; NR = not reported; PP = per protocol; TED = thyroid eye disease; TEP = teprotumumab; vs. = versus.

^aOne patient was randomized to the teprotumumab group but withdrew from the study before receiving the first infusion. In the additional efficacy analyses, this patient was added back to the teprotumumab group in the TED01RV study (to align with the ITT definitions for the TEP-301 and TEP-303 studies) and was counted as having discontinued.

^bThree patients received ≥ 1 dose of the wrong treatment (vs. their randomized assignment) and were analyzed using the first treatment actually received for the safety population.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TED01RV,²³ TEP-301,²⁴ and TEP-303 Clinical Study Reports.²⁵

Protocol Deviations

TED01RV Study

There were 10 protocol deviations occurring in the study (teprotumumab versus placebo: 6 versus 4). The protocol deviations that most commonly excluded patients from the PP population were related to study drug administration (teprotumumab versus placebo: 7.0% [N = 3] versus 2.3% [N = 1]), deviations from exclusion criteria (2.3% [N = 1] versus 4.5% [N = 2]), deviations from inclusion criteria (4.7% [N = 2] in the teprotumumab group), and deviation from visit window (2.3% [N = 1] in the placebo group).

TEP-301 Study

There were 26 major protocol deviations occurring in the study (teprotumumab versus placebo: 14 versus 12). The most common major deviations noted were associated with study drug dispensing and/or dosing (teprotumumab versus placebo: 14.6% [N = 6] versus 16.7% [N = 7]); visit and/or assessment schedule (teprotumumab versus placebo: 12.2% [N = 5] versus 7.1% [N = 3]), and eligibility criteria (teprotumumab versus placebo: 9.8% [N = 4] versus 7.1% [N = 3]).

A total of 16 participants (8 patients in each group) were excluded from the PP analysis set. Reasons for this included week 24 assessments being conducted outside the visit window (teprotumumab versus placebo: 2 versus 2); patients not completing treatment (teprotumumab versus placebo: 2 versus 2); receipt of prohibited medications (teprotumumab versus placebo: 3 versus 0); different assessors for Hertel measurements at baseline and week 24 (teprotumumab versus placebo: 2 versus 1); randomization occurring more than 9 months from the time of TED symptoms onset (teprotumumab versus placebo: 1 versus 2); and a patient undergoing a restricted surgical procedure (teprotumumab versus placebo: 0 versus 1).

TEP-303 Study

There were 10 major protocol deviations occurring in the study (teprotumumab versus placebo: 5 versus 5). The most common major deviation noted was associated with the visit and/or assessment schedule (teprotumumab versus placebo: 4 versus 5).

A total of 7 participants (teprotumumab versus placebo: 4 versus 3) were excluded from the PP analysis set. Major protocol deviations that led to this exclusion in the teprotumumab arm were associated with out-of-window visits due to COVID-19, protocol deviations regarding proptosis assessment at baseline (the investigator misunderstood the procedure of the Hertel measurements), participants not receiving the drug in weeks 15 and 21 (due to a TEAE of neurosensory hypoacusis), and different ophthalmologists assessing the clinical measures of severity at week 24. Major protocol deviations that led to exclusion from the PP analysis set in the placebo arm were associated with protocol deviations regarding proptosis assessment at baseline (the investigator misunderstood the procedure of the Hertel measurements), the use of restricted medication (steroid pulse therapy), patients not receiving treatment in weeks 15, 18, and 21 due to concerns about the development of hyperglycemia during a high-dose steroid pulse for TED, and patients not receiving treatment in weeks 18 and 21 due to a TEAE of neurosensory hypoacusis.

Baseline Characteristics

TED01RV Study

In the TED01RV study, there was a higher proportion of female patients in the placebo group compared to the teprotumumab group (81.8% [N = 36] versus 65.1% [N = 28]) (Table 11). The mean age of patients in the teprotumumab arm was 51.6 years (SD = 10.67 years), and the mean age of patients in the placebo arm was 54.2 years (SD = 12.98 years). The majority of participants in the 2 treatment groups were white (teprotumumab versus placebo: 86% versus 86.4%). More patients were current tobacco users in the placebo group (40.9%) than in the teprotumumab group (25.6%). The mean times since diagnosis of TED were 4.7 months (SD = 2.06 months) in the teprotumumab group and 5.2 months (SD = 2.40 months) in the placebo group. Other clinical and disease characteristics of patients in the TED01RV study are presented in Table 11.

TEP-301 Study

In the TEP-301 study, there were 70.7% female patients (N = 29) in the teprotumumab group compared with 73.8% (N = 31) in the placebo group (Table 11). The mean age of patients in the teprotumumab group was 51.6 years (SD = 12.63 years), and the mean age of patients in the placebo group was 48.9 years (SD = 12.96 years). The majority of participants in the 2 treatment groups were white (teprotumumab group versus placebo group: 85.4% versus 88.1%). More than half of the patients in the 2 treatment groups had never smoked (teprotumumab group versus placebo group: 56.1% versus 59.5%). Patients who were currently smoking accounted for 22% and 19% of patients in the teprotumumab group and placebo group, respectively. The mean times since diagnosis of TED were 6.2 months (SD = 2.33 months) in the teprotumumab group and 6.4 months (SD = 2.38 months) in the placebo group. Hyperthyroidism was reported among 14.6% and 31.0% of patients in the teprotumumab and placebo groups, respectively. Approximately 14% of patients in each treatment arm had a surgical history of thyroidectomy. Other clinical and disease characteristics of patients in the TEP-301 study are presented in Table 11.

TEP-303 Study

In the TEP-303 study, there was a higher proportion of female patients in the placebo arm compared to the teprotumumab group (74.1% [N = 20] versus 66.7% [N = 18]) (Table 11). The mean age of patients in the teprotumumab group was 46.6 years (SD = 14.18 years), and the mean age of patients in the placebo group was 50.0 years (SD = 13.35 years). The study was conducted exclusively in patients of Asian ethnicity. About 40% of the patients in the 2 treatment groups had never smoked (teprotumumab versus placebo: 37% versus 40.7%). Patients who currently smoked accounted for 14.8% of patients in both the teprotumumab and placebo groups. The mean times since diagnosis of TED were 4.3 months (SD = 2.42 months) in the teprotumumab group and 5.2 months (SD = 2.16) in the placebo group. There were no patients reporting hyperthyroidism. History of thyroidectomy was reported by 1 patient (3.7%) in the teprotumumab group and 2 patients (7.4%) in the placebo group. Other clinical and disease characteristics of patients in the TEP-303 study are presented in Table 11.

Table 11: Summary of Baseline Characteristics in the Active TED Studies Included in the Systematic Review — Safety Population

ITT = intention to treat; NA = not applicable; NR = not reported; SD = standard deviation; TED = thyroid eye disease; TEP = teprotumumab.

Notes: The ITT and safety populations of the TEP-303 study were identical; thus, the safety population has been used for consistency.

Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TED01RV,²³ TEP-301,²⁴ and TEP-303 Clinical Study Reports.²⁵

Exposure to Study Treatments

TED01RV Study

In the TED01RV study, the proportions of patients who completed all 8 infusions of the treatment were 88.4% and 90.9% in teprotumumab and placebo groups, respectively. The mean number of infusions was 7.5 (SD = 1.6) in the teprotumumab group and 7.6 (SD = 1.6) in the placebo group (Table 12).

TEP-301 Study

In TEP-301 study, the proportions of patients who completed all 8 infusions of the treatment were 92.7% and 95.2% in teprotumumab and placebo groups, respectively. The mean number of infusions was 7.7 (SD = 1.33) in the teprotumumab group and 7.8 (SD = 0.89) in the placebo group (Table 12).

TEP-303 Study

In the TEP-303 study, the proportions of patients who completed all 8 infusions of the treatment were 88.9% and 85.2% in teprotumumab and placebo groups, respectively. The mean number of infusions was 7.9 (SD = 0.46) in the teprotumumab group and 7.7 (SD = 0.71) in the placebo group (Table 12).

Table 12: Summary of Patient Exposure in the Active TED Studies Included in the Systematic Review — Safety Analysis Set

NR = not reported; SD = standard deviation; TED = thyroid eye disease; TEP = teprotumumab.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TED01RV,²³ TEP-301,²⁴ and TEP-303 Clinical Study Reports.²⁵

Concomitant Medications

TED01RV Study

During the TED01RV trial, all patients in both the teprotumumab and placebo groups received concomitant medications (Table 13). The most commonly reported concomitant medications (received in the teprotumumab versus placebo groups, respectively) included thyroid hormones (62.8% versus 52.3%), sulphur-containing imidazole derivatives (34.9% versus 45.5%), and other ophthalmological drugs (e.g., carmellose, carmellose sodium) (32.6% versus 34.1%).

TEP-301 Study

During the TEP-301 trial, all patients in both the teprotumumab and placebo groups received concomitant medications (Table 14). The most commonly reported concomitant medications (received in the teprotumumab versus placebo groups, respectively), included sulphur-containing imidazole derivatives (53.7% versus 61.9%), thyroid hormones (46.3% versus 33.3%), vitamin D and analogues (31.7% versus 26.2%), and other ophthalmological drugs (e.g., polyvinyl alcohol, carmellose sodium) (19.5% versus 35.7%).

