A Study of IBI3031 in Participants With Thyroid Eye Disease

IBI3031 is an IGF-1R(Insulin-like growth factor 1 receptor)/TSHR(Thyroid-stimulating hormone receptor) bispecific antibody with potential synergistic therapeutic efficacy in TED and modulatory effects on thyroid function. As the first-in-human trial of IBI3031, this study evaluates the safety, tolerability, PK(Pharmacokinetics)/PD(Pharmacodynamics) profiles, immunogenicity, and efficacy of IBI3031 in TED participants. The trial is conducted in two stages: Stage 1- a single-ascending-dose (SAD) study involving single SC or IV administration of IBI3031; Stage 2- a multiple-ascending-dose (MAD) study involving three SC administrations of IBI3031. Approximately 66 TED participants are planned for enrollment: 36 in Stage 1 (allocated at a 3:1 ratio) and 30 in Stage 2 (allocated at a 4:1 ratio).

Key Inclusion Criteria:

• Written informed consent.
• Aged between 18 and 75 years at screening.
• Weight between 45 kg and 100 kg.
• Moderate-to-severe active TED:

• CAS ≥ 3 in the study eye at screening and baseline;
• Usually associated with at least two of the following: lid retraction ≥ 2 mm, moderate or severe soft tissue involvement, exophthalmos ≥ 3 mm above normal, and/or inconstant or constant diplopia;
• ≤ 12 months since the onset of active TED symptoms according to subjects' chief complaint or medical record at screening;
• Exophthalmos ≥ 18 mm in the study eye at baseline. (Only applicable to Stage 2)
• Participants must be clinically and biochemically euthyroid, or have mild hypothyroidism or mild-to-moderate hyperthyroidism at screening.
• Positive for Thyrotrophin Receptor Antibody (TRAb) at screening.
• No prior treatment with antithyroid medications and/or thyroid hormone replacement therapy, or having taken antithyroid medications and/or thyroid hormone replacement therapy on a stable dose for at least 6 weeks prior to the first dose, or having not been treated with antithyroid medications and/or thyroid hormone replacement therapy due to intolerable side effects for at least 6 weeks prior to the first dose.
• Infertile female participants or fertile female participants with negative blood pregnancy test results during the screening period and agree to take contraceptive measures from screening to 120 days after the last dose; male participants should agree to use contraceptive measures from screening to 120 days after the last dose.

Key Exclusion Criteria:

Participants to be excluded (Participants meeting any of the following criteria will be regarded as ineligible):

• The CAS of the study eye at baseline is reduced by ≥ 2 points compared with that at screening, or the proptosis of the study eye at baseline is reduced by ≥ 2 mm compared with that at screening;
• Participants previously diagnosed with dysthyroid optic neuropathy (DON), or with DON as determined by the investigator at screening;
• Patients with corneal ulcers that are not relieved after treatment at the investigator's discretion;
• Presence of other non-TED ophthalmic diseases that may affect the interpretation of study results or the safety of participants as determined by the investigator (e.g., proptosis not primarily caused by TED);
• At screening, clinical or laboratory evidence of significant hypothyroidism (presence of clinical symptoms of hypothyroidism, or FT3 or FT4 (Free Thyroxine)<0.5×lower limit of normal [LLN], or TSH>1.5×upper limit of normal [ULN]); or severe hyperthyroidism during the screening period (FT3 and FT4(Free Thyroxine)>2×ULN, or presence of thyroid storm).
• Other medical history and abnormal test results during the screening period that are judged by the investigator to be clinically significant, may cause the participant to fail to comply with the study protocol or complete the trial, or endanger safety, including but not limited to:

• History of hepatic insufficiency (Child-Pugh Class B or C) or liver cirrhosis; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 × ULN at screening;
• Glomerular filtration rate (GFR) < 60 ml/min/1.73 m2;
• Poorly controlled diabetes mellitus or hypertension;
• Confirmed or clinically suspected inflammatory bowel disease, gastrointestinal bleeding, or peptic ulcer disease.
• History of of chronic or recurrent infections; opportunistic infection within 180 days prior to screening;
• Positive for human immunodeficiency virus antibody (HIV Ab), hepatitis C virus antibody (HCV Ab), non-specific syphilis antibody (e.g., RPR(Rapid Plasma Reagin), TRUST), hepatitis B virus surface antigen (HBsAg) or e-antigen (HBeAg), or interferon-gamma release assay (IGRA).
• History of tinnitus or other hearing impairment in either ear during the screening period; or abnormal pure tone audiometry results (defined as an average bone conduction hearing threshold of ≥ 25 dB(decibe) at 0.5, 1, 2, and 4 kHz(kilohertz), or a bone conduction hearing threshold of ≥ 40 dB at any frequency);
• Scheduled radioactive iodine therapy or thyroidectomy at any time before screening or during the study;
• Scheduled orbital radiotherapy at any time before screening or during the study, or surgical treatment for TED, including orbital decompression, strabismus surgery, and eyelid surgery;
• Cumulative dose of glucocorticoids used to treat TED ≥ 1 g of methylprednisolone equivalents within 90 days prior to screening;
• Oral or intravenous glucocorticoids within 30 days prior to screening;
• Peribulbar/periorbital injection of glucocorticoids within 90 days prior to screening;
• Oral or intravenous administration of any other non-steroidal immunosuppressants within 90 days prior to screening;
• Use of glucocorticoid eye drops/ointments or use of non-steroidal immunosuppressant eye drops within 14 days prior to screening;
• Received antibody therapy targeting IGF-1R, TSHR, CD20(cluster of differentiation antigen 20), IL-6, or IL-6 receptor (IL-6R) at any time before screening;
• Received any other TED therapeutic drugs under development (including but not limited to biologics targeting IGF-1R, FcRn(neonatal Fc recepto), IL-6, or IL-6R) at any time before screening;
• Use of any other monoclonal antibody within 90 days prior to screening;
• Have received live vaccines within 180 days prior to screening, or plan to receive live vaccines during the study;
• Female participants in pregnancy or lactation.