Is there any evidence/recommendation to support the use of a second course of teprotumumab in patients with Graves' ophthalmopathy?

Comment by InpharmD Researcher

The recommendation to support the use of a second course of teprotumumab in patients with Graves' ophthalmopathy stems from the OPTIC-X trial, which can be found in Table 1. This trial was supported by Horizon Therapeutics, the manufacturer of teprotumumab. Data evaluating the use of a second course of teprotumumab in patients with Graves’ ophthalmopathy (thyroid eye disease) is largely limited to two studies, one of which is the OPTIC-X trial (see Table 1). In the OPTIC-X trial, it was determined that patients who were nonresponders or who experienced disease flare during the preceding OPTIC trial benefited from a second course of teprotumumab. Another study found that patients of older age are more likely to receive a second course of teprotumumab, but the study lacked evaluation of clinical outcomes for such patients.

Background

A 2024 pooled analysis of long-term outcomes from three clinical trials explored the durability of teprotumumab in individuals with thyroid eye disease (TED). The collective data involved 112 patients who completed seven or eight infusions of teprotumumab within the Phase 2, Phase 3 OPTIC, and OPTIC-X (see Table 1) studies. Clinical endpoints, including a reduction in Clinical Activity Score (CAS) by ≥2 points, improvements in proptosis (≥2 mm reduction), diplopia (≥1 Gorman grade), quality of life (GO-QoL), and overall response (proptosis + CAS improvement), were evaluated over an extended follow-up period. Data were assessed at multiple time points, from the study baseline to week 24 (therapy period) and beyond, with the longest follow-up extending to 99 weeks. Key findings demonstrated a sustained response in inflammatory activity and ophthalmic outcomes, with 91.2% of patients achieving CAS response and 89.5% reporting improvements in the composite European Group of Graves’ Orbitopathy outcome at 72 weeks. Proptosis response was maintained in 67.9% of participants, with a mean reduction of 2.68 mm at week 72, while 72.9% exhibited diplopia improvement. Quality-of-life measures reflected clinically meaningful gains, with a mean increase of 15.22 points in GO-QoL scores at 72 weeks. Notably, 82% of participants did not require additional TED-specific therapies (e.g., steroids, surgeries) up to 99 weeks. Adverse events were consistent with prior reports and predominantly mild to moderate, with no new safety signals identified during follow-up. These results underscore the prolonged benefits of teprotumumab on clinical and patient-reported outcomes in moderate-to-severe TED, highlighting its potential as a durable therapeutic strategy, including when used with a second course following initial nonresponse or disease flare. [1]

References:

[1] Kahaly GJ, Subramanian PS, Conrad E, Holt RJ, Smith TJ. Long-Term Efficacy of Teprotumumab in Thyroid Eye Disease: Follow-Up Outcomes in Three Clinical Trials. Thyroid. 2024;34(7):880-889. doi:10.1089/thy.2023.0656

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there any evidence/recommendation to support the use of a second course of teprotumumab in patients with Graves' ophthalmopathy?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-2 for your response.


 

Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment: OPTIC-X Study

Design

Multinational, open-label extension study of a phase 3, randomized, double-masked, placebo-controlled, parallel-group trial (OPTIC)

N= 14

Objective

To evaluate teprotumumab safety and efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare

Study Groups

Teprotumumab nonresponders receiving second course (n= 5)

Disease flare patients receiving second course (n= 9)

Inclusion Criteria

Placebo- and teprotumumab-treated proptosis nonresponders (<2-mm decrease in the study eye at week 24) who completed the OPTIC trial, patients from OPTIC follow-up who demonstrated a disease flare (increase in proptosis in study of 2 mm or more, increase in clinical activity score [CAS] of 2 points or more with total CAS score of 4 or more in the study, or both)

Exclusion Criteria

N/A

Methods

Nonresponders from the OPTIC trial or patients who experienced a disease flare during follow-up of the OPTIC trial were eligible to receive teprotumumab for the first time (patients who received placebo) or for the second time (teprotumumab nonresponders or disease flare during follow-up). Patients received 8 open-label infusions of teprotumumab 10 mg/kg for the first infusion followed by 20 mg/kg for the remaining 7 infusions over the course of 24 weeks.

Duration

Follow-up: 24 weeks

Outcome Measures

Primary: proptosis responder rate at week 24

Secondary: percentage of patients with a CAS of 0 or 1 at week 24, mean change to week 24 in proptosis, diplopia responder rate, and mean change to week 24 in Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire aggregate score

Baseline Characteristics

 

Second course of teprotumumab (n= 14)

 

Age, years

56.1 ± 11.5  

Female

78.6%  

White

78.6%  

Years since diagnosis of Graves' disease (range)

1.7 (0.79 to 28.78)  

Months since diagnosis of TED (range)

16.5 (8.52 to 22.50)  

Smoker

21.4%  

CAS

3.5 ± 1.6  

Proptosis measurement, mm

21.0 ± 4.2  

Thyroid hormone level, pmol/L

Free triiodothyronine (FT3)

Free thyroxine (FT4)

 

4.7 ± 0.8

16.5 ± 3.2

 

Thyrotropin level, mIU/L

2.47 ± 2.46  

Results

Endpoint

Teprotumumab nonresponders receiving second course (n= 5)

Disease flare patients receiving second course (n= 9)

Proptosis responder rate

2 (40%)

n= 8*

5 (62.5%)

Change in proptosis from baseline of OPTIC-X, mm

-1.5 ± 0.9

-1.9 ± 1.2

Change in proptosis from baseline of OPTIC, mm

-2.5 ± 0.9

-3.3 ± 0.7

Diplopia responder rate 

n= 1

1 (100%)

n= 3

3 (100%)

CAS reduction

n= 3

3 (100%)

Not reported

CAS of 0 or 1

n= 3

0

n= 7

4 (57.1%)

Change in GO-QOL score

Not reported

17.9 ± 12.4

*One patient was excluded from the week 24 summaries due to COVID-19.