TEP-303 Study

During the TEP-303 trial, all patients in both the teprotumumab and placebo groups received concomitant medications (Table 15). The most commonly reported concomitant medications (received in the teprotumumab versus placebo groups, respectively), included sulphur-containing imidazole derivatives (81.5% versus 85.2%), thyroid hormones (33.3% versus 18.5%), other ophthalmological drugs (48.1% versus 40.7%), and propionic acid derivatives (33.3% versus 11.1%).

Table 13: Summary of Concomitant Treatments Used by Greater Than or Equal to 10.0% of Patients in the TED01RV Study — Safety Population

ACE = angiotensin-converting enzyme inhibitor; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TED01RV Clinical Study Report.²³

Table 14: Summary of Concomitant Treatments Used by Greater Than or Equal to 10.0% of Patients in the TEP-301 Study — Safety Population

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-301 Clinical Study Report.²⁴

Table 15: Summary of Concomitant Treatments Used by Greater Than or Equal to 10.0% of Patients in the TEP-303 Study — Safety Population

H₂ = histamine type 2; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-303 Clinical Study Report.²⁵

Efficacy

Overall Responder Rates

TED01RV Study: Primary Outcome

In the TED01RV trial, the primary prespecified logistic regression analyses yielded an OR of 8.86 (95% CI, 3.293 to 23.825; P < 0.001) for the ORR comparison of teprotumumab to placebo. Sensitivity analyses conducted on the PP and modified ITT populations, as well as analyses using variable approaches to handling missing data, yielded results consistent with those of the primary analysis, with ORs ranging from 8.86 to 14.86 and 95% CIs ranging from 3.29 to 43.08 (Appendix 1).

The additional analyses conducted by the sponsor to support comparisons across trials in active TED demonstrated that, at week 24, the proportions of patients experiencing overall response were 71.4% in the teprotumumab group and 20.0% in the placebo group. A between-group difference in ORR of 50.32% (95% CI, 32.11% to 68.52%) was observed for the comparison of teprotumumab to placebo (Table 16).

TEP-301 Study: Secondary Outcome

At week 24, the proportions of patients experiencing overall response were 78.0% in the teprotumumab group and 7.1% in the placebo group. In the ITT population of the TEP-301 study, the difference in ORR between the teprotumumab and placebo groups at 24 weeks was 70.82% (95% CI, 55.89% to 85.75%; P < 0.001) (Table 16).

Findings of the sensitivity analyses performed using only patients with available data for the study eye were aligned with those of the primary analysis (Appendix 1).

Table 16: Summary of Key Efficacy Results in the Active TED Studies Included in the Systematic Review (TED01RV, TEP-301, and TEP-303 Studies) — ITT Population

AP = Appearance; CAS = clinical activity score; CI = confidence interval; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; LS = least squares; SE = standard error; TED = thyroid eye disease; TEP = teprotumumab; VF = Visual Functioning; vs. = versus.

Note: The categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

^aTreatment difference and P value from the integrated summary of efficacy analyses (Cochran-Mantel-Haenszel test) to provide a consistent estimate of the treatment difference between the TED01RV and the TEP-301 and TEP-303 studies.

^bP values indicate statistical significance within a hierarchical testing strategy to adjust for multiple comparisons.

^cP value indicates a nonsignificant result within the hierarchical testing strategy to adjust for multiple comparisons.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TED01RV,²³ TEP-301,²⁴ and TEP-303²⁵ clinical study reports.⁶⁹

Figure 4: ORR (Study Eye) by Study Visit in Patients With Active TED (TEP-301 Study) — ITT Population

ITT = intention to treat; ORR = overall responder rate; PBO = placebo; TED = thyroid eye disease.

Notes: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

P < 0.001 (2-sided); P values were calculated at weeks 6, 12, 18, and 24, but only the week 24 value was tested within the hierarchical sequence.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-301 Clinical Study Report.²⁴

TEP-303 Study: Secondary Outcome

At week 24, the proportions of patients experiencing overall response were 77.8% in the teprotumumab group and 3.7% in the placebo group. In the ITT population of the TEP-303 study, the difference in ORR between the teprotumumab and placebo groups at 24 weeks was 74.07 (95% CI, 56.9% to 91.3%; P < 0.0001) (Table 16, Figure 5).

The results of the sensitivity analyses including patients with nonmissing values were identical to those of the primary analyses, given that there were no patients with missing evaluations in the trial (Appendix 1).

Figure 5: ORR (Study Eye) by Study Visit in Patients With Active TED (TEP-303 Study) — ITT Population

ITT = intention to treat; ORR = overall responder rate; TED = thyroid eye disease.

Note: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-303 Clinical Study Report.²⁵

Proptosis Responder Rates

TED01RV Study: Exploratory Outcome

In the TED01RV trial, the proportions of patients experiencing response in proptosis in the study eye were 71.4% in the teprotumumab group and 20.0% in the placebo group. Similarly, the integrated summary of efficacy analyses demonstrated a between-group difference in proptosis responder rate of 52.45% (95% CI, 34.39 to 70.51; P < 0.0001) (Table 16).

TEP-301 Study: Primary Outcome

At week 24, the proportions of patients experiencing response in proptosis in the study eye were 82.9% in the teprotumumab group and 9.5% in the placebo group. In the ITT population of the TEP-301 study, the difference in proptosis responder rate between the teprotumumab and placebo groups at 24 weeks was 73.45% (95% CI, 58.89% to 88.01%; P < 0.001) (Table 16, Figure 6). The sensitivity analyses conducted on the PP and modified ITT populations, as well as analyses using variable approaches to handling missing data, reported findings that aligned with those of the primary analysis (Appendix 1).

Higher proportions of patients receiving teprotumumab achieved a proptosis response than patients receiving placebo across all subgroups of interest for this review, including tobacco use status (nonusers: 87.1% versus 9.4%; users: 77.8% versus 12.5%), age group (younger than 65 years: 83.9% versus 11.1%; 65 years or older: 88.9% versus 0%), and sex (male: 90.9% versus 0%; female: 82.8% versus 13.3%) (Figure 18).

Figure 6: Proptosis Responder Rate (Study Eye) by Study Visit in Patients With Active TED (TEP-301 Study) — ITT Population

ITT = intention to treat; PBO = placebo; TED = thyroid eye disease.

Notes: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

P < 0.001 (2-sided); P values were calculated at weeks 6, 12, 18, and 24, but only the week 24 value was tested within the hierarchical sequence.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-301 Clinical Study Report.²⁴

TEP-303 Study: Primary Outcome

At week 24, the proportions of patients experiencing response in proptosis in the study eye were 88.9% in the teprotumumab group and 11.1% in the placebo group. In the ITT population of the TEP-303 study, difference in proptosis responder rates between the teprotumumab and placebo groups at 24 weeks was 77.78% (95% CI, 60.7% to 94.8%; P < 0.0001) (Table 16, Figure 7). Sensitivity analyses conducted on the PP population reported findings that aligned with those of the primary analysis (Appendix 1).

Higher proportions of patients receiving teprotumumab achieved a proptosis response than those receiving placebo across all subgroups of interest for this review, including tobacco use status (nonusers: 91.3% versus 8.7%; users: 75.0% versus 25.0%), age group (younger than 65 years: 88.0% versus 4.3%; 65 years or older: 100% versus 50.0%), and sex (male: 77.8% versus 0%; female: 94.4% versus 15.0%) (Figure 19).

Figure 7: Proptosis Responder Rate (Study Eye) by Study Visit in Patients With Active TED (TEP-303 Study) — ITT Population

ITT = intention to treat; LS = least squares; TED = thyroid eye disease.

Note: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and TEP-303 Clinical Study Report.²⁵

Change From Baseline in Proptosis

TED01RV Study: Secondary Outcome

At week 24, the mean changes from baseline in proptosis were −2.46 (SE = 0.20) in the teprotumumab group and −0.15 (SE = 0.19) in the placebo group. In the TED01RV trial, the findings assessing change from baseline in proptosis demonstrated a mean difference of −2.31 (95% CI, −2.84 to −1.77; P < 0.001) for the comparison of teprotumumab to placebo (Table 16).

TEP-301 Study: Secondary Outcome

At week 24, the mean changes from baseline in proptosis were −2.82 (SE = 0.19) in the teprotumumab group and −0.54 (SE = 0.19) in the placebo group. In the TEP-301 trial, the findings assessing change from baseline in proptosis demonstrated a mean difference of −2.28 (95% CI, −2.77 to −1.80; P < 0.001) for the comparison of teprotumumab to placebo (Table 16, Figure 8).

Figure 8: Change From Baseline in Proptosis (Study Eye) by Visit in Patients With Active TED (TEP-301 Study) — ITT Population

BL = baseline; ITT = intention to treat; PBO = placebo; SE = standard error; TED = thyroid eye disease.

