A research team led by Academician Xianqun Fan from the Ninth People’s Hospital,affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), in collaboration with Tianjin Medical University Eye Hospital, The First Hospital of China Medical University, The Second Affiliated Hospital of Dalian Medical University, and 20 other centers nationwide, hascompleted the Phase III clinical trial (RESTORE-1) of China’s first recombinant human anti–insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, IBI311, in patients with moderate-to-severe active Thyroid Eye Disease (TED). The results showed that after eight doses of IGF-1R monoclonal antibody, the proptosis response rate reached 85.8%,which was significantly higher than the 3.8% in the placebo group. The study achieved its primary endpoint, confirming that IGF-1R inhibition provides superior improvement in proptosis and Clinical Activity Score (CAS) compared with placebo, with an overall favorable safety profile. Supported by these pivotal data, the National Medical Products Administration (NMPA) of China approved IBI311 in March 2025,marking it as the first domestically developed targeted biologic for TED. This breakthrough offers Chinese patients a novel, effective, and accessible disease-modifying therapy. Thecomplete study has been published online in the prestigious international journalJAMA Ophthalmology.

01. Challenge: Significant Unmet Needs in the Treatment of Thyroid Eye Disease

Thyroid eye disease (TED) is an autoimmune disorder that affects orbital tissues and is commonly associated with Graves’ disease, making it the most frequent orbital condition in adults. TED often manifests as proptosis, eyelid retraction, diplopia, corneal ulceration, and, in severe cases, may lead to vision loss or blindness, severely impairing patients’ appearance, visual function, and quality of life. For decades, therapeutic options for TED have been limited. The first-line treatment for moderate-to-severe active TED remains intravenous corticosteroid pulse therapy, while other approaches, such as orbital radiotherapy and immunosuppressants, offer limited efficacy in reversing proptosis and may cause considerable side effects. Thus, there is an urgent need for targeted therapies addressing the core pathophysiological mechanisms of the disease.

Although the exact pathogenesis of TED is not yet fully understood, it is now widely recognized that insulin-like growth factor 1 receptor (IGF-1R) is overexpressed in orbital fibroblasts, B cells, and T cells of TED patients. Activation of the IGF-1R signaling pathway promotes fibroblast activation and differentiation, leading to excessive extracellular matrix deposition andthe production of inflammatory cytokines, which drive the abnormal expansion of orbital muscles and adipose tissues. In 2020, the world’s first IGF-1R monoclonal antibody, Teprotumumab, was approved by the U.S. FDA as the first targeted therapy for TED. By blocking the central signaling hub of disease progression, Teprotumumab effectively reverses orbital changes and improves symptoms such as proptosis, diplopia, and periorbital inflammation. However, the drug has not yet been launched in China, and its extremely high cost—over 2 million yuan per treatment course—has severely limited accessibility for Chinese patients.

02. Breakthrough: High-Level Clinical Evidence from China’s Phase III Trial

To address the urgent treatment needs of Chinese patients with TED, the Department of Ophthalmology at Ninth People’s Hospitalaffiliated to SJTUSM, in collaboration with Innovent Biologics, initiated the nation’sfirst clinical investigation of an insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, known as IBI311. Following the successful completion of early-stage clinical development, a Phase III clinical trial (RESTORE-1) was formally launched to evaluate the efficacy and safety of IBI311 in Chinese patients with moderate tosevere active TED. A total of 82 participants with moderate-to-severe active TED were enrolled and randomly assigned (2:1) to receive either IBI311 or placebo, administered via intravenous infusion every three weeks for a total of eight doses. The primary endpoint was the proptosis response rate at week 24, defined as the percentage of patients who achieved a reduction of≥2 mm in proptosis in the study eye without a corresponding increase of≥2 mm in the fellow eye.

RESTORE-1研究流程图

RESTORE-1 Study Flow Chart

The results showed that patients treated with IBI311 achieved a significantly higher proptosis response rate compared with those receivingaplacebo. At week 24, the proptosis response rate was 85.8% in the IBI311 group versus 3.8% in the placebo group, corresponding to a rate difference of 81.9% (95% CI: 69.8–93.9; P < 0.0001).

