Validating IGF-1R targeted therapy for thyroid eye disease in Asian patients

The management of thyroid eye disease (TED) has undergone a paradigm shift, transitioning from broad immunosuppression to precise molecular targeting. Orbital infiltrating fibrocytes, progenitor cells which have been shown to express the thyroid stimulating hormone (TSA) receptor and the insulin-like growth factor-1 (IGF-1) receptor, are potential pathogenic drivers for the remodelling of orbital tissues, especially promoting adipogenesis and hyaluronan accumulation, hallmarks of the disease (1).

Teprotumumab, the first approved drug for TED, has become, where available, the gold standard for insulin-like growth factor-1 receptor (IGF-1R) inhibition (2,3); however, its global reach has been limited by regional availability—as highlighted by international consensus guidelines—and a lack of large-scale data in diverse ethnic cohorts, given that Asian patients comprised only about 4% of the pivotal trial populations (4,5).

Ethnic differences in TED presentation are well documented. Asian patients tend to exhibit distinct phenotypic features, including lower mean proptosis and varying patterns of extraocular muscle involvement, compared to Caucasian cohorts (6-8). These clinical differences are driven by a multifactorial interplay of structurally shallower orbital volumes (9), distinct genetic backgrounds such as specific human leukocyte antigen (HLA) associations (10), and varying environmental factors. Furthermore, while the pharmacokinetics of monoclonal antibodies are generally comparable across ethnic groups, inter-individual variability in body composition, disease burden, and HLA-driven immunogenicity can influence both treatment response and safety profiles (11,12). These considerations underscore the critical importance of generating ethnicity-specific efficacy and safety data, especially given that the pivotal teprotumumab trials enrolled predominantly Caucasian populations. It is within this context that the RESTORE-1 trial, evaluating IBI311 in a purely Chinese cohort, addresses this gap in the therapeutic landscape.

As reported by Zhang et al. (13) in the RESTORE-1 trial, IBI311 is a recombinant, fully human monoclonal antibody designed to block the IGF-1R signalling pathway with high affinity. Although IBI311 shares an identical amino acid sequence with teprotumumab, early-phase data suggest its formulation processes have been optimized for clinical administration efficiency. While the specific biochemical details of these optimizations are proprietary, Phase 3 results indicate they do not adversely alter the drug’s immunogenic profile. Notably, the anti-drug antibody rate for IBI311 was exceedingly low (1.8%, 1/54 patients), closely mirroring the low rates (~2.3%) observed in pivotal teprotumumab trials (14).

The trial met the primary endpoint: at week 24, the proptosis response rate in the IBI311 group was 85.8%, compared to only 3.8% in the placebo group (P < 0.001). While proptosis response rates were highly comparable across trials, notable differences in clinical activity score (CAS) outcomes were observed. RESTORE-1 achieved a CAS 0-1 response of 83.5%, substantially higher than the 59% reported in the OPTIC-J trial. Although the baseline CAS in RESTORE-1 was slightly lower than the Japanese court (mean 4.3 vs. 4.5), the consistently low placebo response rates across all geographic studies (ranging from 17% to 21%) suggest that this discrepancy is not an artifact of subjective grading or baseline differences. Instead, it may reflect a genuinely robust anti-inflammatory response within the Chinese population.

To provide a comprehensive perspective on the clinical significance of the RESTORE-1 findings, it is essential to trace the therapeutic trajectory of IGF-1R inhibitors over the last decade. This journey began with the first randomized multicenter trial in 2017, which first demonstrated the potential of teprotumumab (3), followed by the landmark OPTIC Phase 3 trial (2020) that led to its regulatory approval in the United States (15). Subsequently, the OPTIC-X extension open-label study (2022) explored the long-term durability of the response and its efficacy in non-responsive cases (16). More recently, the OPTIC-J trial (2025) provided the first specific insights into the drug's performance within an East Asian (Japanese) cohort (17). By positioning the RESTORE-1 data alongside these pivotal studies, we can evaluate how IBI311 integrates into the current global standards of care, as summarized in the comparative analysis below (Table 1).