Note: P < 0.001 (2-sided); P values were calculated at weeks 6, 12, 18, and 24, but only the week 24 value was tested within the hierarchical sequence.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-301 Clinical Study Report.²⁴

TEP-303 Study: Secondary Outcome

At week 24, the mean changes from baseline in proptosis were −2.36 (SE = 0.30) in the teprotumumab group and −0.37 (SE = 0.30) in the placebo group. In the TEP-303 trial, findings assessing change from baseline in proptosis demonstrated a mean difference of −1.99 (95% CI, −2.75 to −1.22; P < 0.0001) for the comparison of teprotumumab to placebo (Table 16, Figure 9).

Figure 9: Change From Baseline in Proptosis (Study Eye) by Visit in Patients With Active TED (TEP-303 Study) — ITT Population

CI = confidence interval; ITT intention to treat; LS = least squares; TED = thyroid eye disease.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-303 Clinical Study Report.²⁵

CAS Categorical Responder Rates

TED01RV Study

CAS categorical responder rates were not analyzed in the TED01RV study.

TEP-301 Study: Secondary Outcome

At week 24, the proportions of patients experiencing response in CAS were 58.5% in the teprotumumab group and 21.4% in the placebo group. In the ITT population of the TEP-301 study, the difference in CAS categorical responder rate in the study eye between the teprotumumab and placebo groups at 24 weeks was 36.03% (95% CI, 17.39 to 54.67; P < 0.001) (Table 16, Figure 10).

Figure 10: CAS Categorical Responder Rate (Study Eye) by Study Visit in Patients With Active TED (TEP-301 Study) — ITT Population

CAS = clinical activity score; ITT = intention to treat; PBO = placebo; TED = thyroid eye disease.

Notes: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

P < 0.01 (2-sided); P values were calculated at weeks 6, 12, 18, and 24, but only the week 24 value was tested within the hierarchical sequence.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-301 Clinical Study Report.²⁴

TEP-303 Study: Secondary Outcome

At week 24, the proportions of patients experiencing response in CAS were 59.3% in the teprotumumab group and 22.2% in the placebo group. In the ITT population of the TEP-303 study, the difference in CAS categorical responder rate in the study eye between the teprotumumab and placebo groups at 24 weeks was 37.04% (95% CI, 12.5 to 61.6; P = 0.0031) (Table 16, Figure 11).

Figure 11: CAS Categorical Responder Rate (Study Eye) by Study Visit in Patients With Active TED (TEP-303 Study) — ITT Population

CAS = clinical activity score; ITT = intention to treat; TED = thyroid eye disease.

Note: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-303 Clinical Study Report.²⁵

Change From Baseline in CAS

TED01RV Study: Secondary Outcome

At week 24, the mean changes from baseline in CAS were −3.43 (SE = 0.18) in the teprotumumab group and −1.85 (SE = 0.17) in the placebo group. In the TED01RV trial, the findings assessing change from baseline in CAS demonstrated a mean difference of −1.59 (95% CI, −2.073 to −1.098; P < 0.001) for the comparison of teprotumumab to placebo (Table 16).

TEP-301 Study: Exploratory Outcome

At week 24, the mean changes from baseline in CAS were −3.46 (SE = 0.23) in the teprotumumab group and −2.07 (SE = 0.23) in the placebo group. In the TEP-301 trial, the findings assessing change from baseline in CAS demonstrated a mean difference of –1.39 (95% CI, −1.97, −0.81; P < 0.001) for the comparison of teprotumumab to placebo (Table 16).

TEP-303 Study: Exploratory Outcome

At week 24, the mean changes from baseline in CAS were █████ (SE = ████) in the teprotumumab group and █████ (SE = ████) in the placebo group. In the TEP-303 trial, findings assessing change from baseline in CAS demonstrated a mean difference of █████ (95% CI, ██████ █████; P = ██████) for the comparison of teprotumumab to placebo (Table 16).

Diplopia Responder Rates

TED01RV Study: Exploratory Outcome

In the TED01RV trial, the primary prespecified analyses found that the proportions of diplopia responders in the study eye were 68.4% in the teprotumumab group and 25.6% in the placebo groups (P < 0.001). Similarly, the additional efficacy analyses, conducted by the sponsor to support comparisons across trials in active TED, demonstrated that at week 24, the proportions of patients experiencing response in diplopia were 68.4% in the teprotumumab group and 25.6% in the placebo group. A between-group difference in diplopia responder rate of 39.51% (95% CI, 17.78% to 61.24%; P = 0.0004) was observed for the comparison of teprotumumab to placebo (Table 16).

TEP-301 Study: Secondary Outcome

At week 24, the proportions of patients experiencing response in diplopia were 67.9% in the teprotumumab group and 28.6% in the placebo group. In the ITT population of the TEP-301 study, the difference in diplopia responder rate in the study eye between the teprotumumab and placebo groups at 24 weeks was 39.29% (95% CI, 15.55% to 63.02%; P = 0.001) (Table 16, Figure 12). The sensitivity analyses included patients with nonmissing values and reported findings that aligned with those of the primary analysis (Appendix 1).

Figure 12: Diplopia Responder Rate (Study Eye) by Visit in Active TED (TEP-301 Study) — ITT Population With Diplopia at Baseline

ITT = intention to treat; PBO = placebo; TED = thyroid eye disease.

Notes: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

P < 0.001 (2-sided); P values were calculated at weeks 6, 12, 18, and 24, but only the week 24 value was tested within the hierarchical sequence.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-301 Clinical Study Report.²⁴

TEP-303 Study: Secondary Outcome

At week 24, the proportions of patients experiencing response in diplopia were 63.6% in the teprotumumab group and 45.0% in the placebo group. In the ITT population of the TEP-303 study, the difference in binocular diplopia responder rate between the teprotumumab and placebo groups at 24 weeks was 16.82% (95% CI, −11.4% to 45.1%; P = 0.2430) (Table 16, Figure 13).

Sensitivity analyses included patients with nonmissing values, with results identical to those of the primary analyses, given that there were no patients with missing evaluation in the trial (Appendix 1).

Figure 13: Binocular Diplopia Responder Rate by Visit in Patients With Active TED (TEP-303 Study) — ITT Population With Diplopia at Baseline

ITT = intention to treat; TED = thyroid eye disease.

Note: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-303 Clinical Study Report.²⁵

Complete Diplopia Responder Rate at Week 24

TED01RV Study

Complete diplopia response was not analyzed in the TED01RV study.

TEP-301 Study

Complete diplopia response was not analyzed in the TEP-301 study.

TEP-303 Study: Secondary Outcome

At week 24, the proportions of patients experiencing response in complete binocular diplopia were 50.0% in the teprotumumab group and 20.0% in the placebo group. In the ITT population of the TEP-303 study, the difference in the complete binocular diplopia responder rate between the teprotumumab and placebo groups at 24 weeks was 29.09% (95% CI, 0.9% to 57.3%; P = 0.043) (Table 16).

Sensitivity analyses included patients with nonmissing values, with findings identical to those of the primary analyses, given that there were no patients with missing evaluation in the trial (Appendix 1).

Change From Baseline in GO-QoL Overall Score

TED01RV Study: Secondary Outcome

At week 24, the mean changes from baseline in GO-QoL overall score were 17.28 (SE = 2.41) in the teprotumumab group and 6.42 (SE = 2.24) in the placebo group. In the TED01RV trial, findings assessing change from baseline in GO-QoL overall score demonstrated a mean difference of 10.86 (95% CI, 4.48 to 17.24; P = 0.001) for the comparison of teprotumumab to placebo at 24 weeks (Table 16).

TEP-301 Study: Secondary Outcome

At week 24, the mean changes from baseline in GO-QoL overall score were 13.79 (SE = 2.07) in the teprotumumab group and 4.43 (SE = 2.10) in the placebo group. In the TEP-301 trial, findings assessing change from baseline in GO-QoL overall score demonstrated a mean difference of 9.36 (95% CI, 4.08 to 14.64; P < 0.001) for the comparison of teprotumumab to placebo at 24 weeks (Table 16, Figure 14).

TEP-303 Study: Secondary Outcome

At week 24, the mean changes from baseline in GO-QoL overall score were 17.39 (SE = 3.36) in the teprotumumab group and 6.39 (SE = 3.35) in the placebo group. In the TEP-303 trial, findings assessing change from baseline in GO-QoL overall score demonstrated a mean difference of 11.01 (95% CI, 2.65 to 19.36; P = 0.0109) for the comparison of teprotumumab to placebo at 24 weeks (Table 16).

Change From Baseline in GO-QoL VF Subscale Score

TED01RV Study: Secondary Outcome

At week 24, the mean changes from baseline in GO-QoL VF subscale score were 21.10 (SE = 2.90) in the teprotumumab group and 6.80 (SE = 2.66) in the placebo group. In the TED01RV trial, findings assessing change from baseline using the GO-QoL VF subscale demonstrated a mean difference of 14.30 (95% CI, 6.66 to 21.94; P < 0.001) for the comparison of teprotumumab to placebo at 24 weeks (Table 16). Sensitivity analyses conducted on the PP population reported findings that aligned with those of the primary analysis (Appendix 1).