For key secondary endpoints, the IBI311 group consistently outperformed placebo (P < 0.0001) in: overall proptosis response rate of the study eye, proportion of patients achieving a CAS of 0 or 1, and mean change in proptosis from baseline. Additionally, more than 60% of patients achieved a diplopia response (defined as≥1-grade improvement in diplopia score), accompanied by a notable improvement in quality of life. Overall, the RESTORE-1 trial validated the efficacy of IBI311 in treating patients with moderate tosevere activeTED. In terms of safety, IBI311 demonstrated a favorable safety profile. All treatment-emergent adverse events (TEAEs) were mild to moderate in severity, including menstrual irregularities, hyperuricemia, hyperglycemia, and auditory disturbances. No serious adverse events were reported, and the overall impact on treatment compliance was minimal.

Primary and Key Secondary Endpoints

03. Significance: A Breakthrough Domestic Therapy Benefiting Chinese TED Patients

As the first multicenter, prospective, randomized, controlled Phase III clinical trial of an IGF-1R monoclonal antibody for TED conducted in China, the RESTORE-1 study not only facilitated the regulatory approval of the first domestically developed IGF-1R monoclonal antibody but also significantly reduced treatment costs and addressed the long-standing issue of limited drug accessibility for Chinese patients. Importantly, RESTORE-1 filled a critical evidence gap by providing high-level clinical data on IGF-1R antibody therapy in Chinese TED populations. The study systematically demonstrated that anti–IGF–1R therapy offers multifaceted clinical benefits,including improvement in proptosis, reduction in disease activity, and enhanced quality of life, while maintaining a favorable safety profile.

Moreover, this trial was the first RCT to introduce quantitative MRI-based orbital imaging assessments and novel radiologic endpoints to evaluate therapeutic efficacy in TED. The detailed imaging analysis results will be published in subsequent reports. At present, the team is leading multiple nationwide, multicenter clinical trials of first-in-class therapeutic antibodies targeting IGF-1R, TSHR, and FcRn for the treatment of TED. In collaboration with the Chinese Consortium of Thyroid Eye Disease (CCTED), these studies aim to promote high-quality clinical research and standardize clinical management nationwide. This series of research initiatives is expected to expand the range of targeted therapeutic options available to TED patients and advance precision medicine for TED patients in China.

The principal investigator of this study is Prof. Xianqun Fan, Academician of the Chinese Academy of Engineering, Dean of the SJTUSM, andDiscipline leader of the Department of Ophthalmology atShanghai’sNinth People’s Hospital affiliated to SJTUSM. Prof. Huifang Zhou serves as the co-corresponding author. Dr. Haiyang Zhang (Physician), Dr. Jing Sun (Chief Physician), and Dr. Yinwei Li (Associate Chief Physician) are the co-first authors of the paper.

Last Corresponding Author

Academician Xianqun Fan

Prof. XianqunFanis Vice President of SJTU,Chancellorof SJTUSM, Chief Physician, Professor and Doctoral Supervisor oftheDepartment of Ophthalmology,Ninth People’s Hospital affiliated to SJTUSM. He is an Academician of the Chinese Academy of Engineering, the Academia Ophthalmologica Internationalis (AOI),theAcademy of Asia-Pacific Professors of Ophthalmology, and an Honorary Fellow of the Royal College of Surgeons of Edinburgh. He was awarded the Fellowship oftheRoyal College of Ophthalmologists (UK). Prof. Fan also serves as Director of the State Key Laboratory of Eye Health andas Director of the Center for Basic Medical Research and Innovation in Visual System Diseases, under the Ministry of Education. His research focuses on both the clinical management and fundamental mechanisms of ophthalmic diseases. As principal investigator, he has led major national programs including the National Basic Science Center Project, the National Key R&D program, the National 863 projects, and multiple major, key and international cooperation projects funded by the National Natural Science Foundation (NSFC). He has published over 360 peer-reviewed SCI papers as the first author or corresponding author. Asthe first contributor, he has received two Second Prizes of the National Science and Technology Progress Awards, one First Class National Teaching Achievement Award, and three First Prizes of the Shanghai Science and Technology Progress Awards. His other honors include the Ho Leung Ho Lee Foundation Award for Scientific and Technological Progress, theInaugural Innovator Awardof AAPPO, theAsia-Pacific Ophthalmology Outstanding Contribution Award,and the Outstanding Contribution Award of the Chinese Ophthalmological Society.

