Who benefits most from IGF-1R inhibition?
The strongest evidence points to patients with active, moderate-to-severe thyroid eye disease (TED) — meaning they have visible inflammation (clinical activity score of 3 or higher) and significant eye bulging. In a 2025 randomized, double-blind, placebo-controlled trial in 82 Chinese patients, the IGF-1R inhibitor IBI311 produced a proptosis response (≥2 mm reduction in eye bulging) in 85.8% of treated patients versus 3.8% on placebo, and 83.5% achieved a clinical activity score of 0 or 1 (no inflammation) versus 16.6% on placebo [1]. This trial excluded patients with sight-threatening TED or those who had already had steroid pulse therapy, radiation, or surgery, so the results apply to a specific, common patient group.
The benefit also extends to reducing inflammation and improving double vision, though the evidence is more mixed. In the same trial, 80.2% of IBI311 patients had both proptosis reduction and a ≥2-point drop in clinical activity score, versus 3.6% on placebo [1]. However, the improvement in double vision (diplopia) was not statistically significant (66.0% vs 53.3%, p=0.46) [1]. This suggests that while IGF-1R inhibition is highly effective for the main signs of TED, its effect on double vision may be less predictable.
Does the effect last? The catch with durability
A major caveat is that the benefits can fade over time. A 2023 retrospective study of 119 patients who completed all 8 teprotumumab infusions found that, among those with follow-up visits, 65.38% of eyes that initially improved later regressed, with an average loss of 2.43 mm of proptosis reduction [5]. More concerning, 25.64% of eyes ended up with more proptosis than before treatment [5]. This means that while most patients maintain some improvement, a significant minority do not, and the effect is not permanent for everyone.
The timing of regression varied: about half of regressions occurred within 6 months of finishing treatment, and a quarter occurred more than a year later [5]. This highlights the need for long-term monitoring and possibly repeat or adjunctive treatments. Importantly, the occurrence of regression was independent of how long a patient had TED before treatment, so even early treatment doesn't guarantee durability [5].
Are newer IGF-1R inhibitors better?
Newer drugs are being developed that may offer advantages, but they are not yet proven in large trials. Lonigutamab, a next-generation antibody, works by a different mechanism: it causes the IGF-1 receptor to be internalized and degraded, rather than just blocking its activation. In laboratory studies on orbital fibroblasts from TED patients, lonigutamab reduced mature IGF-1R levels by ~75% within 24 hours and significantly reduced hyaluronan production — a key driver of tissue swelling [2][6]. This could potentially lead to more complete and longer-lasting effects, but clinical data are still early.
Another candidate, veligrotug, is a full antagonist that blocks IGF-1 binding almost completely, whereas teprotumumab only partially inhibits it (plateauing at ~50% inhibition) [4]. In preclinical studies, veligrotug also did not bind to the insulin receptor, which may reduce the risk of hyperglycemia [4]. However, these are preclinical findings; the phase 3 trials (THRIVE and THRIVE-2) have reported positive results, but the full data are not yet published [4]. So while these newer agents hold promise, they are not yet available in routine practice.
What are the safety concerns?
IGF-1R inhibitors are generally well-tolerated, but they do have side effects that need monitoring. In the IBI311 trial, all adverse events of interest — including infusion reactions, hearing impairment, hyperglycemia, muscle spasms, and nausea or diarrhea — were mild or moderate, with no serious adverse events or deaths [1]. However, hearing issues are a particular concern. A 2024 prospective study cited in a 2025 commentary found that among 52 patients with baseline audiometry, 62% had normal hearing; of those, only 3% developed hearing loss after teprotumumab, but among the 38% with abnormal baseline hearing, a higher proportion developed worsening [3]. This suggests that pre-existing hearing problems may increase risk, and that hearing should be checked before and during treatment.
Hyperglycemia is another side effect, likely because IGF-1R is related to insulin signaling. In the IBI311 trial, hyperglycemia was reported but was mild or moderate [1]. Veligrotug's preclinical data showing no insulin receptor binding may reduce this risk, but this has not been confirmed in humans [4]. Overall, the safety profile is acceptable for a serious disease, but patients need baseline and follow-up monitoring for hearing and blood sugar.
About These Sources
This answer is built on 6 peer-reviewed studies — published from 2023 to 2026, 5 from 2024 or later, 3 in Q1 journals — selected as the most relevant from 8 studies that passed quality screening, drawn from 48 papers retrieved from a database of over 500 million.
Sources used in this answer
IGF-1R Inhibitor IBI311 for the Treatment of Active Thyroid Eye Disease in Chinese Patients
In a randomized, double-blind, placebo-controlled phase 3 trial in 82 Chinese patients with active moderate-to-severe TED, IBI311 (an IGF-1R inhibitor) achieved a proptosis response in 85.8% vs 3.8% on placebo, and 83.5% achieved clinical activity score 0 or 1, with no serious adverse events.
OR31-06 Lonigutamab (Anti-IGF-1R Monoclonal Antibody) Induces Efficient Degradation of IGF-1R in Thyroid Eye Disease Orbital Fibroblasts
In laboratory studies, lonigutamab (a next-generation anti-IGF-1R antibody) reduced mature IGF-1R levels by ~75% in TED orbital fibroblasts within 24 hours, by promoting internalization and degradation via proteasomal and lysosomal pathways.
Thyroid eye disease and the IGF-1 receptor
A commentary on teprotumumab safety cites a 2024 prospective study where, among 52 patients with baseline audiometry, 62% had normal hearing; of those, only 3% developed hearing loss after treatment, but among the 38% with abnormal baseline hearing, a higher proportion developed worsening.
Preclinical pharmacology, pharmacokinetics, and pharmacodynamics of veligrotug, a full antagonist antibody to the IGF-1 receptor in development for thyroid eye disease
Preclinical studies of veligrotug (an anti-IGF-1R antibody) showed it is a full antagonist, providing near-complete inhibition of IGF-1 binding and receptor phosphorylation, unlike teprotumumab which plateaued at ~50% inhibition; it also did not bind to the insulin receptor.
Proptosis Regression After Teprotumumab Treatment for Thyroid Eye Disease
A retrospective study of 119 patients who completed teprotumumab found that 65.38% of initially improved eyes later regressed (average 2.43 mm), and 25.64% of eyes ended up worse than before treatment, with regression often occurring within 6 months to 1 year.
Lonigutamab Inhibits Hyaluronan Production by Reducing IGF-1R Levels in Thyroid Eye Disease Orbital Fibroblasts.
Lonigutamab significantly reduced basal and IGF-1-induced hyaluronan production in TED orbital fibroblasts by promoting IGF-1R internalization and degradation, supporting its unique mechanism of action.