TEP-301 Study: Exploratory Outcome

At week 24, mean change from baseline in GO-QoL VF subscale score was 12.39 (SE = 2.98) in the teprotumumab group and 4.21 (SE = 3.03) in the placebo group. In the TEP-301 trial, findings assessing change from baseline in GO-QoL VF subscale demonstrated a mean difference of 8.18 (95% CI, 0.59 to 15.76; P = 0.035) for the comparison of teprotumumab to placebo at 24 weeks (Table 16, Figure 14).

Figure 14: Change From Baseline by Visit in GO-QoL VF Subscale Scores in Patients With Active TED (TEP-301 Study) — ITT Population, Observed Cases

BL = baseline; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; ITT = intention to treat; LS = least squares; PBO = placebo; SE = standard error; TED = thyroid eye disease; VF = Visual Functioning.

Note: Nominal P ≤ 0.05.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-301 Clinical Study Report.²⁴

TEP-303 Study: Secondary Outcome

At week 24, the mean changes from baseline in GO-QoL VF subscale scores were 16.22 (SE = 3.96) in the teprotumumab group and 4.39 (SE = 3.97) in the placebo group. In the TEP-303 trial, the findings assessing change from baseline in GO-QoL VF subscale score demonstrated a mean difference of 11.83 (95% CI, 1.82 to 21.83; P = 0.0215) for the comparison of teprotumumab to placebo at 24 weeks (Table 16, Figure 15).

Figure 15: Change From Baseline in GO-QoL Questionnaire VF Subscale Scores by Visit in Patients With Active TED (TEP-303 Study) — ITT Population

CI = confidence interval; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; ITT = intention to treat; LS = least squares; TED = thyroid eye disease; VF = Visual Functioning.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-303 Clinical Study Report.²⁵

Change From Baseline in GO-QoL AP Subscale Score

TED01RV Study: Secondary Outcome

At week 24, the mean changes from baseline in GO-QoL AP subscale score were 12.92 (SE = 2.84) in the teprotumumab group and 6.60 (SE = 2.66) in the placebo group. In the TED01RV trial, the findings assessing change from baseline in GO-QoL AP subscale score demonstrated a mean difference of 6.32 (95% CI, −1.25 to 13.90; P = 0.101) for the comparison of teprotumumab to placebo at 24 weeks (Table 16). Sensitivity analyses conducted on the PP population reported findings aligned with those of the primary analysis (Appendix 1).

TEP-301 Study: Exploratory Outcome

At week 24, the mean changes from baseline in GO-QoL AP subscale score were 14.43 (SE = 2.40) in the teprotumumab group and 4.22 (SE = 2.41) in the placebo group. In the TEP-301 trial, findings assessing change from baseline in GO-QoL AP subscale score demonstrated a mean difference of 10.21 (95% CI, 4.10 to 16.32; P = 0.001) for the comparison of teprotumumab to placebo at 24 weeks (Table 16, Figure 16).

Figure 16: Change From Baseline by Visit in GO-QoL AP Subscale Transformed Scores (TEP-301 Study) — ITT Population, Observed Cases

AP = Appearance; BL = baseline; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; ITT = intention to treat; LS = least squares; PBO = placebo; SE = standard error.

Note: P ≤ 0.050.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-301 Clinical Study Report.²⁴

TEP-303 Study: Secondary Outcome

At week 24, the mean changes from baseline in GO-QoL AP subscale score were 19.35 (SE = 3.93) in the teprotumumab group and 8.69 (SE = 3.93) in the placebo group. In the TEP-303 trial, findings assessing change from baseline in GO-QoL AP subscale score demonstrated a mean difference of 10.66 (95% CI, 1.04 to 20.28; P = 0.0306) for the comparison of teprotumumab to placebo at 24 weeks (Table 16, Figure 17).

Figure 17: Change From Baseline by Visit in GO-QoL Questionnaire AP Subscale Score in the TEP-303 Study — ITT Population

AP = Appearance; CI = confidence interval; GO-QoL = Graves Ophthalmopathy Quality of Life questionnaire; ITT = intention to treat; LS = least squares.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-303 Clinical Study Report.²⁵

Figure 18: Summary of Key Subgroup Analyses for Proptosis Responder Rates at Week 24 in the TEP-301 Study (Study Eye) — ITT Analysis Set, Observed Cases

AA = African American; Eur = Europe; ITT = intention to treat; PBO = placebo; Tbco = tobacco.

Notes: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

The percentages are based on the number of patients with nonmissing evaluations. Proptosis responders were defined as patients with a ≥ 2 mm reduction from baseline in proptosis in the study eye without deterioration (i.e., a ≥ 2 mm increase) of proptosis in the fellow eye at week 24.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-301 Clinical Study Report.²⁴

Figure 19: Summary of Key Subgroup Analyses for Proptosis Responder Rates at Week 24 in the TEP-303 Study (Study Eye) — ITT Analysis Set

ITT = intention to treat.

Notes: The categories used in the figure are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Proptosis responders were defined as participants with a greater than or equal to 2 mm reduction from baseline in proptosis in the study eye without deterioration (i.e., ≥ 2 mm increase) of proptosis in the fellow eye at week 24.

Sources: Details included in the figure are from the sponsor’s Summary of Clinical Evidence¹ and the TEP-303 Clinical Study Report.²⁵

Harms

Refer to Table 17 for harms data in active TED.

TED01RV Study

A total of 32 patients (74.4%) in the teprotumumab group and 32 patients (72.7%) in the placebo group reported at least 1 AE. The most commonly reported AEs in the teprotumumab group were infections and infestations (30.2%), nausea (18.6%), muscle spasms (18.6%), diarrhea (14%), and hyperglycemia (11.6%). The most commonly reported AEs in the placebo group were infections and infestations (20.5%), fatigue (13.6%), and nausea (9.1%).

TEP-301 Study

A total of 35 patients (85.4%) in the teprotumumab group and 29 patients (69.0%) in the placebo group reported at least 1 AE. The most commonly reported AEs in the teprotumumab group were infections and infestations (39.0%), muscle spasms (31.7%), alopecia (19.5%), and nausea (14.6%). The most commonly reported AEs in the placebo group were infections and infestations (23.8%), diarrhea (11.9%), and alopecia (11.9%).

TEP-303 Study

A total of 25 patients (92.6%) in the teprotumumab group and 21 patients (77.8%) in the placebo group reported at least 1 AE. The most commonly reported AEs in the teprotumumab group were infections and infestations (22.20%), alopecia (18.5%), seasonal allergy (14.8%), COVID-19 (14.8%), muscle spasms (11.1%), tinnitus (11.1%), and diarrhea (11.1%). The most commonly reported AEs in the placebo group were infections and infestations (33.3%) and COVID-19 (11.1%).

Serious AEs

TED01RV Study

The proportions of patients experiencing SAEs were 11.6% in the teprotumumab group and 2.3% in the placebo group.

TEP-301 Study

The proportions of patients experiencing SAEs were 4.9% in the teprotumumab group and 2.4% in the placebo group.

TEP-303 Study

The proportion of patients experiencing SAEs in the teprotumumab group was 3.7%. In the placebo group, no patients experienced SAEs.

Withdrawals Due to AEs

TED01RV Study

In the TED01RV study, more patients discontinued treatment due to AEs in the teprotumumab group (11.6%) than in the placebo group (2.3%).

TEP-301 Study

In TEP-301, 1 patient in the teprotumumab group (2.4%) and 1 patient in the placebo group (2.4%) discontinued treatment due to AEs.

TEP-303 Study

In the TEP-303 study, 1 patient in the teprotumumab group (3.7%) and 1 patient in the placebo group (3.7%) discontinued treatment due to AEs.

Mortality

Studies TED01RV, TEP-301, and TEP-303

There were no deaths reported during any of these 3 active TED trials.

Notable Harms

TED01RV Study

AEs of special interest were more commonly reported in patients receiving teprotumumab (18.6%) than in patients receiving placebo (2.3%). The following notable harms were reported in the teprotumumab arm: infusion reactions (4.7%), hyperglycemia (14.0%), muscle spasm (18.6%), and diarrhea (14.0%). The following notable harms were reported in the placebo group: hyperglycemia (4.5%), muscle spasm 4.5%), and diarrhea (4.5%).

TEP-301 Study

AEs of special interest were more commonly reported in patients receiving teprotumumab (48.8%) than in patients receiving placebo (23.8%). The following notable harms were reported in the teprotumumab arm: muscle spasm (31.7%), infusion reactions (14.6%), diarrhea (9.8%), hearing impairment (9.8%), and hyperglycemia (4.9%). The following notable harms were reported in the placebo group: diarrhea (11.9%), infusion reactions (9.5%), and muscle spasm (9.5%).

TEP-303 Study

AEs of special interest were more commonly reported in patients receiving teprotumumab (33.3%) than in patients receiving placebo (11.1%). The following notable harms were reported in the teprotumumab arm: hyperglycemia (22.2%), hearing impairment (14.8%), muscle spasm (11.1%), diarrhea (11.1%), and infusion reactions (3.7%). The following notable harms were reported in the placebo group: infusion reactions (3.7%), hyperglycemia (3.7%), diarrhea (3.7%), and hearing impairment (3.7%).

