Treatment of Graves' Orbitopathy to Reduce Proptosis With Teprotumumab Infusions in an Open-Label Clinical Extension Study

This is a multi-center, open-label extension study of HZNP-TEP-301 (NCT03298867) examining the safety and efficacy of teprotumumab in the treatment of TED in adult participants. Participants who complete the 24-week double-masked Treatment Period in Study HZNP-TEP-301 and are proptosis non-responders or are proptosis responders at Week 24 but meet the criteria for re-treatment due to relapse during the Follow-Up Period of HZNP-TEP-301 will be eligible for enrollment.

All participants who choose to participate will receive 8 infusions of teprotumumab (10 mg/kg for the first infusion followed by 20 mg/kg for the remaining 7 infusions) in an open-label fashion. The Baseline (Day 1) Visit of this extension study will occur within 14 days after the final visit of Study HZNP-TEP-301 (Week 24 for proptosis non-responders and up to Week 72 for participants who relapse). During the open-label Treatment Period, study drug infusions are scheduled for Day 1 (Baseline), and Weeks 3, 6, 9, 12, 15, 18, and 21, (with the final visit at Week 24). After completion of the Treatment Period, subjects who were proptosis non-responders in Study HZNP-TEP-301 will enter a 24-week Follow-Up Period during which study drug will not be administered and clinic visits are scheduled for 1, 3, and 6 months (Visits Month 7, 9, and 12) after the Week 24 visit. Subjects will be contacted 6 and 12 months later by phone or email to enquire if any treatment for TED had been received since the last study contact.

Participants who relapse during the Follow-Up Period of HZNP-TEP-301 and choose to enter this extension study will not participate in the Follow-Up Period of this study but will be contacted by phone or email 6 and 12 months after the Week 24 visit.

Study acquired from Horizon in 2024.

• Teprotumumab (Biological), also known as HZN-001: Teprotumumab is a fully human anti-IGF-1R mAb. Teprotumumab will be provided in single-dose 20 mL glass vials as a freeze-dried powder. Each vial of teprotumumab must be reconstituted with 10 mL of water for injection. Reconstituted teprotumumab solution must be further diluted in 0.9% (w/v) sodium chloride (NaCl) solution prior to administration. Teprotumumab will be administered in 100 mL or 250 mL infusion bags (100 mL infusion bags for doses up to 1800 mg and 250 mL infusion bags for doses > 1800 mg).

Primary outcomes

• Percentage of Participants With a ≥ 2 mm Reduction From Baseline in the Study Eye Without Deterioration of Proptosis in the Fellow Eye at Week 24 [Baseline, Week 24]: Proptosis responders were defined as participants with a ≥ 2 mm reduction from study baseline in proptosis in the study eye, without deterioration (≥ 2 mm increase) of proptosis in the fellow eye at Week 24. Participants missing Week 24 values were considered non-responders, aside from those with missing data related to the COVID-19 pandemic.

Secondary outcomes

• Percentage of Participants With a European Group on Graves' Ophthalmopathy (EUGOGO) Amended Clinical Activity Score (CAS) Total Score of 0 or 1 in the Study Eye at Week 24 [Week 24]: CAS responders were defined as participants with a reduction to a CAS of 0 or 1 (no or minimal inflammatory symptoms) as a categorical response variable at Week 24. The 7-item CAS assigns 1 point for each of the following items present in the study eye: spontaneous orbital pain; gaze evoked orbital pain; eyelid swelling that is considered to be due to active (inflammatory phase) thyroid eye disease/Graves' ophthalmopathy (TED/GO); eyelid erythema; conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (ignore "equivocal" redness); chemosis; inflammation of caruncle or plica. The sum of these points is the total score (0 to 7), with higher scores indicating worse symptoms.
• Change in Proptosis From Baseline to Week 24 [Study Baseline, Week 24]: Mean change from study baseline to Week 24 in proptosis measurement (mm) in the study eye at Week 24.
• Percentage of Participants Who Were Diplopia Responders at Week 24 [Week 24]: Diplopia responders were defined as participants with 1 grade or greater reduction in diplopia score in the study eye without worsening by at least 1 grade in the fellow eye at Week 24. The subjective diplopia score (0=no diplopia; 1=intermittent, i.e. diplopia in primary position of gaze, when tired or when first awakening; 2=inconstant, i.e. diplopia at extremes of gaze; 3=constant, i.e. continuous diplopia in primary or reading position) was recorded for each eye. A participant was considered to have diplopia if a score > 0 is observed in the study eye at study baseline.
• Mean Change From Baseline to Week 24 in the Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire Overall Score [Study Baseline, Week 24]: The GO-QoL is a 16-item self-administered questionnaire divided into 2 subsets and used to assess the perceived effects of TED by the participants on (i) their daily physical activity as it relates to visual function, and (ii) psychosocial functioning. The sum of the scores from each set of 8 questions was calculated and transformed to a scale from 0 (worst) to 100 (best) - one for visual function (VF), one for appearance (A) and one for the overall combined (VF + A) score. Scores were transformed as follows: Transformed score = \[(sum of each score - number of completed items) / (2 * number of completed items)\] * 100. The "overall combined (VF + A) score" is also 0 to 100, with higher scores indicating a better outcome.