The RESTORE-1 trial confirms the efficacy of IGF-1R inhibition in the management of TED. Despite the well-documented orbital anatomic differences in Caucasian and Asian patients — with the latter typically exhibiting lower baseline proptosis levels — the blockade of the IGF-1R receptor has proven to be a highly effective as a therapeutic target. The exceptionally high proptosis response rate of 85.8% aligns with the robust results seen in Western cohorts and the Japanese OPTIC-J trial (89%). While indirect cross-trial comparisons cannot definitively confirm equivalence, this consistent pattern across independent studies strongly suggests that the underlying pathophysiological mechanism of TED remains consistent across different ethnic and genetic backgrounds. Although the diplopia response in the RESTORE-1 trial did not achieve statistical significance—likely due to statistical power limitations within that specific patient subgroup—this outcome carries important practical implications. When counselling Asian patients with prominent diplopia, clinicians should emphasize that while IBI311 provides robust and consistent proptosis reduction, patients must be realistically advised that adjunctive therapies, such as prisms or subsequent strabismus surgery, may still be necessary for comprehensive visual rehabilitation once the disease reaches the inactive phase.

A comparative analysis of hearing-related AEs highlights the impact of monitoring protocols on reported safety profiles (Table 2). In the Pivotal Study, OPTIC, and OPTIC-X trials, where audiometric testing was performed only upon symptom reporting, hearing AEs ranged from 7% to 12%. Similarly, the Japanese OPTIC-J trial, which utilized a symptom-driven approach without mandatory baseline audiometry, reported a rate of 15%. In contrast, the RESTORE-1 trial implemented a rigorous surveillance protocol requiring systematic pure-tone audiometry and tympanometry for all participants at every visit. This proactive screening likely accounts for the higher reported incidence of 20.4%, unmasking mild or subclinical events that may have gone undetected in previous studies. Importantly, across all trials, these events were predominantly mild to moderate and generally reversible, suggesting that the increased rate in RESTORE-1 reflects higher detection sensitivity rather than enhanced toxicity of the IBI311 molecule. Rather than indicating enhanced toxicity, these findings strongly advocate for making proactive, systematic audiometric monitoring a standard requirement in clinical practice and future trials for all IGF-1R inhibitors.

The 25.9% incidence of menstrual disorders in the IBI311 group aligns with the approximately 23% incidence reported in menstruating women during teprotumumab trials and postmarketing surveillance, confirming this as a class effect of IGF-1R inhibition rather than a novel toxicity. Given these findings, rigorous clinical counselling for women of childbearing age is imperative prior to initiating therapy. Following established safety guidelines for IGF-1R inhibitors, patients must undergo a negative pregnancy test before starting treatment and utilize effective contraception during therapy and for a mandatory 6-month washout period following the final dose due to teratogenicity risks. Patients should be counselled to anticipate potential transient menstrual irregularities (such as amenorrhea). Because pregnancy is strictly contraindicated during the 6-month washout, these irregularities do not inherently delay immediate conception plans; however, if menstrual symptoms persist beyond this 6-month post-treatment window, a targeted gynaecological evaluation is highly recommended.

The emergence of hyperuricemia (20.4%) in the IBI311 group represents a novel safety finding. We suspect this reflects both a population-specific nuance and an underreported class effect of IGF-1R inhibition. Epidemiologically, the Chinese population exhibits a high baseline prevalence of hyperuricemia (approximately 16.4%) (18). Mechanistically, IGF-1R signalling is intrinsically linked to urate homeostasis via renal transporters, and the insulin resistance commonly induced by IGF-1R blockade further impairs urate excretion (19). Because this metabolic disruption is a plausible class effect, incorporating routine serum uric-acid evaluations into the standard safety monitoring protocols for all patients receiving targeted IGF-1R therapy is highly advisable.

By improving sustainability and access to effective, disease-modifying targeted therapies in regions where they were previously unavailable, IBI311 may become a significant advancement toward a more universal management of TED. Beyond overcoming regulatory hurdles, the introduction of a competing IGF-1R inhibitor is an important development from a health economics perspective. The high cost of biologic therapies is frequently a significant hurdle to their widespread adoption; therefore, emerging alternatives like IBI311 hold the potential to foster market competition. This dynamic can ultimately help to drive down treatment prices and facilitate broader, more sustainable access across diverse health systems.

However, the interpretation of the RESTORE-1 trial should be contextualized within its design boundaries. The lack of baseline diplopia as a stratification factor likely underpowered the functional outcomes, while the 24-week follow-up period precludes definitive conclusions regarding long-term response durability. Looking ahead, long-term extension data—particularly focusing on the durability of proptosis reduction and dedicated subgroup analyses on the long-term trajectory of diplopia—will be essential to cement the role of routine IGF-1R inhibition within the treatment algorithm for Asian populations.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0011/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0011/coif). The authors have no conflicts of interest to declare.

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