Table 17: Summary of Harms Results From the Active TED Studies Included in the Systematic Review (TED01RV, TEP-301, and TEP-303 Studies) — Safety Population

NA = not applicable; NR = not reported; SAE = serious adverse event; TED = thyroid eye disease; TEP = teprotumumab.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence¹ and the TED01RV,²³ TEP-301,²⁴ and TEP-303 Clinical Study Reports.²⁵

Critical Appraisal

Internal Validity

Three randomized, double-masked, multicentre studies (the phase II TED01RV study, the phase III TEP-301 study, and the phase III TEP-303 study) of patients with active TED were submitted by the sponsor for the current review.

Treatment allocation was performed appropriately through a central interactive voice and web response systems (the TED01RV and TEP-301 studies) or electronic data capture (the TEP-303 study). A randomization ratio of 1:1 was implemented in the trials, with smoking used as a stratification variable. Despite this, there was a notable imbalance in the proportion of people who were currently smoking in the phase II TED01RV trial, with approximately 25% and 40% of patients declaring themselves “current smokers” in the teprotumumab and placebo groups, respectively. Moreover, certain imbalances were observed in sex distributions in the TED01RV and TEP-303 studies. Considering that smoking and male sex are factors that may worsen the prognosis of thyroid-associated orbitopathy, according to the experts consulted, these baseline imbalances could have caused bias in the intervention effects observed, the quantity of which is unknown.⁷⁰

Regarding masking, both patients and investigators were blinded to the study treatment; the only unblinded person engaged in the study trial was a pharmacist, who was responsible solely for preparing and dispensing the treatment solutions. Additional steps to maintain masking were undertaken by using a matching placebo solution in the trials. However, it should be acknowledged that, across the 3 trials, patients in the teprotumumab group experienced more notable harms, such as hyperglycemia, hearing impairment, and muscle spasms, than those in the placebo group. This could make it possible for patients or investigators to infer who was receiving active treatment, potentially undermining the trial’s masking. The impact of such unmasking (e.g., patients believing they were assigned to the treatment group rather than to placebo) could have introduced bias in outcomes that were assessed subjectively in the studies (e.g., CAS, GO-QoL).

The proportions of patients who completed treatment in both the teprotumumab and placebo groups were high (≥ 88% and ≥ 87%, respectively), and the rates of discontinuation due to AEs were generally low (≤ 3.7%), except in the teprotumumab group (11.9%) of the phase II TED01RV trial, suggesting a lower possibility of attrition bias in the TEP-301 and TEP-303 studies. In an attempt to account for missing data for the primary outcomes of the trials, the sponsor performed a variety of sensitivity analyses (including last observation carried forward, analyses of patients with nonmissing values only, and modified ITT analyses), the findings of which were aligned with those of the base case. Moreover, despite the varying proportion of patients being excluded from the PP dataset across the studies (11% to 19%), the PP sensitivity analyses results were similar to those of the primary analyses. As such, the impacts of missing data or protocol deviations on the primary estimand effects were limited.

The primary outcome of both the TEP-301 and TEP-303 studies was proptosis responder rate, defined as the proportion of patients experiencing at least a 2 mm reduction from baseline in proptosis in the study eye without deterioration of 2 mm or greater in the fellow eye. In the TED01RV study, ORR, which was a composite outcome embedding the proptosis response rate and inflammation through CAS measures, was the primary outcome. To increase the consistency of proptosis measurements, the same Hertel exophthalmometer instrument and observer were used at each assessment during the trials. Nevertheless, the experts consulted during this CDA-AMC review reported that inaccuracy and inconsistency in Hertel measurements for proptosis are common and that reproducibility is often low, even when the same rater measures proptosis with the same instrument at different time points. However, the masking of observers would have ensured that the outcome measurement error was distributed evenly across the 2 arms. Therefore, the observed differences for each of the outcomes could not be completely attributed to errors.

The sponsor controlled for multiplicity using hierarchical testing procedures, which were applied for different outcomes across the trials. Each hypothesis was formally tested only if the preceding hypothesis was significant at the 2-sided 5% level. Of note, significance was reached across all multiplicity-controlled end points in the TEP-301 study, while the hierarchy failed at the last outcome tested in the TED01RV study (i.e., GO-QoL AP subscale score) and the fourth outcome out of 7 tested in the TEP-303 study (i.e., diplopia responder rate). The findings for the outcomes with failed hierarchies are considered descriptive; no definitive conclusions can be drawn from these analyses.

Subgroup analyses were not conducted in the TED01RV study. In the TEP-301 and TEP-303 studies, a consistent benefit of teprotumumab over placebo was observed for the primary outcomes across all the subgroups of interest for this CDA-AMC review (i.e., smoking status, age, and sex). However, none of the subgroup comparisons were adjusted for multiple statistical comparison; thus, no definitive conclusion can be drawn regarding the effects of teprotumumab across subgroups of interest.

Measures of diplopia — specifically diplopia responder rate (a secondary outcome in the TEP-301 and TEP-303 studies and an exploratory outcome in the TED01RV study) and complete binocular diplopia responder rate (not assessed in the TED01RV and TEP-301 studies, but a secondary outcome in the TEP-303 study) — were of interest for the current review. Double vision was measured on a scale ranging from 0 (no diplopia) to 3 (constant diplopia).⁶⁰ According to the experts, this subjective measure is inappropriate to accurately capture the treatment effects of teprotumumab versus placebo on diplopia. The experts noted that objective measures (i.e., prism measurement) should have been adopted in the trials. It is also important to note that the findings for the diplopia outcomes of the TEP-303 study are considered descriptive only due to the failure to reach statistical significance within the prespecified multiplicity hierarchy.

Measures of HRQoL, specifically the GO-QoL AP and VF subscales, were reported as secondary outcomes in the TED01RV and TEP-303 studies and as exploratory outcomes in the TEP-301 study. The instrument has been validated in the literature and correlates with TED severity assessment, with lower scores indicating greater severity of disease.^61,63,65 Limitations of the evidence regarding GO-QoL scores include failed hierarchy leading to only descriptive findings for the GO-QoL AP subscale scores in the TED01RV study and for both the AP and VF subscale scores in the TEP-303 study, and to analyses not adjusted for multiplicity in these subscales in the TEP-301 study. Therefore, the HRQoL outcomes may be considered supportive of the overall treatment effect, but it is uncertain whether teprotumumab significantly improved patients’ overall quality of life.

Regarding concomitant treatments adopted in the trials, the clinical experts perceived that concomitant use of GCs and teprotumumab might influence efficacy outcomes. In the active TED trials, concomitant use of GCs was reported in a varying proportion of patients (teprotumumab versus placebo: approximately 11% versus 20% in the TED01RV study; approximately 12% versus 0% in the TEP-301 study; approximately 12% versus 7% in the TEP-303 study), but no further analyses were reported to explore the impact of concomitant use on the efficacy measures of the trials. Nevertheless, the experts anticipated that the evidence regarding concomitant use will evolve as the combination therapy with other treatments for TED is more frequently adopted in clinical practice and assessed in studies.

In total, there were 7, 4, and 3 protocol amendments in the TED01RV, TEP-301, and TEP-303 trials, respectively. The results reported in the clinical study reports were based on the studies’ latest database locks, all of which occurred after the last amendments were made, suggesting that their ability to affect the end results or imply bias due to patient selection is limited.

External Validity

The active TED trials were multicentre trials spanning 39 sites in Europe, Japan, and the US; there were no sites in Canada. The selection criteria adopted in the trials (i.e., clinical diagnosis of Graves disease associated with active inflammation [i.e., a CAS of ≥ 4 in the TED01RV and TEP-301 studies or a CAS ≥ 3 in the TEP-303 study], moderate to severe active TED that was not sight-threatening, no requirement for surgical intervention, and no recent optic neuropathy or previous treatment for TED) were broadly aligned with the proposed indication for teprotumumab. Although the clinical experts acknowledged the methodological rationale for the selection criteria adopted in the trials, they anticipated that the target population for teprotumumab in clinical practice in Canada will have different disease characteristics, and that patients with more severe disease, such as those with sight-threatening disease or whose disease had an inadequate response to prior therapies, will be offered teprotumumab treatment.

The clinical experts consulted for this review acknowledged that either CAS (which was used in the teprotumumab pivotal trials) or VISA may be used to assess and identify active TED pathology in clinical practice in Canada; the selection is based on the preference of the treating clinician. Notably, the clinicians reported that the 2 tools are considered comparable, with the inflammatory portion of the VISA tool being most aligned with the items of the CAS tool. As such, the experts reported no issues with the use of either tool for identifying eligible patients for teprotumumab or assessing treatment response.

The clinical experts consulted for this review believed that the baseline demographic characteristics of patients in the active TED studies were generally consistent with those of their clinical populations. Of note, most of the patients in the TED01RV and TEP-301 studies were white, while the study population in the TEP-303 study was Asian, which did not reflect the multicultural setting of Canada.

