Evaluating the Efficacy and Safety of Teprotumumab N01 in Patients With Thyroid Eye Disease.

The overall response rate is defined as the proportion of subjects achieving a predefined therapeutic response in the study eye.

A response is defined as improvement in ≥2 of the following 5 criteria compared with baseline, with no worsening in any criterion in either eye:

• Clinical Activity Score (CAS) reduction ≥2 points (7-item CAS: eyelid erythema, eyelid edema, conjunctival injection, chemosis, caruncle swelling, spontaneous retrobulbar pain, pain on eye movement; 1 point each);
• Proptosis reduction ≥2 mm;
• Palpebral fissure width (height) reduction ≥2 mm;
• Diplopia improvement (≥1 grade improvement on the Bahn-Gorman subjective diplopia scale [0-3]) or improvement in ocular motility ≥8°;
• Soft tissue involvement improvement ≥2 grades (based on class 2 NOSPECS grading and EUGOGO color atlas evaluation).

Response will be assessed using [¹⁸F]AlF-NOTA-FAPI-04 PET/CT . These imaging modalities will quantitatively evaluate orbital inflammation, fibroblast activation, and structural changes in the orbit. Imaging-based response will be defined as significant reduction in radiotracer uptake on PET/CT compared with baseline.

Response will be assessed using 5.0-T high-resolution magnetic resonance imaging (MRI). These imaging modalities will quantitatively evaluate orbital inflammation, fibroblast activation, and structural changes in the orbit. Imaging-based response will be defined as improvement in anatomical and inflammatory parameters on MRI compared with baseline.

The overall response rate is defined as the proportion of subjects achieving a predefined therapeutic response in the study eye. A response is defined as improvement in ≥2 of the following 5 criteria compared with baseline, with no worsening in any criterion in either eye: 1.Clinical Activity Score (CAS) reduction ≥2 points (7-item CAS: eyelid erythema, eyelid edema, conjunctival injection, chemosis, caruncle swelling, spontaneous retrobulbar pain, pain on eye movement; 1 point each); 2.Proptosis reduction ≥2 mm; 3.Palpebral fissure width (height) reduction ≥2 mm; 4.Diplopia improvement (≥1 grade improvement on the Bahn-Gorman subjective diplopia scale [0-3]) or improvement in ocular motility ≥8°; 5.Soft tissue involvement improvement ≥2 grades (based on class 2 NOSPECS grading and EUGOGO color atlas evaluation).

The recurrence rate is defined as the proportion of subjects who relapse at Week 48 among those who achieved a response at Week 24.

Recurrence is defined as the occurrence of dysthyroid optic neuropathy (DON), or worsening of ≥2 of the following 5 criteria compared with Week 24 in either eye:

• CAS increase ≥2 points;
• Proptosis increase ≥2 mm;
• Palpebral fissure width (height) increase ≥2 mm;
• New-onset diplopia or worsening diplopia (≥1 grade increase on the Bahn-Gorman scale) or increased limitation of ocular motility ≥8°;
• Soft tissue involvement worsening ≥2 grades (based on class 2 NOSPECS and EUGOGO color atlas evaluation).

Proportion of subjects with Clinical Activity Score reduction ≥2 points or Clinical Activity Score <3.

The original Clinical Activity Score evaluates seven inflammatory parameters, each scored as 1 point if present and 0 if absent, yielding a total score ranging from 0 to 7:

• Spontaneous retrobulbar pain
• Pain on attempted up- or down-gaze
• Redness of the eyelids
• Redness of the conjunctiva
• Swelling of the eyelids
• Chemosis
• Inflammation of the caruncle and/or plica A CAS ≥ 3/7 is generally considered indicative of active disease, suggesting ongoing inflammation that may respond to immunosuppressive or anti-inflammatory therapy.

Proptosis response rate, defined as a reduction ≥2 mm in the study eye without an increase ≥2 mm in the contralateral eye.

Response rate, defined as a reduction ≥2 mm in the study eye without an increase ≥2 mm in the contralateral eye.

Diplopia was evaluated using the Bahn-Gorman subjective diplopia scoring system. The grading criteria were defined as follows:

Grade 0: No diplopia; Grade 1: Intermittent diplopia, occurring in the primary gaze position under conditions of fatigue or upon awakening; Grade 2: Inconstant (nonpersistent) diplopia, elicited only at extreme gaze positions; Grade 3: Constant diplopia, present in the primary gaze or reading position. Scores were assigned based on the participants' subjective reports. An improvement of ≥1 grade was considered clinically meaningful.

Ocular motility limitation in the horizontal and vertical directions was assessed using the corneal light reflex method. Under ambient room lighting, the examiner directed a penlight toward the participant's eyes and observed the tested eye along the visual axis. Participants were instructed to move the eye in the four cardinal directions (adduction, abduction, elevation, and depression), while the examiner evaluated the position of the corneal light reflex on the corneal surface in each gaze position.An ocular rotation of 45°, 30°, and 15° was estimated when the reflex was located at the limbus, midway between the limbus and the pupillary margin, and at the pupillary margin, respectively.The degree of movement limitation in each gaze direction was recorded sequentially for each eye.

Soft tissue response rate, defined as improvement ≥2 grades in the study eye without worsening ≥2 grades in the contralateral eye, based on class 2 NOSPECS grading and EUGOGO color atlas evaluation.

Class 2 NOSPECS classification was graded as follows:

Grade 0: No signs or symptoms; Grade 1 (Mild): Eyelid and conjunctival edema, conjunctival hyperemia, eyelid fullness, orbital fat prolapse, and a palpable lacrimal gland or enlarged extraocular muscle detectable through the lower eyelid; Grade 2 (Moderate): In addition to the above signs, marked conjunctival edema (chemosis) and lagophthalmos; Grade 3 (Severe): More pronounced ocular signs with marked severity.

The EUGOGO color atlas evaluation:

Severity was assessed by comparison with representative atlas images of eyelid edema, eyelid erythema, conjunctival hyperemia, and chemosis, and graded on a 0-3 ordinal scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe), allowing for standardized and reproducible evaluation.

Mean change from baseline in BCVA of the study eye.

Mean change from baseline in IOP of the study eye.

Mean change from baseline in total Graves' Ophthalmopathy Quality of Life (GO-QoL) score.

The Graves' ophthalmopathy-specific quality-of-life (GO-QoL) questionnaire was used to assess disease-specific visual function and psychosocial impact. It comprises two subscales: visual functioning (questions 1-8), evaluating limitations in daily activities such as cycling, driving, walking, reading, watching TV, and hobbies; and appearance/life impact (questions 9-16), assessing perceived changes in appearance, social interactions, self-confidence, and coping behaviors. Each item is scored on a 3-point scale (0 = severely limited/affected, 1 = somewhat limited/affected, 2 = not limited/affected), with subscale scores calculated separately. Subscale scores range from 0 (worst) to 32 (best). Patients were instructed to focus on the past week when responding.

Mean change from baseline in:

Thyrotropin receptor antibody (TRAb).

• Incidence of grade ≥3 serious adverse events (SAEs), assessed according to CTCAE version 5.0;
• Incidence, number, severity, and relationship of all ocular and systemic adverse events, serious adverse events, and adverse drug reactions, including events related to underlying disease (e.g., thyroid dysfunction, sight-threatening TED) and events potentially related to teprotumumab N01 (e.g., menstrual disorders, infusion reactions, exacerbation of inflammatory bowel disease, hyperglycemia, hearing impairment, sinus bradycardia).