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

* Written informed consent.
* Completed the 24-week double-masked Treatment Period in Study HZNP-TEP-301 (NCT03298867).
* Proptosis non-responder (< 2 mm reduction in proptosis in the study eye) at Week 24 of Study HZNP-TEP-301 OR proptosis responder at Week 24 who relapses during the Follow-Up Period of Study HZNP-TEP-301.
* Participant must be euthyroid with the baseline disease under control, or have mild hypo- or hyperthyroidism (defined as free thyroxine \[FT4\] and free triiodothyronine \[FT3\] levels < 50% above or below the normal limits) at the most recent clinic visit. Every effort should be made to correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid state for the full duration of the clinical trial.
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 times the upper limit of normal (ULN) or serum creatinine <1.5 times the upper limit of normal (ULN; according to age) at the most recent clinic visit.
* Diabetic participants must have well-controlled disease (defined as hemoglobin A1C \[HbA1c\] < 9.0% at most recent clinic visit).
* Does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the course of the study.
* Women of childbearing potential must have a negative urine pregnancy test at Baseline/Day 1. Participants who are sexually active with a non-vasectomized male partner must agree to use 2 reliable forms of contraception during the trial and continue for 180 days after the last dose of study drug. One of the 2 forms of contraception is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be in use for at least one full cycle prior to Baseline. Highly effective contraceptive methods (with a failure rate less than 1% per year), when used consistently and correctly, includes implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner.
* Male participants must be surgically sterile or, if sexually active with a female partner of childbearing potential, must agree to use a barrier contraceptive method from Baseline through 180 days after the last dose of study drug.
* Participant is willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the study.
* Has not received any treatment for TED since Week 24 of the of the HZNP-TEP-301 study.

Exclusion Criteria:

* Participants will be ineligible if, in the opinion of the Investigator, they are unlikely to comply with the study protocol or have a concomitant disease or condition that could interfere with the conduct of the study or potentially put the participant at unacceptable risk.
* The exclusion criteria (except those related to screening) of protocol HZNP-TEP-301(NCT03298867) also apply to this open-label extension study.

Participant flow

Outcome results

• Percentage of Participants With a ≥ 2 mm Reduction From Baseline in the Study Eye Without Deterioration of Proptosis in the Fellow Eye at Week 24 (Primary), Number, percentage of participants: Teprotumumab (OPTIC Placebo) 89.2; Teprotumumab (OPTIC Teprotumumab) 53.8
• Percentage of Participants With a European Group on Graves' Ophthalmopathy (EUGOGO) Amended Clinical Activity Score (CAS) Total Score of 0 or 1 in the Study Eye at Week 24 (Secondary), Number, percentage of participants: Teprotumumab (OPTIC Placebo) 65.6; Teprotumumab (OPTIC Teprotumumab) 36.4
• Change in Proptosis From Baseline to Week 24 (Secondary), Mean, mm: Teprotumumab (OPTIC Placebo) -3.47 +/- 1.732; Teprotumumab (OPTIC Teprotumumab) -1.77 +/- 1.126
• Percentage of Participants Who Were Diplopia Responders at Week 24 (Secondary), Number, percentage of participants: Teprotumumab (OPTIC Placebo) 60.9; Teprotumumab (OPTIC Teprotumumab) 75.0
• Mean Change From Baseline to Week 24 in the Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire Overall Score (Secondary), Mean, score on a scale: Teprotumumab (OPTIC Placebo) 13.39 +/- 17.890; Teprotumumab (OPTIC Teprotumumab) 14.73 +/- 11.777

Adverse events

Time frame: All-Cause Mortality and Serious Adverse Events (AEs): from informed consent through 30 days after study discontinuation. Mean days on study was 332.9 and 218.8 for Teprotumumab (OPTIC Placebo) and Teprotumumab (OPTIC Teprotumumab) arms, respectively.

Serious adverse events by term

Other adverse events by term

64 more terms not shown.

• Results publication: Xin Y, Xu F, Gao Y, Bhatt N, Chamberlain J, Sile S, Hammel S, Holt RJ, Ramanathan S. Pharmacokinetics and Exposure-Response Relationship of Teprotumumab, an Insulin-Like Growth Factor-1 Receptor-Blocking Antibody, in Thyroid Eye Disease. Clin Pharmacokinet. 2021 Aug;60(8):1029-1040. doi: 10.1007/s40262-021-01003-3. Epub 2021 Mar 26. PMID 33768488

• Study Protocol (PDF, 2019-01-31)
• Statistical Analysis Plan (PDF, 2020-06-17)

• MD, Study director, Amgen

NIH grants: 2017