Although a placebo comparator can be considered appropriate for establishing the efficacy of teprotumumab in a clinical trial setting, the clinical experts noted that off-label treatments (i.e., IVMP, rituximab, tocilizumab) are currently available for patients with active TED. The clinical experts highlighted the lack of direct evidence comparing teprotumumab to other available biologics. Concomitant medications applied in the active TED trials were reflective of clinical practice in Canada, according to the experts. The experts anticipated that the evidence regarding concomitant use will evolve as the combination therapy with other treatments for TED becomes more frequently adopted in clinical practice and assessed in studies.

The clinical experts agreed with the outcomes of importance identified in the patient and clinician group input, namely preservation of vision, reduction in double vision, and improved HRQoL, as relevant goals of therapy for patients with TED. However, the trials were not designed to assess these outcomes. Instead, the primary outcomes of the active TED trials largely included measures of proptosis. While some patient and clinical groups identified proptosis as an important outcome influencing quality of life, the clinical experts consulted considered proptosis to have limited clinical relevance. According to the experts, the timing of the efficacy end point assessment (i.e., 24 weeks) was appropriate in the context of a clinical trial to detect a difference between groups. However, they stated that the 24-week period was not long enough for assessing long-term effectiveness and safety, especially considering the concerns about hearing safety reported in postmarketing studies^48-50 and the high levels of relapse rates reported in the literature.⁵¹

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for the outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^71,72

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of the effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from the RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and its location relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

For the GRADE assessments, findings from the active TED trials were considered together and summarized narratively per outcome and per comparison because these studies were similar in their populations, interventions, designs, and outcome measures.

The selection of outcomes for the GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes for patients with active TED was finalized in consultation with expert committee members:

• proptosis responder rate

• ORR

• diplopia responder rate and complete binocular diplopia responder rate

• HRQoL outcomes (based on GO-QoL VF and AP subscale scores)

• harms (hyperglycemia and hearing impairment).

Additional findings from the CAS measures in the active TED trials are provided as supportive evidence in the Systematic Review section of this report.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for teprotumumab versus placebo.

Long-Term Extension Studies

The contents within this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the review team.

Description of Studies

The following are summaries of the extension studies of patients who participated in the TED01RV and TEP301 studies described previously. The durations of the follow-up periods ranged from 24 to 48 weeks.

TED01RV Study: Follow-Up Period

This was an off-treatment, 48-week follow-up period that began after the 24-week double-masked treatment period of the phase II TED01RV trial from week 28 to week 72. Patients were not allowed to receive additional treatments for TED during at least the first 12 weeks, unless medically indicated. Patients attended clinic visits at weeks 28, 36, 48, 60, and 72 for safety assessments; efficacy was measured only at weeks 28 and 72.

TEP-301 Study: Follow-Up Period

This was an off-treatment, 48-week follow-up period in patients with moderate to severe TED from the phase III TEP301 trial, following the 24-week double-masked treatment period. At the end of the double-masked treatment period (week 24), patients who were proptosis nonresponders or who had relapsed were eligible to enter an OLE, referred to as the OPTIC-X study (details summarized later in this section). Proptosis responders and nonresponders who chose not to enrol in the OPTIC-X study entered a follow-up period during which the study drug was not administered. Patients who discontinued during the treatment-free follow-up period before completing 48 weeks of follow-up underwent the scheduled week 72 assessments before study discharge. Patients who completed the 48-week treatment-free follow-up period had been off the study drug for a total of 51 weeks at the time of the final visit (week 72).

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

The OPTIC-X study was a phase III, multicentre, OLE trial of the safety and efficacy of teprotumumab in patients who completed the 24-week double-masked treatment period of the TEP-301 study and were proptosis nonresponders or responders at week 24, but met the criteria for re-treatment due to relapse during the follow-up period of the TEP-301 study (Figure 20). Relapse was defined as previously stated. The baseline (day 1) visit of this extension trial occurred within 14 days after the final visit of the TEP-301 study (i.e., week 24 for proptosis nonresponders and up to week 72 for proptosis responders who relapsed). Patients who were proptosis nonresponders or who had received placebo in the TEP-301 study and entered the OLE completed a 24-week treatment period, followed by a 24-week off-treatment follow-up period. For patients who entered the OPTIC-X study because they were responders who subsequently relapsed in the TEP-301 study, there was no follow-up period after the OPTIC-X study treatment period. For these patients, the last clinic visit was at week 24 of the open-label treatment period. Those who completed the week 24 visit were contacted 6 and 12 months later by phone or email so that study personnel could inquire about any treatment for TED that they might have received since the last trial contact, including the type of treatment and the outcome or response.

Populations

TED01RV Study: Follow-Up Period

Patients entering the follow-up period were those from the pivotal trial (i.e., there were no changes to the inclusion or exclusion criteria).

TEP-301 Study: Follow-Up Period

Patients entering the follow-up period were those from the pivotal trial (i.e., there were no changes to the inclusion or exclusion criteria).

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

The inclusion criteria generally aligned with those of the TEP-301 study, with the additional requirement that for patients to be eligible, they should have completed the 24-week double-masked treatment period in the TEP-301 study and be proptosis nonresponders (< 2 mm reduction in proptosis in the study eye) at week 24 or proptosis responders at week 24 who relapsed during the follow-up period. The same exclusion criteria of the TEP-301 study also applied to this OLE.

Relapse was defined as either of the following:

• an increase in proptosis of greater than or equal to 2 mm in the study eye since week 24 of the TEP-301 study

• an increase in CAS of greater than or equal to 2 points since week 24, with an absolute CAS of greater than or equal to 4 in the study eye following week 24 of the TEP-301 study.

• In addition to the criteria, the investigator was to consider the patients’ symptomology to ensure a relapse had occurred (e.g., new onset of double vision).

Patients who had received placebo in the TEP-301 trial before entering the long-term OPTIC-X study were referred to as “first-course patients,” and those who were proptosis nonresponders at week 24 of the TEP-301 study or relapsed during follow-up of the TEP-301 study and enrolled in the OPTIC-X study were referred to as “second-course patients.”

Figure 20: OPTIC-X Study Design

AE = adverse event; M = month; W = week 1.

Notes: The categories used in the figure footnotes are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Asterisks indicate infusion of the trial drug.

If a patient participated in the follow-up period and discontinued prematurely (i.e., before month 12), they returned to the clinic and underwent the month 12 assessments before trial discharge.

¹Teprotumumab 10 mg/kg on day 1 followed by 20 mg/kg every 3 weeks for the remaining 7 infusions.

²Visit windows were ± 1 day for weeks 1 and 4, ± 3 days for weeks 3, 6, 9, 12, 15, 18, and 21, and ± 7 days for week 24.

³Visit windows of ± 7 days.

⁴Proptosis nonresponders from the TEP-301 (OPTIC-X) study who completed the month 12 visit and proptosis responders who relapsed during the follow-up period of the TEP-301 (OPTIC-X) study and completed the week 24 visit.

⁵Visit must have occurred within 14 days after the final visit of the TEP-301 (i.e., OPTIC-X) study.

⁶Patients were contacted by phone or email the day after their first and second infusions for safety and tolerability assessments. Phone or email contacts also occurred on the day after any clinic visit during which a patient experienced an infusion-related AE.

⁷If a patient discontinued dosing, they returned to the clinic and underwent the scheduled week 24 assessments.

Source: Clinical Study Report, TEP-302 (OPTIC-X) study.⁷³

Interventions

TED01RV Study: Follow-Up Period

Not applicable because the study drug was not administered during the long-term extension follow-up.

TEP-301 Study: Follow-Up Period

Not applicable because the study drug was not administered during the long-term extension follow-up.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

A total of 8 infusions of teprotumumab (10 mg/kg on day 1 followed by 20 mg/kg every 3 weeks for the remaining infusions) were administered during the 24-week treatment period.

Outcomes

TED01RV Study: Follow-Up Period

The primary efficacy end point was ORR analyzed at week 28 and week 72 (defined as a decrease in overall CAS of ≥ 2 points, a reduction in proptosis of ≥ 2 mm, and no deterioration in the nonstudy eye [i.e., increase in CAS of ≥ 2 points or increase in proptosis of ≥ 2 mm]). Other efficacy end points of interest included proptosis responder rate (defined as reduction in proptosis of ≥ 2 mm from baseline), diplopia responder rate, change from baseline in CAS, proptosis, GO-QoL scores, and the proportion of proptosis responders who relapsed.

TEP-301 Study: Follow-Up Period

The primary efficacy end point was proptosis responder rate (defined as patients with a ≥ 2 mm reduction from baseline in proptosis in the study eye without deterioration [i.e., a ≥ 2 mm increase] of proptosis in the fellow eye). Other efficacy end points of interest included ORR, CAS categorical responder rate, diplopia responder rate, change from baseline in proptosis, and change in GO-QoL scores.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

The primary efficacy end point was proptosis responder rate (i.e., the percentage of patients with a ≥ 2 mm reduction from baseline in proptosis in the study eye without deterioration [i.e., ≥ 2 mm increase] of proptosis in the fellow eye) at week 24. Other efficacy end points of interest included the percentage of patients with a CAS of 0 or 1 in the study eye at week 24, mean change from baseline to week 24 in proptosis measurement in the study eye, diplopia responder rate, and mean change from baseline to week 24 in GO-QoL overall score.