Adverse Events

Common Adverse Events (for all patients receiving second course): muscle spasm (28.6%), arthralgia (14.3%), back pain (14.3%), nasal dryness (14.3%), alopecia (14.3%), dry skin (14.3%), hearing impairment (14.3%), diarrhea (7.1%)

Serious Adverse Events (for all patients receiving second course): cerebral hemorrhage (7.1%), infusion-related reaction (7.1%)

Percentage that Discontinued due to Adverse Events: Two patients in the nonresponder group discontinued treatment, but it is unclear if it was related to adverse events.

Study Author Conclusions

Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.

InpharmD Researcher Critique

Due to a limited number of patients, further high-quality analysis of patients receiving a second course of teprotumumab is necessary to confirm its safety and efficacy.



References:

Douglas RS, Kahaly GJ, Ugradar S, et al. Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment: OPTIC-X Study. Ophthalmology. 2022;129(4):438-449. doi:10.1016/j.ophtha.2021.10.017

 

The Rate of Re-Treatment in Patients Treated with Teprotumumab — A Multicenter Study of 119 Patients with 1 Year of Follow-up

Design

Multicenter, retrospective case series

N= 119

Objective

To determine the rate of re-treatment in patients who receive a full course of teprotumumab therapy for thyroid eye disease (TED) and drivers of re-treatment

Study Groups

Re-treatment (n= 29)

No re-treatment (n= 90)

Inclusion Criteria

Patients treated with teprotumumab who had received a full course of therapy, available data at 1 year after initial treatment, uninterrupted treatment course

Exclusion Criteria

Not explicitly stated

Methods

Charts were reviewed for patients who received a full course of teprotumumab therapy (10 mg/kg for the first infusion and 20 mg/kg for subsequent infusions every 3 weeks to complete 8 infusions over 24 weeks). Patients who received a second course (re-treatment) were evaluated. Criteria for re-treatment across all study sites was a clinical activity score (CAS) of 3 or more, worsening proptosis of 2 mm or more, or worsening diplopia in the presence of inflammatory signs.

Duration

Treated with teprotumumab: March 2020 to July 2023

Outcome Measures

Variables associated with re-treatment, proptosis response (2-mm or more reduction from baseline)

Baseline Characteristics

 

Re-treatment (n= 29)

No re-treatment (n= 90)

 

Age, years

60 ± 12 53 ± 16  

Female

79.3% 75.6%  

Diplopia score

0

1

2

3

Missing

 

20.7%

17.2%

27.6%

23.1%

10.3%

 

26.7%

17.8%

12.2%

30%

13.3%

 

TED treatment

No treatment

Steroids

Surgery

Orbital radiation

Multiple treatments

Immunovant trial

Missing

 

34.5%

31%

17.2%

6.9%

6.9%

3.4%

0

 

45.6%

25.6%

14.4%

1.1%

7.8%

2.2%

3.3%

 

Results

Endpoints

Re-treatment (n= 29)

No re-treatment (n= 90)

p-value

Variables evaluated for association with re-treatment 

Age, years

CAS at baseline

Proptosis at baseline, mm

Diplopia score at baseline

TED duration, months

 

60 ± 12

4.8 ± 2.1

23.6 ± 3.6

1.6 ± 1.1

48.5 ± 82.9

 

53 ± 16

3.7 ± 1.9

22.5 ± 3.6

1.6 ± 1.3

43.9 ± 54.6

 

0.0182

0.0067

0.0651

0.4835

0.4286

Proptosis response after initial treatment course

82% 68% 0.16

At the end of the first course of therapy, no difference in CAS (p= 0.3), proptosis (p= 0.4), or diplopia score (p= 0.4) was found between the re-treated group and the no re-treatment group. Additionally, the use of other treatments before the first infusion of teprotumumab and baseline thyroid dysfunction was not significantly different between groups (p= 0.06 and p= 0.09, respectively).

A logistic regression model identified age as the only significant predictor of re-treatment. Re-treated patients were 7 years older than those who were not re-treated (60 vs. 53 years; p<0.05).

Adverse Events

Not disclosed

Study Author Conclusions

Our study revealed that the rate of re-treatment in patients who received a full course of uninterrupted treatment of teprotumumab is 24.4%. Analysis of the rate of retreatment is an indirect measure of the durability of the effect of teprotumumab on TED. However, given the growing body of evidence that suggests TED is a chronic disease, it is likely that a group of patients receiving teprotumumab will require further treatment. Our study revealed that this group of patients is likely to be older. Having identified a re-treatment rate and a risk factor, it may be possible to better inform patients before initiating treatment.

InpharmD Researcher Critique

This study did not extensively evaluate clinical outcomes associated with re-treatment but rather focused on evaluating variables associated with re-treatment.

 

References:

Ugradar S, Parunakian E, Malkhasyan E, et al. The Rate of Re-treatment in Patients Treated with Teprotumumab: A Multicenter Study of 119 Patients with 1 Year of Follow-up. Ophthalmology. 2025;132(1):92-97. doi:10.1016/j.ophtha.2024.07.018