A five-infusion course of veligrotug, a full antagonist monoclonal antibody to the insulin-like growth factor-1 receptor (IGF-1R), over 12 weeks results in improved diplopia, proptosis, and disease activity and is well tolerated in patients with active thyroid eye disease (TED), as shown in the phase III THRIVE study. Moreover, the therapeutic effect persists through week 52.
“These results support veligrotug’s potential to advance TED management by offering a next-generation therapy that targets the underlying pathophysiologic features and its clinical manifestations,” the researchers said.
Overall, 113 adult patients with moderate-to-severe active TED (onset ≤15 months, proptosis ≥3 mm above normal, and clinical activity score [CAS] ≥3) received either veligrotug 10 mg/kg (n=75) or placebo (n=38) administered every 3 weeks for a total of five intravenous infusions. Baseline characteristics were similar between the two groups. [Ophthalmology 2026;133:1085-1096]
Response
Improvements were noted at week 3. Patients treated with veligrotug vs placebo showed a significantly greater response at week 15 (p<0.001) across all endpoints, including proptosis responder rate (PRR) by Hertel (70 percent vs 5 percent) and PRR by MRI or computed tomography (71 percent vs 9 percent).
Likewise, objective response rate was higher in the veligrotug group (67 percent vs 5 percent), as were mean proptosis reduction (Hertel: 2.90 vs 0.48 mm; MRI/computed tomography: 2.96 vs 0.58 mm), diplopia improvement (59 percent vs 20 percent), and diplopia resolution (49 percent vs 12 percent).
Among initial responders, 70 percent maintained proptosis response through week 52. Furthermore, veligrotug was well tolerated, with a mere 4-percent discontinuation rate. Adverse events (AEs) were mostly mild and resolved. No serious treatment-related AEs were reported, and no changes in the safety profile were observed at week 52.
“The significant and clinically meaningful improvements observed across proptosis, diplopia, and disease activity were accompanied by corresponding clinically meaningful improvements in quality of life,” the researchers said.
Recurrence
TED is a chronic autoimmune disease, so it may be possible for some patients to experience recurrence after treatment, the researchers said. Previous studies estimated proptosis recurrence after IGF-1R inhibition (ie, teprotumumab) in clinical practice to range from 24 percent to 66 percent, with varying definitions and follow-up periods. [Am J Ophthalmol 2024;263:152-159; Endocr Rev 2024;45:843-857]
“In the current study, 70 percent of initial responders (at week 15) maintained proptosis response through week 52,” the researchers noted. “This suggests a … durable benefit of veligrotug therapy, although longer-term follow-up could help to estimate the need for retreatment in real-world use.”
Treatment
In patients with active TED, the traditional therapeutic landscape includes orbital radiation, surgical interventions, and off-label medications, each with its own limitations. Corticosteroids are the standard first-line therapy, but these do not address the cause of TED symptoms and have limited efficacy in addressing diplopia or proptosis. [Front Immunol 2025;16:1647602]
High-dose steroids may also result in significant adverse effects, including mood or sleep issues and metabolic, hepatic, and cardiovascular complications.
On the other hand, previous trials of immunomodulatory strategies, including interleukin-6 inhibition and B-cell depletion, report a clinically meaningful benefit in CAS and quality of life, but the effects of these mechanisms on proptosis and diplopia are less consistent than with IGF-1R inhibition. [Eur J Endocrinol 2021;185:G43-G67; J Clin Endocrinol Metab 2015;100:432-441]
“Orbital radiation and surgical decompression may provide relief, but these approaches carry procedural risks,” the researchers said.
“In particular, orbital decompression surgery generally yields 3- to 6-mm proptosis reduction that is typically durable, but requires 4 to 6 weeks’ recovery time and is associated with procedural risks, including an increased risk of new-onset or worsening diplopia,” they added. [Laryngoscope Investig Otolaryngol 2026;11:e70351; Indian J Ophthalmol 2024;72(suppl 2):S233-S239]