Statistical Analysis

TED01RV Study: Follow-Up Period

The ITT population included all patients who were randomized and received at least 1 dose of the study drug (either teprotumumab or placebo) during the 24-week treatment phase. The ITT population was the primary population used for the efficacy analyses. The safety population included all patients who were dosed with any study drug (teprotumumab or placebo) during the 24-week treatment phase. The safety population was used for all safety analyses.

Descriptive summaries were provided by treatment group. All statistical tests were 2 sided and performed at the 5% significance level, except where otherwise noted. Baseline characteristics and safety tables were presented for the safety population unless otherwise specified. Efficacy tables were presented for the ITT population. Baseline was defined as the last predose measurement unless otherwise specified. Change from baseline was the measurement at each time point minus baseline. Continuous end point summaries included the number of patients (n) with nonmissing values, mean, SD, median, minimum, and maximum. Categorical end point summaries included the frequencies and percentages of patients in each category. In general, the denominator for the percentage calculation was based upon the total number of patients in the study population for each treatment, unless otherwise specified.

TEP-301 Study: Follow-Up Period

The ITT population was used for all efficacy analyses, and the safety population was used for all analyses of safety end points. Sustained responder rates (proptosis, overall, CAS categorical, and diplopia) at each visit in the follow-up period were provided for patients who were responders for the variable at week 24. Descriptive summaries of each responder rate (proptosis, overall, CAS categorical, and diplopia) were provided for the study eye and fellow eye (using definitions analogous to that used for the study eye) by treatment group for each visit in the follow-up period. Sustained response was defined as continuing to meet the response definition and receiving no additional TED treatment at the time of the visit. Patients who were missing values at a visit were considered nonresponders at that visit. Descriptive summaries of changes from baseline in proptosis for the study eye and changes from baseline in transformed scores from the GO-QoL were provided by treatment group for each visit in the follow-up period.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

The ITT population was defined as all enrolled patients and was used in the efficacy and safety analyses. Study baseline was defined as the last measurement taken before the first dose in the OPTIC-X study (considering unscheduled visits when available). If a study baseline value was not obtained in the OPTIC-X study before dosing, the last value measured in the TEP-301 study was used.

All efficacy end points were summarized using descriptive statistics, with summaries stratified by trial drug received in the TEP-301 study and overall. Sustained responder rates (for proptosis, overall, CAS categorical, and diplopia) at each visit in the follow-up period were provided for patients who were proptosis nonresponders in the TEP-301 study at week 24 and were responders for the variables at week 24 in this extension trial. Sustained response was defined as continuing to meet the response definition and receiving no additional TED treatments at the time of the visit. Patients who were missing values at a visit were considered nonresponders at that visit.

Results

Patient Disposition

TED01RV Study: Follow-Up Period

A total of 76 patients (39 patients [86.7%] in the placebo group and 37 patients [88.1%] in the teprotumumab group) completed the study treatment (week 24). Of these, 74 patients (38 patients [84.4%] in the placebo group and 36 patients (85.7%)] in the teprotumumab group) completed the off-treatment follow-up period week 72 visit (Table 18).

TEP-301 Study: Follow-Up Period

A total of 79 patients (40 patients [95.2%] in the placebo group and 39 patients [95.1%] in the teprotumumab groups) completed the study treatment period (week 24). Of these, 23 patients (3 patients [7.1%] in the placebo group and 20 patients [48.8%] in the teprotumumab group) completed the follow-up period (week 72) (Table 18). Of all the patients who received teprotumumab, 10 patients (24.4%) in the teprotumumab group were discontinued from the follow-up period due to disease relapse and 9 patients (90.0%) enrolled in the OPTIC-X study. Among the 4 patients in the placebo group who had data collected in the follow-up period, 1 patient (25.0%) met the relapse criteria and was enrolled in the OPTIC-X study.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

Fifty-one patients entered the OPTIC-X study and were included in the ITT population (Table 19). Thirty-seven patients (72.5%) received placebo in the TEP-301 study (referred to as the first-course group), and 14 patients (27.5%) received teprotumumab in the TEP-301 study (referred to as the second-course group). Of the 37 patients in the first-course group, 36 patients (97.3%) were proptosis nonresponders in the TEP-301 study and 1 patient (2.7%) relapsed during the TEP-301 study follow-up period. Of the 14 patients in the second-course group, 5 patients (35.7%) were proptosis nonresponders in the TEP-301 study and 9 patients (64.3%) relapsed during the TEP-301 study follow-up period. One patient in the second-course group did not complete the treatment period and did not continue in the follow-up period due to hospitalization (SAE of cerebral hemorrhage).

Protocol Deviations

Major protocol deviations were reported for 15 of the 37 patients in the first-course group and for 5 of the 14 patients in the second-course group. The majority of the deviations were related to visits or assessments, trial drug dispensing, and dosing.

Table 18: Patient Disposition in the TED01RV Study and TEP-301 Study Follow-Up Periods

ITT = intention to treat; NA = not applicable.

Notes: The categories used in the table footnotes are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

For the TEP-301 study, patient disposition was summarized, including the number of patients screened, the number of patients screened out, the number of patients in each analysis population, and the numbers and percentages of patients who completed the double-masked treatment period, discontinued early from the double-masked treatment period, enrolled in the OPTIC-X study overall, had any data collected during the follow-up period, met the relapse criteria during the follow-up period overall (by reason for relapse), completed the study overall, and discontinued early from the study overall (with reasons for early study discontinuation provided for all).

^aInformation is presented for those who completed the follow-up period to week 72.

^bOne patient was randomized to placebo but received teprotumumab. This patient was analyzed under placebo for efficacy (ITT population, analyzed based on randomized treatment) and under teprotumumab for safety (safety population, analyzed based on treatment received).

^cAll discontinuations due to adverse events occurred during the treatment phase.

^dOne patient elected to withdraw to pursue eye surgery and 1 patient elected to pursue surgery to correct diplopia, respectively.

^eOne patient elected to withdraw from the double-masked treatment period due to risk of allergy (last dose of study drug administered on day 43). The patient returned for the week 24 visit and entered the follow-up period; they were discontinued from the follow-up period (day 337) due to physician decision when the sponsor indicated that further investigation was not necessary.

^fOne patient was discontinued as a nonresponder (on day 310) and entered the OPTIC-X trial; the patient was incorrectly assessed at the site as a week 24 responder and entered the follow-up period. Another patient was discontinued (day 339) due to compliance issues regarding the remaining visits through study completion.

^gOne patient discontinued due to meeting the relapse criteria (day 197) and entered the OPTIC-X trial. The reason given for discontinuation was relapse.

Source: Clinical Study Report addendum, TED01RV⁷⁴ and TEP-301 (OPTIC) studies.⁷⁵

Table 19: Patient Disposition in the OPTIC-X Study

ITT = intention to treat population.

Notes: The categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

First-course group refers to participants who received placebo in the TEP-301 study; second-course group refers to participants who received teprotumumab in the TEP-301 study.

Source: Clinical Study Report for Study TEP-302.⁷³

Baseline Characteristics

TED01RV Study: Follow-Up Period

Baseline characteristics of the safety population are presented in Table 20. This has been previously summarized in the Systematic Review section of the report.

TEP-301 Study: Follow-Up Period

Baseline characteristics of the safety population are presented in Table 20. This has been previously summarized in the Systematic Review section of the report.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

Most patients were female (first-course group: 73.0%; second-course group: 78.6%), white (first-course group: 89.2%; second-course group: 78.6%), and tobacco nonusers (first-course group: 78.4%; second-course group: 78.6%) (Table 20).The mean times since diagnosis of TED were 16.5 months in the second-course group and 12.26 months in the first-course group.

Table 20: Baseline Characteristics in the TED01RV Study (ITT Population), TEP-301 Study (Safety Population), and TEP-302 (OPTIC-X) Study (ITT Population)

ITT = intention to treat; NA = not applicable; SD = standard deviation; TED = thyroid eye disease.

Notes: Tobacco use status for the TEP-302 study is reported from the time of the TEP-301 study randomization

First-course group refers to participants who received placebo in the TEP-301 study; second-course group refers to participants who received teprotumumab in the TEP-301 study.

The categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Sources: Clinical Study Report Addendum, TED01RV study;⁷⁴ Clinical Study Report Addendum, TEP-301 (OPTIC) study;⁷⁵ and Clinical Study Report, TEP-302 study.⁷³

Exposure to Study Treatments

TED01RV Study: Follow-Up Period

Not applicable because there was no administration of the study drug during the follow-up period.

Concomitant Treatments Used During Follow-Up

Of 10 patients, 4 patients (40.0%) who received teprotumumab and 6 patients (60.0%) who received placebo during the 24-week double-masked treatment period of the phase II TED01RV trial received additional TED treatment with either corticosteroids, rituximab, or orbital decompression therapy during the off-treatment follow-up period. Of the 6 patients in the placebo group, 5 patients (83.3%) required orbital decompression, 3 in combination with corticosteroids and 1 with the addition of rituximab; 1 additional patient (16.7%) was treated with corticosteroids only. Of the 4 patients who received teprotumumab, 2 patients (50.0%) received corticosteroids, 1 patient (25.0%) required orbital decompression in combination with corticosteroids, and 1 patient (25.0%) required orbital decompression only.