Co-corresponding Author

Professor Huifang Zhou

上海交通大学医学院附属上海儿童医学中心党委书记，上海交通大学医学院附属第九人民医院眼科主任医师、教授、博士生导师、国家级人才。担任亚太眼整形学会理事，中华医学会眼科分会眼免疫学组委员，中国医师协会眼科整形眼眶病学组委员等。以第一或通信作者发表论文100余篇，编写指南/共识6部、专著9部；授权专利18项，实现成果转化6项；领衔全国多中心新药新技术临床研究8项。获国家科技进步二等奖、教育部高等学校科技进步一等奖、上海市科技进步一等奖等9项科技奖项；被授予庆祝中华人民共和国成立70周年纪念章；荣获中国最美女医师、国之名医、仁心医者·上海市杰出专科医师奖等荣誉称号。

Prof. HuifangZhouserves as the Party Secretary of Shanghai Children’s Medical Center (SCMC) affiliated to SJTUSM and is also a Chief Ophthalmologist, Professor, and Doctoral Supervisor at the Department of Ophthalmology, Ninth People’s Hospital affiliated to SJTUSM. She is recognized as a national-level talent in China. Prof. Zhou currently serves as a Board Member of the Asia-Pacific Society of Ophthalmic Plastic and Reconstructive Surgery (APSOPRS), a member of the Ocular Immunology Group of the Ophthalmology Branch of the Chinese Medical Association, and a member of the Oculoplastic and Orbital Diseases Group of the Chinese Medical Doctor Association. She has published over 100 research papers asthe first or corresponding author, contributed to six national clinical guidelines and expert consensus statements, and authored or co-authored nine academic monographs. She holds 18 authorized patents, with six successfully translated into clinical applications, and has led eight national multicenter clinical studies on novel drugs and technologies. She has received nine major scientific awards, including the Second Prize oftheNational Science and Technology Progress Awards, the First Prize of theMinistry of Education’s Higher Education Science and Technology Progress Award, and the First Prize of the Shanghai Science and Technology Progress Award. She was honored with thecommemorativemedalto markthe 70thanniversary of thefounding of the People’s Republic of China, and has been recognized with several prestigious titles, includingthe nation’s “Most Beautiful Doctor”, “NationalFamous Doctor”, and theShanghai Outstanding Specialist Physician Award for Benevolent Physicians.

First Author

Dr. Zhang Haiyang

Ophthalmologist, PhD, Department of Ophthalmology, Shanghai Ninth People’s Hospital, affiliated toSJTUSM. He graduated from the eight-year program in clinical medicine atSJTUSM. His primary research focuses on the clinical and basic research of orbital diseases. Dr. Zhang has published 29 SCI-indexed papers as first or co-first author in journals includingJAMA Ophthalmology,Journal of Neuroinflammation, andAdvanced Functional Materials, with 20 papers in JCR Q1 journals. He has led one project funded by the NSFC and one by the Shanghai Natural ScienceFoundation and holds 4 national patents as first inventor. He has also participated in multiple multi-center clinical trials on TED. He serves as Deputy Director of the Youth Committee of the Shanghai Society of Image and Graphics and is a young editorial board member of the journalVisual Neuroscience. Dr. Zhang has received honors including the National Scholarship, Shanghai University Student of the Year, and Outstanding Graduate of Shanghai.