TEP301 Study: Follow-Up Period

Not applicable because there was no administration of the study drug during the follow-up period.

Concomitant Treatments Used During Follow-Up

The medication classes most commonly used (i.e., by ≥ 25.0% of all patients) during the follow-up period included thyroid hormones for the treatment of hypothyroidism (overall, 52.5%; teprotumumab, 55.6% [20 of 36 patients]; placebo, 25.0% [1 of 4 patients]); sulphur-containing imidazole derivatives for the treatment of Graves disease (overall, 47.5%; teprotumumab, 44.4% [16 of 36 patients]; placebo, 75.0% [3 of 4 patients]); vitamin D and analogues (overall, 37.5%; teprotumumab, 33.3% [12 of 36 patients]; placebo, 75.0% [3 of 4 patients]); and other ophthalmological drugs, typically artificial tears or lubricating eye drops (overall, 32.5%; teprotumumab, 30.6% [11 of 36 patients]; placebo, 50.0% [2 of 4 patients]).

Of the 36 patients in the teprotumumab group, 33 patients (91.7%) received no TED treatments (i.e., no medications, procedures, surgeries, or orbital radiation), and 3 patients (8.3%) received 1 or more TED treatments during the follow-up period (1 patient each received GC for strabismus surgery for diplopia, worsening active orbitopathy, and left temporal headache and/or tenderness).

Of the 4 patients in the placebo group, 3 patients (75.0%) received no treatment for TED, and 1 patient (25.0%) received 1 or more treatments for TED during the follow-up period.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

The majority of patients received all 8 infusions of teprotumumab (Table 21). The mean numbers of doses in the first-course and second-course groups, respectively, were 7.9 (SD = 0.33) and 7.4 (SD = 1.40). One patient in the first-course group and 3 patients in the second-course group received fewer than 8 infusions of teprotumumab.

Concomitant Medications During the Treatment Period

Concomitant medication classes used by greater than or equal to 10.0% of all patients during the treatment period are summarized in Appendix 1 (Table 45). The majority of patients (56.9%) received sulphur-containing imidazole derivatives for treatment of Graves’ disease (24 of 27 patients [64.9%] in the first-course group and 5 of 14 patients [35.7%] in the second-course group).

The use of thyroid hormones for the treatment of hypothyroidism was reported in 13 of 37 patients (35.1%) in the first-course group and 6 of 14 patients [42.9%] in the second-course group.

The use of GCs was reported for 6 patients, 4 of whom were in the first-course group and 2 of whom were in the second-course group. Of these 6 patients, major protocol deviations were noted for 4; the remaining 2 patients received GCs as part of a premedication regimen for infusion-related reaction prophylaxis. Other medications reported in greater than or equal to 10.0% of all patients included selective beta-blocking drugs, platelet aggregation inhibitors excluding heparin, propionic acid derivatives, vitamins (plain multivitamins, vitamin D, and analogues), and other ophthalmological drugs.

Table 21: Duration of Exposure to Teprotumumab in the OPTIC-X Study — ITT Population

ITT = intention to treat; SD = standard deviation.

Note: First-course group refers to participants who received placebo in the TEP-301 study; second-course group refers to participants who received teprotumumab in the TEP-301 study.

^aOf the 3 patients in the second-course group who received fewer than 8 infusions, 1 patient each received 3, 6, and 7 doses.

^bOne patient in the first-course group received 6 doses.

Source: Clinical Study Report Addendum, TEP-302 study.⁷³

Efficacy

Overall Response Rate

TED01RV Study: Follow-Up Period

The number of overall responders declined over time during the follow-up period. At week 72, the proportion of overall responders was 45.2% (19 of 42 patients) in the teprotumumab group compared to 22.2% (10 of 45 patients) in the placebo group, with a between-group difference of 23.0% (95% CI, 3.7% to 42.4%; P = 0.023) (Table 22).

TEP-301 Study: Follow-Up Period

The proportion of sustained overall responders declined over time during the follow-up period relative to week 24 responders. Of the 32 patients in the teprotumumab group, 56.3% (18 of 32 patients) were sustained overall responders at week 72 (Table 24). Of the 3 patients in the placebo group, 66.7% (2 of 3 patients) were sustained overall responders at week 72.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

Of the 24 patients in the first-course group who were overall responders at week 24 relative to study baseline (initially, these patients were proptosis nonresponders in the TEP-301 study), 22 patients (91.6%) had sustained response at week 48 of the OPTIC-X study (Table 29). Of the 5 patients in the second-course group who were overall responders at week 24 relative to study baseline (including 1 proptosis nonresponder in the TEP-301 study and 4 patients who relapsed during the follow-up period of the TEP-301 study), 1 patient (initially a proptosis nonresponder in the TEP-301 study) had sustained response at week 48 of the OPTIC-X study.

Table 22: Proportion of Overall Responders for the Study Eye in the TED01RV Study — ITT Population

CI = confidence interval; ITT = intention to treat; TED = thyroid eye disease; vs. = versus.

Notes: The categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Patients who received TED treatment during the off-treatment follow-up period were treated as nonresponders from the time of TED treatment forward. Patients who discontinued treatment for any reason were treated as nonresponders; therefore, the analysis included all patients randomized in the ITT population.

^aA responder was defined as a patient with a reduction in CAS of ≥ 2 points, a reduction in proptosis of ≥ 2 mm in the study eye, and no deterioration (i.e., increase in CAS of ≥ 2 points or increase in proptosis of ≥ 2 mm) in the nonstudy eye.

^bChi-square test comparing responder vs. nonresponder. The difference is equal to the responder proportion in the teprotumumab group minus the responder proportion in the placebo group.

^cResponder was defined as a reduction in proptosis ≥ 2 mm from baseline.

^dChi-square test comparing responder versus other (stable, worsening, missing, or dropped out). The difference is equal to the responder proportion in the teprotumumab group minus the responder proportion in the placebo group.

Sources: Clinical Study Report Addendum of TED01RV study;⁷⁴ Clinical Study Report Addendum table and figures of TED01RV study.⁷⁶

Proptosis (Responder Rate, Change From Baseline)

TED01RV Study: Follow-Up Period

The proportion of proptosis responders was the same as the results of the overall responder in both teprotumumab and placebo groups at week 72 (Table 22). The mean change from baseline in the teprotumumab group was −2.11 mm compared to −1.13 mm in the placebo group at week 72 (Table 23). The change from baseline was clinically meaningful in the teprotumumab group.

TEP-301 Study: Follow-Up Period

Of the 34 patients who were proptosis responders at week 24 of the double-masked treatment period, 19 patients (55.9%) were proptosis responders at week 72 in the teprotumumab group, suggesting a decline in proptosis response over time (Table 24). Of the 4 patients in the placebo group, 50.0% (2 of 4 patients) were sustained proptosis responders at week 72. Among the 15 patients receiving teprotumumab who were not sustained proptosis responders at week 72, 8 patients relapsed during the follow-up period and enrolled in the OPTIC-X study.

The mean changes from baseline in proptosis were −3.62 mm (mean percentage change from baseline: −16.27) (n = 21) in the teprotumumab group and −2.67 mm (mean percentage change from baseline: −12.27) (n = 3) in the placebo group at week 72 (Table 25). While the observed mean changes from baseline in proptosis were clinically meaningful at week 72, the sample sizes were small in both groups.

TEP-302 (OPTIC-X) Study: OLE of the TEP-301 Study

The proportions of proptosis responders at week 24 relative to study baseline were 89.2% (33 of 37 patients) and 53.8% (7 of 13 patients) in first-course and second-course groups, respectively (Table 29). Of the 32 patients in the first-course group (initially also proptosis nonresponders in the TEP-301 study) and 2 patients in the second-course group (initially proptosis nonresponders in the TEP-301 study), 29 patients (90.6%) in the first-course group and 1 patient (50.0%) in the second-course group had a sustained proptosis response at week 48 of the OPTIC-X study. Additionally, of the 1 patient in the first-course group and 9 patients in the second-course group who relapsed during the follow-up period, all patients except 3 in the second-course group were responders at week 24 relative to study baseline in the OPTIC-X study.

The mean changes from study baseline to week 24 in proptosis in the study eye were −3.47 mm in the first-course group and −1.77 mm in the second-course group (Table 29). No additional results were available during the follow-up period of the OPTIC-X study.

Table 23: Change From Baseline in CAS and Proptosis in the TED01RV Study — ITT Population

CAS = clinical activity score; ITT = intention to treat; SD = standard deviation.

Source: Clinical Study Report Addendum table and figures, TED01RV study.⁷⁶

Table 24: Sustained Proptosis Responder Rate, Overall Responder Rate, CAS Responder Rate, and Diplopia Responder Rate in the Follow-Up Period of the TEP-301 Study — Week 24 Proptosis Responders, Overall Responders, CAS Responders, and Diplopia Responders